Cutis

Porphyria cutanea tarda (PCT) typically presents with complaints of fragile skin, dorsal hand vesicles, erosions, and scars, and increased levels of uroporphyrins. A case of PCT caused by iron overload associated with hereditary hemochromatosis (HH) is reported. The laboratory workup revealed the patient was homozygous for the Cys282Tyr mutation in the HFE (hemochromatosis) gene. The associated diagnosis of HH was critical because without early treatment, damage to vital organs and premature death could occur. This report highlights the important association of PCT with HH and reviews the role of key genetic and hormonal factors in iron regulation.

Case Report
A 41-year-old white woman presented with a 3-month history of fragile skin and blisters on her hands. She took oral contraceptives and occasionally consumed alcoholic beverages. There was no family history of liver disease. A full skin examination revealed erosions; scars; and 1-mm, firm, white papules consistent with milia on the dorsal hands. Based on the complaint of fragile skin and the physical findings, porphyria cutanea tarda (PCT) was suspected. To confirm this suspicion, porphyrin levels were obtained. The level of uroporphyrin was elevated and the coproporphyrin level was within reference range, consistent with PCT. The patient was advised to discontinue her use of oral contraceptives and alcohol, and to protect herself from the sun. Because PCT can be associated with iron overload and liver disease, the patient underwent additional testing. Her serum ferritin level was elevated, but other liver studies, including transaminases and hepatitis serologies, were within reference range. To further characterize the iron overload, additional studies were performed, including genetic testing for hereditary hemochromatosis (HH). These studies revealed that the patient was homozygous for the Cys282Tyr mutation in the HFE (hemochromatosis) gene; therefore, the cause of the patient's PCT was almost certainly HH. A phlebotomy treatment program was instituted, both to treat the PCT-associated skin lesions and to prevent sequelae of systemic iron overload (eg, diabetes mellitus, cirrhosis of the liver, hepatocellular carcinoma, cardiomyopathy, early death). Lifelong monitoring of iron stores was recommended. 

Comment
This patient's laboratory workup for PCT identified HH, an autosomal recessive disease associated with iron overload. HH was almost certainly responsible for the PCT because iron overload causes decreased uroporphyrinogen decarboxylase activity. HH is common; it is the most frequent genetic disease in individuals of Northern European descent. Because the patient described here had no family history of HH, iron overload was not suspected prior to the diagnosis of PCT. HH should be suspected when the serum ferritin level is elevated and when the transferrin saturation exceeds 55%. Early clinical symptoms of HH generally are nonspecific, such as fatigue, arthralgia, and arthritis. Later findings can include generalized metallic gray hyperpigmentation of the skin, diabetes mellitus, cirrhosis of the liver, hepatocellular carcinoma, and congestive heart failure, all of which are secondary to iron overload.1 Premenopausal women with HH are partially protected from end-organ damage because of the loss of iron during menstruation. Early diagnosis and treatment can prevent serious end-organ damage,2 and individuals with HH can expect a normal lifespan if the excess iron stores are depleted prior to the development of cirrhosis. Environmental factors are important in hemochromatosis; for example, ethanol intake accentuates the risk of morbid complications of HH, including cirrhosis of the liver and cancer.3 Life expectancy is reduced if there is a delay in diagnosis and treatment.4 HH caused this patient's PCT. Strongly suggestive of PCT are complaints of fragile skin worsened by trauma or sunlight, along with the findings of vesicles or bullae on the hands or evidence of resolution of these lesions, such as erosions, scars, or milia.5 Other bullous diseases, including bullous pemphigoid and epidermolysis bullosa acquisita, also should be considered, but these diagnoses generally are excluded by the physical examination and histologic results. Two hereditary porphyrias—variegate porphyria and hereditary coproporphyria—as well as pseudoporphyria can present with skin findings similar to PCT.5 However, both variegate porphyria and hereditary coproporphyria commonly are associated with extracutaneous manifestations, and pseudoporphyria is associated with renal failure. In addition, different porphyrin profiles make it possible to distinguish PCT from the other porphyrias. PCT is the most common porphyria, with an incidence of approximately 1 per 70,000 people.6,7 PCT is caused by decreased activity of uroporphyrinogen decarboxylase.8 Estrogens, iron, alcohol, hepatitis C,9 and human immunodeficiency virus10 can be associated with PCT. It is poorly understood how they interfere with the activity of uroporphyrinogen decarboxylase, but iron overload is thought to be a common feature.5 When PCT is suspected, a laboratory evaluation is obtained to assess iron stores and liver function. Serum ferritin levels usually are at the upper limits of the reference range or elevated in patients with PCT.11 The understanding of iron overload has been enhanced by the identification of the HFE gene12 and the genes for the transferrin receptor 2 (TFR2) and hemojuvelin (HJV)(Table). The locus that most frequently accounts for HH is HFE, the class I major histocompatibility complex–related protein on chromosome 6p21.3.13 At least 37 different HFE mutations causing HH have been detected,14 including Cys282Tyr, Hys63Asp, and Ser65Cys. The most common mutation, the substitution of a tyrosine for a cysteine at protein residue 282 (Cys282Tyr), is caused by a G-to-A substitution at nucleotide 845 of the HFE transcript.15

Genetic testing revealed that the patient described here was homozygous for the Cys282Tyr mutation, which was not particularly surprising because this mutation is most common in patients with a Northern European ancestry. About 85% to 90% of patients of Northern European descent with HH are Cys282Tyr homozygotes.16 This mutation is almost certainly associated with increased iron absorption, though population surveys have revealed that some Cys282Tyr homozygotes do not have elevated iron stores.17 The Cys282Tyr mutation is most common in white individuals, but this mutation does not account for iron overload in nonwhite individuals, including Pacific Islanders and Asians.18 In addition, several other genes have been implicated in iron overload. The Leu490Arg and Val561Xaa mutations in the TFR2 gene have been identified in Japanese patients with hemochromatosis lacking mutations in HFE.19 Also, mutations in the HJV gene have been identified in patients with juvenile HH.20 Hepcidin is a key hormone in iron regulation.21 Its expression is decreased by mutations in HFE, TFR2, and HJV, all of which can contribute to iron overload in patients with HH. Hepcidin is a 25–amino acid peptide that was first identified in urine and plasma during a search for antimicrobial peptides.22 When there are increased iron stores in the body, HFE triggers hepcidin expression, which decreases the level of iron in the blood.21 The loss of hepcidin in upstream stimulatory factor 2 knockout mice is associated with increased intestinal iron absorption and increased circulating iron levels, akin to HH.23 Reduced hepcidin expression occurs in HH regardless of the genetic etiology. Although current treatment for HH is phlebotomy, a future treatment may be exogenous hepcidin.21 

Conclusion
The homozygous Cys282Tyr mutation in the HFE gene was identified as the cause of PCT and HH in a 41-year-old woman. An understanding of iron overload has been enhanced by the identification of genes that control hepcidin, including HFE, TFR2, and HJV. Mutations in these genes are associated with reduced levels of hepcidin, resulting in iron overload observed in HH. 

Porphyria cutanea tarda (PCT) typically presents with complaints of fragile skin, dorsal hand vesicles, erosions, and scars, and increased levels of uroporphyrins. A case of PCT caused by iron overload associated with hereditary hemochromatosis (HH) is reported. The laboratory workup revealed the patient was homozygous for the Cys282Tyr mutation in the HFE (hemochromatosis) gene. The associated diagnosis of HH was critical because without early treatment, damage to vital organs and premature death could occur. This report highlights the important association of PCT with HH and reviews the role of key genetic and hormonal factors in iron regulation.

Case Report
A 41-year-old white woman presented with a 3-month history of fragile skin and blisters on her hands. She took oral contraceptives and occasionally consumed alcoholic beverages. There was no family history of liver disease. A full skin examination revealed erosions; scars; and 1-mm, firm, white papules consistent with milia on the dorsal hands. Based on the complaint of fragile skin and the physical findings, porphyria cutanea tarda (PCT) was suspected. To confirm this suspicion, porphyrin levels were obtained. The level of uroporphyrin was elevated and the coproporphyrin level was within reference range, consistent with PCT. The patient was advised to discontinue her use of oral contraceptives and alcohol, and to protect herself from the sun. Because PCT can be associated with iron overload and liver disease, the patient underwent additional testing. Her serum ferritin level was elevated, but other liver studies, including transaminases and hepatitis serologies, were within reference range. To further characterize the iron overload, additional studies were performed, including genetic testing for hereditary hemochromatosis (HH). These studies revealed that the patient was homozygous for the Cys282Tyr mutation in the HFE (hemochromatosis) gene; therefore, the cause of the patient's PCT was almost certainly HH. A phlebotomy treatment program was instituted, both to treat the PCT-associated skin lesions and to prevent sequelae of systemic iron overload (eg, diabetes mellitus, cirrhosis of the liver, hepatocellular carcinoma, cardiomyopathy, early death). Lifelong monitoring of iron stores was recommended. 

Comment
This patient's laboratory workup for PCT identified HH, an autosomal recessive disease associated with iron overload. HH was almost certainly responsible for the PCT because iron overload causes decreased uroporphyrinogen decarboxylase activity. HH is common; it is the most frequent genetic disease in individuals of Northern European descent. Because the patient described here had no family history of HH, iron overload was not suspected prior to the diagnosis of PCT. HH should be suspected when the serum ferritin level is elevated and when the transferrin saturation exceeds 55%. Early clinical symptoms of HH generally are nonspecific, such as fatigue, arthralgia, and arthritis. Later findings can include generalized metallic gray hyperpigmentation of the skin, diabetes mellitus, cirrhosis of the liver, hepatocellular carcinoma, and congestive heart failure, all of which are secondary to iron overload.1 Premenopausal women with HH are partially protected from end-organ damage because of the loss of iron during menstruation. Early diagnosis and treatment can prevent serious end-organ damage,2 and individuals with HH can expect a normal lifespan if the excess iron stores are depleted prior to the development of cirrhosis. Environmental factors are important in hemochromatosis; for example, ethanol intake accentuates the risk of morbid complications of HH, including cirrhosis of the liver and cancer.3 Life expectancy is reduced if there is a delay in diagnosis and treatment.4 HH caused this patient's PCT. Strongly suggestive of PCT are complaints of fragile skin worsened by trauma or sunlight, along with the findings of vesicles or bullae on the hands or evidence of resolution of these lesions, such as erosions, scars, or milia.5 Other bullous diseases, including bullous pemphigoid and epidermolysis bullosa acquisita, also should be considered, but these diagnoses generally are excluded by the physical examination and histologic results. Two hereditary porphyrias—variegate porphyria and hereditary coproporphyria—as well as pseudoporphyria can present with skin findings similar to PCT.5 However, both variegate porphyria and hereditary coproporphyria commonly are associated with extracutaneous manifestations, and pseudoporphyria is associated with renal failure. In addition, different porphyrin profiles make it possible to distinguish PCT from the other porphyrias. PCT is the most common porphyria, with an incidence of approximately 1 per 70,000 people.6,7 PCT is caused by decreased activity of uroporphyrinogen decarboxylase.8 Estrogens, iron, alcohol, hepatitis C,9 and human immunodeficiency virus10 can be associated with PCT. It is poorly understood how they interfere with the activity of uroporphyrinogen decarboxylase, but iron overload is thought to be a common feature.5 When PCT is suspected, a laboratory evaluation is obtained to assess iron stores and liver function. Serum ferritin levels usually are at the upper limits of the reference range or elevated in patients with PCT.11 The understanding of iron overload has been enhanced by the identification of the HFE gene12 and the genes for the transferrin receptor 2 (TFR2) and hemojuvelin (HJV)(Table). The locus that most frequently accounts for HH is HFE, the class I major histocompatibility complex–related protein on chromosome 6p21.3.13 At least 37 different HFE mutations causing HH have been detected,14 including Cys282Tyr, Hys63Asp, and Ser65Cys. The most common mutation, the substitution of a tyrosine for a cysteine at protein residue 282 (Cys282Tyr), is caused by a G-to-A substitution at nucleotide 845 of the HFE transcript.15

Genetic testing revealed that the patient described here was homozygous for the Cys282Tyr mutation, which was not particularly surprising because this mutation is most common in patients with a Northern European ancestry. About 85% to 90% of patients of Northern European descent with HH are Cys282Tyr homozygotes.16 This mutation is almost certainly associated with increased iron absorption, though population surveys have revealed that some Cys282Tyr homozygotes do not have elevated iron stores.17 The Cys282Tyr mutation is most common in white individuals, but this mutation does not account for iron overload in nonwhite individuals, including Pacific Islanders and Asians.18 In addition, several other genes have been implicated in iron overload. The Leu490Arg and Val561Xaa mutations in the TFR2 gene have been identified in Japanese patients with hemochromatosis lacking mutations in HFE.19 Also, mutations in the HJV gene have been identified in patients with juvenile HH.20 Hepcidin is a key hormone in iron regulation.21 Its expression is decreased by mutations in HFE, TFR2, and HJV, all of which can contribute to iron overload in patients with HH. Hepcidin is a 25–amino acid peptide that was first identified in urine and plasma during a search for antimicrobial peptides.22 When there are increased iron stores in the body, HFE triggers hepcidin expression, which decreases the level of iron in the blood.21 The loss of hepcidin in upstream stimulatory factor 2 knockout mice is associated with increased intestinal iron absorption and increased circulating iron levels, akin to HH.23 Reduced hepcidin expression occurs in HH regardless of the genetic etiology. Although current treatment for HH is phlebotomy, a future treatment may be exogenous hepcidin.21 

Conclusion
The homozygous Cys282Tyr mutation in the HFE gene was identified as the cause of PCT and HH in a 41-year-old woman. An understanding of iron overload has been enhanced by the identification of genes that control hepcidin, including HFE, TFR2, and HJV. Mutations in these genes are associated with reduced levels of hepcidin, resulting in iron overload observed in HH. 

Porphyria cutanea tarda (PCT) typically presents with complaints of fragile skin, dorsal hand vesicles, erosions, and scars, and increased levels of uroporphyrins. A case of PCT caused by iron overload associated with hereditary hemochromatosis (HH) is reported. The laboratory workup revealed the patient was homozygous for the Cys282Tyr mutation in the HFE (hemochromatosis) gene. The associated diagnosis of HH was critical because without early treatment, damage to vital organs and premature death could occur. This report highlights the important association of PCT with HH and reviews the role of key genetic and hormonal factors in iron regulation.

Case Report
A 41-year-old white woman presented with a 3-month history of fragile skin and blisters on her hands. She took oral contraceptives and occasionally consumed alcoholic beverages. There was no family history of liver disease. A full skin examination revealed erosions; scars; and 1-mm, firm, white papules consistent with milia on the dorsal hands. Based on the complaint of fragile skin and the physical findings, porphyria cutanea tarda (PCT) was suspected. To confirm this suspicion, porphyrin levels were obtained. The level of uroporphyrin was elevated and the coproporphyrin level was within reference range, consistent with PCT. The patient was advised to discontinue her use of oral contraceptives and alcohol, and to protect herself from the sun. Because PCT can be associated with iron overload and liver disease, the patient underwent additional testing. Her serum ferritin level was elevated, but other liver studies, including transaminases and hepatitis serologies, were within reference range. To further characterize the iron overload, additional studies were performed, including genetic testing for hereditary hemochromatosis (HH). These studies revealed that the patient was homozygous for the Cys282Tyr mutation in the HFE (hemochromatosis) gene; therefore, the cause of the patient's PCT was almost certainly HH. A phlebotomy treatment program was instituted, both to treat the PCT-associated skin lesions and to prevent sequelae of systemic iron overload (eg, diabetes mellitus, cirrhosis of the liver, hepatocellular carcinoma, cardiomyopathy, early death). Lifelong monitoring of iron stores was recommended. 

Comment
This patient's laboratory workup for PCT identified HH, an autosomal recessive disease associated with iron overload. HH was almost certainly responsible for the PCT because iron overload causes decreased uroporphyrinogen decarboxylase activity. HH is common; it is the most frequent genetic disease in individuals of Northern European descent. Because the patient described here had no family history of HH, iron overload was not suspected prior to the diagnosis of PCT. HH should be suspected when the serum ferritin level is elevated and when the transferrin saturation exceeds 55%. Early clinical symptoms of HH generally are nonspecific, such as fatigue, arthralgia, and arthritis. Later findings can include generalized metallic gray hyperpigmentation of the skin, diabetes mellitus, cirrhosis of the liver, hepatocellular carcinoma, and congestive heart failure, all of which are secondary to iron overload.1 Premenopausal women with HH are partially protected from end-organ damage because of the loss of iron during menstruation. Early diagnosis and treatment can prevent serious end-organ damage,2 and individuals with HH can expect a normal lifespan if the excess iron stores are depleted prior to the development of cirrhosis. Environmental factors are important in hemochromatosis; for example, ethanol intake accentuates the risk of morbid complications of HH, including cirrhosis of the liver and cancer.3 Life expectancy is reduced if there is a delay in diagnosis and treatment.4 HH caused this patient's PCT. Strongly suggestive of PCT are complaints of fragile skin worsened by trauma or sunlight, along with the findings of vesicles or bullae on the hands or evidence of resolution of these lesions, such as erosions, scars, or milia.5 Other bullous diseases, including bullous pemphigoid and epidermolysis bullosa acquisita, also should be considered, but these diagnoses generally are excluded by the physical examination and histologic results. Two hereditary porphyrias—variegate porphyria and hereditary coproporphyria—as well as pseudoporphyria can present with skin findings similar to PCT.5 However, both variegate porphyria and hereditary coproporphyria commonly are associated with extracutaneous manifestations, and pseudoporphyria is associated with renal failure. In addition, different porphyrin profiles make it possible to distinguish PCT from the other porphyrias. PCT is the most common porphyria, with an incidence of approximately 1 per 70,000 people.6,7 PCT is caused by decreased activity of uroporphyrinogen decarboxylase.8 Estrogens, iron, alcohol, hepatitis C,9 and human immunodeficiency virus10 can be associated with PCT. It is poorly understood how they interfere with the activity of uroporphyrinogen decarboxylase, but iron overload is thought to be a common feature.5 When PCT is suspected, a laboratory evaluation is obtained to assess iron stores and liver function. Serum ferritin levels usually are at the upper limits of the reference range or elevated in patients with PCT.11 The understanding of iron overload has been enhanced by the identification of the HFE gene12 and the genes for the transferrin receptor 2 (TFR2) and hemojuvelin (HJV)(Table). The locus that most frequently accounts for HH is HFE, the class I major histocompatibility complex–related protein on chromosome 6p21.3.13 At least 37 different HFE mutations causing HH have been detected,14 including Cys282Tyr, Hys63Asp, and Ser65Cys. The most common mutation, the substitution of a tyrosine for a cysteine at protein residue 282 (Cys282Tyr), is caused by a G-to-A substitution at nucleotide 845 of the HFE transcript.15

Genetic testing revealed that the patient described here was homozygous for the Cys282Tyr mutation, which was not particularly surprising because this mutation is most common in patients with a Northern European ancestry. About 85% to 90% of patients of Northern European descent with HH are Cys282Tyr homozygotes.16 This mutation is almost certainly associated with increased iron absorption, though population surveys have revealed that some Cys282Tyr homozygotes do not have elevated iron stores.17 The Cys282Tyr mutation is most common in white individuals, but this mutation does not account for iron overload in nonwhite individuals, including Pacific Islanders and Asians.18 In addition, several other genes have been implicated in iron overload. The Leu490Arg and Val561Xaa mutations in the TFR2 gene have been identified in Japanese patients with hemochromatosis lacking mutations in HFE.19 Also, mutations in the HJV gene have been identified in patients with juvenile HH.20 Hepcidin is a key hormone in iron regulation.21 Its expression is decreased by mutations in HFE, TFR2, and HJV, all of which can contribute to iron overload in patients with HH. Hepcidin is a 25–amino acid peptide that was first identified in urine and plasma during a search for antimicrobial peptides.22 When there are increased iron stores in the body, HFE triggers hepcidin expression, which decreases the level of iron in the blood.21 The loss of hepcidin in upstream stimulatory factor 2 knockout mice is associated with increased intestinal iron absorption and increased circulating iron levels, akin to HH.23 Reduced hepcidin expression occurs in HH regardless of the genetic etiology. Although current treatment for HH is phlebotomy, a future treatment may be exogenous hepcidin.21 

Conclusion
The homozygous Cys282Tyr mutation in the HFE gene was identified as the cause of PCT and HH in a 41-year-old woman. An understanding of iron overload has been enhanced by the identification of genes that control hepcidin, including HFE, TFR2, and HJV. Mutations in these genes are associated with reduced levels of hepcidin, resulting in iron overload observed in HH. 

Piebaldism is a rare autosomal dominant disorder characterized by congenital poliosis and leukoderma. We present a case of a 10-year-old girl with a typical clinical presentation, followed by a concise review of the literature discussing the etiology, clinical features, diagnosis, and management of the condition.

Case Report
A 10-year-old girl presented for evaluation of a white forelock and multiple white patches of skin on the trunk and extremities (Figure). The white forelock was present at birth and a few white patches appeared on the chest at 3 months of age. During the subsequent 4 years, the white patches gradually progressed to involve the central forehead, abdomen, and extremities. Multiple frecklelike macules also appeared within the patches and the surrounding healthy skin.

Physical examination revealed a healthy girl with a prominent, large, diamond-shaped, depigmented patch on the central forehead that was associated with a white forelock. The hairs of the medial eyebrows and the eyelashes also were depigmented. Large, irregularly shaped, depigmented patches were present on the trunk and anterior extremities. There were multiple hyperpigmented macules overlying both the depigmented patches and the adjacent normally pigmented skin. The rest of the physical examination and the results of routine blood tests and urinalysis were unremarkable. The patient's mother and 4 siblings also were born with a white forelock. Similar depigmented patches on the trunk and extremities with a similar pattern and distribution were noted in all of them. Neither the patient nor her mother and siblings had midfacial anomalies, deafness, or heterochromia irides.

Comment
Piebaldism is a rare autosomal dominant disorder of melanocyte development resulting from mutations of the c-kit protooncogene.1,2 The disorder is characterized clinically by congenital poliosis and leukoderma. A white forelock is present at birth and may be the only manifestation in most affected individuals.3 The white forelock may have a triangular or diamond shape, and the underlying skin of the scalp also is amelanotic. Typical piebald lesions are typified by well-circumscribed, irregular, chalk white patches, often with hyperpigmented frecklelike macules noted on both depigmented and unaffected adjacent skin.4 The lesions often exhibit a classic distribution, involving the central forehead and anterior trunk, with extension to the flanks and anterior midarms, midknees, and midlegs. The medial third of the eyebrows and eyelashes also may be affected in severe cases.4 Characteristically, there is sparing of the dorsal midline, hands, feet, and periorificial areas. Piebaldism generally is a static disorder of pigmentation, though contraction of the affected areas with time or the appearance of new hyperpigmented macular lesions has been described.5 Progression of the depigmented patches has been reported in isolated cases with a novel Val620Ala mutation in Kit.6 Piebaldism rarely is associated with other disorders such as Hirschsprung disease, neurofibromatosis type 1, congenital dyserythropoietic anemia type II, Diamond-Blackfan anemia, and Grover disease.7-11 Individual case reports with associated deafness also have been described.12 Histopathologic evaluation of the depigmented lesions reveals absent or considerably reduced melanocytes. The hyperpigmented macules have a normal number of melanocytes and an increased number of melanosomes in the melanocytes and keratinocytes.4 The molecular basis of piebaldism was traced by Giebel and Spritz1 and Fleischman et al13 to mutations of the c-kit protooncogene. To date, 14 point mutations, 9 deletion mutations, 2 nucleotide splicing mutations, and 3 insertions of Kit have been described.6,14 c-kit Mutations are found in about 75% of patients with piebaldism.14 Mutations in the slug gene, which is a zinc-finger neural crest transcription factor, have been reported in piebaldism that lacked mutations in Kit.15 The human kit gene encodes the tyrosine kinase transmembrane cellular receptor for mast/stem cell growth factor, which is a critical factor for melanoblast migration, proliferation, differentiation, and survival.6 It would be pertinent to note here that the severity of the phenotype in piebaldism correlates with the site of the mutation within the kit gene. The most severe phenotypes are caused by mutations involving the intracellular tyrosine kinase domain, whereas the mildest phenotypes result from mutations involving the amino-terminal extracellular ligand-binding domain.6 The differential diagnosis of piebaldism includes any condition that may present with a depigmented lesion. Vitiligo is characterized by acquired depigmentation, typically in an acral and periorificial distribution. Piebaldism generally is distinguished from vitiligo by the presence of lesions from birth, hyperpigmented macules within and at the border of depigmented areas, and its static course. Moreover, piebaldism spares the dorsal midline, hands, feet, and periorificial areas. Waardenburg syndrome is an autosomal dominant disorder characterized by a congenital white forelock, lateral displacement of the medial canthi, a hypertrophic nasal root, heterochromia irides, and sensorineural hearing loss.16 At least 4 types of Waardenburg syndrome have been described based on the clinical and genetic criteria. The presence of hyperpigmented patches within the islands of depigmentation and on healthy skin; the absence of midfacial lesions, heterochromia irides, and deafness; and the location of depigmented patches on the trunk and extremities help to distinguish piebaldism from the various forms of Waardenburg syndrome.16 Ziprkowski-Margolis syndrome is a rare X-linked recessive syndrome characterized by deaf-mutism, heterochromic irides, piebaldlike hypomelanosis, and hyperpigmented macules, with a geographic appearance developing mainly on the trunk and extremities.17 Woolf syndrome is an autosomal recessive disorder consisting of piebaldism and deafness. Audiometry is crucial to exclude this diagnosis.18 Depending on its presentation, other conditions to consider include Addison disease, albinism, and systemic sclerosis, as well as use of depigmenting agents. Piebaldism is considered a relatively benign disorder, but it may have psychological impact because it is socially disabling, which presents a therapeutic challenge. Depigmented skin in piebaldism generally is considered unresponsive to medical or light therapy. Of note, the diagnosis of piebaldism should alert the clinician to the possibility of Waardenburg syndrome as determined by the results of ocular and auditory examinations. Sunscreens are recommended to avoid sunburns and to reduce the carcinogenic potential. To camouflage the exposed areas, makeup or temporary pigmenting agents such as the tanning product dihydroxyacetone may be used.19 The lesions of piebaldism do not respond to the topical agents used to treat vitiligo. Different surgical techniques have been tried, with variable success, including thin split-thickness grafts, minigrafting, transplant of autologous cultured melanocytes, and a combination of dermabrasion and grafting of the pigmented skin into the depigmented areas.20,21 Guerra et al22 reported achromic epidermis removed with the erbium:YAG laser and autologous cultured epidermal grafts were applied to the recipient bed in 6 patients. Autologous cultured epidermis, bearing a controlled number of melanocytes, induced repigmentation of all piebald lesions. The mean percentage repigmentation was 95.45%.22

Piebaldism is a rare autosomal dominant disorder characterized by congenital poliosis and leukoderma. We present a case of a 10-year-old girl with a typical clinical presentation, followed by a concise review of the literature discussing the etiology, clinical features, diagnosis, and management of the condition.

Case Report
A 10-year-old girl presented for evaluation of a white forelock and multiple white patches of skin on the trunk and extremities (Figure). The white forelock was present at birth and a few white patches appeared on the chest at 3 months of age. During the subsequent 4 years, the white patches gradually progressed to involve the central forehead, abdomen, and extremities. Multiple frecklelike macules also appeared within the patches and the surrounding healthy skin.

Physical examination revealed a healthy girl with a prominent, large, diamond-shaped, depigmented patch on the central forehead that was associated with a white forelock. The hairs of the medial eyebrows and the eyelashes also were depigmented. Large, irregularly shaped, depigmented patches were present on the trunk and anterior extremities. There were multiple hyperpigmented macules overlying both the depigmented patches and the adjacent normally pigmented skin. The rest of the physical examination and the results of routine blood tests and urinalysis were unremarkable. The patient's mother and 4 siblings also were born with a white forelock. Similar depigmented patches on the trunk and extremities with a similar pattern and distribution were noted in all of them. Neither the patient nor her mother and siblings had midfacial anomalies, deafness, or heterochromia irides.

Comment
Piebaldism is a rare autosomal dominant disorder of melanocyte development resulting from mutations of the c-kit protooncogene.1,2 The disorder is characterized clinically by congenital poliosis and leukoderma. A white forelock is present at birth and may be the only manifestation in most affected individuals.3 The white forelock may have a triangular or diamond shape, and the underlying skin of the scalp also is amelanotic. Typical piebald lesions are typified by well-circumscribed, irregular, chalk white patches, often with hyperpigmented frecklelike macules noted on both depigmented and unaffected adjacent skin.4 The lesions often exhibit a classic distribution, involving the central forehead and anterior trunk, with extension to the flanks and anterior midarms, midknees, and midlegs. The medial third of the eyebrows and eyelashes also may be affected in severe cases.4 Characteristically, there is sparing of the dorsal midline, hands, feet, and periorificial areas. Piebaldism generally is a static disorder of pigmentation, though contraction of the affected areas with time or the appearance of new hyperpigmented macular lesions has been described.5 Progression of the depigmented patches has been reported in isolated cases with a novel Val620Ala mutation in Kit.6 Piebaldism rarely is associated with other disorders such as Hirschsprung disease, neurofibromatosis type 1, congenital dyserythropoietic anemia type II, Diamond-Blackfan anemia, and Grover disease.7-11 Individual case reports with associated deafness also have been described.12 Histopathologic evaluation of the depigmented lesions reveals absent or considerably reduced melanocytes. The hyperpigmented macules have a normal number of melanocytes and an increased number of melanosomes in the melanocytes and keratinocytes.4 The molecular basis of piebaldism was traced by Giebel and Spritz1 and Fleischman et al13 to mutations of the c-kit protooncogene. To date, 14 point mutations, 9 deletion mutations, 2 nucleotide splicing mutations, and 3 insertions of Kit have been described.6,14 c-kit Mutations are found in about 75% of patients with piebaldism.14 Mutations in the slug gene, which is a zinc-finger neural crest transcription factor, have been reported in piebaldism that lacked mutations in Kit.15 The human kit gene encodes the tyrosine kinase transmembrane cellular receptor for mast/stem cell growth factor, which is a critical factor for melanoblast migration, proliferation, differentiation, and survival.6 It would be pertinent to note here that the severity of the phenotype in piebaldism correlates with the site of the mutation within the kit gene. The most severe phenotypes are caused by mutations involving the intracellular tyrosine kinase domain, whereas the mildest phenotypes result from mutations involving the amino-terminal extracellular ligand-binding domain.6 The differential diagnosis of piebaldism includes any condition that may present with a depigmented lesion. Vitiligo is characterized by acquired depigmentation, typically in an acral and periorificial distribution. Piebaldism generally is distinguished from vitiligo by the presence of lesions from birth, hyperpigmented macules within and at the border of depigmented areas, and its static course. Moreover, piebaldism spares the dorsal midline, hands, feet, and periorificial areas. Waardenburg syndrome is an autosomal dominant disorder characterized by a congenital white forelock, lateral displacement of the medial canthi, a hypertrophic nasal root, heterochromia irides, and sensorineural hearing loss.16 At least 4 types of Waardenburg syndrome have been described based on the clinical and genetic criteria. The presence of hyperpigmented patches within the islands of depigmentation and on healthy skin; the absence of midfacial lesions, heterochromia irides, and deafness; and the location of depigmented patches on the trunk and extremities help to distinguish piebaldism from the various forms of Waardenburg syndrome.16 Ziprkowski-Margolis syndrome is a rare X-linked recessive syndrome characterized by deaf-mutism, heterochromic irides, piebaldlike hypomelanosis, and hyperpigmented macules, with a geographic appearance developing mainly on the trunk and extremities.17 Woolf syndrome is an autosomal recessive disorder consisting of piebaldism and deafness. Audiometry is crucial to exclude this diagnosis.18 Depending on its presentation, other conditions to consider include Addison disease, albinism, and systemic sclerosis, as well as use of depigmenting agents. Piebaldism is considered a relatively benign disorder, but it may have psychological impact because it is socially disabling, which presents a therapeutic challenge. Depigmented skin in piebaldism generally is considered unresponsive to medical or light therapy. Of note, the diagnosis of piebaldism should alert the clinician to the possibility of Waardenburg syndrome as determined by the results of ocular and auditory examinations. Sunscreens are recommended to avoid sunburns and to reduce the carcinogenic potential. To camouflage the exposed areas, makeup or temporary pigmenting agents such as the tanning product dihydroxyacetone may be used.19 The lesions of piebaldism do not respond to the topical agents used to treat vitiligo. Different surgical techniques have been tried, with variable success, including thin split-thickness grafts, minigrafting, transplant of autologous cultured melanocytes, and a combination of dermabrasion and grafting of the pigmented skin into the depigmented areas.20,21 Guerra et al22 reported achromic epidermis removed with the erbium:YAG laser and autologous cultured epidermal grafts were applied to the recipient bed in 6 patients. Autologous cultured epidermis, bearing a controlled number of melanocytes, induced repigmentation of all piebald lesions. The mean percentage repigmentation was 95.45%.22

Piebaldism is a rare autosomal dominant disorder characterized by congenital poliosis and leukoderma. We present a case of a 10-year-old girl with a typical clinical presentation, followed by a concise review of the literature discussing the etiology, clinical features, diagnosis, and management of the condition.

Case Report
A 10-year-old girl presented for evaluation of a white forelock and multiple white patches of skin on the trunk and extremities (Figure). The white forelock was present at birth and a few white patches appeared on the chest at 3 months of age. During the subsequent 4 years, the white patches gradually progressed to involve the central forehead, abdomen, and extremities. Multiple frecklelike macules also appeared within the patches and the surrounding healthy skin.

Physical examination revealed a healthy girl with a prominent, large, diamond-shaped, depigmented patch on the central forehead that was associated with a white forelock. The hairs of the medial eyebrows and the eyelashes also were depigmented. Large, irregularly shaped, depigmented patches were present on the trunk and anterior extremities. There were multiple hyperpigmented macules overlying both the depigmented patches and the adjacent normally pigmented skin. The rest of the physical examination and the results of routine blood tests and urinalysis were unremarkable. The patient's mother and 4 siblings also were born with a white forelock. Similar depigmented patches on the trunk and extremities with a similar pattern and distribution were noted in all of them. Neither the patient nor her mother and siblings had midfacial anomalies, deafness, or heterochromia irides.

Comment
Piebaldism is a rare autosomal dominant disorder of melanocyte development resulting from mutations of the c-kit protooncogene.1,2 The disorder is characterized clinically by congenital poliosis and leukoderma. A white forelock is present at birth and may be the only manifestation in most affected individuals.3 The white forelock may have a triangular or diamond shape, and the underlying skin of the scalp also is amelanotic. Typical piebald lesions are typified by well-circumscribed, irregular, chalk white patches, often with hyperpigmented frecklelike macules noted on both depigmented and unaffected adjacent skin.4 The lesions often exhibit a classic distribution, involving the central forehead and anterior trunk, with extension to the flanks and anterior midarms, midknees, and midlegs. The medial third of the eyebrows and eyelashes also may be affected in severe cases.4 Characteristically, there is sparing of the dorsal midline, hands, feet, and periorificial areas. Piebaldism generally is a static disorder of pigmentation, though contraction of the affected areas with time or the appearance of new hyperpigmented macular lesions has been described.5 Progression of the depigmented patches has been reported in isolated cases with a novel Val620Ala mutation in Kit.6 Piebaldism rarely is associated with other disorders such as Hirschsprung disease, neurofibromatosis type 1, congenital dyserythropoietic anemia type II, Diamond-Blackfan anemia, and Grover disease.7-11 Individual case reports with associated deafness also have been described.12 Histopathologic evaluation of the depigmented lesions reveals absent or considerably reduced melanocytes. The hyperpigmented macules have a normal number of melanocytes and an increased number of melanosomes in the melanocytes and keratinocytes.4 The molecular basis of piebaldism was traced by Giebel and Spritz1 and Fleischman et al13 to mutations of the c-kit protooncogene. To date, 14 point mutations, 9 deletion mutations, 2 nucleotide splicing mutations, and 3 insertions of Kit have been described.6,14 c-kit Mutations are found in about 75% of patients with piebaldism.14 Mutations in the slug gene, which is a zinc-finger neural crest transcription factor, have been reported in piebaldism that lacked mutations in Kit.15 The human kit gene encodes the tyrosine kinase transmembrane cellular receptor for mast/stem cell growth factor, which is a critical factor for melanoblast migration, proliferation, differentiation, and survival.6 It would be pertinent to note here that the severity of the phenotype in piebaldism correlates with the site of the mutation within the kit gene. The most severe phenotypes are caused by mutations involving the intracellular tyrosine kinase domain, whereas the mildest phenotypes result from mutations involving the amino-terminal extracellular ligand-binding domain.6 The differential diagnosis of piebaldism includes any condition that may present with a depigmented lesion. Vitiligo is characterized by acquired depigmentation, typically in an acral and periorificial distribution. Piebaldism generally is distinguished from vitiligo by the presence of lesions from birth, hyperpigmented macules within and at the border of depigmented areas, and its static course. Moreover, piebaldism spares the dorsal midline, hands, feet, and periorificial areas. Waardenburg syndrome is an autosomal dominant disorder characterized by a congenital white forelock, lateral displacement of the medial canthi, a hypertrophic nasal root, heterochromia irides, and sensorineural hearing loss.16 At least 4 types of Waardenburg syndrome have been described based on the clinical and genetic criteria. The presence of hyperpigmented patches within the islands of depigmentation and on healthy skin; the absence of midfacial lesions, heterochromia irides, and deafness; and the location of depigmented patches on the trunk and extremities help to distinguish piebaldism from the various forms of Waardenburg syndrome.16 Ziprkowski-Margolis syndrome is a rare X-linked recessive syndrome characterized by deaf-mutism, heterochromic irides, piebaldlike hypomelanosis, and hyperpigmented macules, with a geographic appearance developing mainly on the trunk and extremities.17 Woolf syndrome is an autosomal recessive disorder consisting of piebaldism and deafness. Audiometry is crucial to exclude this diagnosis.18 Depending on its presentation, other conditions to consider include Addison disease, albinism, and systemic sclerosis, as well as use of depigmenting agents. Piebaldism is considered a relatively benign disorder, but it may have psychological impact because it is socially disabling, which presents a therapeutic challenge. Depigmented skin in piebaldism generally is considered unresponsive to medical or light therapy. Of note, the diagnosis of piebaldism should alert the clinician to the possibility of Waardenburg syndrome as determined by the results of ocular and auditory examinations. Sunscreens are recommended to avoid sunburns and to reduce the carcinogenic potential. To camouflage the exposed areas, makeup or temporary pigmenting agents such as the tanning product dihydroxyacetone may be used.19 The lesions of piebaldism do not respond to the topical agents used to treat vitiligo. Different surgical techniques have been tried, with variable success, including thin split-thickness grafts, minigrafting, transplant of autologous cultured melanocytes, and a combination of dermabrasion and grafting of the pigmented skin into the depigmented areas.20,21 Guerra et al22 reported achromic epidermis removed with the erbium:YAG laser and autologous cultured epidermal grafts were applied to the recipient bed in 6 patients. Autologous cultured epidermis, bearing a controlled number of melanocytes, induced repigmentation of all piebald lesions. The mean percentage repigmentation was 95.45%.22