Piebaldism E70.35

Congenital, autosomal-dominantly inherited, circumscribed white spotting of the skin, caused by (mostly) complete absence of melanocytes in lesional skin. Mutations in the KIT (see kit below) and SLUG (SNAI2 - Snail homologue 2 transcription factor) genes have been detected (Saleem MD et al. 2019).

The "classical" Piebaldism is a pure skin anomaly.

Poliosis as a congenital or acquired, heart-shaped white discoloration of the hair (white curl of hair in the forehead area) can occur as a partial symptom of various other syndromes (see below).

Prevalence: 3-5/100,000 inhabitants/year.

Incidence < 1: 20,000 people (Agarwal S et al. 2012).

M:w=1:1; there are no ethnic predilections.

Piebaldism is caused by mutations that affect the development and migration of melanoblasts from the neural crest to the skin. In humans, piebaldism is caused by heterozygous loss-of-function mutations of the KIT gene, which was mapped on chromosome 4q12. To date, 90 different mutations are known. The KIT receptor consists of an extracellular domain with 5 immunoglobulin repeats, a transmembrane domain and an intracellular tyrosine kinase domain. The mutations of cKIT identified in piebaldimsus patients range from gross deletions to missense defects and are all inherited in an autosomal dominant manner.

There is a correlation between the genotype and the resulting clinical phenotype, depending on the position of the mutation within the KIT gene.

• Mutations (of any type) located in or near the transmembrane region are associated with a moderately severe phenotype.
• Frameshift mutations in the amino-terminal extracellular ligand binding domain lead to a milder form of the disease.
• Point mutations in the intracellular tyrosine kinase domain are associated with the most severe phenotype.

SCF and SNAI2 mutations have also been identified in human piebaldism. In particular, piebaldism has been associated with inactivating mutations or deletions in the SANAI2 (SLUG) gene on chromosome 8q11. These mutations lead to reduced receptor tyrosine kinase signaling, impaired melanoblast development and a decrease in melanogenesis. Heterozygous deletions in the SNAI2 coding region have been found in people with piebaldism who lack c-KIT mutations. An SNAI2 (SLUG) mutation has also been identified in Waardenburg syndrome type 2, and one mechanism thought to be responsible for these effects involves the binding of MITF to the SLUG promoter.

Some patients have been reported to have sporadic non-familial piebaldism, associated with dysmorphic features and usually mental retardation, due to chromosomal deletions and other rearrangements affecting the KIT gene.

Many patients with atypical manifestations of piebaldism have no detectable defects of KIT or SLUG, suggesting that these patients may have mutations in other genes that have not yet been deciphered.

There are reports of a KIT mutation carrier with sensorineural deafness and no cutaneous pigmentary changes, suggesting a possible overlap syndrome between piebaldism and Waardenburg syndrome.

In addition, mutations in SNAI2 gene within locus 8q11.21, a transcription factor of KIT and E-cadherin, which is important for the maintenance of melanoblast homeostasis, have been detected (Agarwal S et al. 2012).

The c-Kit receptor is a protein of the tyrosine kinase family of transmembrane receptors. Among other things, c-Kit is expressed on the surface of melanocytes and acts as a receptor for growth factors. A reduction or even the absence of c-Kit-dependent signal transduction leads to reduced proliferation and migration of embryonic melanoblasts from the neural crest. This usually results in the complete absence or significant reduction of melanocytes in the corresponding skin areas.

A clinical picture analogous to piebaldism in humans is frequently observed in horses (piebald) and cows (black and white cows) and is referred to as leucism . The gene mutation described above can also be detected in these mammals.

White forelock -poliosis-(more rarely on other parts of the capillitium; see illustration) at birth, other foci after a few months.

Depigmentation of the skin and poliosis occur at birth in a characteristic ventral midline pattern. The most common finding is a white forelock in a triangular shape, which occurs in up to 90% of cases (poliosis circumscripta) (Thomas I et al. 2004). The middle eyebrows and eyelashes may also be affected. The classic distribution of well-circumscribed depigmented patches includes the central forehead, the front of the trunk and the middle part of the extremities. Hyperpigmentation may be present at the edges of the depigmented areas. Normally pigmented areas may also be present in the center of the white patches. Piebaldism is characterized by the absence of extracutaneous manifestations!

Already present at birth, coin-sized to palm-sized, sharply defined, depigmented, symmetrical, but also completely asymmetrical, also systematically occurring spots, white forelock. Characteristic are skin islands with normal coloration. Hyperpigmented areas at the edge of the white spotting are less common.

Six-field complex: Poliosis circumscripta and pigment deficiency on the chin, neck, mid-torso and distal extremities.

Piebaldsimus is a partial symptom of the following syndromes:

• Klein-Waardenburg syndrome (mutations in the PAX3 gene/important regulator gene for the differentiation of neural crest cells)
• Tietz syndrome (Tietz albinism deafness syndrome/ mutation in the MITF gene which codes for the transcription factor MITF = microphthalmia-associated transcription factor. MIFT acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis.
• Chédiak-Higashi syndrome (lysosomal storage disease. Mutation in the LYST gene that encodes a protein that controls intracellular protein traffic in endosomes and is thus involved in pigmentation). In cytotoxic T cells and natural killer cells (NK), it plays a role in regulating the size, number and exocytosis of lytic granules.
• Facultative in Stargardt syndrome:

• Chromosome 4q deletion syndrome

In the lesional areas, melanin and melanocytes are completely absent from both the surface and follicular epithelium. No sign of inflammation in the dermis (DD. vitiligo).

Clinical:

Vitiligo: Rarely isolated focus. Not congenital but acquired.

Albinism: Congenital disorder of melanin synthesis with normal intraepidermal melanocyte count (!). Never localized but generalized hypomelanosis of skin, hair and eyes (oculocutaneous albinism) or only of the eyes (ocular albinism).

Nevus depigmentosus. So far, an actually existing difference of both anomalies has not been clarified. Systematized"(cutaneous mosaics) depigmentations have been described for both syndromes.

In nevus depigmentosus, melanocytes are typically detectable in the epidermis. There is a disturbance of melanosome transfer.

Nevus anaemicus: Evidence is provided by the friction test, which is negative in nevus anaemicus.

Although piebaldism is benign and limited to the skin, it can be a social nuisance for those affected. Treatment is aimed at improving the appearance.

This includes skin grafts, cell transplants, camouflage techniques and the use of hair dyes for poliosis.

Consistent textile and physical/chemical sun protection is also recommended.

If piebaldism is suspected, a careful examination should be performed to rule out overlapping syndromes with extracutaneous manifestations, such as Waardenburg syndrome(Saleem MD 2019).

The phenotypic findings of piebaldism become visible at birth. Due to the incomplete penetrance and variable expression, a detailed family history is useful to determine an inherited genetic cause. In the postnatal period, a careful physical examination, including an ophthalmologic and neurologic examination, can help distinguish piebaldism from syndromic causes of the pigmentary disorder, such as:

• Waardenburg syndrome
• peripheral demyelinating neuropathy
• central dysmyelinating leukodystrophy
• Hirschsprung's disease (PCWH)

must be distinguished.

Although Waardenburg syndrome has a similar phenotypic appearance to piebaldism, there are also extracutaneous features such as congenital deafness and heterochromia. Concomitant Hirschsprung disease is important for PCWH.

3 year old boy who had a stripe-like white spot since birth and later developed a white curl(poliosis) in this area. Since early infancy the mother observed further whitish spots on the belly and later on the left arm and right knee. In the last few weeks, after repeated exposure to the sun, single pigmented spots appeared within the depigmented area on the abdomen. The boy was mentally completely normal and showed no other physical retardations. Medium exposure to sunlight leads to premature dermatitis solaris in the lesional areas.

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