Piebaldism

2000-06-01   Lidia Larizza , Alessandro Beghini 

Medical Genetics, San Paolo School of Medicine, University of Milan Via A. di Rudini, 8, 20142 Milano, Italy

Identity

Name

Piebaldism

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

Omim

172800

Mesh

D016116

Orphanet

2884 Piebaldism

Umls

C0080024

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 condition

    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

    Description

    21 exons

    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.

    • Note

    is also deleted in patients with interstitial cytogenetic deletions (contiguous gene syndrome)

    Alias

    SCF\/MGF

    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

    Pubmed IDLast YearTitleAuthors