Background
The following congenital hypopigmentary diseases result from a failure of pigment cells (melanocytes) in the skin, eyes, and/or ears to become completely or partially established in their target sites during embryogenesis:
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Waardenburg syndrome (types I, II, and III)
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Pfeiffer syndrome
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Jackson-Weiss syndrome
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Waardenburg syndrome type IV (Hirschsprung syndrome)
Patients with these congenital patterned leukodermas may also present with extrapigmentary findings consisting of megacolon and musculoskeletal defects of the face and upper trunk.
Pathophysiology
The unifying abnormality of these congenital patterned leukodermas is a complete or partial absence of melanocytes in the skin and hair. Mutations in genes that regulate the multistep process of commitment of neural crest cells to a differentiated cell type (primarily the melanocyte) are the basis for these diseases. These mutations result in a failure of melanocytes to reach their normal destinations in developing skin, hair, eyes, and ears during embryogenesis. [1, 2, 3, 4, 5, 6, 7]
Etiology
The causes of these congenital patterned leukodermas are mutations in specific genes. [5, 8]
Type I and type III Waardenburg syndromes result from mutations in the PAX3 gene, [9] which maps to band 2q35-q37.3. The syndrome is inherited as an autosomal dominant trait. The PAX3 gene encodes a transcription factor with a paired box domain, an octapeptide domain, and a homeobox domain essential for survival of melanocytes during development. The genes up-regulated by this transcription factor have not been identified; however, the PAX3 gene product can bind to the promoter of the MITF gene. [6, 10, 11, 12, 13]
Type II Waardenburg syndrome results from mutations in the microphthalmia transcription factor (MITF) gene, [14] which maps to band 3p12. The syndrome is inherited as an autosomal dominant trait. The MITF gene encodes a transcription factor containing a basic-helix-loop-helix-leucine zipper. The genes up-regulated by this transcription factor during embryogenesis have not been identified. [15]
Type IV Waardenburg syndrome (Hirschsprung syndrome) results from mutations in either (1) the SOX10 gene, which maps to band 22q13, or (2) the EDN3 gene, which maps to band 20q13.2-q13.3. The SOX10 gene encodes a member of the high-mobility group-domain Sox family of transcription factors that regulate neural crest development. The genes up-regulated by this transcription factor during embryogenesis have not been identified; however, the SOX10 gene product can bind to the promoter of the MITF gene. The EDN3 gene encodes a ligand called endothelin-3 for the endothelin-B receptor. [10, 11, 16, 17]
Apert, Pfeiffer, Jackson-Weiss, and Crouzon syndromes result from mutations in the fibroblast growth factor receptor-2 (FGFR2) gene, which maps to band 10q25-q26. These syndromes are inherited as autosomal dominant traits. The FGFR2 gene encodes a tyrosine kinase receptor with 3 immunoglobulin domains, a signal sequence, an acidic region in the extracellular ligand binding site, and 2 tyrosine kinase domains localized intracellularly. Some patients with Pfeiffer syndrome have demonstrated mutations in the fibroblast growth factor receptor-1 (FGFR1) gene, which maps to band 8p11.2-12. [18, 19]
Hirschsprung syndrome type 2 results from mutations in the endothelin-B receptor (EDNRB) gene, which maps to band 13q22. This syndrome is inherited as an autosomal recessive trait. The EDNRB gene encodes a G protein–coupled plasma membrane receptor with 7 transmembrane domains and 2 autophosphorylation sites.
Piebaldism results from mutations in the c-KIT gene, which maps to band 4q12. This syndrome is inherited as an autosomal dominant trait. The KIT gene encodes a plasma membrane receptor with a ligand-binding domain containing 5 immunoglobulinlike regions and 2 tyrosine kinase domains in the cytoplasm. Specific mutations of c-KIT correlate with the severity (ie, extent) of the cutaneous hypopigmentation. [10, 20, 21, 22] According to Yang et al, deletion of the SNAI2 gene causes human piebaldism. [7]
Epidemiology
Frequency
The approximate prevalences of the listed congenital patterned leukodermas are as follows:
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Waardenburg syndrome (types I, II, and III) - 1 case per 15,000 population
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Apert syndrome - 1 case per 65,000 population
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Pfeiffer syndrome - Unknown (rare)
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Jackson-Weiss syndrome - Unknown (rare)
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Crouzon syndrome - 1 case per 25,000 population
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Waardenburg syndrome type IV (Hirschsprung syndrome) - 1 case per 5000 population
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Piebaldism – Unknown (rare)
Race
All races appear to be equally affected by the associated mutations in congenital patterned leukodermas.
Sex
The prevalence of these congenital patterned leukodermas is equal for males and females.
Age
All of these congenital patterned leukodermas are present at birth.
Prognosis
In the congenital patterned leukodermas, an absence of protective pigment in the skin results in increased sensitivity to solar irradiation. Affected individuals may be at increased risk of developing skin cancers. Sensorineural deafness can be extensive in patients with Waardenburg syndromes and Hirschsprung syndrome but is usually minimal or absent in those with Apert, Pfeiffer, Jackson-Weiss, or Crouzon syndromes. Persons with piebaldism only rarely have sensorineural deafness. Visual acuity does not appear to be impaired in any of the syndromes.
