Piebaldism

7/16/2019 Piebaldism

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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 hai

has been observed throughout history, with the first description

dating to early Egyptian, Greek, and Roman writings. Generationafter generation demonstrated a distinctive predictable familia

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, a white forelock

that his father and grandfather also shared.

The word piebald itself has been attributed to a combination o

the "pie" in the magpie (a bird of black and white plumage) and

the "bald" of the bald eagle (the United States' national birdwhich 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 poin



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, wherea

mild piebaldism appears related to mutations occurring in the

amino terminal extracellular ligand-binding domain with resultan

haplo insufficiency.

Most piebald patients have the above-described mutation of the

KIT gene encoding a tyrosine kinase receptor involved in pigmen

cell development.[3]

The white hair and patches of such patient

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 Val620Alamutation in their KIT gene and showed progressive

depigmentation. These findings are consistent with the

hypothesis that progressive piebaldism might result from digeni

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, latera

displacement of inner canthi, and deafness.[5]



Pathophysiology

Piebaldism is an autosomal dominant genetic disorder o

pigmentation characterized by congenital patches of white skin

and hair that lack melanocytes. Piebaldism results frommutations of the KIT proto-oncogene, which encodes the ce

surface receptor transmembrane tyrosine kinase for an

embryonic growth factor, steel factor.[6]

Several pathologi

mutations of the KIT gene now have been identified in differen

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 serie

of piebald phenotypes. KIT mutations in the vicinity of codon 620

lead to the usual phenotype of static piebaldism. Mutations o

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 atypica

clinical features or family histories, and 4 patients with othe

disorders that involve white spotting), novel pathologi

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. Patient

without apparent KIT mutations had no apparent abnormalitie



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 networ

of interacting genes regulates embryonic melanocyte

development.

Piebaldism almost always has a static course. Genetic analysis o

a mother and daughter with progressive piebaldism revealed a

novel Val620Ala (1859T>C) mutation in the KIT gene. This KI

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 o

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 intracellula

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 importan

approach for studying gene function and establishing human

disease models.[8]

Mouse mutants generated and screened fo

dominant mutations yielded several mice with fur colo

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.[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

http://emedicine.medscape.com/article/1050580-overview





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, eithe

continuously or discontinuously with the forelock.

White spots may be observed on the face, trunk, and extremitie

and tend to be symmetrical in distribution and irregular in shapeThey represent a focal lack of melanocytes. This depigmented

skin may show a narrow border of hyperpigmentation or island o

pigmentation and has white hair that is otherwise norma

emanating from it.

White patches of hair may be located other than frontally insome 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 withultraviolet A (10 J/cm

2) 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 minigraftin

may be a good option for selected patients. Autologou

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

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Piebaldism

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