Piebaldism

Piebaldism (ICD-9-CM 709.09)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Piebaldism is a rare genetic disorder of pigmentation with variable phenotype. It is characterized by stark patches of white skin (leukoderma) and white hair (poliosis). It is evident at birth, with cutaneous depigmentation ranging from only a white forelock with minimal ventral depigmentation, to almost an entire body and hair depigmentation.

Characteristic findings on physical examination

On physical examination, clinical findings may vary and include congenital patches of white skin, mainly on the midforehead, chest, abdomen and extremities, and a white forelock (Figure 1,Figure 2). A characteristic feature of piebaldsim is that these patches may sometimes contain hyperpigmented macules (Figure 3). The white forelock is a triangular or diamond-shaped midline white macule on the front scalp or forehead. The medial portions of the eyebrows and eyelashes may be white.

Figure 1.

Figure 2.

Figure 3.

In piebaldism, the white patches are both congenital and stable in size and shape. However, in milder cases, limited repigmentation has been reported.

Café-au-lait spots are a common finding in piebaldism, and axillary and/or inguinal freckling also occurs frequently, resulting in several patients with piebaldism being misdiagnosed as having neurofibromatosis. Melanocytes in the eye or ear are rarely affected in this disease. Unlike Waardenburg syndrome, piebaldism is not accompanied by deafness and it more commonly results in white, depigmented (melanocyte-free) areas of skin rather than hair involvement.

Expected results of diagnostic studies

Histologically, melanocytes are completely absent in the depigmented macules. However, a skin biopsy is usually not necessary as the diagnosis of piebaldism is usually made on clinical grounds. Laboratory evaluation or imaging studies do not contribute to diagnosis. As piebaldism is a hereditary condition, the family history should be checked. In patients with an atypical presentation and suspicion of piebaldism, a high-resolution karyotype, and possibly fluorescent in situ hybridization (FISH) using a KIT probe, will confirm diagnosis.

Diagnosis confirmation

Differential diagnosis of piebaldism includes other congenital or acquired disorders characterized by depigmented skin lesions:

Acquired depigmentation disorders

Vitiligo: it is not present at birth. The condition usually starts in childhood or young adulthood. Depigmented hair. Depigmented white patches with symmetrical involvement. Tendency for periorificial skin. Koebner phenomenon. May be progressive. Association with autoimmune diseases (Hashimoto thyroiditis, Graves’ disease, alopecia areata, insulin-dependent diabetes mellitus, pernicious anemia)

Vogt-Koyanagi-Harada syndrome: an autoimmune disease affecting the eyes, skin, auditory system and central nervous system. Rare in white-skinned individuals. Autoimmune disease. Four successive phases: prodromal phase (fever, headache, vomiting, meningismus, mental status changes), uveitic phase, convalescent phase (vitiligo, poliosis of the scalp, eyebrows, eyelashes and hairs of the axillae), fourth phase of recurrent attacks of uveitis

Congenital depigmentation disorders:

Oculocutaneous albinism: Cutaneous sensitivity to ultraviolet radiation, visual defects (nystagmus, photophobia, decreased visual acuity), increased risk of nonmelanoma skin cancers

Hermansky-Pudlak syndrome: Rare, oculocutaneous albinism, platelet storage pool deficiency resulting in bleeding diathesis, ceroid storage disease resulting in pulmonary fibrosis, kidney failure, granulomatous colitis. Fatal in the fourth or fifth decade of life from pulmonary fibrosis

Chediak-Higashi syndrome: Extremely rare, oculocutaneous albinism, neutropenia, recurrent infections, thrombocytopenia, bleeding diathesis, neurologic defects. Fatal in the first decade of life from infections or bleeding

Griscelli syndrome: Extremely rare, oculocutaneous albinism, severe immunodeficiency, neurologic defects. Fatal within the first decade of life

Waardenburg’s sydnrome (types 1-4): white patches of skin, congenital deafness, heterochromia iridis, dystopia canthorum.

Other skin diseases with hypopigmented macules

Hypopigmented mycosis fungoides (MF): This is a rare variant of MF, reported mainly in patients of Asian or African descent. It presents with persistent, often pruritic, hypopigmented patches on non-photodistributed areas of the body.

Tuberous sclerosis: Specific diagnostic criteria must be met for diagnosis. Hypopigmented (off-white) lesions include segmental hypomelanosis, confetti-like hypopigmented macules, ash-leaf macules.

Tinea versicolor: Cutaneous fungal dermatosis caused by Malassezia furfur. Hypopigmented plaques with scaling, most commonly located on the trunk. Recurrence is common

Nevus depigmentosus: Congenital hypopigmeted macule or plaque. Stable. Does not cross the midline. Expression of mosaicism

Nevus anemicus: Congenital, localized vascular disorder. Hypopigmented macule. Normal melanocytes and melanin. Rubbing the lesion does not cause erythema. Disappears with diascopy

Who is at Risk for Developing this Disease?

Piebaldism is rare, with an estimated incidence of 1 per 100,000. It is inherited as a typical autosomal dominant disorder, with equal frequencies in males and females. A positive family history is present. Some patients have been reported with sporadic, nonfamilial piebaldism, assocated with dysmorphic features and usually mental retardation.

Prenatal diagnosis of piebaldism is possible by DNA-based mutation analysis of the KIT gene. Mutations of the KIT gene are not found in about a quarter of patients with typical piebaldism, suggesting that additional, yet unidentified, human piebaldism loci may play a role.

What is the Cause of the Disease?

Etiology

Piebaldism is a rare, autosomal dominant human congenital disorder of pigmentation characterized by hypomelanosis. The pathway of melanocyte development and function is complex, and mutations in different strategic points give rise to distinct disease states. In particular, mutations may affect:

• melanobast migration from the neural crest to the skin (Waardenburg syndrome, piebaldism)

• melanin synthesis in the melanosome (oculocutaneous albinism)

• melanosome formation in the melanocytes (Hermansky-Pudlak syndrome, Chediak-Higashi syndrome)

• mature melanosome transfer to the tips of the dendrites

Pathophysiology

Piebaldism originates from mutations involving melanoblast development and migration from the neural crest to the skin. Human piebaldism results from heterozygous “loss-of’-fuction” mutations of the KIT gene, which has been mapped to chromosome 4q12. KIT encodes the cell surface transmembrane tyrosine kinase receptor for KIT ligand (mast-cell growth factor, stem-cell factor, steel factor) involved in pigment cell development.

The KIT receptor consists of an extracellular domain of 5 immunoglobulin repeats, a transmembrane domain, and an intracellular tyrosine kinase domain. The mutations of cKIT that have been identified in piebald patients range from gross deletions to missense defects, and are all inherited as autosomal dominant traits, suggesting dosage effect. There is a correlation between genotype and the resultant clinical phenotype, depending on the location of the mutation within the KIT gene. Mutations (whatever type) located at or near the transmembrane region are associated with an intermediate severity phenotype. Frameshift mutations in the aminoterminal extracellular ligand binding domain result in a milder form of the disorder, whereas point missense mutations in the intracellular tyrosine kinase domain are associated with the most severe phenotype.

Also, SCF and SLUG mutations have been identified in human piebaldism. In particular, piebaldism has been linked to inactivating muations or deletions in the SLUG gene on chromosome 8q11. These mutations result in decreased receptor tyrosine kinase signalling, impaired melanoblast development, and a decrease in melanogenesis. Humans with piebaldism lacking c-KIT mutations, were found to have heterozygous deletions encompassing the SLUG coding region. SLUG mutation was also reported in Waardenburg syndrome type 2, and a mechanism proposed to account for these effects involves the binding of MITF to the SLUG promoter.

Some patients have been reported in whom sporadic, nonfamilial piebaldism, associated with dysmorphic features and usually mental retardation, results from chromosomal deletions and other rearrangements affecting the KIT gene. Many patients with atypical presentations 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 have been reports of a KIT mutation carrier with sensorineural deafness and no cutaneous pigmentary changes, suggesting a potential overlap syndrome between piebaldism and Waardenburg syndrome.

Systemic Implications and Complications

Piebaldism is a benign disorder that only poses a cosmetic problem. So, patients with piebaldism typically exhibit only the characteristic depigmentation affecting the skin and hair.

In piebald patients, pigmentation of the retina and irises is normal, there are none of the abnormalities of the optic tracts associated with albinism, and vision is normal.

Melanocytes in the ear are rarely affected in piebaldism, and thus, unlike Waardenburg syndrome, piebaldism is not accompanied by deafness.

Treatment Options

Treatment options are summarized in Table I.