Piebaldism

Identity

Atlas_Id	10030
Genes implicated in	KIT  KITLG  SNAI2
Note	defect in melanocyte development; one of the first genetic disorders for which a pedigree was presented in 1786
Inheritance	autosomal dominant; frequency is about 2.5/105 newborns

Clinics

Phenotype and clinics	congenital patches of white skin and white hair, principally located on the scalp, forehead, chest and abdomen and on the limbs; several patients report lifelong severe constipation; a hierarchical correlation has been elaborated between severe or mild phenotypic traits and the associated KIT mutations; in a few patients with interstitial deletions mental retardation and congenital anomalies have been also described etiology : defective melanoblasts proliferation, survival and migration from the neural crest during development and defective migration of enteric-plexus ganglion cells from the neural crest to the gut pathology : white spotting in human piebaldism results from the absence of melanocytes from the nonpigmented patches of skin and from hairbulbs in the white patches of hair; occasionally, individuals lack ganglion cells of the intestinal enteric neural plexus, which like melanoblasts, are derived from the neural crest
Neoplastic risk	an increased risk of epithelioma has been reported
Prognosis	in contrast to vitiligo, piebaldism is both congenital and non-progressive

Cytogenetics

Inborn conditions

a few patients with interstitial deletions of chromosome 4q12-q21.1 have been identified; they are charaterized by multiple congenital anomalies, short stature and mental retardation.

Genes involved and Proteins

Gene Name	KIT
Location	in 4q12

DNA/RNA
Description	21 exons

Protein
Description	transmembrane SCF/MGF receptor with tyrosine kinase activity; binding of ligand (SCF) induces receptor dimerization, autophosphorylation and signal transduction via molecules containing SH2- domains

Mutations
Note	see diagram: Loss-of-function mutations
Germinal	loss of function mutations resulting in haploinsufficiency of the receptor; different kinds of point mutations have been identified (diagram): missense substitutions (Glu583Lys; Phe584Leu; Ala621Thr; His650Pro; Gly664Arg; Gly791Arg; Arg796Gly; Val812Gly; Glu861Ala) and small deletions (641del2; 892 del12) in the intracellular tyrosine kinase domain; correlate with severe piebald phenotypes, because of dominant-negative inhibition of the KIT receptor via formation of impaired receptor heterodimers between a normal and a mutant KIT monomer, and a 75% decrease of KIT- dependent signal transduction. proximal frameshifts (84del1; 249del4); Trp557Term; and missense mutations (Cys136Arg; Ala178Thr; Met318Gly) associated with a mild piebald phenotype, the result of pure haploinsufficiency due to a 50% decrease of KIT-dependent signal transduction distal frameshifts: 630insA; and splice junction mutations (IVS1+4G-A; IVS12+1G- A), located near the intracellular TK domain associated with variable phenotypes, as the truncated polypeptides via incorporation into nonfunctional receptor heterodimers would decrease KIT-dependent signal transduction by 50-75%, depending on their stability complete deletions of the entire KIT gene ("null" mutations) result in a mild- intermediate phenotype.

Gene Name	PDGFRA
Location	4q12
Note	is also deleted in patients with interstitial cytogenetic deletions (contiguous gene syndrome)

Gene Name	KITLG
Alias	SCF/MGF
Location	12q22
Note	no alteration of this gene has been so far identified in typical patients; at difference with the mouse system, where "steel" mice bearing SCF mutations show the "white spotting" phenotype likewise W mice bearing kit mutations; however, as mutations of KIT could not be detected in a consistent fraction of these patients, involvement of SCF is still an open question.

Bibliography

Novel mutations and deletions of the KIT (steel factor receptor) gene in human piebaldism.

Ezoe K, Holmes SA, Ho L, Bennett CP, Bolognia JL, Brueton L, Burn J, Falabella R, Gatto EM, Ishii N

American journal of human genetics. 1995 ; 56 (1) : 58-66.

PMID 7529964

Mutations in the ligand-binding domain of the kit receptor: an uncommon site in human piebaldism.

Fleischman RA, Gallardo T, Mi X

The Journal of investigative dermatology. 1996 ; 107 (5) : 703-706.

PMID 8875953

A 12-bp deletion (7818del12) in the c-kit protooncogene in a large Italian kindred with piebaldism.

Riva P, Milani N, Gandolfi P, Larizza L

Human mutation. 1995 ; 6 (4) : 343-345.

PMID 8680409

Piebaldism with deafness: molecular evidence for an expanded syndrome.

Spritz RA, Beighton P

American journal of medical genetics. 1998 ; 75 (1) : 101-103.

PMID 9450866

Citation

This paper should be referenced as such :

Larizza, L ; Beghini, A

Piebaldism

Atlas Genet Cytogenet Oncol Haematol. 2000;4(3):157-158.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/piebaldID10030.html

History of this paper:

Larizza, L ; Beghini, A. Piebaldism. Atlas Genet Cytogenet Oncol Haematol. 1999;3(1):44-45.

http://documents.irevues.inist.fr/bitstream/handle/2042/37494/09-1998-piebaldID10030.pdf

External links

OMIM	172800
Orphanet	Piebaldism
MeSH	D016116
MedGen	D016116
UMLS	C0080024
ICD-10	E70.3
HGMD	120117

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

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indexed on : Fri Jun 30 11:24:33 CEST 2017

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