Piebaldism

Background

This is an autosomal dominant disorder of melanocyte development characterized by white skin (leukoderma) and white hair (poliosis). In general, piebaldism is distinguished from vitiligo by the following:

Presence of lesions from birth
Hyperpigmented macules of depigmented and normal skin
Static course

OUTLINE

Disease Associations

Pathogenesis

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DISEASE ASSOCIATIONS CHARACTERIZATION

CONGENITAL DYSERYTHROPOIETIC ANEMIA

Piebaldism associated with congenital dyserythropoietic anemia type II (HEMPAS).

Koklu S, Ertugrul D, Onat AM, Karakus S, Haznedaroglu IC, Buyukasik Y, Sayinalp N, Ozcebe O, Dundar SV.

Department of Hematology, Hacettepe University Medical School, Ankara, Turkey.
Am J Hematol 2002 Mar;69(3):210-3 Abstract quote
Congenital dyserythropoietic anemias (CDAs) are a group of relatively rare inherited anemias. They are characterized by ineffective erythropoiesis and classified as three major groups and a number of variants. CDA type II, also known as hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS), is the most frequent one. A number of associations with CDA II have been reported, although each described only one or a few patients.

Here we presented a piebald woman with vaginal atresia who was tested for anemia and diagnosed as CDA type II. Piebaldism and anemia association were previously described in the mouse. Our case was the first that shows the features of both piebaldism and CDA in the same patient.

This association may suggest a stem cell defect to cause both hematopoietic and cutaneous manifestations.

GROVER'S DISEASE

Grover disease (transient acantholytic dermatosis) and piebaldism.

Kiwan RA, Mutasim DF.

Department of Dermatology, University of Cincinnati College of Medicine, Ohio 45267-0592, USA.

Cutis 2002 Jun;69(6):451-3 Abstract quote
A 35-year-old white man with lifelong stable white lesions on the anterior trunk and extremities presented with a pruritic papular eruption limited to the white patches. Results of a histologic examination led to a diagnosis of Grover disease (transient acantholytic dermatosis).

To our knowledge, this article is the first to report an association between Grover disease and piebaldism or other depigmented disorders. We review the literature and speculate on the association between these conditions.

PATHOGENESIS CHARACTERIZATION

Mutations in the KIT gene
KIT gene encodes the cell surface receptor tyrosine kinase for an embryonic growth factor called �mast cell growth factor,� �stem cell growth factor,� �kit ligand,� or �steel factor.�

KIT receptor is a type III receptor, with an extracellular domain of 5 immunoglobulin repeats, a transmembrane domain, and an intracellular tyrosine kinase domain

Binding of the kit ligand to the extracellular domain causes dimerization of the KIT receptor polypeptide, which activates the intracellular tyrosine kinase

This activation phosphorylates tyrosine residues on both KIT itself and other more distal proteins of the KIT-mediated pathway of signal transduction, leading to cell proliferation

Experimentally induced reduction of KIT function results in inhibition of melanocyte proliferation in vitro and migration of melanoblasts into the dermis during development requires KIT function

Insufficient KIT-mediated signal transduction likely results in inadequate proliferation of melanoblasts before migration during embryogenesis

The localized absence of pigmentation of the hair and skin in patients with piebaldism has been explained by the abnormal migration of melanocytes into affected areas and is confirmed by the absence of KIT protein at sites of involvement

A novel KIT mutation results in piebaldism with progressive depigmentation
J Am Acad Dermatol 2001;44:288-92

Autosomal dominant

Novel Val620Ala (1859T>C) mutation in the KIT gene, which was not detected in family members without progressive piebaldism or in 52 normal control individuals

This KIT mutation affects the intracellular tyrosine kinase domain and thus predicts a severe phenotype

Although other KIT mutations in the vicinity of codon 620 lead to the standard phenotype of static piebaldism, the Val620Ala mutation is novel and may result in a previously undescribed phenotype with melanocyte instability, leading to progressive loss of pigmentation as well as the progressive appearance of the hyperpigmented macules

Human piebaldism: six novel mutations of the proto-oncogene KIT.

Syrris P, Heathcote K, Carrozzo R, Devriendt K, Elcioglu N, Garrett C, McEntagart M, Carter ND.

Medical Genetics Unit, St George's Hospital Medical School, London, United Kingdom.
Hum Mutat 2002 Sep;20(3):234 Abstract quote
Human piebaldism is a rare autosomal dominant disorder that comprises congenital patchy depigmentation of the scalp, forehead, trunk and limbs. It is caused by mutations in the cell-surface receptor tyrosine kinase gene (KIT, also c-kit).

We screened three families and three isolated cases of piebaldism from different countries for mutations in the KIT gene using automated sequencing methods. We report six novel KIT point mutations: three missense (C788R, W835R, P869S) at highly conserved amino acid sites; one nonsense (Q347X) that results in termination of translation of the KIT gene in exon 6; and two splice site nucleotide substitutions (IVS13+2T>G, IVS17-1G>A) that are predicted to impair normal splicing.

These mutations were not detected in over 100 normal individuals and are likely to be the cause of piebaldism in our subjects.

Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.

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Last Updated 5/25/2003

Disease Associations
Pathogenesis
Commonly Used Terms
Internet Links

DISEASE ASSOCIATIONS	CHARACTERIZATION
CONGENITAL DYSERYTHROPOIETIC ANEMIA
Piebaldism associated with congenital dyserythropoietic anemia type II (HEMPAS). Koklu S, Ertugrul D, Onat AM, Karakus S, Haznedaroglu IC, Buyukasik Y, Sayinalp N, Ozcebe O, Dundar SV. Department of Hematology, Hacettepe University Medical School, Ankara, Turkey.	Am J Hematol 2002 Mar;69(3):210-3 Abstract quote Congenital dyserythropoietic anemias (CDAs) are a group of relatively rare inherited anemias. They are characterized by ineffective erythropoiesis and classified as three major groups and a number of variants. CDA type II, also known as hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS), is the most frequent one. A number of associations with CDA II have been reported, although each described only one or a few patients. Here we presented a piebald woman with vaginal atresia who was tested for anemia and diagnosed as CDA type II. Piebaldism and anemia association were previously described in the mouse. Our case was the first that shows the features of both piebaldism and CDA in the same patient. This association may suggest a stem cell defect to cause both hematopoietic and cutaneous manifestations.
GROVER'S DISEASE
Grover disease (transient acantholytic dermatosis) and piebaldism. Kiwan RA, Mutasim DF. Department of Dermatology, University of Cincinnati College of Medicine, Ohio 45267-0592, USA.	Cutis 2002 Jun;69(6):451-3 Abstract quote A 35-year-old white man with lifelong stable white lesions on the anterior trunk and extremities presented with a pruritic papular eruption limited to the white patches. Results of a histologic examination led to a diagnosis of Grover disease (transient acantholytic dermatosis). To our knowledge, this article is the first to report an association between Grover disease and piebaldism or other depigmented disorders. We review the literature and speculate on the association between these conditions.

PATHOGENESIS	CHARACTERIZATION
Mutations in the KIT gene	KIT gene encodes the cell surface receptor tyrosine kinase for an embryonic growth factor called �mast cell growth factor,� �stem cell growth factor,� �kit ligand,� or �steel factor.� KIT receptor is a type III receptor, with an extracellular domain of 5 immunoglobulin repeats, a transmembrane domain, and an intracellular tyrosine kinase domain Binding of the kit ligand to the extracellular domain causes dimerization of the KIT receptor polypeptide, which activates the intracellular tyrosine kinase This activation phosphorylates tyrosine residues on both KIT itself and other more distal proteins of the KIT-mediated pathway of signal transduction, leading to cell proliferation Experimentally induced reduction of KIT function results in inhibition of melanocyte proliferation in vitro and migration of melanoblasts into the dermis during development requires KIT function Insufficient KIT-mediated signal transduction likely results in inadequate proliferation of melanoblasts before migration during embryogenesis The localized absence of pigmentation of the hair and skin in patients with piebaldism has been explained by the abnormal migration of melanocytes into affected areas and is confirmed by the absence of KIT protein at sites of involvement
A novel KIT mutation results in piebaldism with progressive depigmentation	J Am Acad Dermatol 2001;44:288-92 Autosomal dominant Novel Val620Ala (1859T>C) mutation in the KIT gene, which was not detected in family members without progressive piebaldism or in 52 normal control individuals This KIT mutation affects the intracellular tyrosine kinase domain and thus predicts a severe phenotype Although other KIT mutations in the vicinity of codon 620 lead to the standard phenotype of static piebaldism, the Val620Ala mutation is novel and may result in a previously undescribed phenotype with melanocyte instability, leading to progressive loss of pigmentation as well as the progressive appearance of the hyperpigmented macules
Human piebaldism: six novel mutations of the proto-oncogene KIT. Syrris P, Heathcote K, Carrozzo R, Devriendt K, Elcioglu N, Garrett C, McEntagart M, Carter ND. Medical Genetics Unit, St George's Hospital Medical School, London, United Kingdom.	Hum Mutat 2002 Sep;20(3):234 Abstract quote Human piebaldism is a rare autosomal dominant disorder that comprises congenital patchy depigmentation of the scalp, forehead, trunk and limbs. It is caused by mutations in the cell-surface receptor tyrosine kinase gene (KIT, also c-kit). We screened three families and three isolated cases of piebaldism from different countries for mutations in the KIT gene using automated sequencing methods. We report six novel KIT point mutations: three missense (C788R, W835R, P869S) at highly conserved amino acid sites; one nonsense (Q347X) that results in termination of translation of the KIT gene in exon 6; and two splice site nucleotide substitutions (IVS13+2T>G, IVS17-1G>A) that are predicted to impair normal splicing. These mutations were not detected in over 100 normal individuals and are likely to be the cause of piebaldism in our subjects.