Piebaldism

Background Piebaldism is a rare autosomal dominant disorder of melanocyte development characterized by a congenital white forelock and multiple symmetrical hypopigmented or depigmented macules. This striking phenotype of depigmented patches of skin and hair has been observed throughout history, with the first descriptions dating to early Egyptian, Greek, and Roman writings. Generation after generation demonstrated a distinctive predictable familial marka white forelock. Families have sometimes been known for this mark of distinction, carrying such surnames as Whitlock, Horlick, and Blaylock. Note the image below. Distinguished physician with mark of distinction, a white forelock that his father and grandfather also shared. The word piebald itself has been attributed to a combination of the "pie" in the magpie (a bird of black and white plumage) and the "bald" of the bald eagle (the United States' national bird, which has a white feathered head). Piebaldism is due to an absence of melanocytes in affected skin and hair follicles as a result of mutations of the KIT protooncogene.[1] As of a 2001 review by Richards et al, 14 point

mutations, 9 deletions, 2 nucleotide splice mutations, and 3 insertions of the KIT gene were believed to be mutations causing piebaldism.[2] The severity of phenotypic expression in piebaldism correlates with the site of the mutation within the KIT gene. The most severe mutations seem to be dominant negative missense mutations of the intracellular tyrosine kinase domain, whereas mild piebaldism appears related to mutations occurring in the amino terminal extracellular ligand-binding domain with resultant haplo insufficiency. Most piebald patients have the above-described mutation of the KIT gene encoding a tyrosine kinase receptor involved in pigment cell development.[3] The white hair and patches of such patients are completely formed at birth and do not usually expand thereafter. However, 2 novel cases of piebaldism were described in which both mother and daughter had a novel Val620Ala mutation in their KIT gene and showed progressive depigmentation. These findings are consistent with the hypothesis that progressive piebaldism might result from digenic inheritance of the KIT (V620A) mutation that causes piebaldism and a second, unknown locus that causes progressive depigmentation.[4] Piebaldism is one of the cutaneous signs of Waardenburg syndrome, along with heterochromia of the irides, lateral displacement of inner canthi, and deafness.[5]

Pathophysiology Piebaldism is an autosomal dominant genetic disorder of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. Piebaldism results from mutations of the KIT proto-oncogene, which encodes the cell surface receptor transmembrane tyrosine kinase for an embryonic growth factor, steel factor.[6] Several pathologic mutations of the KIT gene now have been identified in different patients with piebaldism.[7] Correlation of these mutations with the associated piebald phenotypes has led to the recognition of a hierarchy of 3 classes of mutations that result in a graded series of piebald phenotypes. KIT mutations in the vicinity of codon 620 lead to the usual phenotype of static piebaldism. Mutations of the KIT proto-oncogene produce variations in phenotype in relation to the site of the KIT gene mutation. In an analysis of 26 unrelated patients with piebaldismlike hypopigmentation (ie, 17 typical patients, 5 patients with atypical clinical features or family histories, and 4 patients with other disorders that involve white spotting), novel pathologic mutations or deletions of the KIT gene were observed in 10 (59%) of the typical patients and in 2 (40%) of the atypical patients. Overall, pathologic KIT gene mutations were identified in 21 (75%) of 28 unrelated patients with typical piebaldism. Patients without apparent KIT mutations had no apparent abnormalities

of the gene encoding steel factor itself; however, genetic linkage analyses in 2 of these families implied linkage of the piebald phenotype to KIT. Thus, most patients with typical piebaldism seem to have abnormalities of the KIT gene. A complex network of interacting genes regulates embryonic melanocyte development. Piebaldism almost always has a static course. Genetic analysis of a mother and daughter with progressive piebaldism revealed a novel Val620Ala (1859T>C) mutation in the KIT gene. This KIT mutation affects the intracellular tyrosine kinase domain and implies a severe phenotype. This is a newly described phenotype with melanocyte instability leading to advancing loss of pigmentation and the progressive appearance of the hyperpigmented macules. A South African girl of Xhosa ancestry with severe piebaldism and profound congenital sensorineural deafness had a novel missense substitution at a highly conserved residue in the intracellular kinase domain of the KIT proto-oncogene, R796G. Although auditory anomalies in mice with dominant white spotting due to KIT mutations may occur, deafness is not typical in human piebaldism. Thus, sensorineural deafness extends considerably the phenotypic range of piebaldism due to KIT gene mutation in humans and strengthens the clinical similarity between piebaldism and the various forms of Waardenburg syndrome.

Manipulation of the mouse genome may be an important approach for studying gene function and establishing human disease models.[8] Mouse mutants generated and screened for dominant mutations yielded several mice with fur color abnormalities. One causes a phenotype similar to dominantwhite spotting (W) allele mutants. This strain may serve as a new disease model of human piebaldism. Genetic factors determining piebaldism in Italian Holstein and Italian Simmental cattle breeds were studied.[9] Variability in the microphthalmia-associated transcription factor gene explained the differences between spotted and nonspotted phenotypes, although other genetic factors were also important. Epidemiology Mortality/Morbidity Piebaldism is a benign disorder.

History Graft versus host disease may arise solely within an area affected by piebaldism; therefore, piebaldism-affected skin may be immunologically different from normal skin.[10] Physical

The white forelock is evident in 80-90% of those affected. Both hair and skin in the central frontal scalp are permanently white from birth or when hair color first becomes apparent. Regression of the white forelock has been described.[11] The forelock and white skin may have a triangular shape. The eyebrow and eyelash hair may also be affected, either continuously or discontinuously with the forelock. White spots may be observed on the face, trunk, and extremities and tend to be symmetrical in distribution and irregular in shape. They represent a focal lack of melanocytes. This depigmented skin may show a narrow border of hyperpigmentation or island of pigmentation and has white hair that is otherwise normal emanating from it. White patches of hair may be located other than frontally in some patients. The only pigmentation change of skin or hair may be a white forelock in some patients. Causes Piebaldism is a rare autosomal dominant genetic disorder. Differential Diagnoses

Addison Disease Albinism

Alezzandrini Syndrome Leprosy Skin Lightening and Depigmenting Agents Systemic Sclerosis Tinea Versicolor Vitiligo Vogt-Koyanagi-Harada Syndrome Waardenburg Syndrome Yaws Medical Care Depigmented skin in piebaldism is generally considered unresponsive to medical or light treatment. In 12 adults, dermabrasion and thin split-skin grafts were applied initially, with residual leukodermic patches subsequently treated using a minigrafting method.[17] Additional irradiation with ultraviolet A (10 J/cm2) was provided. This new combined approach led to 95-100% repigmentation of the leukoderma. An almost perfect color match with the surrounding nonlesional skin was noted in all cases; therefore, dermabrasion and split-skin grafting followed by minigrafting may be a good option for selected patients. Autologous punch grafting for repigmentation in piebaldism may be considered in selected individuals.[18] Surgical Care

Surgical approaches may be considered for patients with stable vitiligo.[19, 20] Surgical transplant may use noncultured cellular grafting, which can repigment vitiligo 5-10 times the size of the donor skin and can be completed on the same day in an outpatient setting. Proceed to Follow-up