Piebaldism

2000-06-01   Lidia Larizza  , Alessandro Beghini, PhD 

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.

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    75299641995Novel mutations and deletions of the KIT (steel factor receptor) gene in human piebaldism.Ezoe K et al
    88759531996Mutations in the ligand-binding domain of the kit receptor: an uncommon site in human piebaldism.Fleischman RA et al
    86804091995A 12-bp deletion (7818del12) in the c-kit protooncogene in a large Italian kindred with piebaldism.Riva P et al
    94508661998Piebaldism with deafness: molecular evidence for an expanded syndrome.Spritz RA et al

    Citation

    Lidia Larizza ; Alessandro Beghini, PhD

    Piebaldism

    Atlas Genet Cytogenet Oncol Haematol. 2000-06-01

    Online version: http://atlasgeneticsoncology.org/cancer-prone-disease/10030/piebaldism

    Historical Card

    1998-09-01 Piebaldism by  Lidia Larizza,Alessandro Beghini 

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