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.
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.
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?
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
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 are summarized in Table I.
|Medical Treatment||Surgical procedures||Physical modalities|
|PUVA||Noncultured epidermal rafting||Cosmetic camouflage|
|Variable results (generally not responsive)||Cultured epithelial grafts|
PUVA, psoralen plus ultraviolet A.
Optimal Therapeutic Approach for this Disease
Explain the natural history of piebaldism to the patient before beginning treatment. It is a stable, noncontagious disease, which essentially poses only a cosmetic problem. As it is solely a cosmetic problem, most patients do not seek treatment. Also, the leukodermal patches are resistant to medical treatment. In case of limited disease, cosmetic camouflage may be of value.
Patients may desire treatment when the white patches are located on the face. Treatment of the lesions with either topical 8-methoxpsoralen plus ultraviolet irradiation A (PUVA) or oral methoxpsoralen plus UVA has been employed.
Autologous minigrafts of normally pigmented skin or autologous cultured melanocytes transplantation into depigmented areas, have been used with success in some patients, especially with mild, limited disease. The use of noncultured epidermal grafting was introduced in 1992.
The main advantage of the noncultured epidermal cellular grafting technique is the possibility to treat larger areas by using only a small piece of autologus donor skin without culturing the cells. A donor sample is taken from normally pigmented skin of the gluteal area with a shave biopsy. It is treated with trypsin, and cellular suspension is prepared which is then inoculated at the recipient area (ablated with a pulsed CO2 laser.
Repigmentation has been successful in the majority of cases with piebaldism. Final repigmentation is achieved after a mean of 10 months post-treatment in reported patients. Some color mismatch (hyperpigmentation and hypopigmentation) is occasionally observed between the treated area and the surrounding skin, without being reported as disturbing by the majority of patients. There have been reports of complications associated with other grafting techniques, including cobblestoned surface with mini punch grafting.
Explain that piebaldism is a benign, stable skin condition. Inform the patient about the hereditary nature of piebaldism.
As depigmented skin is lacking melanin, it is extremely vulnerable to the detrimental effects of solar radiation, such as solar burns, photoaging and photocarcinogenesis. Patients should be instructed to take adequate sun protective measures, including the use of sunscreens and of protective clothing (hat, sunglasses, long-sleeved clothing), and the avoidance of exposure to the sun, especially during hours when sunlight is more intense (11 am to 3 pm).
Unusual Clinical Scenarios to Consider in Patient Management
Despite the static nature of piebaldism, there has been a report of two patients (mother and daughter) by Richards et al, of a phenotype of typical piebaldism but with progressive depigmentation. It was associated with a novel Val620Ala (1859T>C) mutation of the KIT gene. This KIT mutation affects the intracellular tyrosine kinase domain, which is associated with a severe phenotype, as was the case in the reported family.
What is the Evidence?
Dessinioti, C, Stratigos, AJ, Rigopoulos, D, Katsambas, AD. “A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes”. Exp Dermatol. vol. 18. 2009. pp. 741-9. (A comprehensive review of the basic concepts of melanocyte biology and of molecular defects in melanocyte development and function resulting in the development of hypopigmentary hereditary skin diseases, including Waardenburg syndrome, piebaldism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, oculocutaneous albinism and Griscelli syndrome.)
Spritz, RA, Nordlund, JJ, Boissy, RE, Hearing, VJ, King, RA, Oetting, WS, Ortonne, JP. “Genetic hypomelanoses: disorders characterized by congenital white spotting-piebaldism, Waardenburg syndrome, and related genetic disorders of melanocyte development-clinical aspects”. The pigmentary system: physiology and pathophysiology. 2006. pp. 541-50. (This book encompasses the physiology of the pigmentary system, as well as the pathophysiology, clinical presentation and treatment strategies of congenital and acquired disorders of pigmentation (hypopigmentation, depigmentation, hyperpigmentation). The specific chapter focuses on the clinical presentations of disorders characterized by congenital white spotting, such as piebaldism, Waardenburg syndrome, and the albinism-deafness syndrome.)
Bondanza, S, Bellini, M, Roversi, G. “Piebald trait: Implication of kit mutaiton on in vitro melanocyte survival and on the clinical application of cultured epidermal autografts”. J Invest Dermatol. vol. 127. 2007. pp. 676-86. (A study showing that the type of kit mutation is implicated on in vitro melanocyte survival and on the clinical application of cultured epidermal autografts.)
Van Geel, N, Wallaeys, E, Goh , BK. “Long-term results of noncultured epidermal cellular grafting in vitiligo, halo naevi, piebaldism and naevus depigmentosus”. Br j Dermatol. vol. 163. 2010. pp. 1186-93. (Autologous noncultured epidermal cellular grafting was associated with a high percentage of repigmentation which was maintained during a mean follow up of 4 years in the majority of patients.)
Richards, KA, Fukai, K, Oiso, N. ” A novel KIT mutation results in piebaldism with progressive depigmentation”. J Am Acad Dermatol. vol. 44. 2001. pp. 288-92. (A novel kit mutation (Val620Ala) was identified in a mother and daughter with progressive piebaldism.)
Chang, GS, Wasserman, DI, Byers, HR. “Hypopigmented T-cell dyscrasia evolving to hypopigmented mycosis fungoides during etanercept therapy”. J Am Acad Dermatol. vol. 59. 2008. pp. s121-22. (The report of a case of mycosis fungoides presenting with hypopigmented patches.)
Sleiman, R. “Poliosis circumscripta: Overview and underlying causes”. J Am Acad Dermatol. vol. 69. 2013. pp. 625-33. (This review describes different conditions that may present with poliosis, including
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- Are You Confident of the Diagnosis?
- Who is at Risk for Developing this Disease?
- What is the Cause of the Disease?
- Systemic Implications and Complications
- Treatment Options
- Optimal Therapeutic Approach for this Disease
- Patient Management
- Unusual Clinical Scenarios to Consider in Patient Management
- What is the Evidence?