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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
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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]
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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
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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.
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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
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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
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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
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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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