Pigmentation Disorders

Sturge-Weber syndrome (SWS) is a disease of dermatologic, neurologic, and ocular significance.¹ The most distinctive manifestation is facial capillary malformation, commonly referred to as a port-wine stain or nevus flammeus. The dysregulated angiogenesis, caused by somatic mutations of the G protein subunit alpha Q gene, GNAQ, also affects the central nervous system.² Seizures, intellectual disability, and glaucoma are common consequences.¹ Not all port-wine stains are associated with SWS.³ Distribution in the ophthalmic dermatome is associated with increased risk for SWS, with 8% of patients with port-wine stains also having SWS.⁴ The disease is more serious when bilateral lesions are present.⁵ Diagnosis is clinical based on dermatologic, nervous system, and ophthalmologic findings.⁶ The disease is nonheritable because the mutation is found only in the somatic cell lines.² The possibility of epigenetic influence on disease development has to be investigated. The treatment is aimed at managing complications, as there is no cure.⁷

Infantile hemangioma (IH) likewise represents a disruption in the process of vascular development but without the widespread consequences of SWS. The pathogenesis of hemangioma development has not been fully elucidated, with presence of GLUT1 (glucose transporter 1) protein implicated in lesions.⁴ Facial infantile hemangiomas have an incidence of approximately 5 in every 100 births, and the prevalence decreases with age. Most hemangiomas undergo growth followed by an involution process, with most lesions vanishing by 5 years of age.⁴ They typically are seen at 2 to 3 weeks of age, growing rapidly for the first 6 months, which is a contrast to the static nature of nevus flammeus. Infantile hemangiomas are regarded as sporadic, though autosomal-dominant inheritance patterns have been observed.⁴ Our patient demonstrated facial IH at birth, which is a rare and interesting finding suggesting that some epigenetic factors influenced this modification of the disease course in this patient.

Cutis marmorata telangiectatica congenita (CMTC) is a rare cutaneous vascular condition found in newborns. Its extraordinary infrequency is reflected in the fact that only 300 cases have been reported worldwide.⁸ At birth, CMTC manifests as a pinkish reticulated pattern all over the body mimicking cutis marmorata; however, unlike cutis marmorata, the lesions do not improve with warming.⁹ The lesions of CMTC gradually lighten as the patient ages.⁸ Limb asymmetry is the most common extravascular complication of CMTC and, similar to SWS, glaucoma also can occur.¹⁰ Cutis marmorata telangiectatica congenita has been known to occur simultaneously with SWS or IH, but the combination of all 3 conditions in our patient is unique. Due to the scarcity of cases, the pathophysiology and treatment is poorly understood, with appropriate monitoring for sequelae recommended.⁹

Case Report

The patient was born at 39 weeks’ gestation following an uncomplicated pregnancy and delivery. She weighed 2950 g, her length was 19 in, and her head circumference was 13.25 in, correlating to the 10th, 50th, and 25th percentiles, respectively. Her Apgar score was 8/9 at 1 and 5 minutes. Her parents were nonconsanguineous and in good health. The patient’s family lived in poverty, which led us to conjecture about the role that toxins played in the epigenetics of the patient and her family. It was the mother’s third pregnancy; both prior pregnancies resulted in healthy children. The patient was breastfed. No family history of heritable vascular disorders was reported.

On the first day of life during the newborn examination, dark red pigment changes were noticed under the nose and erythematous pigmentation over the whole body was observed (Figure). On examination, 2-toned reticular lesions identified as extensive nevus flammeus were found bilaterally over the distribution of the ophthalmic division of the trigeminal nerve. A separate erythematous plaque over the maxilla also was recognized. The pediatrician suspected SWS and facial IH. The patient was discharged after 3 days with a referral to pediatric dermatology, and appropriate follow-up with a pediatrician was scheduled. The patient returned for these appointments and the significance of SWS was explained to her parents. Consultation with pediatric dermatology at 2 weeks of age confirmed the diagnosis of SWS as well as facial IH.

Upon further follow-up with pediatric dermatology at 2 months of age, the patient received an additional diagnosis of CMTC. These exceedingly rare lesions were located over the back, trunk, arms, and legs. The patient’s parents were counseled about the management of these conditions and appropriate follow-up.

 

Comment

This case describes 3 different vascular malformations in the same patient. Cutis marmorata telangiectatica congenita is rare and yet is described in this patient along with 2 other notable endothelial abnormalities. The clinical interest of this case is heightened by the presence of CMTC.

The causative factor of SWS is a well-documented mutation of the GNAQ gene, but there is considerable variability in how it affects the patient. Unlike in SWS, no single factor can be attributed to the development of IH. This case shows that these 3 diseases are not mutually exclusive and can present with unusually severe features when they occur concomitantly. The embryologic basis of SWS traces its roots back to the first trimester during vascular development, where lack of regression and development of the primitive cephalic venous plexus occur.¹⁰The presence of a large IH on the patient’s philtrum that demonstrated markers of pericyte and neural crest cells illustrates that the developmental origins of one neurocutaneous disorder do not necessarily interfere with the development of other cutaneous conditions.¹¹

The severity of the SWS in our patient was highlighted by the extensive nevus flammeus. These lesions occurred over the face, trunk, arms, and legs. The port-wine stain with dermatomal distribution of the ophthalmic nerve was the most concerning feature regarding the development of neurologic complications in this patient. Although the developmental delays associated with SWS can be serious, early intervention is important and can improve long-term outcomes. The facial IH arising at birth was contrary to the typical presentation. All of these factors will be kept in mind as the patient progresses and patient-centered care is provided. Because this patient’s presentation differed from other patients with IH, we will be more vigilant in providing close follow-up and monitoring for other medical problems involving other organs (eg, the brain); for instance, we will monitor for seizures and developmental delay.

Conclusion

In our patient, a unique pattern of SWS, facial IH, and CMTC are described in a pediatric patient. Many disciplines are involved in the treatment. In the patient’s first days of life, extensive collaboration between pediatrics and dermatologists was pivotal, with ophthalmology, pathology, and radiology consultations at hand. This case highlights that several vascular malformations of different origins can occur in the same patient. Epigenetic along with genetic factors likely contributed to this fascinating presentation. The importance of parental education and maintaining appropriate follow-up for this patient is crucial for a favorable outcome.

Sturge-Weber syndrome (SWS) is a disease of dermatologic, neurologic, and ocular significance.¹ The most distinctive manifestation is facial capillary malformation, commonly referred to as a port-wine stain or nevus flammeus. The dysregulated angiogenesis, caused by somatic mutations of the G protein subunit alpha Q gene, GNAQ, also affects the central nervous system.² Seizures, intellectual disability, and glaucoma are common consequences.¹ Not all port-wine stains are associated with SWS.³ Distribution in the ophthalmic dermatome is associated with increased risk for SWS, with 8% of patients with port-wine stains also having SWS.⁴ The disease is more serious when bilateral lesions are present.⁵ Diagnosis is clinical based on dermatologic, nervous system, and ophthalmologic findings.⁶ The disease is nonheritable because the mutation is found only in the somatic cell lines.² The possibility of epigenetic influence on disease development has to be investigated. The treatment is aimed at managing complications, as there is no cure.⁷

Infantile hemangioma (IH) likewise represents a disruption in the process of vascular development but without the widespread consequences of SWS. The pathogenesis of hemangioma development has not been fully elucidated, with presence of GLUT1 (glucose transporter 1) protein implicated in lesions.⁴ Facial infantile hemangiomas have an incidence of approximately 5 in every 100 births, and the prevalence decreases with age. Most hemangiomas undergo growth followed by an involution process, with most lesions vanishing by 5 years of age.⁴ They typically are seen at 2 to 3 weeks of age, growing rapidly for the first 6 months, which is a contrast to the static nature of nevus flammeus. Infantile hemangiomas are regarded as sporadic, though autosomal-dominant inheritance patterns have been observed.⁴ Our patient demonstrated facial IH at birth, which is a rare and interesting finding suggesting that some epigenetic factors influenced this modification of the disease course in this patient.

Cutis marmorata telangiectatica congenita (CMTC) is a rare cutaneous vascular condition found in newborns. Its extraordinary infrequency is reflected in the fact that only 300 cases have been reported worldwide.⁸ At birth, CMTC manifests as a pinkish reticulated pattern all over the body mimicking cutis marmorata; however, unlike cutis marmorata, the lesions do not improve with warming.⁹ The lesions of CMTC gradually lighten as the patient ages.⁸ Limb asymmetry is the most common extravascular complication of CMTC and, similar to SWS, glaucoma also can occur.¹⁰ Cutis marmorata telangiectatica congenita has been known to occur simultaneously with SWS or IH, but the combination of all 3 conditions in our patient is unique. Due to the scarcity of cases, the pathophysiology and treatment is poorly understood, with appropriate monitoring for sequelae recommended.⁹

Case Report

The patient was born at 39 weeks’ gestation following an uncomplicated pregnancy and delivery. She weighed 2950 g, her length was 19 in, and her head circumference was 13.25 in, correlating to the 10th, 50th, and 25th percentiles, respectively. Her Apgar score was 8/9 at 1 and 5 minutes. Her parents were nonconsanguineous and in good health. The patient’s family lived in poverty, which led us to conjecture about the role that toxins played in the epigenetics of the patient and her family. It was the mother’s third pregnancy; both prior pregnancies resulted in healthy children. The patient was breastfed. No family history of heritable vascular disorders was reported.

On the first day of life during the newborn examination, dark red pigment changes were noticed under the nose and erythematous pigmentation over the whole body was observed (Figure). On examination, 2-toned reticular lesions identified as extensive nevus flammeus were found bilaterally over the distribution of the ophthalmic division of the trigeminal nerve. A separate erythematous plaque over the maxilla also was recognized. The pediatrician suspected SWS and facial IH. The patient was discharged after 3 days with a referral to pediatric dermatology, and appropriate follow-up with a pediatrician was scheduled. The patient returned for these appointments and the significance of SWS was explained to her parents. Consultation with pediatric dermatology at 2 weeks of age confirmed the diagnosis of SWS as well as facial IH.

Upon further follow-up with pediatric dermatology at 2 months of age, the patient received an additional diagnosis of CMTC. These exceedingly rare lesions were located over the back, trunk, arms, and legs. The patient’s parents were counseled about the management of these conditions and appropriate follow-up.

 

Comment

This case describes 3 different vascular malformations in the same patient. Cutis marmorata telangiectatica congenita is rare and yet is described in this patient along with 2 other notable endothelial abnormalities. The clinical interest of this case is heightened by the presence of CMTC.

The causative factor of SWS is a well-documented mutation of the GNAQ gene, but there is considerable variability in how it affects the patient. Unlike in SWS, no single factor can be attributed to the development of IH. This case shows that these 3 diseases are not mutually exclusive and can present with unusually severe features when they occur concomitantly. The embryologic basis of SWS traces its roots back to the first trimester during vascular development, where lack of regression and development of the primitive cephalic venous plexus occur.¹⁰The presence of a large IH on the patient’s philtrum that demonstrated markers of pericyte and neural crest cells illustrates that the developmental origins of one neurocutaneous disorder do not necessarily interfere with the development of other cutaneous conditions.¹¹

The severity of the SWS in our patient was highlighted by the extensive nevus flammeus. These lesions occurred over the face, trunk, arms, and legs. The port-wine stain with dermatomal distribution of the ophthalmic nerve was the most concerning feature regarding the development of neurologic complications in this patient. Although the developmental delays associated with SWS can be serious, early intervention is important and can improve long-term outcomes. The facial IH arising at birth was contrary to the typical presentation. All of these factors will be kept in mind as the patient progresses and patient-centered care is provided. Because this patient’s presentation differed from other patients with IH, we will be more vigilant in providing close follow-up and monitoring for other medical problems involving other organs (eg, the brain); for instance, we will monitor for seizures and developmental delay.

Conclusion

In our patient, a unique pattern of SWS, facial IH, and CMTC are described in a pediatric patient. Many disciplines are involved in the treatment. In the patient’s first days of life, extensive collaboration between pediatrics and dermatologists was pivotal, with ophthalmology, pathology, and radiology consultations at hand. This case highlights that several vascular malformations of different origins can occur in the same patient. Epigenetic along with genetic factors likely contributed to this fascinating presentation. The importance of parental education and maintaining appropriate follow-up for this patient is crucial for a favorable outcome.

Sturge-Weber syndrome (SWS) is a disease of dermatologic, neurologic, and ocular significance.¹ The most distinctive manifestation is facial capillary malformation, commonly referred to as a port-wine stain or nevus flammeus. The dysregulated angiogenesis, caused by somatic mutations of the G protein subunit alpha Q gene, GNAQ, also affects the central nervous system.² Seizures, intellectual disability, and glaucoma are common consequences.¹ Not all port-wine stains are associated with SWS.³ Distribution in the ophthalmic dermatome is associated with increased risk for SWS, with 8% of patients with port-wine stains also having SWS.⁴ The disease is more serious when bilateral lesions are present.⁵ Diagnosis is clinical based on dermatologic, nervous system, and ophthalmologic findings.⁶ The disease is nonheritable because the mutation is found only in the somatic cell lines.² The possibility of epigenetic influence on disease development has to be investigated. The treatment is aimed at managing complications, as there is no cure.⁷

Infantile hemangioma (IH) likewise represents a disruption in the process of vascular development but without the widespread consequences of SWS. The pathogenesis of hemangioma development has not been fully elucidated, with presence of GLUT1 (glucose transporter 1) protein implicated in lesions.⁴ Facial infantile hemangiomas have an incidence of approximately 5 in every 100 births, and the prevalence decreases with age. Most hemangiomas undergo growth followed by an involution process, with most lesions vanishing by 5 years of age.⁴ They typically are seen at 2 to 3 weeks of age, growing rapidly for the first 6 months, which is a contrast to the static nature of nevus flammeus. Infantile hemangiomas are regarded as sporadic, though autosomal-dominant inheritance patterns have been observed.⁴ Our patient demonstrated facial IH at birth, which is a rare and interesting finding suggesting that some epigenetic factors influenced this modification of the disease course in this patient.

Cutis marmorata telangiectatica congenita (CMTC) is a rare cutaneous vascular condition found in newborns. Its extraordinary infrequency is reflected in the fact that only 300 cases have been reported worldwide.⁸ At birth, CMTC manifests as a pinkish reticulated pattern all over the body mimicking cutis marmorata; however, unlike cutis marmorata, the lesions do not improve with warming.⁹ The lesions of CMTC gradually lighten as the patient ages.⁸ Limb asymmetry is the most common extravascular complication of CMTC and, similar to SWS, glaucoma also can occur.¹⁰ Cutis marmorata telangiectatica congenita has been known to occur simultaneously with SWS or IH, but the combination of all 3 conditions in our patient is unique. Due to the scarcity of cases, the pathophysiology and treatment is poorly understood, with appropriate monitoring for sequelae recommended.⁹

Case Report

The patient was born at 39 weeks’ gestation following an uncomplicated pregnancy and delivery. She weighed 2950 g, her length was 19 in, and her head circumference was 13.25 in, correlating to the 10th, 50th, and 25th percentiles, respectively. Her Apgar score was 8/9 at 1 and 5 minutes. Her parents were nonconsanguineous and in good health. The patient’s family lived in poverty, which led us to conjecture about the role that toxins played in the epigenetics of the patient and her family. It was the mother’s third pregnancy; both prior pregnancies resulted in healthy children. The patient was breastfed. No family history of heritable vascular disorders was reported.

On the first day of life during the newborn examination, dark red pigment changes were noticed under the nose and erythematous pigmentation over the whole body was observed (Figure). On examination, 2-toned reticular lesions identified as extensive nevus flammeus were found bilaterally over the distribution of the ophthalmic division of the trigeminal nerve. A separate erythematous plaque over the maxilla also was recognized. The pediatrician suspected SWS and facial IH. The patient was discharged after 3 days with a referral to pediatric dermatology, and appropriate follow-up with a pediatrician was scheduled. The patient returned for these appointments and the significance of SWS was explained to her parents. Consultation with pediatric dermatology at 2 weeks of age confirmed the diagnosis of SWS as well as facial IH.

Upon further follow-up with pediatric dermatology at 2 months of age, the patient received an additional diagnosis of CMTC. These exceedingly rare lesions were located over the back, trunk, arms, and legs. The patient’s parents were counseled about the management of these conditions and appropriate follow-up.

 

Comment

This case describes 3 different vascular malformations in the same patient. Cutis marmorata telangiectatica congenita is rare and yet is described in this patient along with 2 other notable endothelial abnormalities. The clinical interest of this case is heightened by the presence of CMTC.

The causative factor of SWS is a well-documented mutation of the GNAQ gene, but there is considerable variability in how it affects the patient. Unlike in SWS, no single factor can be attributed to the development of IH. This case shows that these 3 diseases are not mutually exclusive and can present with unusually severe features when they occur concomitantly. The embryologic basis of SWS traces its roots back to the first trimester during vascular development, where lack of regression and development of the primitive cephalic venous plexus occur.¹⁰The presence of a large IH on the patient’s philtrum that demonstrated markers of pericyte and neural crest cells illustrates that the developmental origins of one neurocutaneous disorder do not necessarily interfere with the development of other cutaneous conditions.¹¹

The severity of the SWS in our patient was highlighted by the extensive nevus flammeus. These lesions occurred over the face, trunk, arms, and legs. The port-wine stain with dermatomal distribution of the ophthalmic nerve was the most concerning feature regarding the development of neurologic complications in this patient. Although the developmental delays associated with SWS can be serious, early intervention is important and can improve long-term outcomes. The facial IH arising at birth was contrary to the typical presentation. All of these factors will be kept in mind as the patient progresses and patient-centered care is provided. Because this patient’s presentation differed from other patients with IH, we will be more vigilant in providing close follow-up and monitoring for other medical problems involving other organs (eg, the brain); for instance, we will monitor for seizures and developmental delay.

Conclusion

In our patient, a unique pattern of SWS, facial IH, and CMTC are described in a pediatric patient. Many disciplines are involved in the treatment. In the patient’s first days of life, extensive collaboration between pediatrics and dermatologists was pivotal, with ophthalmology, pathology, and radiology consultations at hand. This case highlights that several vascular malformations of different origins can occur in the same patient. Epigenetic along with genetic factors likely contributed to this fascinating presentation. The importance of parental education and maintaining appropriate follow-up for this patient is crucial for a favorable outcome.

To the Editor:

A 55-year-old man presented with hyperpigmented brown macules on the lips, hands, and fingertips of 6 years’ duration. The spots were persistent, asymptomatic, and had not changed in size. The patient denied a history of alopecia or dystrophic nails. He also denied a family history of similar skin findings. He had no personal history of cancer and a colonoscopy performed 5 years prior revealed no notable abnormalities. His medications included amlodipine and hydrocodone-acetaminophen. His mother died of “abdominal bleeding” at 74 years of age and his father died of a brain tumor at 64 years of age. Physical examination demonstrated numerous well-defined, dark brown macules of variable size distributed on the lower and upper mucosal lips (Figure 1A), buccal mucosa, hard palate, and gingiva, as well as the dorsal aspect of the fingers (Figure 1B) and volar aspect of the fingertips (Figure 1C).

A shave biopsy of a dark brown macule from the lower lip (Figure 2) was performed. Histopathologic examination revealed pigmentation of the basal layer of the epidermis with pigment-laden cells in the dermis immediately deep to the surface epithelium. Immunoperoxidase stains showed a normal number and distribution of melanocytes.

A diagnosis of Laugier-Hunziker syndrome (LHS) was made given the age of onset; distribution of pigmentation; and lack of pathologic colonoscopic findings, personal history of cancer, or gastrointestinal tract symptoms.

 

Benign hyperpigmentation of the lips and fingers has been reported.¹ The average age of onset of LHS is 52 years, and it typically is diagnosed in white adults.^1,2 In LHS, pigmentation is most commonly distributed on the lips, especially the lower lips and oral mucosa.² Pigmentation of the nails in the form of longitudinal melanonychia is present in approximately half of cases.^2,3 There also may be pigmentation of the neck; thorax; abdomen; and acral surfaces, especially the fingertips.^1-3 Rarely, pigmented macules can occur on the genitalia or sclera.^1,2 Unlike Peutz-Jeghers syndrome, the diagnosis of LHS does not result from a germline mutation and carries no risk of gastrointestinal polyposis or internal malignancy.^3,4 The histopathology of a pigmented macule of LHS shows a normal number and morphology of melanocytes. Epidermal basement membrane pigmentation is common, with pigment-laden macrophages evident in the papillary dermis.³

RELATED ARTICLE: Asymptomatic Lower Lip Hyperpigmentation From Laugier-Hunziker Syndrome

The differential diagnosis of multiple lentigines is broad and includes Peutz-Jeghers syndrome; LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness) syndrome; Carney complexes, including LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, blue nevi) and NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelide) syndromes⁵; primary adrenocortical insufficiency (Addison disease); and idiopathic melanoplakia^.2 Peutz-Jeghers syndrome, an autosomal-dominant syndrome with mucocutaneous lentigines, has a similar clinical appearance to LHS; therefore, it is necessary to exclude this diagnosis due to its association with intestinal hamartomatous polyps and internal malignancies (Table).^3,6,7

Peutz-Jeghers syndrome is characterized by mucocutaneous hyperpigmentation and intestinal hamartomatous polyposis and is associated with internal malignancies of the colon, breast, pancreas, stomach, small intestines, ovaries, lung, and Sertoli cells in men.^6,7 Associated gastrointestinal tract malignancies in descending order of frequency are colon (39%), pancreatic (36%), gastric (29%), and small intestine (13%).¹ It is caused by a germ line mutation of the serine/threonine kinase 11 gene, STK11. Although the appearance and distribution of the mucocutaneous lentigines is similar to individuals with LHS, by contrast the lentiginosis in individuals with Peutz-Jeghers syndrome is present from birth or develops during infancy.⁶ Aggressive cancer screening guidelines aid in early detection and begin at 8 years of age with a baseline colonoscopy and esophagogastroduodenoscopy; future screening is dictated by the presence or absence of polyps. If no polyps are detected at 8 years of age, a colonoscopy and esophagogastroduodenoscopy are repeated at 18 years of age and then every 3 years until 50 years of age.⁸

In an adult patient, the diagnosis of LHS can be made clinically and a correct diagnosis prevents frequent and unpleasant gastrointestinal tract cancer screening examinations. Lampe et al² described a man with LHS who was incorrectly diagnosed with Peutz-Jeghers syndrome and experienced a colonic perforation as a complication of a screening colonoscopy. Their case report underscores the importance of making the correct diagnosis of LHS to avoid undertaking unnecessary aggressive cancer screening regimens.²

Although LHS is a benign condition that does not require treatment, Q-switched alexandrite or erbium:YAG laser therapy has been shown to improve the pigmentary findings associated with LHS.^9,10 It has been suggested that LHS should be renamed Laugier-Hunziker pigmentation² or mucocutaneous lentiginosis of Laugier and Hunziker¹ to differentiate LHS as simply a disorder of pigmentation rather than a potentially morbid genetic defect, as in Peutz-Jeghers syndrome.

To the Editor:

A 55-year-old man presented with hyperpigmented brown macules on the lips, hands, and fingertips of 6 years’ duration. The spots were persistent, asymptomatic, and had not changed in size. The patient denied a history of alopecia or dystrophic nails. He also denied a family history of similar skin findings. He had no personal history of cancer and a colonoscopy performed 5 years prior revealed no notable abnormalities. His medications included amlodipine and hydrocodone-acetaminophen. His mother died of “abdominal bleeding” at 74 years of age and his father died of a brain tumor at 64 years of age. Physical examination demonstrated numerous well-defined, dark brown macules of variable size distributed on the lower and upper mucosal lips (Figure 1A), buccal mucosa, hard palate, and gingiva, as well as the dorsal aspect of the fingers (Figure 1B) and volar aspect of the fingertips (Figure 1C).

A shave biopsy of a dark brown macule from the lower lip (Figure 2) was performed. Histopathologic examination revealed pigmentation of the basal layer of the epidermis with pigment-laden cells in the dermis immediately deep to the surface epithelium. Immunoperoxidase stains showed a normal number and distribution of melanocytes.

A diagnosis of Laugier-Hunziker syndrome (LHS) was made given the age of onset; distribution of pigmentation; and lack of pathologic colonoscopic findings, personal history of cancer, or gastrointestinal tract symptoms.

 

Benign hyperpigmentation of the lips and fingers has been reported.¹ The average age of onset of LHS is 52 years, and it typically is diagnosed in white adults.^1,2 In LHS, pigmentation is most commonly distributed on the lips, especially the lower lips and oral mucosa.² Pigmentation of the nails in the form of longitudinal melanonychia is present in approximately half of cases.^2,3 There also may be pigmentation of the neck; thorax; abdomen; and acral surfaces, especially the fingertips.^1-3 Rarely, pigmented macules can occur on the genitalia or sclera.^1,2 Unlike Peutz-Jeghers syndrome, the diagnosis of LHS does not result from a germline mutation and carries no risk of gastrointestinal polyposis or internal malignancy.^3,4 The histopathology of a pigmented macule of LHS shows a normal number and morphology of melanocytes. Epidermal basement membrane pigmentation is common, with pigment-laden macrophages evident in the papillary dermis.³

RELATED ARTICLE: Asymptomatic Lower Lip Hyperpigmentation From Laugier-Hunziker Syndrome

The differential diagnosis of multiple lentigines is broad and includes Peutz-Jeghers syndrome; LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness) syndrome; Carney complexes, including LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, blue nevi) and NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelide) syndromes⁵; primary adrenocortical insufficiency (Addison disease); and idiopathic melanoplakia^.2 Peutz-Jeghers syndrome, an autosomal-dominant syndrome with mucocutaneous lentigines, has a similar clinical appearance to LHS; therefore, it is necessary to exclude this diagnosis due to its association with intestinal hamartomatous polyps and internal malignancies (Table).^3,6,7

Peutz-Jeghers syndrome is characterized by mucocutaneous hyperpigmentation and intestinal hamartomatous polyposis and is associated with internal malignancies of the colon, breast, pancreas, stomach, small intestines, ovaries, lung, and Sertoli cells in men.^6,7 Associated gastrointestinal tract malignancies in descending order of frequency are colon (39%), pancreatic (36%), gastric (29%), and small intestine (13%).¹ It is caused by a germ line mutation of the serine/threonine kinase 11 gene, STK11. Although the appearance and distribution of the mucocutaneous lentigines is similar to individuals with LHS, by contrast the lentiginosis in individuals with Peutz-Jeghers syndrome is present from birth or develops during infancy.⁶ Aggressive cancer screening guidelines aid in early detection and begin at 8 years of age with a baseline colonoscopy and esophagogastroduodenoscopy; future screening is dictated by the presence or absence of polyps. If no polyps are detected at 8 years of age, a colonoscopy and esophagogastroduodenoscopy are repeated at 18 years of age and then every 3 years until 50 years of age.⁸

In an adult patient, the diagnosis of LHS can be made clinically and a correct diagnosis prevents frequent and unpleasant gastrointestinal tract cancer screening examinations. Lampe et al² described a man with LHS who was incorrectly diagnosed with Peutz-Jeghers syndrome and experienced a colonic perforation as a complication of a screening colonoscopy. Their case report underscores the importance of making the correct diagnosis of LHS to avoid undertaking unnecessary aggressive cancer screening regimens.²

Although LHS is a benign condition that does not require treatment, Q-switched alexandrite or erbium:YAG laser therapy has been shown to improve the pigmentary findings associated with LHS.^9,10 It has been suggested that LHS should be renamed Laugier-Hunziker pigmentation² or mucocutaneous lentiginosis of Laugier and Hunziker¹ to differentiate LHS as simply a disorder of pigmentation rather than a potentially morbid genetic defect, as in Peutz-Jeghers syndrome.

To the Editor:

A 55-year-old man presented with hyperpigmented brown macules on the lips, hands, and fingertips of 6 years’ duration. The spots were persistent, asymptomatic, and had not changed in size. The patient denied a history of alopecia or dystrophic nails. He also denied a family history of similar skin findings. He had no personal history of cancer and a colonoscopy performed 5 years prior revealed no notable abnormalities. His medications included amlodipine and hydrocodone-acetaminophen. His mother died of “abdominal bleeding” at 74 years of age and his father died of a brain tumor at 64 years of age. Physical examination demonstrated numerous well-defined, dark brown macules of variable size distributed on the lower and upper mucosal lips (Figure 1A), buccal mucosa, hard palate, and gingiva, as well as the dorsal aspect of the fingers (Figure 1B) and volar aspect of the fingertips (Figure 1C).

A shave biopsy of a dark brown macule from the lower lip (Figure 2) was performed. Histopathologic examination revealed pigmentation of the basal layer of the epidermis with pigment-laden cells in the dermis immediately deep to the surface epithelium. Immunoperoxidase stains showed a normal number and distribution of melanocytes.

A diagnosis of Laugier-Hunziker syndrome (LHS) was made given the age of onset; distribution of pigmentation; and lack of pathologic colonoscopic findings, personal history of cancer, or gastrointestinal tract symptoms.

 

Benign hyperpigmentation of the lips and fingers has been reported.¹ The average age of onset of LHS is 52 years, and it typically is diagnosed in white adults.^1,2 In LHS, pigmentation is most commonly distributed on the lips, especially the lower lips and oral mucosa.² Pigmentation of the nails in the form of longitudinal melanonychia is present in approximately half of cases.^2,3 There also may be pigmentation of the neck; thorax; abdomen; and acral surfaces, especially the fingertips.^1-3 Rarely, pigmented macules can occur on the genitalia or sclera.^1,2 Unlike Peutz-Jeghers syndrome, the diagnosis of LHS does not result from a germline mutation and carries no risk of gastrointestinal polyposis or internal malignancy.^3,4 The histopathology of a pigmented macule of LHS shows a normal number and morphology of melanocytes. Epidermal basement membrane pigmentation is common, with pigment-laden macrophages evident in the papillary dermis.³

RELATED ARTICLE: Asymptomatic Lower Lip Hyperpigmentation From Laugier-Hunziker Syndrome

The differential diagnosis of multiple lentigines is broad and includes Peutz-Jeghers syndrome; LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness) syndrome; Carney complexes, including LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, blue nevi) and NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelide) syndromes⁵; primary adrenocortical insufficiency (Addison disease); and idiopathic melanoplakia^.2 Peutz-Jeghers syndrome, an autosomal-dominant syndrome with mucocutaneous lentigines, has a similar clinical appearance to LHS; therefore, it is necessary to exclude this diagnosis due to its association with intestinal hamartomatous polyps and internal malignancies (Table).^3,6,7

Peutz-Jeghers syndrome is characterized by mucocutaneous hyperpigmentation and intestinal hamartomatous polyposis and is associated with internal malignancies of the colon, breast, pancreas, stomach, small intestines, ovaries, lung, and Sertoli cells in men.^6,7 Associated gastrointestinal tract malignancies in descending order of frequency are colon (39%), pancreatic (36%), gastric (29%), and small intestine (13%).¹ It is caused by a germ line mutation of the serine/threonine kinase 11 gene, STK11. Although the appearance and distribution of the mucocutaneous lentigines is similar to individuals with LHS, by contrast the lentiginosis in individuals with Peutz-Jeghers syndrome is present from birth or develops during infancy.⁶ Aggressive cancer screening guidelines aid in early detection and begin at 8 years of age with a baseline colonoscopy and esophagogastroduodenoscopy; future screening is dictated by the presence or absence of polyps. If no polyps are detected at 8 years of age, a colonoscopy and esophagogastroduodenoscopy are repeated at 18 years of age and then every 3 years until 50 years of age.⁸

In an adult patient, the diagnosis of LHS can be made clinically and a correct diagnosis prevents frequent and unpleasant gastrointestinal tract cancer screening examinations. Lampe et al² described a man with LHS who was incorrectly diagnosed with Peutz-Jeghers syndrome and experienced a colonic perforation as a complication of a screening colonoscopy. Their case report underscores the importance of making the correct diagnosis of LHS to avoid undertaking unnecessary aggressive cancer screening regimens.²

Although LHS is a benign condition that does not require treatment, Q-switched alexandrite or erbium:YAG laser therapy has been shown to improve the pigmentary findings associated with LHS.^9,10 It has been suggested that LHS should be renamed Laugier-Hunziker pigmentation² or mucocutaneous lentiginosis of Laugier and Hunziker¹ to differentiate LHS as simply a disorder of pigmentation rather than a potentially morbid genetic defect, as in Peutz-Jeghers syndrome.

Imipramine is a tricyclic medication uncommonly used to treat depression, anxiety, and other psychiatric illnesses. Although relatively rare, it has been associated with hyperpigmentation of the skin including slate gray discoloration of sun-exposed areas.

We present the case of a 63-year-old woman who had been taking imipramine for more than 20 years when she developed bluish gray discoloration on the face and neck. Histopathology of biopsy specimens showed numerous perivascular and interstitial brown globules in the dermis that were composed of melanin only, as evidenced by positive Fontana-Masson staining and negative Perls Prussian blue staining. A diagnosis of imipramine-induced hyperpigmentation was made based on histopathology and clinical history.

In addition to the case presentation, we provide a review of drugs that commonly cause hyperpigmentation as well as their associated histopathologic staining characteristics.

Case Report

A 63-year-old woman presented with blue-gray discoloration on the face and neck. She first noted the discoloration on the left side of the forehead 3 years prior; it then spread to the right side of the forehead, cheeks, and neck. She denied pruritus, pain, redness, and scaling of the involved areas; any recent changes in medications; or the use of any topical products on the affected areas. Her medical history was remarkable for hypertension, which was inconsistently controlled with lisinopril and hydrochlorothiazide, and depression, which had been managed with oral imipramine.

Physical examination disclosed blue-gray hyperpigmented patches with irregular borders on the bilateral forehead, temples, and periorbital skin (Figure 1). Reticulated brown patches were noted on the bilateral cheeks, and the neck displayed diffuse muddy brown patches with sparing of the submental areas.

Punch biopsies obtained from the lateral forehead showed an unremarkable epidermis with deposition of numerous golden brown granules in the upper and mid dermis and in perivascular macrophages (Figure 2). The pigmented granules showed positive staining with Fontana-Masson (Figure 3), and a Perls Prussian blue stain for hemosiderin was negative. Based on the clinical history, a diagnosis of imipramine-induced hyperpigmentation was made.

The patient revealed that she had taken imipramine for more than 20 years for depression as prescribed by her mental health professional. She had tried several other antidepressants but none were as effective as imipramine. Therefore, she was not willing to discontinue it despite the likelihood that the hyperpigmentation would persist and could worsen with continued use of the medication. Diligent photoprotection was advised. Additionally, she started taking lisinopril some time after the appearance of the hyperpigmentation presented and had not taken hydrochlorothiazide consistently for several years. Although these drugs are known to cause various cutaneous reactions, it was not considered likely in this case.

 

Comment

Drug-induced hyperpigmentation accounts for 10% to 20% of all cases of acquired hyperpigmentation.¹ Common causative drugs include amiodarone, antimalarials, minocycline, and rarely psychotropics including phenothiazines and tricyclic antidepressants such as imipramine.^1-4 Although amiodarone-induced hyperpigmentation is associated with lipofuscin in addition to melanin, most other medications, including imipramine, induce cutaneous effects through deposition of melanin and/or hemosiderin. A review of the histopathologic staining characteristics in pigment anomalies caused by these drugs is summarized in the Table.

Imipramine-induced hyperpigmentation presents as slate gray discrete macules and patches on sun-exposed skin that may appear anywhere from 2 to 22 years after initiating the medication.^1-4 Affected areas include the malar cheeks, temples, periorbital areas, hands, forearms, and seldom the iris and sclera.^2-4 Although the blue to slate gray coloring is classic, other colors have been described including brown, golden brown, and purple.²

Histopathology of imipramine-induced hyperpigmentation shows golden brown, round to oval granules in the superficial dermis and within dermal macrophages.^1,3 Generally, Fontana-Masson staining is positive for melanin and Perls Prussian blue staining is negative for iron.^1,2,4

Imipramine-induced hyperpigmentation likely results from photoexcitation of imipramine or one of its metabolites. These compounds activate tyrosinase, increasing melanogenesis and leading to formation of melanin-imipramine or melanin-metabolite complexes.^1-3 Complexes are deposited in the dermis and basal layer or are engulfed by dermal macrophages and darkened on sun exposure due to their high melanin content.¹ Other possible mechanisms of hyperpigmentation include nonspecific inflammation caused by the drug in the skin, hemosiderin deposition from vessel damage and subsequent erythrocyte extravasation, or deposition of newly formed pigments related to the drug.¹

Most patients report satisfactory resolution of imipramine-induced discoloration within 1 year of stopping imipramine or switching to a different antidepressant.^1,4 Patients who are unwilling to discontinue imipramine may achieve resolution with alexandrite or Q-switched ruby laser therapy.^1,4 Strict sun protective measures are necessary, both to prevent new deposition of melanin and to prevent darkening of existing pigment.

Despite the advent of new psychotropic medications, imipramine remains the antidepressant of choice for many patients. Although rare, it is important to be able to recognize imipramine-induced hyperpigmentation and to encourage patient-psychiatrist communication to determine an antidepressant regimen that avoids unnecessary cutaneous side effects.

Imipramine is a tricyclic medication uncommonly used to treat depression, anxiety, and other psychiatric illnesses. Although relatively rare, it has been associated with hyperpigmentation of the skin including slate gray discoloration of sun-exposed areas.

We present the case of a 63-year-old woman who had been taking imipramine for more than 20 years when she developed bluish gray discoloration on the face and neck. Histopathology of biopsy specimens showed numerous perivascular and interstitial brown globules in the dermis that were composed of melanin only, as evidenced by positive Fontana-Masson staining and negative Perls Prussian blue staining. A diagnosis of imipramine-induced hyperpigmentation was made based on histopathology and clinical history.

In addition to the case presentation, we provide a review of drugs that commonly cause hyperpigmentation as well as their associated histopathologic staining characteristics.

Case Report

A 63-year-old woman presented with blue-gray discoloration on the face and neck. She first noted the discoloration on the left side of the forehead 3 years prior; it then spread to the right side of the forehead, cheeks, and neck. She denied pruritus, pain, redness, and scaling of the involved areas; any recent changes in medications; or the use of any topical products on the affected areas. Her medical history was remarkable for hypertension, which was inconsistently controlled with lisinopril and hydrochlorothiazide, and depression, which had been managed with oral imipramine.

Physical examination disclosed blue-gray hyperpigmented patches with irregular borders on the bilateral forehead, temples, and periorbital skin (Figure 1). Reticulated brown patches were noted on the bilateral cheeks, and the neck displayed diffuse muddy brown patches with sparing of the submental areas.

Punch biopsies obtained from the lateral forehead showed an unremarkable epidermis with deposition of numerous golden brown granules in the upper and mid dermis and in perivascular macrophages (Figure 2). The pigmented granules showed positive staining with Fontana-Masson (Figure 3), and a Perls Prussian blue stain for hemosiderin was negative. Based on the clinical history, a diagnosis of imipramine-induced hyperpigmentation was made.

The patient revealed that she had taken imipramine for more than 20 years for depression as prescribed by her mental health professional. She had tried several other antidepressants but none were as effective as imipramine. Therefore, she was not willing to discontinue it despite the likelihood that the hyperpigmentation would persist and could worsen with continued use of the medication. Diligent photoprotection was advised. Additionally, she started taking lisinopril some time after the appearance of the hyperpigmentation presented and had not taken hydrochlorothiazide consistently for several years. Although these drugs are known to cause various cutaneous reactions, it was not considered likely in this case.

 

Comment

Drug-induced hyperpigmentation accounts for 10% to 20% of all cases of acquired hyperpigmentation.¹ Common causative drugs include amiodarone, antimalarials, minocycline, and rarely psychotropics including phenothiazines and tricyclic antidepressants such as imipramine.^1-4 Although amiodarone-induced hyperpigmentation is associated with lipofuscin in addition to melanin, most other medications, including imipramine, induce cutaneous effects through deposition of melanin and/or hemosiderin. A review of the histopathologic staining characteristics in pigment anomalies caused by these drugs is summarized in the Table.

Imipramine-induced hyperpigmentation presents as slate gray discrete macules and patches on sun-exposed skin that may appear anywhere from 2 to 22 years after initiating the medication.^1-4 Affected areas include the malar cheeks, temples, periorbital areas, hands, forearms, and seldom the iris and sclera.^2-4 Although the blue to slate gray coloring is classic, other colors have been described including brown, golden brown, and purple.²

Histopathology of imipramine-induced hyperpigmentation shows golden brown, round to oval granules in the superficial dermis and within dermal macrophages.^1,3 Generally, Fontana-Masson staining is positive for melanin and Perls Prussian blue staining is negative for iron.^1,2,4

Imipramine-induced hyperpigmentation likely results from photoexcitation of imipramine or one of its metabolites. These compounds activate tyrosinase, increasing melanogenesis and leading to formation of melanin-imipramine or melanin-metabolite complexes.^1-3 Complexes are deposited in the dermis and basal layer or are engulfed by dermal macrophages and darkened on sun exposure due to their high melanin content.¹ Other possible mechanisms of hyperpigmentation include nonspecific inflammation caused by the drug in the skin, hemosiderin deposition from vessel damage and subsequent erythrocyte extravasation, or deposition of newly formed pigments related to the drug.¹

Most patients report satisfactory resolution of imipramine-induced discoloration within 1 year of stopping imipramine or switching to a different antidepressant.^1,4 Patients who are unwilling to discontinue imipramine may achieve resolution with alexandrite or Q-switched ruby laser therapy.^1,4 Strict sun protective measures are necessary, both to prevent new deposition of melanin and to prevent darkening of existing pigment.

Despite the advent of new psychotropic medications, imipramine remains the antidepressant of choice for many patients. Although rare, it is important to be able to recognize imipramine-induced hyperpigmentation and to encourage patient-psychiatrist communication to determine an antidepressant regimen that avoids unnecessary cutaneous side effects.

Imipramine is a tricyclic medication uncommonly used to treat depression, anxiety, and other psychiatric illnesses. Although relatively rare, it has been associated with hyperpigmentation of the skin including slate gray discoloration of sun-exposed areas.

We present the case of a 63-year-old woman who had been taking imipramine for more than 20 years when she developed bluish gray discoloration on the face and neck. Histopathology of biopsy specimens showed numerous perivascular and interstitial brown globules in the dermis that were composed of melanin only, as evidenced by positive Fontana-Masson staining and negative Perls Prussian blue staining. A diagnosis of imipramine-induced hyperpigmentation was made based on histopathology and clinical history.

In addition to the case presentation, we provide a review of drugs that commonly cause hyperpigmentation as well as their associated histopathologic staining characteristics.

Case Report

A 63-year-old woman presented with blue-gray discoloration on the face and neck. She first noted the discoloration on the left side of the forehead 3 years prior; it then spread to the right side of the forehead, cheeks, and neck. She denied pruritus, pain, redness, and scaling of the involved areas; any recent changes in medications; or the use of any topical products on the affected areas. Her medical history was remarkable for hypertension, which was inconsistently controlled with lisinopril and hydrochlorothiazide, and depression, which had been managed with oral imipramine.

Physical examination disclosed blue-gray hyperpigmented patches with irregular borders on the bilateral forehead, temples, and periorbital skin (Figure 1). Reticulated brown patches were noted on the bilateral cheeks, and the neck displayed diffuse muddy brown patches with sparing of the submental areas.

Punch biopsies obtained from the lateral forehead showed an unremarkable epidermis with deposition of numerous golden brown granules in the upper and mid dermis and in perivascular macrophages (Figure 2). The pigmented granules showed positive staining with Fontana-Masson (Figure 3), and a Perls Prussian blue stain for hemosiderin was negative. Based on the clinical history, a diagnosis of imipramine-induced hyperpigmentation was made.

The patient revealed that she had taken imipramine for more than 20 years for depression as prescribed by her mental health professional. She had tried several other antidepressants but none were as effective as imipramine. Therefore, she was not willing to discontinue it despite the likelihood that the hyperpigmentation would persist and could worsen with continued use of the medication. Diligent photoprotection was advised. Additionally, she started taking lisinopril some time after the appearance of the hyperpigmentation presented and had not taken hydrochlorothiazide consistently for several years. Although these drugs are known to cause various cutaneous reactions, it was not considered likely in this case.

 

Comment

Drug-induced hyperpigmentation accounts for 10% to 20% of all cases of acquired hyperpigmentation.¹ Common causative drugs include amiodarone, antimalarials, minocycline, and rarely psychotropics including phenothiazines and tricyclic antidepressants such as imipramine.^1-4 Although amiodarone-induced hyperpigmentation is associated with lipofuscin in addition to melanin, most other medications, including imipramine, induce cutaneous effects through deposition of melanin and/or hemosiderin. A review of the histopathologic staining characteristics in pigment anomalies caused by these drugs is summarized in the Table.

Imipramine-induced hyperpigmentation presents as slate gray discrete macules and patches on sun-exposed skin that may appear anywhere from 2 to 22 years after initiating the medication.^1-4 Affected areas include the malar cheeks, temples, periorbital areas, hands, forearms, and seldom the iris and sclera.^2-4 Although the blue to slate gray coloring is classic, other colors have been described including brown, golden brown, and purple.²

Histopathology of imipramine-induced hyperpigmentation shows golden brown, round to oval granules in the superficial dermis and within dermal macrophages.^1,3 Generally, Fontana-Masson staining is positive for melanin and Perls Prussian blue staining is negative for iron.^1,2,4

Imipramine-induced hyperpigmentation likely results from photoexcitation of imipramine or one of its metabolites. These compounds activate tyrosinase, increasing melanogenesis and leading to formation of melanin-imipramine or melanin-metabolite complexes.^1-3 Complexes are deposited in the dermis and basal layer or are engulfed by dermal macrophages and darkened on sun exposure due to their high melanin content.¹ Other possible mechanisms of hyperpigmentation include nonspecific inflammation caused by the drug in the skin, hemosiderin deposition from vessel damage and subsequent erythrocyte extravasation, or deposition of newly formed pigments related to the drug.¹

Most patients report satisfactory resolution of imipramine-induced discoloration within 1 year of stopping imipramine or switching to a different antidepressant.^1,4 Patients who are unwilling to discontinue imipramine may achieve resolution with alexandrite or Q-switched ruby laser therapy.^1,4 Strict sun protective measures are necessary, both to prevent new deposition of melanin and to prevent darkening of existing pigment.

Despite the advent of new psychotropic medications, imipramine remains the antidepressant of choice for many patients. Although rare, it is important to be able to recognize imipramine-induced hyperpigmentation and to encourage patient-psychiatrist communication to determine an antidepressant regimen that avoids unnecessary cutaneous side effects.

 

SAN FRANCISCO – Dermatologists are often on the frontline when it comes to diagnosing polycystic ovary syndrome (PCOS), which is one reason they should be up to date and aware of the changing diagnostic criteria for the condition, according to Kanade Shinkai, MD.

About one-quarter of patients who are diagnosed with PCOS are seen first by a dermatologist. That’s because skin conditions may be more concerning than reproductive issues in young women.

“Sometimes, people don’t see [irregular menstruation] as a problem,” explained Dr. Shinkai of the department of dermatology at the University of California, San Francisco. “Maybe they’re young, or they’re not trying to get pregnant. But if their hair is falling out, they see that as a problem, or if they have bad acne, or they’re becoming hirsute, they see that as a problem. So, they present to a dermatologist.”

Early recognition of PCOS is important, because many women with the condition go on to develop diabetes, impaired glucose intolerance, hyperlipidemia, hypertension, fertility problems, and obesity.

Speaking at the annual meeting of the Pacific Dermatologic Association, Dr. Shinkai also noted that the diagnostic criteria for PCOS have shifted recently.

It used to be that physicians expected patients with PCOS to have menstrual irregularities, biochemical or clinical evidence of hyperandrogenism, and evidence of polycystic ovaries on ultrasound. But just two of the three are now considered enough to warrant a diagnosis.

“Our original view of the classic patient has gone away, and it’s really a heterogeneous phenotype,” Dr. Shinkai said. “Originally, it was all three [criteria], and the patient was obese, and they all had diabetes. Now, we know that’s not true. Every woman who has PCOS has her own version of PCOS.”

Dr. Shinkai’s team conducted a study of clinical markers associated with PCOS and found that some of the classic signs of PCOS may be unreliable.

“Alopecia turns out not to be a very reliable marker,” she explained. “That’s paradigm shifting, I think, because often if patients present with hair loss in a hormonal pattern, they get worked up for PCOS, and it turns out that workup is not always fruitful.” Acne can also be misleading, given its frequency in the general population.

More reliable signs include hirsutism and acanthosis nigricans; 70%-80% of women with hirsutism have PCOS, and 53% of patients with PCOS have hirsutism, most commonly on the trunk. Acanthosis nigricans occurs in 37% of PCOS patients.

“Those are the best specific signs for PCOS,” said Dr. Shinkai. “If we see those, we should probably work the patient up.”

In preparation, the patient should be off of birth control treatment for at least 4 weeks, because hormonal treatment can interfere with test results, Dr Shinkai noted.

She also recommended a transvaginal ultrasound and a free-testosterone test. Consensus statements recommend testing of 17-hydroxyprogesterone, but Dr. Shinkai said she isn’t so sure. “That’s only going to capture about 3% of your patients with cutaneous hyperandrogenism, so it’s pretty low yield,” she said.

For treatment of cutaneous symptoms of PCOS, it’s important for the patient to understand that treatment courses will last at least 6 months. “It’s not a quick fix,” said Dr. Shinkai. Oral contraceptives are a mainstay, and are often sufficient for mild hirsutism. But moderate or severe cases call for high doses of spironolactone (150-200 mg/day). She said she usually combines spironolactone with oral contraceptives, because the drug can lead to menstrual irregularities, which birth control pills can relieve.

Dr. Shinkai reported having no relevant financial disclosures.

 

SAN FRANCISCO – Dermatologists are often on the frontline when it comes to diagnosing polycystic ovary syndrome (PCOS), which is one reason they should be up to date and aware of the changing diagnostic criteria for the condition, according to Kanade Shinkai, MD.

About one-quarter of patients who are diagnosed with PCOS are seen first by a dermatologist. That’s because skin conditions may be more concerning than reproductive issues in young women.

“Sometimes, people don’t see [irregular menstruation] as a problem,” explained Dr. Shinkai of the department of dermatology at the University of California, San Francisco. “Maybe they’re young, or they’re not trying to get pregnant. But if their hair is falling out, they see that as a problem, or if they have bad acne, or they’re becoming hirsute, they see that as a problem. So, they present to a dermatologist.”

Early recognition of PCOS is important, because many women with the condition go on to develop diabetes, impaired glucose intolerance, hyperlipidemia, hypertension, fertility problems, and obesity.

Speaking at the annual meeting of the Pacific Dermatologic Association, Dr. Shinkai also noted that the diagnostic criteria for PCOS have shifted recently.

It used to be that physicians expected patients with PCOS to have menstrual irregularities, biochemical or clinical evidence of hyperandrogenism, and evidence of polycystic ovaries on ultrasound. But just two of the three are now considered enough to warrant a diagnosis.

“Our original view of the classic patient has gone away, and it’s really a heterogeneous phenotype,” Dr. Shinkai said. “Originally, it was all three [criteria], and the patient was obese, and they all had diabetes. Now, we know that’s not true. Every woman who has PCOS has her own version of PCOS.”

Dr. Shinkai’s team conducted a study of clinical markers associated with PCOS and found that some of the classic signs of PCOS may be unreliable.

“Alopecia turns out not to be a very reliable marker,” she explained. “That’s paradigm shifting, I think, because often if patients present with hair loss in a hormonal pattern, they get worked up for PCOS, and it turns out that workup is not always fruitful.” Acne can also be misleading, given its frequency in the general population.

More reliable signs include hirsutism and acanthosis nigricans; 70%-80% of women with hirsutism have PCOS, and 53% of patients with PCOS have hirsutism, most commonly on the trunk. Acanthosis nigricans occurs in 37% of PCOS patients.

“Those are the best specific signs for PCOS,” said Dr. Shinkai. “If we see those, we should probably work the patient up.”

In preparation, the patient should be off of birth control treatment for at least 4 weeks, because hormonal treatment can interfere with test results, Dr Shinkai noted.

She also recommended a transvaginal ultrasound and a free-testosterone test. Consensus statements recommend testing of 17-hydroxyprogesterone, but Dr. Shinkai said she isn’t so sure. “That’s only going to capture about 3% of your patients with cutaneous hyperandrogenism, so it’s pretty low yield,” she said.

For treatment of cutaneous symptoms of PCOS, it’s important for the patient to understand that treatment courses will last at least 6 months. “It’s not a quick fix,” said Dr. Shinkai. Oral contraceptives are a mainstay, and are often sufficient for mild hirsutism. But moderate or severe cases call for high doses of spironolactone (150-200 mg/day). She said she usually combines spironolactone with oral contraceptives, because the drug can lead to menstrual irregularities, which birth control pills can relieve.

Dr. Shinkai reported having no relevant financial disclosures.

 

SAN FRANCISCO – Dermatologists are often on the frontline when it comes to diagnosing polycystic ovary syndrome (PCOS), which is one reason they should be up to date and aware of the changing diagnostic criteria for the condition, according to Kanade Shinkai, MD.

About one-quarter of patients who are diagnosed with PCOS are seen first by a dermatologist. That’s because skin conditions may be more concerning than reproductive issues in young women.

“Sometimes, people don’t see [irregular menstruation] as a problem,” explained Dr. Shinkai of the department of dermatology at the University of California, San Francisco. “Maybe they’re young, or they’re not trying to get pregnant. But if their hair is falling out, they see that as a problem, or if they have bad acne, or they’re becoming hirsute, they see that as a problem. So, they present to a dermatologist.”

Early recognition of PCOS is important, because many women with the condition go on to develop diabetes, impaired glucose intolerance, hyperlipidemia, hypertension, fertility problems, and obesity.

Speaking at the annual meeting of the Pacific Dermatologic Association, Dr. Shinkai also noted that the diagnostic criteria for PCOS have shifted recently.

It used to be that physicians expected patients with PCOS to have menstrual irregularities, biochemical or clinical evidence of hyperandrogenism, and evidence of polycystic ovaries on ultrasound. But just two of the three are now considered enough to warrant a diagnosis.

“Our original view of the classic patient has gone away, and it’s really a heterogeneous phenotype,” Dr. Shinkai said. “Originally, it was all three [criteria], and the patient was obese, and they all had diabetes. Now, we know that’s not true. Every woman who has PCOS has her own version of PCOS.”

Dr. Shinkai’s team conducted a study of clinical markers associated with PCOS and found that some of the classic signs of PCOS may be unreliable.

“Alopecia turns out not to be a very reliable marker,” she explained. “That’s paradigm shifting, I think, because often if patients present with hair loss in a hormonal pattern, they get worked up for PCOS, and it turns out that workup is not always fruitful.” Acne can also be misleading, given its frequency in the general population.

More reliable signs include hirsutism and acanthosis nigricans; 70%-80% of women with hirsutism have PCOS, and 53% of patients with PCOS have hirsutism, most commonly on the trunk. Acanthosis nigricans occurs in 37% of PCOS patients.

“Those are the best specific signs for PCOS,” said Dr. Shinkai. “If we see those, we should probably work the patient up.”

In preparation, the patient should be off of birth control treatment for at least 4 weeks, because hormonal treatment can interfere with test results, Dr Shinkai noted.

She also recommended a transvaginal ultrasound and a free-testosterone test. Consensus statements recommend testing of 17-hydroxyprogesterone, but Dr. Shinkai said she isn’t so sure. “That’s only going to capture about 3% of your patients with cutaneous hyperandrogenism, so it’s pretty low yield,” she said.

For treatment of cutaneous symptoms of PCOS, it’s important for the patient to understand that treatment courses will last at least 6 months. “It’s not a quick fix,” said Dr. Shinkai. Oral contraceptives are a mainstay, and are often sufficient for mild hirsutism. But moderate or severe cases call for high doses of spironolactone (150-200 mg/day). She said she usually combines spironolactone with oral contraceptives, because the drug can lead to menstrual irregularities, which birth control pills can relieve.

Dr. Shinkai reported having no relevant financial disclosures.

The Diagnosis: Lichen Aureus

The clinicopathological findings were diagnostic of lichen aureus (LA). Microscopic examination revealed a relatively sparse, superficial, perivascular and interstitial lymphohistiocytic infiltrate with scattered siderophages in the upper dermis. Extravasation of red blood cells also was noted (Figure 1). An immunohistochemical stain for Melan-A highlighted a normal number and distribution of single melanocytes at the dermoepidermal junction with no evidence of pagetoid scatter. A Perls Prussian blue stain for iron demonstrated abundant hemosiderin in the dermis (Figure 2).

Pigmented purpuric dermatosis (PPD) describes a group of cutaneous lesions that are characterized by petechiae and pigmentary changes. These lesions most commonly present on the lower limbs; however, other sites have been reported.1 This group includes several major clinical forms such as Schamberg disease, LA, purpura annularis telangiectodes of Majocchi, eczematidlike purpura of Doucas and Kapetanakis, and lichenoid PPD of Gougerot and Blum. Lesions typically demonstrate a striking golden brown color clinically and by definition occur in the absence of platelet defects or vasculitis.¹

Factors implicated in the pathogenesis of pigmented purpura include gravitational dependency, venous stasis, infection, and drugs.² It is suggested that cellular immunity may play a role in the development of the disease based on the presence of CD4⁺ T lymphocytes in the infiltrate and the expression of HLA-DR by these lymphocytes and the keratinocytes.³ Lichen aureus differs in that it relates to increased intravascular pressure from an incompetent valve in an underlying perforating vein.⁴

Lichen aureus, also referred to as lichen purpuricus, is one major variant of PPD. The name reflects both the characteristic golden brown color and the histopathologic pattern of inflammation.¹ Lichen aureus usually presents as a unilateral, asymptomatic, confined single lesion located mainly on the leg,¹ though it can develop at other sites or as a localized group of lesions. Extensive lesions have been reported⁵ and cases with a segmental distribution have been described.⁶ In contrast, Schamberg disease demonstrates pinhead-sized reddish lesions giving the characteristic cayenne pepper pigmentation. These lesions coalesce to form thumbprint patches that progress proximally.¹ Majocchi purpura is annular and telangiectatic, while lichenoid purpura of Gougerot and Blum presents with flat-topped, polygonal, violaceous papules that turn brown over time.

Some authors have championed a role for dermoscopy in diagnosis of LA.⁷ By dermoscopy, LA demonstrates a diffuse copper background reflecting the lymphohistiocytic dermal infiltrate, red dots and globules representing the extravasated red blood cells and the dilated swollen vessels, and grey dots that reflect the hemosiderin present in the dermis.⁸

Histologically, LA demonstrates a superficial perivascular infiltrate composed mainly of CD4⁺ lymphocytes surrounding the superficial capillaries. Over time, red cell extravasation leads to the formation of hemosiderin-laden macrophages, which can be highlighted with Perls Prussian blue stain. A bandlike infiltrate with thin strands of collagen separating it from the epidermis also may be noted.⁹

An important consideration in the differential diagnosis of PPD is mycosis fungoides (MF). Mycosis fungoides is a cutaneous T-cell lymphoma that clinically presents as a single or multiple hypopigmented or hyperpigmented patches or as erythematous scaly lesions in the patch or plaque stage. These lesions eventually may evolve into tumor stage.¹⁰ Mycosis fungoides may mimic PPD clinically and/or histopathologically, and rarely PPD also may precede MF.¹¹ Involvement of the trunk, especially the lower abdomen and buttock region, favors a diagnosis of MF. Typically, histopathologic examination of MF demonstrates an epidermotropic lymphocytic infiltrate composed of atypical cerebriform lymphocytes overlying papillary dermal fibrosis. Although classic MF would be difficult to confuse with PPD, the atrophic lichenoid pattern of MF may show remarkable overlap with PPD.¹² Such cases require clinicopathologic correlation, immunophenotyping of the epidermotropic lymphocytes, and occasionally T-cell clonality studies.

Lichen aureus is a chronic persistent disease unless the underlying incompetent perforator vessel is ligated. Various treatments have been used for other forms of pigmented purpura including topical corticosteroids, topical tacrolimus, systemic vasodilators such as prostacyclin and pentoxifylline, and phototherapy.¹ Clinical follow-up is recommended for lesions that show some clinical or histopathological overlap with MF. Additional biopsies also may prove useful in establishing a definitive diagnosis in ambiguous cases.

The Diagnosis: Lichen Aureus

The clinicopathological findings were diagnostic of lichen aureus (LA). Microscopic examination revealed a relatively sparse, superficial, perivascular and interstitial lymphohistiocytic infiltrate with scattered siderophages in the upper dermis. Extravasation of red blood cells also was noted (Figure 1). An immunohistochemical stain for Melan-A highlighted a normal number and distribution of single melanocytes at the dermoepidermal junction with no evidence of pagetoid scatter. A Perls Prussian blue stain for iron demonstrated abundant hemosiderin in the dermis (Figure 2).

Pigmented purpuric dermatosis (PPD) describes a group of cutaneous lesions that are characterized by petechiae and pigmentary changes. These lesions most commonly present on the lower limbs; however, other sites have been reported.1 This group includes several major clinical forms such as Schamberg disease, LA, purpura annularis telangiectodes of Majocchi, eczematidlike purpura of Doucas and Kapetanakis, and lichenoid PPD of Gougerot and Blum. Lesions typically demonstrate a striking golden brown color clinically and by definition occur in the absence of platelet defects or vasculitis.¹

Factors implicated in the pathogenesis of pigmented purpura include gravitational dependency, venous stasis, infection, and drugs.² It is suggested that cellular immunity may play a role in the development of the disease based on the presence of CD4⁺ T lymphocytes in the infiltrate and the expression of HLA-DR by these lymphocytes and the keratinocytes.³ Lichen aureus differs in that it relates to increased intravascular pressure from an incompetent valve in an underlying perforating vein.⁴

Lichen aureus, also referred to as lichen purpuricus, is one major variant of PPD. The name reflects both the characteristic golden brown color and the histopathologic pattern of inflammation.¹ Lichen aureus usually presents as a unilateral, asymptomatic, confined single lesion located mainly on the leg,¹ though it can develop at other sites or as a localized group of lesions. Extensive lesions have been reported⁵ and cases with a segmental distribution have been described.⁶ In contrast, Schamberg disease demonstrates pinhead-sized reddish lesions giving the characteristic cayenne pepper pigmentation. These lesions coalesce to form thumbprint patches that progress proximally.¹ Majocchi purpura is annular and telangiectatic, while lichenoid purpura of Gougerot and Blum presents with flat-topped, polygonal, violaceous papules that turn brown over time.

Some authors have championed a role for dermoscopy in diagnosis of LA.⁷ By dermoscopy, LA demonstrates a diffuse copper background reflecting the lymphohistiocytic dermal infiltrate, red dots and globules representing the extravasated red blood cells and the dilated swollen vessels, and grey dots that reflect the hemosiderin present in the dermis.⁸

Histologically, LA demonstrates a superficial perivascular infiltrate composed mainly of CD4⁺ lymphocytes surrounding the superficial capillaries. Over time, red cell extravasation leads to the formation of hemosiderin-laden macrophages, which can be highlighted with Perls Prussian blue stain. A bandlike infiltrate with thin strands of collagen separating it from the epidermis also may be noted.⁹

An important consideration in the differential diagnosis of PPD is mycosis fungoides (MF). Mycosis fungoides is a cutaneous T-cell lymphoma that clinically presents as a single or multiple hypopigmented or hyperpigmented patches or as erythematous scaly lesions in the patch or plaque stage. These lesions eventually may evolve into tumor stage.¹⁰ Mycosis fungoides may mimic PPD clinically and/or histopathologically, and rarely PPD also may precede MF.¹¹ Involvement of the trunk, especially the lower abdomen and buttock region, favors a diagnosis of MF. Typically, histopathologic examination of MF demonstrates an epidermotropic lymphocytic infiltrate composed of atypical cerebriform lymphocytes overlying papillary dermal fibrosis. Although classic MF would be difficult to confuse with PPD, the atrophic lichenoid pattern of MF may show remarkable overlap with PPD.¹² Such cases require clinicopathologic correlation, immunophenotyping of the epidermotropic lymphocytes, and occasionally T-cell clonality studies.

Lichen aureus is a chronic persistent disease unless the underlying incompetent perforator vessel is ligated. Various treatments have been used for other forms of pigmented purpura including topical corticosteroids, topical tacrolimus, systemic vasodilators such as prostacyclin and pentoxifylline, and phototherapy.¹ Clinical follow-up is recommended for lesions that show some clinical or histopathological overlap with MF. Additional biopsies also may prove useful in establishing a definitive diagnosis in ambiguous cases.

The Diagnosis: Lichen Aureus

The clinicopathological findings were diagnostic of lichen aureus (LA). Microscopic examination revealed a relatively sparse, superficial, perivascular and interstitial lymphohistiocytic infiltrate with scattered siderophages in the upper dermis. Extravasation of red blood cells also was noted (Figure 1). An immunohistochemical stain for Melan-A highlighted a normal number and distribution of single melanocytes at the dermoepidermal junction with no evidence of pagetoid scatter. A Perls Prussian blue stain for iron demonstrated abundant hemosiderin in the dermis (Figure 2).

Pigmented purpuric dermatosis (PPD) describes a group of cutaneous lesions that are characterized by petechiae and pigmentary changes. These lesions most commonly present on the lower limbs; however, other sites have been reported.1 This group includes several major clinical forms such as Schamberg disease, LA, purpura annularis telangiectodes of Majocchi, eczematidlike purpura of Doucas and Kapetanakis, and lichenoid PPD of Gougerot and Blum. Lesions typically demonstrate a striking golden brown color clinically and by definition occur in the absence of platelet defects or vasculitis.¹

Factors implicated in the pathogenesis of pigmented purpura include gravitational dependency, venous stasis, infection, and drugs.² It is suggested that cellular immunity may play a role in the development of the disease based on the presence of CD4⁺ T lymphocytes in the infiltrate and the expression of HLA-DR by these lymphocytes and the keratinocytes.³ Lichen aureus differs in that it relates to increased intravascular pressure from an incompetent valve in an underlying perforating vein.⁴

Lichen aureus, also referred to as lichen purpuricus, is one major variant of PPD. The name reflects both the characteristic golden brown color and the histopathologic pattern of inflammation.¹ Lichen aureus usually presents as a unilateral, asymptomatic, confined single lesion located mainly on the leg,¹ though it can develop at other sites or as a localized group of lesions. Extensive lesions have been reported⁵ and cases with a segmental distribution have been described.⁶ In contrast, Schamberg disease demonstrates pinhead-sized reddish lesions giving the characteristic cayenne pepper pigmentation. These lesions coalesce to form thumbprint patches that progress proximally.¹ Majocchi purpura is annular and telangiectatic, while lichenoid purpura of Gougerot and Blum presents with flat-topped, polygonal, violaceous papules that turn brown over time.

Some authors have championed a role for dermoscopy in diagnosis of LA.⁷ By dermoscopy, LA demonstrates a diffuse copper background reflecting the lymphohistiocytic dermal infiltrate, red dots and globules representing the extravasated red blood cells and the dilated swollen vessels, and grey dots that reflect the hemosiderin present in the dermis.⁸

Histologically, LA demonstrates a superficial perivascular infiltrate composed mainly of CD4⁺ lymphocytes surrounding the superficial capillaries. Over time, red cell extravasation leads to the formation of hemosiderin-laden macrophages, which can be highlighted with Perls Prussian blue stain. A bandlike infiltrate with thin strands of collagen separating it from the epidermis also may be noted.⁹

An important consideration in the differential diagnosis of PPD is mycosis fungoides (MF). Mycosis fungoides is a cutaneous T-cell lymphoma that clinically presents as a single or multiple hypopigmented or hyperpigmented patches or as erythematous scaly lesions in the patch or plaque stage. These lesions eventually may evolve into tumor stage.¹⁰ Mycosis fungoides may mimic PPD clinically and/or histopathologically, and rarely PPD also may precede MF.¹¹ Involvement of the trunk, especially the lower abdomen and buttock region, favors a diagnosis of MF. Typically, histopathologic examination of MF demonstrates an epidermotropic lymphocytic infiltrate composed of atypical cerebriform lymphocytes overlying papillary dermal fibrosis. Although classic MF would be difficult to confuse with PPD, the atrophic lichenoid pattern of MF may show remarkable overlap with PPD.¹² Such cases require clinicopathologic correlation, immunophenotyping of the epidermotropic lymphocytes, and occasionally T-cell clonality studies.

Lichen aureus is a chronic persistent disease unless the underlying incompetent perforator vessel is ligated. Various treatments have been used for other forms of pigmented purpura including topical corticosteroids, topical tacrolimus, systemic vasodilators such as prostacyclin and pentoxifylline, and phototherapy.¹ Clinical follow-up is recommended for lesions that show some clinical or histopathological overlap with MF. Additional biopsies also may prove useful in establishing a definitive diagnosis in ambiguous cases.

The Diagnosis: Incontinentia Pigmenti

The infant's mother was noted to have diffuse hypopigmented patches over the trunk, arms, and legs (present since adolescence) with whorled cicatricial alopecia of the vertex scalp and peg-shaped teeth (Figure). Together, these findings suggested incontinentia pigmenti (IP), which the mother revealed she had been diagnosed with in childhood. The infant's characteristic lesions in the setting of her mother's diagnosed genodermatosis confirmed the diagnosis of IP.

Incontinentia pigmenti is an X-linked dominant disorder that presents with many classic dermatologic, dental, neurologic, and ophthalmologic findings. The causative mutation occurs in IKBKG/NEMO (inhibitor of κ polypeptide gene enhancer in B-cells, kinase γ/nuclear factor-κB essential modulator) gene on Xq28, disabling the resultant protein that normally protects cells from tumor necrosis factor family-induced apoptosis.¹ Incontinentia pigmenti usually is lethal in males and causes an unbalanced X-inactivation in surviving female IP patients. Occurring at a rate of 1.2 per 100,000 births,² IP typically presents in female infants with skin lesions patterned along Blaschko lines that evolve in 4 stages over a lifetime.³ Stage I, presenting in the neonatal period, manifests as vesiculobullous eruptions on the limbs and scalp. Stages II to IV vary in duration from months to years and are comprised of a verrucous stage, a hyperpigmented stage, and a hypopigmented stage, respectively.³ All stages of IP can overlap and coexist. 

The vesiculobullous findings in infants with IP may be mistakenly attributed to other diseases with prominent vesicular or bullous components including herpes simplex virus, epidermolysis bullosa, and infantile acropustulosis. With neonatal herpes simplex virus infection, vesicular skin or mucocutaneous lesions occur 9 to 11 days after birth and can be confirmed by specimen culture or qualitative polymerase chain reaction, while stage I of IP appears within the first 6 to 8 weeks of life and can be present at birth.⁴ The hallmark of epidermolysis bullosa, caused by mutations in keratins 5 and 14, is blistering erosions of the skin in response to frictional stress,¹ thus these lesions do not follow Blaschko lines. Infantile acropustulosis, a nonheritable vesiculopustular eruption of the hands and feet, rarely occurs in the immediate newborn period; it most often appears in the 3- to 6-month age range with recurrent eruptions at 3- to 4-week intervals.⁵ Focal dermal hypoplasia is another X-linked dominant disorder with blaschkolinear findings at birth that presents with pink or red, angular, atrophic macules, in contrast to the bullous lesions of IP.⁶

Incontinentia pigmenti may encompass a wide range of systemic symptoms in addition to the classic dermatologic findings. Notably, central nervous system defects are concurrent in up to 40% of IP cases, with seizures, mental retardation, and spastic paresis being the most common sequelae.⁷ Teeth defects, seen in 35% of patients, include delayed primary dentition and peg-shaped teeth. Many patients will experience ophthalmologic defects including vision problems (16%) and retinopathy (15%).⁷

The cutaneous eruptions of IP may be treated with topical corticosteroids or topical tacrolimus, and vesicles should be left intact and monitored for signs of infection.^8,9 Seizures, if present, should be treated with anticonvulsants, and regular neuropsychiatric monitoring and physical rehabilitation may be warranted. Patients should be regularly monitored for retinopathy beginning at the time of diagnosis. Retinal fibrovascular proliferation is treated with xenon laser photocoagulation to reduce the high risk for retinal detachment in this population.^10,11 Older and younger at-risk relatives must be evaluated by genetic testing or thorough physical examination to clarify their disease status and determine the need for additional genetic counseling.

The Diagnosis: Incontinentia Pigmenti

The infant's mother was noted to have diffuse hypopigmented patches over the trunk, arms, and legs (present since adolescence) with whorled cicatricial alopecia of the vertex scalp and peg-shaped teeth (Figure). Together, these findings suggested incontinentia pigmenti (IP), which the mother revealed she had been diagnosed with in childhood. The infant's characteristic lesions in the setting of her mother's diagnosed genodermatosis confirmed the diagnosis of IP.

Incontinentia pigmenti is an X-linked dominant disorder that presents with many classic dermatologic, dental, neurologic, and ophthalmologic findings. The causative mutation occurs in IKBKG/NEMO (inhibitor of κ polypeptide gene enhancer in B-cells, kinase γ/nuclear factor-κB essential modulator) gene on Xq28, disabling the resultant protein that normally protects cells from tumor necrosis factor family-induced apoptosis.¹ Incontinentia pigmenti usually is lethal in males and causes an unbalanced X-inactivation in surviving female IP patients. Occurring at a rate of 1.2 per 100,000 births,² IP typically presents in female infants with skin lesions patterned along Blaschko lines that evolve in 4 stages over a lifetime.³ Stage I, presenting in the neonatal period, manifests as vesiculobullous eruptions on the limbs and scalp. Stages II to IV vary in duration from months to years and are comprised of a verrucous stage, a hyperpigmented stage, and a hypopigmented stage, respectively.³ All stages of IP can overlap and coexist. 

The vesiculobullous findings in infants with IP may be mistakenly attributed to other diseases with prominent vesicular or bullous components including herpes simplex virus, epidermolysis bullosa, and infantile acropustulosis. With neonatal herpes simplex virus infection, vesicular skin or mucocutaneous lesions occur 9 to 11 days after birth and can be confirmed by specimen culture or qualitative polymerase chain reaction, while stage I of IP appears within the first 6 to 8 weeks of life and can be present at birth.⁴ The hallmark of epidermolysis bullosa, caused by mutations in keratins 5 and 14, is blistering erosions of the skin in response to frictional stress,¹ thus these lesions do not follow Blaschko lines. Infantile acropustulosis, a nonheritable vesiculopustular eruption of the hands and feet, rarely occurs in the immediate newborn period; it most often appears in the 3- to 6-month age range with recurrent eruptions at 3- to 4-week intervals.⁵ Focal dermal hypoplasia is another X-linked dominant disorder with blaschkolinear findings at birth that presents with pink or red, angular, atrophic macules, in contrast to the bullous lesions of IP.⁶

Incontinentia pigmenti may encompass a wide range of systemic symptoms in addition to the classic dermatologic findings. Notably, central nervous system defects are concurrent in up to 40% of IP cases, with seizures, mental retardation, and spastic paresis being the most common sequelae.⁷ Teeth defects, seen in 35% of patients, include delayed primary dentition and peg-shaped teeth. Many patients will experience ophthalmologic defects including vision problems (16%) and retinopathy (15%).⁷

The cutaneous eruptions of IP may be treated with topical corticosteroids or topical tacrolimus, and vesicles should be left intact and monitored for signs of infection.^8,9 Seizures, if present, should be treated with anticonvulsants, and regular neuropsychiatric monitoring and physical rehabilitation may be warranted. Patients should be regularly monitored for retinopathy beginning at the time of diagnosis. Retinal fibrovascular proliferation is treated with xenon laser photocoagulation to reduce the high risk for retinal detachment in this population.^10,11 Older and younger at-risk relatives must be evaluated by genetic testing or thorough physical examination to clarify their disease status and determine the need for additional genetic counseling.

The Diagnosis: Incontinentia Pigmenti

The infant's mother was noted to have diffuse hypopigmented patches over the trunk, arms, and legs (present since adolescence) with whorled cicatricial alopecia of the vertex scalp and peg-shaped teeth (Figure). Together, these findings suggested incontinentia pigmenti (IP), which the mother revealed she had been diagnosed with in childhood. The infant's characteristic lesions in the setting of her mother's diagnosed genodermatosis confirmed the diagnosis of IP.

Incontinentia pigmenti is an X-linked dominant disorder that presents with many classic dermatologic, dental, neurologic, and ophthalmologic findings. The causative mutation occurs in IKBKG/NEMO (inhibitor of κ polypeptide gene enhancer in B-cells, kinase γ/nuclear factor-κB essential modulator) gene on Xq28, disabling the resultant protein that normally protects cells from tumor necrosis factor family-induced apoptosis.¹ Incontinentia pigmenti usually is lethal in males and causes an unbalanced X-inactivation in surviving female IP patients. Occurring at a rate of 1.2 per 100,000 births,² IP typically presents in female infants with skin lesions patterned along Blaschko lines that evolve in 4 stages over a lifetime.³ Stage I, presenting in the neonatal period, manifests as vesiculobullous eruptions on the limbs and scalp. Stages II to IV vary in duration from months to years and are comprised of a verrucous stage, a hyperpigmented stage, and a hypopigmented stage, respectively.³ All stages of IP can overlap and coexist. 

The vesiculobullous findings in infants with IP may be mistakenly attributed to other diseases with prominent vesicular or bullous components including herpes simplex virus, epidermolysis bullosa, and infantile acropustulosis. With neonatal herpes simplex virus infection, vesicular skin or mucocutaneous lesions occur 9 to 11 days after birth and can be confirmed by specimen culture or qualitative polymerase chain reaction, while stage I of IP appears within the first 6 to 8 weeks of life and can be present at birth.⁴ The hallmark of epidermolysis bullosa, caused by mutations in keratins 5 and 14, is blistering erosions of the skin in response to frictional stress,¹ thus these lesions do not follow Blaschko lines. Infantile acropustulosis, a nonheritable vesiculopustular eruption of the hands and feet, rarely occurs in the immediate newborn period; it most often appears in the 3- to 6-month age range with recurrent eruptions at 3- to 4-week intervals.⁵ Focal dermal hypoplasia is another X-linked dominant disorder with blaschkolinear findings at birth that presents with pink or red, angular, atrophic macules, in contrast to the bullous lesions of IP.⁶

Incontinentia pigmenti may encompass a wide range of systemic symptoms in addition to the classic dermatologic findings. Notably, central nervous system defects are concurrent in up to 40% of IP cases, with seizures, mental retardation, and spastic paresis being the most common sequelae.⁷ Teeth defects, seen in 35% of patients, include delayed primary dentition and peg-shaped teeth. Many patients will experience ophthalmologic defects including vision problems (16%) and retinopathy (15%).⁷

The cutaneous eruptions of IP may be treated with topical corticosteroids or topical tacrolimus, and vesicles should be left intact and monitored for signs of infection.^8,9 Seizures, if present, should be treated with anticonvulsants, and regular neuropsychiatric monitoring and physical rehabilitation may be warranted. Patients should be regularly monitored for retinopathy beginning at the time of diagnosis. Retinal fibrovascular proliferation is treated with xenon laser photocoagulation to reduce the high risk for retinal detachment in this population.^10,11 Older and younger at-risk relatives must be evaluated by genetic testing or thorough physical examination to clarify their disease status and determine the need for additional genetic counseling.

To the Editor:

Erythema ab igne (EAI) is a reticular erythematous hyperpigmentation of skin repeatedly exposed to moderate heat.¹ It usually is asymptomatic, though some patients report itching or burning at the site.² Historically caused by exposure to coal stoves or open fires, EAI has become increasingly common among individuals using space heaters, heating pads, or laptop computers near bare skin.^2,3 Although EAI itself is benign and usually resolves with the removal of the exposure, it remains of clinical importance because of its association with underlying chronic disease, as chronic pain often is managed with frequent heating pad or hot water bottle use.² Additionally, accurate diagnosis is important given the future risk for malignancy, as chronic changes of EAI have been reported to lead to squamous cell carcinoma or rarely Merkel cell carcinoma.² Erythema ab igne is not traditionally associated with the formation of bullae; however, we present a case of bullous EAI that we believe highlights the importance of including this condition in the differential diagnosis of bullous disorders.

A 55-year-old man was admitted for presumed cellulitis of the bilateral legs. The patient had developed hyperpigmented discoloration of the medial surface of both legs with subsequent formation of tense bullae over the last 2 months. The dermatology department was consulted, as there was concern for bullous pemphigoid. The patient’s medical history was notable for hypertension, hyperlipidemia, diet-controlled type 2 diabetes mellitus, and hepatitis C virus with cirrhosis. The patient denied pruritus, pain, or known exposure of the legs to potential irritants prior to developing the lesions; however, with additional questioning he did report frequently sitting in front of a space heater with bare legs. Physical examination revealed multiple areas of reticulated erythematous hyperpigmentation with several overlying bullae (Figure 1). Many of the bullae were unroofed with full-thickness ulceration. Biopsies were taken for hematoxylin and eosin staining (Figure 2) and direct immunofluorescence.

Basic hematologic and metabolic laboratory test results as well as blood cultures were negative. Wound culture was positive for methicillin-resistant Staphylococcus aureus. Histologic examination showed interface dermatitis with subepidermal vesicle (Figure 2). Scattered necrotic keratinocytes were present in the adjacent epidermis, and focal subtle vacuolar alteration of the dermoepidermal junction was seen (Figure 3). Sparse perivascular mononuclear cells and scattered melanophages were present in the dermis. Direct immunofluorescence showed no diagnostic immunopathologic abnormality. Focal weak nonspecific vascular positivity for IgG and C3 was seen, but IgA and IgM were negative. Although not specific, these changes were compatible with EAI in the clinical context provided. The diagnosis of bullous EAI with superimposed staphylococcal infection was made.

Although rare, there have been reports of a bullous variant of EAI. Flanagan et al⁴ described 3 cases of bullous EAI with histopathology similar to our case. All 3 biopsies showed subepidermal separation with a mild perivascular dermal lymphocytic infiltrate. Direct immunofluorescence was negative in 2 cases but showed nonspecific weak patchy deposition of IgM along the dermoepidermal junction.⁴ Although our case was negative for IgM, there was a similar weak nonspecific distribution of IgG. Kokturk et al⁵ described a case of bullous EAI in a man with repeated exposure to a space heater. The lesions showed subepidermal separation of the epidermis; increased elastic fibers; dilated dermal capillaries; melanophages in the upper dermis; and a mild, superficial, perivascular-lymphocytic infiltrate. Direct immunofluorescence showed no immune deposits.⁵ Several earlier cases of bullae associated with EAI have been reported in the literature but were thought to be bullous lichen planus superimposed on EAI.⁶ Our case, which exhibited similar historical, physical, and histopathologic findings, strengthens the argument for a defined bullous variant of EAI.

To the Editor:

Erythema ab igne (EAI) is a reticular erythematous hyperpigmentation of skin repeatedly exposed to moderate heat.¹ It usually is asymptomatic, though some patients report itching or burning at the site.² Historically caused by exposure to coal stoves or open fires, EAI has become increasingly common among individuals using space heaters, heating pads, or laptop computers near bare skin.^2,3 Although EAI itself is benign and usually resolves with the removal of the exposure, it remains of clinical importance because of its association with underlying chronic disease, as chronic pain often is managed with frequent heating pad or hot water bottle use.² Additionally, accurate diagnosis is important given the future risk for malignancy, as chronic changes of EAI have been reported to lead to squamous cell carcinoma or rarely Merkel cell carcinoma.² Erythema ab igne is not traditionally associated with the formation of bullae; however, we present a case of bullous EAI that we believe highlights the importance of including this condition in the differential diagnosis of bullous disorders.

A 55-year-old man was admitted for presumed cellulitis of the bilateral legs. The patient had developed hyperpigmented discoloration of the medial surface of both legs with subsequent formation of tense bullae over the last 2 months. The dermatology department was consulted, as there was concern for bullous pemphigoid. The patient’s medical history was notable for hypertension, hyperlipidemia, diet-controlled type 2 diabetes mellitus, and hepatitis C virus with cirrhosis. The patient denied pruritus, pain, or known exposure of the legs to potential irritants prior to developing the lesions; however, with additional questioning he did report frequently sitting in front of a space heater with bare legs. Physical examination revealed multiple areas of reticulated erythematous hyperpigmentation with several overlying bullae (Figure 1). Many of the bullae were unroofed with full-thickness ulceration. Biopsies were taken for hematoxylin and eosin staining (Figure 2) and direct immunofluorescence.

Basic hematologic and metabolic laboratory test results as well as blood cultures were negative. Wound culture was positive for methicillin-resistant Staphylococcus aureus. Histologic examination showed interface dermatitis with subepidermal vesicle (Figure 2). Scattered necrotic keratinocytes were present in the adjacent epidermis, and focal subtle vacuolar alteration of the dermoepidermal junction was seen (Figure 3). Sparse perivascular mononuclear cells and scattered melanophages were present in the dermis. Direct immunofluorescence showed no diagnostic immunopathologic abnormality. Focal weak nonspecific vascular positivity for IgG and C3 was seen, but IgA and IgM were negative. Although not specific, these changes were compatible with EAI in the clinical context provided. The diagnosis of bullous EAI with superimposed staphylococcal infection was made.

Although rare, there have been reports of a bullous variant of EAI. Flanagan et al⁴ described 3 cases of bullous EAI with histopathology similar to our case. All 3 biopsies showed subepidermal separation with a mild perivascular dermal lymphocytic infiltrate. Direct immunofluorescence was negative in 2 cases but showed nonspecific weak patchy deposition of IgM along the dermoepidermal junction.⁴ Although our case was negative for IgM, there was a similar weak nonspecific distribution of IgG. Kokturk et al⁵ described a case of bullous EAI in a man with repeated exposure to a space heater. The lesions showed subepidermal separation of the epidermis; increased elastic fibers; dilated dermal capillaries; melanophages in the upper dermis; and a mild, superficial, perivascular-lymphocytic infiltrate. Direct immunofluorescence showed no immune deposits.⁵ Several earlier cases of bullae associated with EAI have been reported in the literature but were thought to be bullous lichen planus superimposed on EAI.⁶ Our case, which exhibited similar historical, physical, and histopathologic findings, strengthens the argument for a defined bullous variant of EAI.

To the Editor:

Erythema ab igne (EAI) is a reticular erythematous hyperpigmentation of skin repeatedly exposed to moderate heat.¹ It usually is asymptomatic, though some patients report itching or burning at the site.² Historically caused by exposure to coal stoves or open fires, EAI has become increasingly common among individuals using space heaters, heating pads, or laptop computers near bare skin.^2,3 Although EAI itself is benign and usually resolves with the removal of the exposure, it remains of clinical importance because of its association with underlying chronic disease, as chronic pain often is managed with frequent heating pad or hot water bottle use.² Additionally, accurate diagnosis is important given the future risk for malignancy, as chronic changes of EAI have been reported to lead to squamous cell carcinoma or rarely Merkel cell carcinoma.² Erythema ab igne is not traditionally associated with the formation of bullae; however, we present a case of bullous EAI that we believe highlights the importance of including this condition in the differential diagnosis of bullous disorders.

A 55-year-old man was admitted for presumed cellulitis of the bilateral legs. The patient had developed hyperpigmented discoloration of the medial surface of both legs with subsequent formation of tense bullae over the last 2 months. The dermatology department was consulted, as there was concern for bullous pemphigoid. The patient’s medical history was notable for hypertension, hyperlipidemia, diet-controlled type 2 diabetes mellitus, and hepatitis C virus with cirrhosis. The patient denied pruritus, pain, or known exposure of the legs to potential irritants prior to developing the lesions; however, with additional questioning he did report frequently sitting in front of a space heater with bare legs. Physical examination revealed multiple areas of reticulated erythematous hyperpigmentation with several overlying bullae (Figure 1). Many of the bullae were unroofed with full-thickness ulceration. Biopsies were taken for hematoxylin and eosin staining (Figure 2) and direct immunofluorescence.

Basic hematologic and metabolic laboratory test results as well as blood cultures were negative. Wound culture was positive for methicillin-resistant Staphylococcus aureus. Histologic examination showed interface dermatitis with subepidermal vesicle (Figure 2). Scattered necrotic keratinocytes were present in the adjacent epidermis, and focal subtle vacuolar alteration of the dermoepidermal junction was seen (Figure 3). Sparse perivascular mononuclear cells and scattered melanophages were present in the dermis. Direct immunofluorescence showed no diagnostic immunopathologic abnormality. Focal weak nonspecific vascular positivity for IgG and C3 was seen, but IgA and IgM were negative. Although not specific, these changes were compatible with EAI in the clinical context provided. The diagnosis of bullous EAI with superimposed staphylococcal infection was made.

Although rare, there have been reports of a bullous variant of EAI. Flanagan et al⁴ described 3 cases of bullous EAI with histopathology similar to our case. All 3 biopsies showed subepidermal separation with a mild perivascular dermal lymphocytic infiltrate. Direct immunofluorescence was negative in 2 cases but showed nonspecific weak patchy deposition of IgM along the dermoepidermal junction.⁴ Although our case was negative for IgM, there was a similar weak nonspecific distribution of IgG. Kokturk et al⁵ described a case of bullous EAI in a man with repeated exposure to a space heater. The lesions showed subepidermal separation of the epidermis; increased elastic fibers; dilated dermal capillaries; melanophages in the upper dermis; and a mild, superficial, perivascular-lymphocytic infiltrate. Direct immunofluorescence showed no immune deposits.⁵ Several earlier cases of bullae associated with EAI have been reported in the literature but were thought to be bullous lichen planus superimposed on EAI.⁶ Our case, which exhibited similar historical, physical, and histopathologic findings, strengthens the argument for a defined bullous variant of EAI.

 

NEW YORK – When treating patients with skin of color for acne, treatment goals may vary from those of patients with lighter skin, according to Andrew F. Alexis, MD.

For example, in patients with Fitzpatrick skin types V and VI, the desired treatment outcome is not only resolution of acne, but also resolution of hyperpigmentation, said Dr. Alexis, chairman of the department of dermatology at Mount Sinai St. Luke’s and Mount Sinai West, New York, N.Y.

“Postinflammatory hyperpigmentation is often the driving force for the dermatology consult” in individuals with skin of color, Dr. Alexis said at the summer meeting of the American Academy of Dermatology. “They may be just as concerned about their dark spots as underlying acne,” he noted, citing a study that he coauthored (J Clin Aesthet Dermatol. 2014 Jul;7[7]:19-31).

In the study – a survey of patients with acne to determine which treatment outcomes were most important – 41.6% of the nonwhite female patients reported that clearance of postinflammatory hyperpigmentation was the most important goal, compared with 8.4% of white female respondents (P less than .0001).

As with so many conditions that require a prolonged course of treatment, setting expectations is a key part of the dermatologist’s communication with the patient, Dr. Alexis continued. “Make sure that they know that you are going to treat the dark spots,” and that it will take time “to get to the desired endpoint.”

It’s important to avoid undertreating patients, especially darker-skinned patients, where ongoing subclinical inflammation may contribute to hyperpigmentation. Even in lesions that appear grossly noninflamed, biopsies may find histological evidence of inflammation, with increased T-cell infiltration of the pilosebaceous units, Dr. Alexis said.

However, there’s always a balancing act in determining how aggressively to treat patients, he added. Dermatologists have to be aware of the risk of hypertrophic scar formation in darker-skinned individuals, especially in truncal areas.

When addressing the acne, step one is to aggressively reduce acne-associated inflammation to reduce potential sequelae. This can be done with any of a number of agents, such as retinoids, benzoyl peroxide, dapsone, azelaic acid, and even intralesional corticosteroid injections, he said.

“All agents have been considered in darker skin types,” he said, noting that “retinoids are particularly important because they can also treat postinflammatory hyperpigmentation.” Tretinoin 0.1% cream and tazarotene 0.1% cream are both good choices, he added.

Adapalene in a fixed combination with benzoyl peroxide has been studied in darker-skinned patients, with no difference in tolerability or higher incidence of pigmentary sequelae than in lighter-skinned patients, he pointed out.

Dapsone 5% and 7.5% have also been studied in patients with darker skin, and both concentrations showed comparable results for safety and efficacy.

The thinking about second-line agents can shift a bit when treating acne in darker skin. For example, azelaic acid as a 20% cream or 15% gel can be a good choice, and can be helpful in treating postinflammatory hyperpigmentation, but azelaic acid is “not as good an antiacne agent as retinoids,” Dr. Alexis said.

Patients should understand that any of these choices are primarily acne-directed treatments, to be deployed over the first 3-6 months of treatment. Then, beginning at about the 3-month mark and continuing for up to a year, hyperpigmentation can be addressed. “Really emphasize the duration of treatment,” when treating hyperpigmentation, Dr. Alexis advised.

Once the acne is under control and hyperpigmentation can be assessed on its own, dermatologists can consider whether bleaching agents are appropriate. “Should they be used? If so, how?” he asked.

Bleaching agents can be effective, said Dr. Alexis, who recommends lesion-directed rather than broad-field therapy, unless there are many larger hyperpigmented macules. “The more common scenario is smaller, more distributed lesions,” he said. “Superficial chemical peels, if used with caution, can be a good adjunct,” to bleaching agents, he added.

Coming down the road are topical nitric oxide preparations, which he said are looking good for darker skin in clinical trials.

“The key to great outcomes is to initiate a combination regimen that targets inflammation and reduces hyperpigmentation,” said Dr. Alexis. Then, he advised, minimize irritation but don’t undertreat, consider adjunctive chemical peels, and above all, “set realistic timeline expectations.”

Dr. Alexis reported financial relationships with multiple pharmaceutical companies.

koakes@frontlinemedcom.com

On Twitter @karioakes

 

NEW YORK – When treating patients with skin of color for acne, treatment goals may vary from those of patients with lighter skin, according to Andrew F. Alexis, MD.

For example, in patients with Fitzpatrick skin types V and VI, the desired treatment outcome is not only resolution of acne, but also resolution of hyperpigmentation, said Dr. Alexis, chairman of the department of dermatology at Mount Sinai St. Luke’s and Mount Sinai West, New York, N.Y.

“Postinflammatory hyperpigmentation is often the driving force for the dermatology consult” in individuals with skin of color, Dr. Alexis said at the summer meeting of the American Academy of Dermatology. “They may be just as concerned about their dark spots as underlying acne,” he noted, citing a study that he coauthored (J Clin Aesthet Dermatol. 2014 Jul;7[7]:19-31).

In the study – a survey of patients with acne to determine which treatment outcomes were most important – 41.6% of the nonwhite female patients reported that clearance of postinflammatory hyperpigmentation was the most important goal, compared with 8.4% of white female respondents (P less than .0001).

As with so many conditions that require a prolonged course of treatment, setting expectations is a key part of the dermatologist’s communication with the patient, Dr. Alexis continued. “Make sure that they know that you are going to treat the dark spots,” and that it will take time “to get to the desired endpoint.”

It’s important to avoid undertreating patients, especially darker-skinned patients, where ongoing subclinical inflammation may contribute to hyperpigmentation. Even in lesions that appear grossly noninflamed, biopsies may find histological evidence of inflammation, with increased T-cell infiltration of the pilosebaceous units, Dr. Alexis said.

However, there’s always a balancing act in determining how aggressively to treat patients, he added. Dermatologists have to be aware of the risk of hypertrophic scar formation in darker-skinned individuals, especially in truncal areas.

When addressing the acne, step one is to aggressively reduce acne-associated inflammation to reduce potential sequelae. This can be done with any of a number of agents, such as retinoids, benzoyl peroxide, dapsone, azelaic acid, and even intralesional corticosteroid injections, he said.

“All agents have been considered in darker skin types,” he said, noting that “retinoids are particularly important because they can also treat postinflammatory hyperpigmentation.” Tretinoin 0.1% cream and tazarotene 0.1% cream are both good choices, he added.

Adapalene in a fixed combination with benzoyl peroxide has been studied in darker-skinned patients, with no difference in tolerability or higher incidence of pigmentary sequelae than in lighter-skinned patients, he pointed out.

Dapsone 5% and 7.5% have also been studied in patients with darker skin, and both concentrations showed comparable results for safety and efficacy.

The thinking about second-line agents can shift a bit when treating acne in darker skin. For example, azelaic acid as a 20% cream or 15% gel can be a good choice, and can be helpful in treating postinflammatory hyperpigmentation, but azelaic acid is “not as good an antiacne agent as retinoids,” Dr. Alexis said.

Patients should understand that any of these choices are primarily acne-directed treatments, to be deployed over the first 3-6 months of treatment. Then, beginning at about the 3-month mark and continuing for up to a year, hyperpigmentation can be addressed. “Really emphasize the duration of treatment,” when treating hyperpigmentation, Dr. Alexis advised.

Once the acne is under control and hyperpigmentation can be assessed on its own, dermatologists can consider whether bleaching agents are appropriate. “Should they be used? If so, how?” he asked.

Bleaching agents can be effective, said Dr. Alexis, who recommends lesion-directed rather than broad-field therapy, unless there are many larger hyperpigmented macules. “The more common scenario is smaller, more distributed lesions,” he said. “Superficial chemical peels, if used with caution, can be a good adjunct,” to bleaching agents, he added.

Coming down the road are topical nitric oxide preparations, which he said are looking good for darker skin in clinical trials.

“The key to great outcomes is to initiate a combination regimen that targets inflammation and reduces hyperpigmentation,” said Dr. Alexis. Then, he advised, minimize irritation but don’t undertreat, consider adjunctive chemical peels, and above all, “set realistic timeline expectations.”

Dr. Alexis reported financial relationships with multiple pharmaceutical companies.

koakes@frontlinemedcom.com

On Twitter @karioakes

 

NEW YORK – When treating patients with skin of color for acne, treatment goals may vary from those of patients with lighter skin, according to Andrew F. Alexis, MD.

For example, in patients with Fitzpatrick skin types V and VI, the desired treatment outcome is not only resolution of acne, but also resolution of hyperpigmentation, said Dr. Alexis, chairman of the department of dermatology at Mount Sinai St. Luke’s and Mount Sinai West, New York, N.Y.

“Postinflammatory hyperpigmentation is often the driving force for the dermatology consult” in individuals with skin of color, Dr. Alexis said at the summer meeting of the American Academy of Dermatology. “They may be just as concerned about their dark spots as underlying acne,” he noted, citing a study that he coauthored (J Clin Aesthet Dermatol. 2014 Jul;7[7]:19-31).

In the study – a survey of patients with acne to determine which treatment outcomes were most important – 41.6% of the nonwhite female patients reported that clearance of postinflammatory hyperpigmentation was the most important goal, compared with 8.4% of white female respondents (P less than .0001).

As with so many conditions that require a prolonged course of treatment, setting expectations is a key part of the dermatologist’s communication with the patient, Dr. Alexis continued. “Make sure that they know that you are going to treat the dark spots,” and that it will take time “to get to the desired endpoint.”

It’s important to avoid undertreating patients, especially darker-skinned patients, where ongoing subclinical inflammation may contribute to hyperpigmentation. Even in lesions that appear grossly noninflamed, biopsies may find histological evidence of inflammation, with increased T-cell infiltration of the pilosebaceous units, Dr. Alexis said.

However, there’s always a balancing act in determining how aggressively to treat patients, he added. Dermatologists have to be aware of the risk of hypertrophic scar formation in darker-skinned individuals, especially in truncal areas.

When addressing the acne, step one is to aggressively reduce acne-associated inflammation to reduce potential sequelae. This can be done with any of a number of agents, such as retinoids, benzoyl peroxide, dapsone, azelaic acid, and even intralesional corticosteroid injections, he said.

“All agents have been considered in darker skin types,” he said, noting that “retinoids are particularly important because they can also treat postinflammatory hyperpigmentation.” Tretinoin 0.1% cream and tazarotene 0.1% cream are both good choices, he added.

Adapalene in a fixed combination with benzoyl peroxide has been studied in darker-skinned patients, with no difference in tolerability or higher incidence of pigmentary sequelae than in lighter-skinned patients, he pointed out.

Dapsone 5% and 7.5% have also been studied in patients with darker skin, and both concentrations showed comparable results for safety and efficacy.

The thinking about second-line agents can shift a bit when treating acne in darker skin. For example, azelaic acid as a 20% cream or 15% gel can be a good choice, and can be helpful in treating postinflammatory hyperpigmentation, but azelaic acid is “not as good an antiacne agent as retinoids,” Dr. Alexis said.

Patients should understand that any of these choices are primarily acne-directed treatments, to be deployed over the first 3-6 months of treatment. Then, beginning at about the 3-month mark and continuing for up to a year, hyperpigmentation can be addressed. “Really emphasize the duration of treatment,” when treating hyperpigmentation, Dr. Alexis advised.

Once the acne is under control and hyperpigmentation can be assessed on its own, dermatologists can consider whether bleaching agents are appropriate. “Should they be used? If so, how?” he asked.

Bleaching agents can be effective, said Dr. Alexis, who recommends lesion-directed rather than broad-field therapy, unless there are many larger hyperpigmented macules. “The more common scenario is smaller, more distributed lesions,” he said. “Superficial chemical peels, if used with caution, can be a good adjunct,” to bleaching agents, he added.

Coming down the road are topical nitric oxide preparations, which he said are looking good for darker skin in clinical trials.

“The key to great outcomes is to initiate a combination regimen that targets inflammation and reduces hyperpigmentation,” said Dr. Alexis. Then, he advised, minimize irritation but don’t undertreat, consider adjunctive chemical peels, and above all, “set realistic timeline expectations.”

Dr. Alexis reported financial relationships with multiple pharmaceutical companies.

koakes@frontlinemedcom.com

On Twitter @karioakes

Annular atrophic lichen planus (AALP) is a rare variant of lichen planus that was first described by Friedman and Hashimoto¹ in 1991. Clinically, it combines the configuration and morphological features of both annular and atrophic lichen planus. It is a rare entity. We report a case of AALP in a 69-year-old black man. The clinical and histopathological presentation depicted the defining features of this entity with a characteristic loss of elastic fibers corresponding to central atrophy of active lesions.

Case Report

A 69-year-old black man with a history of hepatitis C virus infection and hypothyroidism presented to the dermatology clinic with a pruritic rash on the trunk, extremities, groin, and scalp of 4 months' duration. He denied any new medications, recent illnesses, or sick contacts. Physical examination demonstrated well-demarcated violaceous papules and plaques on the trunk, extensor aspect of the forearms, and thighs involving 10% of the body surface area (Figure 1A). The lesions were annular with raised borders and central depigmented atrophic scarring (Figure 1B). The examination also revealed several large hypopigmented atrophic patches and plaques in the right inguinal region and on the dorsal aspect of the penile shaft and buttocks as well as a single atrophic plaque on the scalp. No oral lesions were seen. An initial punch biopsy was consistent with a nonspecific lichenoid dermatitis (Figure 2), and the patient was prescribed triamcinolone ointment 0.1% for the trunk and extremities and tacrolimus ointment 0.1% for the groin and genital region.

The patient continued to develop new annular atrophic skin lesions over the next several months. Repeat punch biopsies of lesional and uninvolved perilesional skin from the trunk were obtained for histopathologic confirmation and special staining. Lichenoid dermatitis again was noted on the lesional biopsy, and no notable histopathologic changes were observed on the perilesional biopsy. Verhoeff-van Gieson staining for elastic fibers was performed on both biopsies, which revealed destruction of elastic fibers in the central papillary dermis and upper reticular dermis of the lesional biopsy (Figure 3A). The elastic fibers on the perilesional biopsy were preserved (Figure 3B).

The clinical presentation and histopathological findings confirmed a diagnosis of AALP. The patient was prescribed a short taper of oral prednisone, which halted further disease progression. The patient was then started on pentoxifylline and continued on tacrolimus ointment 0.1% with minimal improvement in existing lesions. These medications were discontinued after 3 months. Hydroxychloroquine 400 mg once daily was administered, which initially resulted in some thinning of the plaques on the trunk; however, further progression of the disease was noted after 3 months. Acitretin 25 mg once daily was added to his treatment regimen. Marked thinning of active lesions, hyperpigmentation, and residual scarring was noted after 2 months of combined therapy with acitretin and hydroxychloroquine (Figure 4), with continued improvement appreciable several months later.

 

Comment

Lichen planus is a common pruritic inflammatory disease of the skin, mucous membranes, hair follicles, and nails with a highly variable clinical pattern and disease course that typically affects the adult population.² There are many clinical variants of lichen planus, which all demonstrate lichenoid dermatitis on histology. Annular lichen planus is an uncommon variant most commonly seen in men with asymptomatic lesions involving the axillae and groin.² Atrophic lichen planus is another variant demonstrating atrophic papules and plaques on the trunk and extremities.3 Annular atrophic lichen planus is the rarest variant of lichen planus, incorporating features of both annular and atrophic lichen planus.

The first case of AALP involved a 56-year-old black man with a 25-year history of annular atrophic papules and plaques on the trunk and extremities.¹ The second case reported by Requena et al⁴ in 1994 described a 65-year-old woman with characteristic lesions on the right elbow and left knee. Lipsker et al⁵ reported a third case in a 41-year-old man with a history of Sneddon syndrome who had lesions typical for AALP for 20 years. In all of these cases, histopathologic examination revealed a lichenoid infiltrate with thinning of the epidermis and loss of elastic fibers in the center of the active lesions.

In more recent cases of AALP, the characteristic findings primarily occurred on the trunk and extremities.^6-10 Treatment with topical corticosteroids failed in most cases and some patients noted moderate improvement with tacrolimus ointment 0.1%. Sugashima and Yamamoto¹¹ reported a unique case in 2012 of a 32-year-old woman with AALP on the lower lip. She had notable improvement with tacrolimus ointment 0.1% after 6 months.¹¹

All of the known cases of AALP to date have occurred in adults, both male and female, presenting with a limited number of annular plaques with slightly elevated borders and depressed atrophic centers.^1,3-11 Disease duration of AALP has ranged from 2 months to 25 years.¹¹ Histopathologic findings characteristically demonstrate a lichenoid dermatitis of the raised lesional border with a flattened epidermis, loss of rete ridges, and fibrosis of dermal papillae in the lesion center.⁷ The elastic fibers are destroyed in the papillary dermis of the lesion center, presumably due to elastolytic activity of inflammatory cells.¹ Macrophages present in the lichenoid infiltrate of acute lesions release elastases contributing to this destruction.⁷ Furthermore, elastic fibers appear fragmented on electron microscopy.¹

The clinical course of AALP has proven to be chronic in most cases and frequently is resistant to treatment with topical corticosteroids, retinoids, phototherapy, and immunosuppressive agents.³ Treatment administered early in the disease course may provide a more favorable outcome.¹¹ Lesions characteristically heal with scarring and hyperpigmentation. Our case displayed more extensive involvement than has previously been reported. Our patient showed minimal improvement with topical therapy; however, he demonstrated thinning and regression of active lesions after 2 months of combined treatment with hydroxychloroquine and acitretin. Our use of oral pentoxifylline, hydroxychloroquine, and acitretin has not been previously reported in the other cases of AALP we reviewed. Acitretin is the only systemic agent for lichen planus that has achieved level A evidence, as it previously was shown to be highly effective in a placebo-controlled, double-blind study of 65 patients.¹²

Conclusion

Annular atrophic lichen planus is a known variant of lichen planus characterized by a loss of elastic fibers in the papillary dermis in the center of active lesions. Treatment with topical corticosteroids and phototherapy frequently is ineffective. To our knowledge, there are no studies to date regarding the efficacy of systemic therapy in treatment of AALP. Hydroxychloroquine and acitretin may prove to be beneficial treatment options for resistant AALP. Additional alternative treatments continue to be explored. We encourage reporting additional cases of AALP to further characterize its clinical presentation and response to treatments.

Annular atrophic lichen planus (AALP) is a rare variant of lichen planus that was first described by Friedman and Hashimoto¹ in 1991. Clinically, it combines the configuration and morphological features of both annular and atrophic lichen planus. It is a rare entity. We report a case of AALP in a 69-year-old black man. The clinical and histopathological presentation depicted the defining features of this entity with a characteristic loss of elastic fibers corresponding to central atrophy of active lesions.

Case Report

A 69-year-old black man with a history of hepatitis C virus infection and hypothyroidism presented to the dermatology clinic with a pruritic rash on the trunk, extremities, groin, and scalp of 4 months' duration. He denied any new medications, recent illnesses, or sick contacts. Physical examination demonstrated well-demarcated violaceous papules and plaques on the trunk, extensor aspect of the forearms, and thighs involving 10% of the body surface area (Figure 1A). The lesions were annular with raised borders and central depigmented atrophic scarring (Figure 1B). The examination also revealed several large hypopigmented atrophic patches and plaques in the right inguinal region and on the dorsal aspect of the penile shaft and buttocks as well as a single atrophic plaque on the scalp. No oral lesions were seen. An initial punch biopsy was consistent with a nonspecific lichenoid dermatitis (Figure 2), and the patient was prescribed triamcinolone ointment 0.1% for the trunk and extremities and tacrolimus ointment 0.1% for the groin and genital region.

The patient continued to develop new annular atrophic skin lesions over the next several months. Repeat punch biopsies of lesional and uninvolved perilesional skin from the trunk were obtained for histopathologic confirmation and special staining. Lichenoid dermatitis again was noted on the lesional biopsy, and no notable histopathologic changes were observed on the perilesional biopsy. Verhoeff-van Gieson staining for elastic fibers was performed on both biopsies, which revealed destruction of elastic fibers in the central papillary dermis and upper reticular dermis of the lesional biopsy (Figure 3A). The elastic fibers on the perilesional biopsy were preserved (Figure 3B).

The clinical presentation and histopathological findings confirmed a diagnosis of AALP. The patient was prescribed a short taper of oral prednisone, which halted further disease progression. The patient was then started on pentoxifylline and continued on tacrolimus ointment 0.1% with minimal improvement in existing lesions. These medications were discontinued after 3 months. Hydroxychloroquine 400 mg once daily was administered, which initially resulted in some thinning of the plaques on the trunk; however, further progression of the disease was noted after 3 months. Acitretin 25 mg once daily was added to his treatment regimen. Marked thinning of active lesions, hyperpigmentation, and residual scarring was noted after 2 months of combined therapy with acitretin and hydroxychloroquine (Figure 4), with continued improvement appreciable several months later.

 

Comment

Lichen planus is a common pruritic inflammatory disease of the skin, mucous membranes, hair follicles, and nails with a highly variable clinical pattern and disease course that typically affects the adult population.² There are many clinical variants of lichen planus, which all demonstrate lichenoid dermatitis on histology. Annular lichen planus is an uncommon variant most commonly seen in men with asymptomatic lesions involving the axillae and groin.² Atrophic lichen planus is another variant demonstrating atrophic papules and plaques on the trunk and extremities.3 Annular atrophic lichen planus is the rarest variant of lichen planus, incorporating features of both annular and atrophic lichen planus.

The first case of AALP involved a 56-year-old black man with a 25-year history of annular atrophic papules and plaques on the trunk and extremities.¹ The second case reported by Requena et al⁴ in 1994 described a 65-year-old woman with characteristic lesions on the right elbow and left knee. Lipsker et al⁵ reported a third case in a 41-year-old man with a history of Sneddon syndrome who had lesions typical for AALP for 20 years. In all of these cases, histopathologic examination revealed a lichenoid infiltrate with thinning of the epidermis and loss of elastic fibers in the center of the active lesions.

In more recent cases of AALP, the characteristic findings primarily occurred on the trunk and extremities.^6-10 Treatment with topical corticosteroids failed in most cases and some patients noted moderate improvement with tacrolimus ointment 0.1%. Sugashima and Yamamoto¹¹ reported a unique case in 2012 of a 32-year-old woman with AALP on the lower lip. She had notable improvement with tacrolimus ointment 0.1% after 6 months.¹¹

All of the known cases of AALP to date have occurred in adults, both male and female, presenting with a limited number of annular plaques with slightly elevated borders and depressed atrophic centers.^1,3-11 Disease duration of AALP has ranged from 2 months to 25 years.¹¹ Histopathologic findings characteristically demonstrate a lichenoid dermatitis of the raised lesional border with a flattened epidermis, loss of rete ridges, and fibrosis of dermal papillae in the lesion center.⁷ The elastic fibers are destroyed in the papillary dermis of the lesion center, presumably due to elastolytic activity of inflammatory cells.¹ Macrophages present in the lichenoid infiltrate of acute lesions release elastases contributing to this destruction.⁷ Furthermore, elastic fibers appear fragmented on electron microscopy.¹

The clinical course of AALP has proven to be chronic in most cases and frequently is resistant to treatment with topical corticosteroids, retinoids, phototherapy, and immunosuppressive agents.³ Treatment administered early in the disease course may provide a more favorable outcome.¹¹ Lesions characteristically heal with scarring and hyperpigmentation. Our case displayed more extensive involvement than has previously been reported. Our patient showed minimal improvement with topical therapy; however, he demonstrated thinning and regression of active lesions after 2 months of combined treatment with hydroxychloroquine and acitretin. Our use of oral pentoxifylline, hydroxychloroquine, and acitretin has not been previously reported in the other cases of AALP we reviewed. Acitretin is the only systemic agent for lichen planus that has achieved level A evidence, as it previously was shown to be highly effective in a placebo-controlled, double-blind study of 65 patients.¹²

Conclusion

Annular atrophic lichen planus is a known variant of lichen planus characterized by a loss of elastic fibers in the papillary dermis in the center of active lesions. Treatment with topical corticosteroids and phototherapy frequently is ineffective. To our knowledge, there are no studies to date regarding the efficacy of systemic therapy in treatment of AALP. Hydroxychloroquine and acitretin may prove to be beneficial treatment options for resistant AALP. Additional alternative treatments continue to be explored. We encourage reporting additional cases of AALP to further characterize its clinical presentation and response to treatments.

Annular atrophic lichen planus (AALP) is a rare variant of lichen planus that was first described by Friedman and Hashimoto¹ in 1991. Clinically, it combines the configuration and morphological features of both annular and atrophic lichen planus. It is a rare entity. We report a case of AALP in a 69-year-old black man. The clinical and histopathological presentation depicted the defining features of this entity with a characteristic loss of elastic fibers corresponding to central atrophy of active lesions.

Case Report

A 69-year-old black man with a history of hepatitis C virus infection and hypothyroidism presented to the dermatology clinic with a pruritic rash on the trunk, extremities, groin, and scalp of 4 months' duration. He denied any new medications, recent illnesses, or sick contacts. Physical examination demonstrated well-demarcated violaceous papules and plaques on the trunk, extensor aspect of the forearms, and thighs involving 10% of the body surface area (Figure 1A). The lesions were annular with raised borders and central depigmented atrophic scarring (Figure 1B). The examination also revealed several large hypopigmented atrophic patches and plaques in the right inguinal region and on the dorsal aspect of the penile shaft and buttocks as well as a single atrophic plaque on the scalp. No oral lesions were seen. An initial punch biopsy was consistent with a nonspecific lichenoid dermatitis (Figure 2), and the patient was prescribed triamcinolone ointment 0.1% for the trunk and extremities and tacrolimus ointment 0.1% for the groin and genital region.

The patient continued to develop new annular atrophic skin lesions over the next several months. Repeat punch biopsies of lesional and uninvolved perilesional skin from the trunk were obtained for histopathologic confirmation and special staining. Lichenoid dermatitis again was noted on the lesional biopsy, and no notable histopathologic changes were observed on the perilesional biopsy. Verhoeff-van Gieson staining for elastic fibers was performed on both biopsies, which revealed destruction of elastic fibers in the central papillary dermis and upper reticular dermis of the lesional biopsy (Figure 3A). The elastic fibers on the perilesional biopsy were preserved (Figure 3B).

The clinical presentation and histopathological findings confirmed a diagnosis of AALP. The patient was prescribed a short taper of oral prednisone, which halted further disease progression. The patient was then started on pentoxifylline and continued on tacrolimus ointment 0.1% with minimal improvement in existing lesions. These medications were discontinued after 3 months. Hydroxychloroquine 400 mg once daily was administered, which initially resulted in some thinning of the plaques on the trunk; however, further progression of the disease was noted after 3 months. Acitretin 25 mg once daily was added to his treatment regimen. Marked thinning of active lesions, hyperpigmentation, and residual scarring was noted after 2 months of combined therapy with acitretin and hydroxychloroquine (Figure 4), with continued improvement appreciable several months later.

 

Comment

Lichen planus is a common pruritic inflammatory disease of the skin, mucous membranes, hair follicles, and nails with a highly variable clinical pattern and disease course that typically affects the adult population.² There are many clinical variants of lichen planus, which all demonstrate lichenoid dermatitis on histology. Annular lichen planus is an uncommon variant most commonly seen in men with asymptomatic lesions involving the axillae and groin.² Atrophic lichen planus is another variant demonstrating atrophic papules and plaques on the trunk and extremities.3 Annular atrophic lichen planus is the rarest variant of lichen planus, incorporating features of both annular and atrophic lichen planus.

The first case of AALP involved a 56-year-old black man with a 25-year history of annular atrophic papules and plaques on the trunk and extremities.¹ The second case reported by Requena et al⁴ in 1994 described a 65-year-old woman with characteristic lesions on the right elbow and left knee. Lipsker et al⁵ reported a third case in a 41-year-old man with a history of Sneddon syndrome who had lesions typical for AALP for 20 years. In all of these cases, histopathologic examination revealed a lichenoid infiltrate with thinning of the epidermis and loss of elastic fibers in the center of the active lesions.

In more recent cases of AALP, the characteristic findings primarily occurred on the trunk and extremities.^6-10 Treatment with topical corticosteroids failed in most cases and some patients noted moderate improvement with tacrolimus ointment 0.1%. Sugashima and Yamamoto¹¹ reported a unique case in 2012 of a 32-year-old woman with AALP on the lower lip. She had notable improvement with tacrolimus ointment 0.1% after 6 months.¹¹

All of the known cases of AALP to date have occurred in adults, both male and female, presenting with a limited number of annular plaques with slightly elevated borders and depressed atrophic centers.^1,3-11 Disease duration of AALP has ranged from 2 months to 25 years.¹¹ Histopathologic findings characteristically demonstrate a lichenoid dermatitis of the raised lesional border with a flattened epidermis, loss of rete ridges, and fibrosis of dermal papillae in the lesion center.⁷ The elastic fibers are destroyed in the papillary dermis of the lesion center, presumably due to elastolytic activity of inflammatory cells.¹ Macrophages present in the lichenoid infiltrate of acute lesions release elastases contributing to this destruction.⁷ Furthermore, elastic fibers appear fragmented on electron microscopy.¹

The clinical course of AALP has proven to be chronic in most cases and frequently is resistant to treatment with topical corticosteroids, retinoids, phototherapy, and immunosuppressive agents.³ Treatment administered early in the disease course may provide a more favorable outcome.¹¹ Lesions characteristically heal with scarring and hyperpigmentation. Our case displayed more extensive involvement than has previously been reported. Our patient showed minimal improvement with topical therapy; however, he demonstrated thinning and regression of active lesions after 2 months of combined treatment with hydroxychloroquine and acitretin. Our use of oral pentoxifylline, hydroxychloroquine, and acitretin has not been previously reported in the other cases of AALP we reviewed. Acitretin is the only systemic agent for lichen planus that has achieved level A evidence, as it previously was shown to be highly effective in a placebo-controlled, double-blind study of 65 patients.¹²

Conclusion

Annular atrophic lichen planus is a known variant of lichen planus characterized by a loss of elastic fibers in the papillary dermis in the center of active lesions. Treatment with topical corticosteroids and phototherapy frequently is ineffective. To our knowledge, there are no studies to date regarding the efficacy of systemic therapy in treatment of AALP. Hydroxychloroquine and acitretin may prove to be beneficial treatment options for resistant AALP. Additional alternative treatments continue to be explored. We encourage reporting additional cases of AALP to further characterize its clinical presentation and response to treatments.

Granuloma faciale (GF) is a chronic benign leukocytoclastic vasculitis that can be difficult to treat. It is characterized by single or multiple, soft, well-circumscribed papules, plaques, or nodules ranging in color from red, violet, or yellow to brown that may darken with sun exposure.¹ Lesions usually are smooth with follicular orifices that are accentuated, thus producing a peau d’orange appearance. Lesions generally are slow to develop and asymptomatic, though some patients report pruritus or burning.^2,3 Diagnosis of GF is based on the presence of distinct histologic features. The epidermis usually is spared, with a prominent grenz zone of normal collagen separating the epidermis from a dense infiltrate of neutrophils, lymphocytes, and eosinophils. This mixed inflammatory infiltrate is seen mainly in the superficial dermis but occasionally spreads to the lower dermis and subcutaneous tissues.⁴

As the name implies, GF usually is confined to the face but occasionally involves extrafacial sites.^5-15 The clinical characteristics of these rare extrafacial lesions are not well understood. The purpose of this study was to identify the clinical and demographic features of extrafacial GF in patients treated at Mayo Clinic (Rochester, Minnesota) during a 54-year period.

Methods

This study was approved by the Mayo institutional review board. We searched the Mayo Clinic Rochester dermatology database for all patients with a diagnosis of GF from 1959 through 2013. All histopathology slides were reviewed by a board-certified dermatologist (A.G.B.) and dermatopathologist (A.G.B.) before inclusion in this study. Histologic criteria for diagnosis of GF included the presence of a mixed inflammatory infiltrate of neutrophils, eosinophils, lymphocytes, and histiocytes in the superficial or deep dermis; a prominent grenz zone separating the uninvolved epidermis; and the presence of vascular damage, as seen by fibrin deposition in dermal blood vessels.

Medical records were reviewed for patient demographics and for history pertinent to the diagnosis of GF, including sites involved, appearance, histopathology reports, symptoms, treatments, and outcomes.

Literature Search Strategy
A computerized Ovid MEDLINE database search was undertaken to identify English-language articles concerning GF in humans using the search terms granuloma faciale with extrafacial or disseminated. To ensure that no articles were overlooked, we conducted another search for English-language articles in the Embase database (1946-2013) using the terms granuloma faciale and extrafacial or disseminated.

Statistical Analysis
Descriptive clinical and histopathologic data were summarized using means, medians, and ranges or proportions as appropriate; statistical analysis was performed using SAS software (JMP package).

Results

Ninety-six patients with a diagnosis of GF were identified, and 12 (13%) had a diagnosis of extrafacial GF. Of them, 2 patients had a diagnosis of extrafacial GF supported only by histopathology slides without accompanying clinical records and therefore were excluded from the study. Thus, 10 cases of extrafacial GF were identified from our search and were included in the study group. Clinical data for these patients are summarized in Table 1. The mean age was 58.7 years (range, 26–87 years). Six (60%) patients were male, and all patients were white. Seven patients (70%) had facial GF in addition to extrafacial GF. Six patients reported no symptoms (60%), and 4 (40%) reported pruritus, discomfort, or both associated with their GF lesions.

Extrafacial GF was diagnosed in the following anatomic locations: scalp (n=3 [30%]), posterior auricular area (n=3 [30%]), mid upper back (n=1 [10%]), right shoulder (n=1 [10%]), both ears (n=1 [10%]), right elbow (n=1 [10%]), and left infra-auricular area (n=1 [10%]). Only 1 (10%) patient had multiple extrafacial sites identified.

The lesions were characterized clinically as violet, red, and yellow to brown smooth papules, plaques, and nodules (Figure 1). Biopsies from these lesions showed a subepidermal and adnexal grenz zone; a polymorphous perivascular and periadnexal dermal infiltrate composed of neutrophils, eosinophils, lymphocytes, histiocytes, and plasma cells; and a mild subtle leukocytoclastic vasculitis with subtle mild vascular necrosis (Figure 2).

For the 9 patients who elected to undergo GF treatment, the average number of treatments attempted was 2.8 (range, 1–5). The most common method of treatment was a combination of intralesional and topical corticosteroids (n=5 [50%]). Other methods included surgery (n=3 [30%]), dapsone (n=2 [20%]), radiation therapy (n=2 [20%]), cryosurgery (n=1 [10%]), nitrogen mustard (n=1 [10%]), liquid nitrogen (n=1 [10%]), and tar shampoo and fluocinolone acetonide solution 0.01% (n=1 [10%]).

Treatment outcomes were available for 8 of 9 treated patients. Three patients (patients 7, 8, and 10) had long-term successful resolution of their lesions. Patient 7 had an extrafacial lesion that was successfully treated with intralesional and topical corticosteroids, but the facial lesions recurred. The extrafacial GF lesion in patient 8 was found adjacent to a squamous cell carcinoma and was removed with a wide surgical excision that included both lesions. Patient 10 was successfully treated with a combination of liquid nitrogen and topical corticosteroid. Patients 2 and 4 were well controlled while on dapsone; however, once the treatment was discontinued, primarily due to adverse effects, the lesions returned.

Literature Search
Our search of the English-language literature identified 20 patients with extrafacial GF (Table 2). Fifteen (75%) patients were male, which was similar to our study (6/10 [60%]). Our patient population was slightly older with a mean age of 58.7 years compared to a median age of 54 years among those identified in the literature. Additionally, 3 (30%) patients in our study had no facial lesions, as seen in classic GF, which is comparable to 8 (40%) patients identified in the literature.

 

Comment

Extrafacial GF primarily affects white individuals and is more prevalent in men, as demonstrated in our study. Extrafacial GF was most often found in association with facial lesions, with only 3 patients having exclusively extrafacial sites.

Data from the current study indicate that diverse modalities were used to treat extrafacial GF with variable outcomes (chronic recurrence to complete resolution). The most common first-line treatment, intralesional corticosteroid injection, was used in 5 (50%) patients but resulted in only 1 (10%) successful resolution. Other methods frequently used in our study and prior studies were surgical excision, cryotherapy, electrosurgery, and dermabrasion.^1,20 These treatments do not appear to be uniformly definitive, and the ablative methods may result in scarring.¹ Different laser treatments are emerging for the management of GF lesions. Prior reports of treating facial GF with argon and CO₂ lasers have indicated minimized residual scarring and pigmentation.^21-23 The use of pulsed dye lasers has resulted in complete clearance of facial GF lesions, without recurrence on long-term follow-up.^20,24-26

The latest investigations of immunomodulatory drugs indicate these agents are promising for the management of facial GF. Eetam et al²⁷ reported the successful use of topical tacrolimus to treat facial GF. The relatively low cost and ease of use make these topical medications a competitive alternative to currently available surgical and laser methods. The appearance of all of these novel therapeutic modalities creates the necessity for a randomized trial to establish their efficacy on extrafacial GF lesions.

The wide array of treatments reflects the recalcitrant nature of extrafacial GF lesions. Further insight into the etiology of these lesions is needed to understand their tendency to recur. The important contribution of our study is the observed predilection of extrafacial GF for sun-exposed areas such as the scalp, upper trunk, and arms and legs. This pattern of extrafacial distribution along with the lack of mucosal involvement suggests a possible connection with UV light exposure. Furthermore, one of the extrafacial GF lesions in our study occurred in association with a squamous cell carcinoma, which may be an additional indication that these sites have been subjected to sun damage. This finding strengthens the importance of obtaining an adequate skin biopsy of any well-demarcated plaque or nodule found on the trunk, arms, and legs. The observed GF prevalence on sun-exposed areas and association with photoexacerbation have been speculated in prior studies, but no clear connection has been established.^1,28

Conclusion

The findings from this study and the cases reviewed in the literature provide a unique contribution to the understanding of the clinical and demographic characteristics of extrafacial GF. The rarity of this condition is the single most important constraint of our study, reflected in the emblematic limitations of a retrospective analysis in a select group of patients. The results of analysis of data from our patients were similar to the findings reported in the English-language medical literature. Serious consideration should be given to the development of a national registry for patients with GF. A database containing the clinicopathologic features, treatments, and outcomes for patients with both facial and extrafacial manifestations of GF may be invaluable in evaluating various treatment options and increasing understanding of the etiology and epidemiology of the disease.

Granuloma faciale (GF) is a chronic benign leukocytoclastic vasculitis that can be difficult to treat. It is characterized by single or multiple, soft, well-circumscribed papules, plaques, or nodules ranging in color from red, violet, or yellow to brown that may darken with sun exposure.¹ Lesions usually are smooth with follicular orifices that are accentuated, thus producing a peau d’orange appearance. Lesions generally are slow to develop and asymptomatic, though some patients report pruritus or burning.^2,3 Diagnosis of GF is based on the presence of distinct histologic features. The epidermis usually is spared, with a prominent grenz zone of normal collagen separating the epidermis from a dense infiltrate of neutrophils, lymphocytes, and eosinophils. This mixed inflammatory infiltrate is seen mainly in the superficial dermis but occasionally spreads to the lower dermis and subcutaneous tissues.⁴

As the name implies, GF usually is confined to the face but occasionally involves extrafacial sites.^5-15 The clinical characteristics of these rare extrafacial lesions are not well understood. The purpose of this study was to identify the clinical and demographic features of extrafacial GF in patients treated at Mayo Clinic (Rochester, Minnesota) during a 54-year period.

Methods

This study was approved by the Mayo institutional review board. We searched the Mayo Clinic Rochester dermatology database for all patients with a diagnosis of GF from 1959 through 2013. All histopathology slides were reviewed by a board-certified dermatologist (A.G.B.) and dermatopathologist (A.G.B.) before inclusion in this study. Histologic criteria for diagnosis of GF included the presence of a mixed inflammatory infiltrate of neutrophils, eosinophils, lymphocytes, and histiocytes in the superficial or deep dermis; a prominent grenz zone separating the uninvolved epidermis; and the presence of vascular damage, as seen by fibrin deposition in dermal blood vessels.

Medical records were reviewed for patient demographics and for history pertinent to the diagnosis of GF, including sites involved, appearance, histopathology reports, symptoms, treatments, and outcomes.

Literature Search Strategy
A computerized Ovid MEDLINE database search was undertaken to identify English-language articles concerning GF in humans using the search terms granuloma faciale with extrafacial or disseminated. To ensure that no articles were overlooked, we conducted another search for English-language articles in the Embase database (1946-2013) using the terms granuloma faciale and extrafacial or disseminated.

Statistical Analysis
Descriptive clinical and histopathologic data were summarized using means, medians, and ranges or proportions as appropriate; statistical analysis was performed using SAS software (JMP package).

Results

Ninety-six patients with a diagnosis of GF were identified, and 12 (13%) had a diagnosis of extrafacial GF. Of them, 2 patients had a diagnosis of extrafacial GF supported only by histopathology slides without accompanying clinical records and therefore were excluded from the study. Thus, 10 cases of extrafacial GF were identified from our search and were included in the study group. Clinical data for these patients are summarized in Table 1. The mean age was 58.7 years (range, 26–87 years). Six (60%) patients were male, and all patients were white. Seven patients (70%) had facial GF in addition to extrafacial GF. Six patients reported no symptoms (60%), and 4 (40%) reported pruritus, discomfort, or both associated with their GF lesions.

Extrafacial GF was diagnosed in the following anatomic locations: scalp (n=3 [30%]), posterior auricular area (n=3 [30%]), mid upper back (n=1 [10%]), right shoulder (n=1 [10%]), both ears (n=1 [10%]), right elbow (n=1 [10%]), and left infra-auricular area (n=1 [10%]). Only 1 (10%) patient had multiple extrafacial sites identified.

The lesions were characterized clinically as violet, red, and yellow to brown smooth papules, plaques, and nodules (Figure 1). Biopsies from these lesions showed a subepidermal and adnexal grenz zone; a polymorphous perivascular and periadnexal dermal infiltrate composed of neutrophils, eosinophils, lymphocytes, histiocytes, and plasma cells; and a mild subtle leukocytoclastic vasculitis with subtle mild vascular necrosis (Figure 2).

For the 9 patients who elected to undergo GF treatment, the average number of treatments attempted was 2.8 (range, 1–5). The most common method of treatment was a combination of intralesional and topical corticosteroids (n=5 [50%]). Other methods included surgery (n=3 [30%]), dapsone (n=2 [20%]), radiation therapy (n=2 [20%]), cryosurgery (n=1 [10%]), nitrogen mustard (n=1 [10%]), liquid nitrogen (n=1 [10%]), and tar shampoo and fluocinolone acetonide solution 0.01% (n=1 [10%]).

Treatment outcomes were available for 8 of 9 treated patients. Three patients (patients 7, 8, and 10) had long-term successful resolution of their lesions. Patient 7 had an extrafacial lesion that was successfully treated with intralesional and topical corticosteroids, but the facial lesions recurred. The extrafacial GF lesion in patient 8 was found adjacent to a squamous cell carcinoma and was removed with a wide surgical excision that included both lesions. Patient 10 was successfully treated with a combination of liquid nitrogen and topical corticosteroid. Patients 2 and 4 were well controlled while on dapsone; however, once the treatment was discontinued, primarily due to adverse effects, the lesions returned.

Literature Search
Our search of the English-language literature identified 20 patients with extrafacial GF (Table 2). Fifteen (75%) patients were male, which was similar to our study (6/10 [60%]). Our patient population was slightly older with a mean age of 58.7 years compared to a median age of 54 years among those identified in the literature. Additionally, 3 (30%) patients in our study had no facial lesions, as seen in classic GF, which is comparable to 8 (40%) patients identified in the literature.

 

Comment

Extrafacial GF primarily affects white individuals and is more prevalent in men, as demonstrated in our study. Extrafacial GF was most often found in association with facial lesions, with only 3 patients having exclusively extrafacial sites.

Data from the current study indicate that diverse modalities were used to treat extrafacial GF with variable outcomes (chronic recurrence to complete resolution). The most common first-line treatment, intralesional corticosteroid injection, was used in 5 (50%) patients but resulted in only 1 (10%) successful resolution. Other methods frequently used in our study and prior studies were surgical excision, cryotherapy, electrosurgery, and dermabrasion.^1,20 These treatments do not appear to be uniformly definitive, and the ablative methods may result in scarring.¹ Different laser treatments are emerging for the management of GF lesions. Prior reports of treating facial GF with argon and CO₂ lasers have indicated minimized residual scarring and pigmentation.^21-23 The use of pulsed dye lasers has resulted in complete clearance of facial GF lesions, without recurrence on long-term follow-up.^20,24-26

The latest investigations of immunomodulatory drugs indicate these agents are promising for the management of facial GF. Eetam et al²⁷ reported the successful use of topical tacrolimus to treat facial GF. The relatively low cost and ease of use make these topical medications a competitive alternative to currently available surgical and laser methods. The appearance of all of these novel therapeutic modalities creates the necessity for a randomized trial to establish their efficacy on extrafacial GF lesions.

The wide array of treatments reflects the recalcitrant nature of extrafacial GF lesions. Further insight into the etiology of these lesions is needed to understand their tendency to recur. The important contribution of our study is the observed predilection of extrafacial GF for sun-exposed areas such as the scalp, upper trunk, and arms and legs. This pattern of extrafacial distribution along with the lack of mucosal involvement suggests a possible connection with UV light exposure. Furthermore, one of the extrafacial GF lesions in our study occurred in association with a squamous cell carcinoma, which may be an additional indication that these sites have been subjected to sun damage. This finding strengthens the importance of obtaining an adequate skin biopsy of any well-demarcated plaque or nodule found on the trunk, arms, and legs. The observed GF prevalence on sun-exposed areas and association with photoexacerbation have been speculated in prior studies, but no clear connection has been established.^1,28

Conclusion

The findings from this study and the cases reviewed in the literature provide a unique contribution to the understanding of the clinical and demographic characteristics of extrafacial GF. The rarity of this condition is the single most important constraint of our study, reflected in the emblematic limitations of a retrospective analysis in a select group of patients. The results of analysis of data from our patients were similar to the findings reported in the English-language medical literature. Serious consideration should be given to the development of a national registry for patients with GF. A database containing the clinicopathologic features, treatments, and outcomes for patients with both facial and extrafacial manifestations of GF may be invaluable in evaluating various treatment options and increasing understanding of the etiology and epidemiology of the disease.

Granuloma faciale (GF) is a chronic benign leukocytoclastic vasculitis that can be difficult to treat. It is characterized by single or multiple, soft, well-circumscribed papules, plaques, or nodules ranging in color from red, violet, or yellow to brown that may darken with sun exposure.¹ Lesions usually are smooth with follicular orifices that are accentuated, thus producing a peau d’orange appearance. Lesions generally are slow to develop and asymptomatic, though some patients report pruritus or burning.^2,3 Diagnosis of GF is based on the presence of distinct histologic features. The epidermis usually is spared, with a prominent grenz zone of normal collagen separating the epidermis from a dense infiltrate of neutrophils, lymphocytes, and eosinophils. This mixed inflammatory infiltrate is seen mainly in the superficial dermis but occasionally spreads to the lower dermis and subcutaneous tissues.⁴

As the name implies, GF usually is confined to the face but occasionally involves extrafacial sites.^5-15 The clinical characteristics of these rare extrafacial lesions are not well understood. The purpose of this study was to identify the clinical and demographic features of extrafacial GF in patients treated at Mayo Clinic (Rochester, Minnesota) during a 54-year period.

Methods

This study was approved by the Mayo institutional review board. We searched the Mayo Clinic Rochester dermatology database for all patients with a diagnosis of GF from 1959 through 2013. All histopathology slides were reviewed by a board-certified dermatologist (A.G.B.) and dermatopathologist (A.G.B.) before inclusion in this study. Histologic criteria for diagnosis of GF included the presence of a mixed inflammatory infiltrate of neutrophils, eosinophils, lymphocytes, and histiocytes in the superficial or deep dermis; a prominent grenz zone separating the uninvolved epidermis; and the presence of vascular damage, as seen by fibrin deposition in dermal blood vessels.

Medical records were reviewed for patient demographics and for history pertinent to the diagnosis of GF, including sites involved, appearance, histopathology reports, symptoms, treatments, and outcomes.

Literature Search Strategy
A computerized Ovid MEDLINE database search was undertaken to identify English-language articles concerning GF in humans using the search terms granuloma faciale with extrafacial or disseminated. To ensure that no articles were overlooked, we conducted another search for English-language articles in the Embase database (1946-2013) using the terms granuloma faciale and extrafacial or disseminated.

Statistical Analysis
Descriptive clinical and histopathologic data were summarized using means, medians, and ranges or proportions as appropriate; statistical analysis was performed using SAS software (JMP package).

Results

Ninety-six patients with a diagnosis of GF were identified, and 12 (13%) had a diagnosis of extrafacial GF. Of them, 2 patients had a diagnosis of extrafacial GF supported only by histopathology slides without accompanying clinical records and therefore were excluded from the study. Thus, 10 cases of extrafacial GF were identified from our search and were included in the study group. Clinical data for these patients are summarized in Table 1. The mean age was 58.7 years (range, 26–87 years). Six (60%) patients were male, and all patients were white. Seven patients (70%) had facial GF in addition to extrafacial GF. Six patients reported no symptoms (60%), and 4 (40%) reported pruritus, discomfort, or both associated with their GF lesions.

Extrafacial GF was diagnosed in the following anatomic locations: scalp (n=3 [30%]), posterior auricular area (n=3 [30%]), mid upper back (n=1 [10%]), right shoulder (n=1 [10%]), both ears (n=1 [10%]), right elbow (n=1 [10%]), and left infra-auricular area (n=1 [10%]). Only 1 (10%) patient had multiple extrafacial sites identified.

The lesions were characterized clinically as violet, red, and yellow to brown smooth papules, plaques, and nodules (Figure 1). Biopsies from these lesions showed a subepidermal and adnexal grenz zone; a polymorphous perivascular and periadnexal dermal infiltrate composed of neutrophils, eosinophils, lymphocytes, histiocytes, and plasma cells; and a mild subtle leukocytoclastic vasculitis with subtle mild vascular necrosis (Figure 2).

For the 9 patients who elected to undergo GF treatment, the average number of treatments attempted was 2.8 (range, 1–5). The most common method of treatment was a combination of intralesional and topical corticosteroids (n=5 [50%]). Other methods included surgery (n=3 [30%]), dapsone (n=2 [20%]), radiation therapy (n=2 [20%]), cryosurgery (n=1 [10%]), nitrogen mustard (n=1 [10%]), liquid nitrogen (n=1 [10%]), and tar shampoo and fluocinolone acetonide solution 0.01% (n=1 [10%]).

Treatment outcomes were available for 8 of 9 treated patients. Three patients (patients 7, 8, and 10) had long-term successful resolution of their lesions. Patient 7 had an extrafacial lesion that was successfully treated with intralesional and topical corticosteroids, but the facial lesions recurred. The extrafacial GF lesion in patient 8 was found adjacent to a squamous cell carcinoma and was removed with a wide surgical excision that included both lesions. Patient 10 was successfully treated with a combination of liquid nitrogen and topical corticosteroid. Patients 2 and 4 were well controlled while on dapsone; however, once the treatment was discontinued, primarily due to adverse effects, the lesions returned.

Literature Search
Our search of the English-language literature identified 20 patients with extrafacial GF (Table 2). Fifteen (75%) patients were male, which was similar to our study (6/10 [60%]). Our patient population was slightly older with a mean age of 58.7 years compared to a median age of 54 years among those identified in the literature. Additionally, 3 (30%) patients in our study had no facial lesions, as seen in classic GF, which is comparable to 8 (40%) patients identified in the literature.

 

Comment

Extrafacial GF primarily affects white individuals and is more prevalent in men, as demonstrated in our study. Extrafacial GF was most often found in association with facial lesions, with only 3 patients having exclusively extrafacial sites.

Data from the current study indicate that diverse modalities were used to treat extrafacial GF with variable outcomes (chronic recurrence to complete resolution). The most common first-line treatment, intralesional corticosteroid injection, was used in 5 (50%) patients but resulted in only 1 (10%) successful resolution. Other methods frequently used in our study and prior studies were surgical excision, cryotherapy, electrosurgery, and dermabrasion.^1,20 These treatments do not appear to be uniformly definitive, and the ablative methods may result in scarring.¹ Different laser treatments are emerging for the management of GF lesions. Prior reports of treating facial GF with argon and CO₂ lasers have indicated minimized residual scarring and pigmentation.^21-23 The use of pulsed dye lasers has resulted in complete clearance of facial GF lesions, without recurrence on long-term follow-up.^20,24-26

The latest investigations of immunomodulatory drugs indicate these agents are promising for the management of facial GF. Eetam et al²⁷ reported the successful use of topical tacrolimus to treat facial GF. The relatively low cost and ease of use make these topical medications a competitive alternative to currently available surgical and laser methods. The appearance of all of these novel therapeutic modalities creates the necessity for a randomized trial to establish their efficacy on extrafacial GF lesions.

The wide array of treatments reflects the recalcitrant nature of extrafacial GF lesions. Further insight into the etiology of these lesions is needed to understand their tendency to recur. The important contribution of our study is the observed predilection of extrafacial GF for sun-exposed areas such as the scalp, upper trunk, and arms and legs. This pattern of extrafacial distribution along with the lack of mucosal involvement suggests a possible connection with UV light exposure. Furthermore, one of the extrafacial GF lesions in our study occurred in association with a squamous cell carcinoma, which may be an additional indication that these sites have been subjected to sun damage. This finding strengthens the importance of obtaining an adequate skin biopsy of any well-demarcated plaque or nodule found on the trunk, arms, and legs. The observed GF prevalence on sun-exposed areas and association with photoexacerbation have been speculated in prior studies, but no clear connection has been established.^1,28

Conclusion

The findings from this study and the cases reviewed in the literature provide a unique contribution to the understanding of the clinical and demographic characteristics of extrafacial GF. The rarity of this condition is the single most important constraint of our study, reflected in the emblematic limitations of a retrospective analysis in a select group of patients. The results of analysis of data from our patients were similar to the findings reported in the English-language medical literature. Serious consideration should be given to the development of a national registry for patients with GF. A database containing the clinicopathologic features, treatments, and outcomes for patients with both facial and extrafacial manifestations of GF may be invaluable in evaluating various treatment options and increasing understanding of the etiology and epidemiology of the disease.