Piebaldism 

Updated: Apr 06, 2021
Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD 

Overview

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 mark—a 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, 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 proto-oncogene.[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]  Another novel mutation in KIT was described in two Japanese individuals.[5]

Piebaldism is one of the cutaneous signs of Waardenburg syndrome, along with heterochromia of the irides, lateral displacement of inner canthi, and deafness.[6, 7]

Pathophysiology

Piebaldism is an autosomal dominant genetic disorder of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.[8] 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.[9] Several pathologic mutations of the KIT gene now have been identified in different patients with piebaldism.[10] 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 and others of the tyrosine kinase domain affect the intracellular tyrosine kinase domain and may imply a severe phenotype.[11] 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.[7] A novel mutation of the KIT gene was described in a Chinese family with piebaldism.[12] In 2017, a novel missense mutation in TK1 region of KIT was described in a Chinese family with severe piebaldism.[13]

Manipulation of the mouse genome may be an important approach for studying gene function and establishing human disease models.[14] Mouse mutants generated and screened for dominant mutations yielded several mice with fur color abnormalities. One causes a phenotype similar to dominant-white 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.[15] Variability in the microphthalmia-associated transcription factor gene explained the differences between spotted and nonspotted phenotypes, although other genetic factors were also important.

A splicing mutation, producing the deletion of exon 17 of KIT, and co-segregated it with 2 phenotypes of the severe form of piebaldism and auburn hair color was documented in a Chinese Han family.[16]

Etiology

Piebaldism is a rare autosomal dominant genetic disorder Basically, it is a complex interconnecting regulatory network of mutated genes and synergistic interactions.[8, 17]

Prognosis

Piebaldism is a benign disorder. However, patients are at risk for actinic complications related to absence of cutaneous melanocytes. Although spontaneous repigmentation in an infant with piebaldism has been described, it is most unusual.[18]

Patient Education

Educate patients about the genetic transmission of the disorder.

Educate patients about use of sunscreens, sunprotective measures (eg, wide-brimmed hat, long-sleeved shirts, long pants), sun avoidance during peak hours of ultraviolet exposure during the day, and self-examinations because recurrent sun damage may result in an increased risk of cutaneous malignancy.

Patients who are self-conscious about the appearance of their skin may benefit from use of a camouflage cover-up, such as Dermablend or other similar camouflage measures.

 

Presentation

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.[19]

Physical Examination

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.[20] 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.

Congenital leukoderma suggests the need for evaluation of ocular, auditory, and/or neurologic abnormalities.[21]

 

DDx

Diagnostic Considerations

Also consider the following:

  • Chemical leukoderma
  • Preus syndrome
  • Tuberous sclerosis [22]
  • Vitiligo (distinguished by the presence of lesions from birth, hyperpigmented macules of depigmented and normal skin, and static course)
  • Yaws (frambesia tropica)
  • Ziprkowski-Margolis syndrome

A screening program to detect Waardenburg syndrome among 1763 deaf individuals throughout Colombia identified 95 affected individuals belonging to 95 families, giving a frequency of 5.38% of Waardenburg syndrome among the institutionalized deaf population.[23] Overall, among the 95 propositi, the most frequent features were broad nasal root (58.9%), a first-degree relative affected (37.9%), heterochromia irides (36.8%), skin hypopigmentation (31.6%), white forelock (28%), intense blue iris (27.4%), synophrys (12.6%), premature graying (10.5%), ptosis of the eyelids (9.5%), and hypoplasia alae nasi (1.1%). Poliosis itself may be the first sign of Waardenburg syndrome.[21, 24]

Piebaldism may rarely be seen together with neurofibromatosis type 1 (NF1).[25] Café-au-lait macules (CALMs) may be seen in piebaldism. A few patients have been classified as having both piebaldism and NF1 based on the presence of multiple CALMs and intertriginous freckling, which may not be an accurate conclusion.[26] In a large family with piebaldism, 2 members meet diagnostic criteria for NF1 based on the presence of more than 5 CALMs and intertriginous freckling, but comprehensive NF1 and SPRED1 testing found no mutations, suggesting that piebaldism may occasionally include CALMs and intertriginous freckling, creating diagnostic confusion, especially in the absence of a family history of piebaldism.[27]

Poliosis may also be seen in individuals with tuberous sclerosis and been described in a variety of other settings, including as the first sign of melanoma, and, rarely, with medications such as topical prostaglandin analogs and topical chloramphenicol.[28]

The co-occurrence of piebaldism and neurofibromatosis type 1 has been described in a few patients, but this is most likely coincidental.[29]

Differential Diagnoses

 

Workup

Approach Considerations

Targeted next-generation sequencing can be effectively used for molecular diagnosis.[30]

Regarding histology findings, poliosis has either decreased or absent melanin and/or melanocytes in the hair bulbs of the affected hair follicles, which can be confirmed using special stains for melanin or melanocytes.[28] The epidermal melanocytes are usually unaffected unless there is also vitiligo.

 

Treatment

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.[31] 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.[32]  Another option is autologous cell suspension transplantation using a cell extraction device.[33]

Surgical Care

Surgical approaches may be considered for patients with stable vitiligo.[34, 35] 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. Autologous noncultured cell suspension transplantation can be used with superficial full-surface ablation to a depth of 144 μm recommended as an effective recipient site preparation prior to cell suspension transplantation.[36]  Donor-to-recipient ratios need to be considered in surgical treatment of piebaldism.[37]