Piebaldism

INTRODUCTION — Piebaldism (from the words "pie" [magpie, black and white bird] and "bald" [bald eagle]) or piebald trait (MIM #172800) is a rare, autosomal dominant disorder of melanocyte development and migration, resulting in patchy depigmentation of hair and skin [1]. Affected individuals have lighter patches of skin (leukoderma) and hair (poliosis), most commonly located near the frontal hairline. The localized patch of white hair (white forelock) is the most distinctive feature of piebaldism (picture 1C).

Piebaldism is a nonprogressive, benign disorder and mainly a cosmetic concern that may run in families for generations. Treatment options are limited and include cosmetic camouflage, hair dye, and, for severe cases, autologous skin transplants.

This topic will review the pathogenesis, clinical manifestations, diagnosis, and management of piebaldism. Other disorders of hypopigmentation are discussed separately. (See "Oculocutaneous albinism" and "Hermansky-Pudlak syndrome" and "Chediak-Higashi syndrome" and "The genodermatoses: An overview", section on 'Waardenburg syndrome'.)

EPIDEMIOLOGY — The incidence of piebaldism is unknown but is estimated to be between 1:40,000 and 1:100,000 for White individuals [2]. There is no difference in prevalence based on sex or among ethnic groups, but the disorder is more prominent and easily recognized in individuals with a darker skin complexion.

PATHOGENESIS — Piebaldism is caused by mutations in the KIT and SLUG (SNAI2) genes, which are involved in the development and migration of melanocytes [3].

Overview of melanocyte development — Melanocytes are neural crest derivatives. Their development and migration are regulated by various signaling pathways and transcription factors, including PAX3 (paired box 3), SOX10 (sex-determining region Y box 10), MITF (microphthalmia transcription factor), KIT, EDN3 (endothelin 3), and EDNRB (endothelin receptor B) [3]. Transformation of melanoblasts to functional melanocytes is a complex process requiring interaction between mast cell growth factor (c-kit), a tyrosinase kinase receptor, and Kit ligand (also known as steel factor or stem cell growth factor [SCF]) [4,5]. Activation of c-kit receptor on the surface of melanoblasts leads to Ras-pathway activation, multiple canonical signaling, and post-translational modification of MITF [6]. Mutations leading to a reduction in c-kit impair survival and proper migration of melanoblasts, resulting in failure of their colonization at cutaneous sites most distant to neural crest [7].

The SLUG gene (SNAI2), coding for a zinc-finger 2 neural crest transcription factor, also known as snail 2 protein, is also involved in melanoblast migration and survival [8]. Mutations in the form of deletion and a double nucleotide variant have been described [8,9].

The KIT proto-oncogene encodes a tyrosine kinase receptor that binds the SCF KIT ligand and activates subsequent signal transduction, such as PI3K/Act [10], Src family kinase [11,12], Jak/Stat [13,14], and Ras-Raf-MAP kinase cascade [15,16]. It has been shown that the Ras/mitogen-activated protein kinase (MAPK) signaling pathway activated by SCF/KIT plays a crucial role in regulation of melanocyte migration from neural crest to the epidermal basal layer of hair follicles; cell proliferation, differentiation, and survival; melanogenesis; and melanosome transfer [17-20]. It has also been demonstrated that mutant KIT was able to form a heterodimer with wild type KIT and bind SCF, but the phosphorylation of KIT and downstream signaling factors was markedly decreased [21].

Genetics — In most cases, piebaldism is caused by heterozygous missense variants in the tyrosine kinase (TK) domain of the KIT proto-oncogene, located on chromosome 4q12 [5]. KIT variants are found in approximately 75 percent of patients with typical piebaldism. More than 70 different pathogenic variants have been identified, including missense variants, deletions, splice-site variants, insertions, frame shift variants, duplications, and pericentric chromosomal inversion [22]. KIT has a role in protein signaling that is involved in the development of certain cell types, including melanocytes [5]. Loss-of-function variants in KIT lead to a disruption of growth and proliferation of melanocytes during development, resulting in patches of skin with absent pigmentation.

Heterozygous deletions of SNAI2 have been identified in 3 of 17 unrelated individuals with piebaldism and absent KIT mutations [23]. SNAI2, also known as SLUG, encodes for a snail 2 protein, a zinc-finger transcription factor expressed in migratory neural crest cells. The snail 2 protein is thought to have a role in formation and survival of melanocytes.

A genetic relationship between piebaldism and Waardenburg syndrome, another genetically heterogeneous disorder, has been reported but is not completely understood. Waardenburg syndrome is an auditory-pigmentary disorder characterized by pigment loss and congenital sensorineural hearing loss. Before the age of molecular genetics, some authors observed children with much more severe pigment loss and deafness born to consanguineous parents who each had piebaldism [24].

Eventually, homozygous KIT variants were confirmed in unrelated and consanguineous parents affected with piebaldism who birthed children with more severe findings, such as complete absence of skin and hair pigment, associated facial dysmorphism, and congenital anomalies [24,25]. Homozygous deletions of SNAI2 have been reported in two cases presenting with sensorineural hearing loss and iris heterochromia without any cutaneous or dysmorphic features [26]. Whether these homozygous cases represent true Waardenburg syndrome or a severe, autosomal recessive form of piebaldism remains unclear.

Genotype/phenotype correlation — The severity of the clinical phenotype in patients with piebaldism correlates with the type of mutation and the site of mutation in the KIT gene. Frameshift variants that result in null gene product generally result in a milder phenotype. By contrast, point missense variants that produce an abnormal gene product result in a more severe phenotype [22,27].

The KIT receptor consists of an extracellular domain of five immunoglobulin repeats, a transmembrane domain, and an intracellular TK domain [28]. Variants located at or near the transmembrane region, resulting in KIT haploinsufficiency, are associated with an intermediate severity phenotype. Frameshift variants and point missense variants in the amino-terminal extracellular ligand-binding domain result in a milder form of the disorder [4], whereas dominant-negative point missense variants in the intracellular TK domain are associated with the most severe phenotype [29]. Known variants in the TK domain often result in the development of café-au-lait macules (CALMs) and intertriginous freckling [30-34]. These features have resulted in diagnostic confusion with neurofibromatosis type 1 (NF1). Piebald-affected individuals who do not have serious NF1 complications may meet NF1 clinical diagnostic criteria by the presence of two major features (intertriginous freckling and CALMs) [1,32]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

It has been proposed that CALMs and intertriginous freckling result from Ras/MAPK hyperactivity [35]. SPRED1 normally functions to suppress the Ras/MAPK pathway, and phosphorylation of the KIT-binding domain of SPRED1, by kinases such as KIT, is required for activation and efficient suppression of the Ras/MAPK pathway [36,37]. Thus, inadequate phosphorylation of SPRED1 by a defective KIT TK would result in loss of inhibition of the Ras/MAPK pathway, with a clinical phenotype similar to Legius syndrome. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Legius syndrome'.)

PATHOLOGY — Histologically, melanocytes are completely absent in depigmented areas of skin. However, biopsy is rarely necessary to achieve the diagnosis.

CLINICAL MANIFESTATIONS — Piebaldism is usually apparent at birth but may be unrecognized until a later age, as normal pigmentation matures, especially in individuals with very light complexion.

The white forelock, a triangular or diamond-shaped, midline area of white hair on the frontal scalp, is the most distinctive clinical manifestation of piebaldism and is present in the vast majority of individuals with this trait (picture 1C). The depigmentation may involve the forehead and the medial portions of the eyebrows and eyelashes. White patches of irregular shape and size may be observed on the face, trunk, and extremities (picture 1A-B). They are typically symmetrical and involve both sides of the body. Islands of normally pigmented or hyperpigmented skin are typically present within the depigmented areas. Marginal hyperpigmentation of the depigmented areas is also frequently noted.

The number, size, and distribution of white patches is generally variable from individual to individual. Although many clinicians do not use a formal classification of severity for piebaldism in clinical practice, for descriptive purposes, piebaldism can loosely be classified into three phenotypes based on the size and extension of depigmented areas: mild, moderate, and severe [1].

Occasionally, café-au-lait macules and intertriginous freckling are seen in individuals with piebaldism, leading to diagnostic confusion with neurofibromatosis type 1 (NF1) and Legius syndrome [31,32,34,35]. (See 'Neurofibromatosis type 1/Legius syndrome' below and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

The retinal and iris pigmentation, as well as vision, are normal in individuals with piebaldism.

Clinical course — Piebaldism does not progress throughout a patient's lifetime. However, there is a report of a mother and daughter with a novel variant of the KIT gene and a phenotype of typical piebaldism with progressive depigmentation [29]. Cases of spontaneous repigmentation have been reported in some families with piebaldism [38-41].

DIAGNOSIS AND EVALUATION — The diagnosis of piebaldism can be made clinically in many cases, based on the finding of a white forelock and/or stable, midline, depigmented patches on the forehead, chest, abdomen, and extremities that are present since birth (picture 1A-C). A family history of piebaldism supports the clinical diagnosis.

A skin biopsy is rarely needed for the diagnosis of piebaldism. If performed, it demonstrates a complete lack of melanocytes and melanin pigment in affected areas.

Molecular genetic analysis for KIT and SNAI2 gene mutations can confirm the diagnosis of piebaldism, particularly in atypical presentations, such as patients without a supportive family history or with unexpected associated clinical features.

All children with clinical features of piebaldism should undergo a careful ocular examination for retinal or iris pigment alterations and hearing evaluation to rule out Waardenburg syndrome. If a hearing loss and/or eye color difference (iris heterochromia) is present, molecular testing for mutations in genes associated with Waardenburg syndrome may be helpful to clarify the diagnosis. (See 'Waardenburg syndrome' below.)

In cases presenting with typical piebald depigmentation and café-au-lait macules and intertriginous freckling, testing for NF1 and SPRED1 gene may be indicated to rule out neurofibromatosis type 1 (NF1) or Legius syndrome. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Legius syndrome'.)

DIFFERENTIAL DIAGNOSIS — Piebaldism should be distinguished from Waardenburg syndrome (WS) and other hereditary disorders of melanocyte development or melanin biosynthesis (table 1), and from a number of inherited or acquired disorders presenting with skin or hair hypopigmentation.

Waardenburg syndrome — Waardenburg syndrome (WS, MIM #193500) is a hereditary disorder affecting the migration of melanoblasts during embryogenesis. It results in patchy areas of depigmentation in skin and hair, heterochromia of irides, and sensorineural hearing loss (in approximately 20 percent of patients) and accounts for approximately 1 to 3 percent of complete congenital deafness [42]. (See "Hearing loss in children: Etiology".)

WS is a genetically heterogeneous disorder with six known genes associated with different WS phenotypes (PAX3, MITF, EDN3, EDNRB, SOX10, and SNAI2) [43]. Most forms of WS are inherited in an autosomal dominant fashion. All forms have the clinical features of type 1, which is characterized by a piebald-like distribution of patchy depigmentation of the hair and skin. Other distinctive noncutaneous features include pigmentary abnormalities of the iris (total or partial heterochromia iridium or light blue irides) and broad nasal root secondary to lateral displacement of the inner canthi of the eyes (dystopia canthorum) (picture 2). Occasional findings in WS type 1 include cleft lip and palate and neural tube defects (eg, spina bifida, myelomeningocele) [44].

Neurofibromatosis type 1/Legius syndrome — The coexistence of multiple café-au-lait macules (CALMs) in individuals with piebaldism can lead to diagnostic confusion with neurofibromatosis type 1 (NF1) and Legius syndrome. Unlike piebaldism, patients with NF1 usually have Lisch nodules; scoliosis; cutaneous, subcutaneous, and plexiform neurofibromas; skeletal dysplasia; and optic pathway glioma. Patients with Legius syndrome may have CALMs and intertriginous freckling, macrocephaly, lipomas, and a learning disability, but other systemic manifestations observed in NF1 are not characteristic. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

Other inherited or congenital disorders — The differential diagnosis of piebaldism also includes other inherited disorders of melanocyte development or melanin biosynthesis, and inherited or congenital disorders that are associated or present with hypopigmented or depigmented lesions [45]:

●Oculocutaneous albinism – Oculocutaneous albinism is a group of disorders caused by a defect in melanin biosynthesis, resulting in complete or partial absence of pigment in the skin, hair, and eyes (picture 3 and picture 4). This is a heterogeneous disorder caused by mutations in several genes [46]. Most forms are inherited in an autosomal recessive pattern [47]. Visual defects (eg, nystagmus, photophobia, decreased visual acuity) are invariably present. Affected individuals have sensitivity to ultraviolet radiation and increased risk of nonmelanoma skin cancers. (See "Oculocutaneous albinism".)

●Hermansky-Pudlak syndrome – Hermansky-Pudlak syndrome is a rare form of oculocutaneous albinism (picture 5) caused by lysosomal storage of ceroid lipofuscin. It is associated with bleeding tendency due to platelet abnormality (storage pool deficiency), pulmonary fibrosis, kidney failure, granulomatous colitis, and heart dysfunction. The disorder is common in Puerto Rico, affecting 1 in 1800 individuals there [48]. (See "Hermansky-Pudlak syndrome".)

●Chediak-Higashi syndrome – Chediak-Higashi syndrome is a very rare, autosomal recessive skin disorder associated with hair and eye hypopigmentation (picture 6), neutropenia, recurrent pyogenic infections, thrombocytopenia, bleeding diathesis, and peripheral neuropathy. It is caused by an abnormal lysosomal trafficking regulator protein and decreased phagocytosis [49]. (See "Chediak-Higashi syndrome".)

●Griscelli syndrome – Griscelli syndrome is a rare, autosomal recessive disorder characterized by skin and hair hypopigmentation and immunodeficiency. It is usually fatal in early childhood. (See "Syndromic immunodeficiencies" and "Syndromic immunodeficiencies", section on 'Griscelli syndrome'.)

●Tuberous sclerosis complex – Tuberous sclerosis is a complex multisystem disorder characterized by benign hamartomas of the brain, eyes, heart, lung, liver, kidney, and skin [50,51]. Skin manifestations include segmental hypomelanosis; confetti-like, hypopigmented macules; and ash-leaf macules (picture 7). Specific diagnostic criteria must be met for diagnosis (table 2). (See "Tuberous sclerosis complex: Clinical features".)

●Nevus depigmentosus – Nevus depigmentosus (achromicus) is a congenital, nonprogressive, hypopigmented macule or plaque (birthmark) (picture 8). Its size may increase in proportion to body growth. (See "Acquired hypopigmentation disorders other than vitiligo", section on 'Nevus depigmentosus'.)

●Nevus anemicus – Nevus anemicus is a congenital, vascular anomaly that presents as a pale macule or patch (picture 9). Melanocytes and melanin are normal. Lesions become more prominent by warming and rubbing, their borders disappear with diascopy, and they do not accentuate with Wood's lamp examination. Nevus anemicus is a benign and asymptomatic lesion found more frequently in patients with NF1 [52,53]. (See "Acquired hypopigmentation disorders other than vitiligo", section on 'Nevus anemicus'.)

Acquired depigmentation disorders — Based on the presence of stable, depigmented macules since birth, piebaldism is usually easily distinguished from acquired hypopigmentation disorders. However, in patients with light skin in whom the depigmented lesions were not detected at birth, piebaldism may be confused with vitiligo or other acquired conditions characterized by localized hypopigmentation. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis" and "Acquired hypopigmentation disorders other than vitiligo".)

Vitiligo is an acquired skin condition characterized by destruction of functional melanocytes, resulting in the appearance of well-circumscribed, white macules and patches. The condition is not present at birth and usually starts in childhood or young adulthood (picture 10) [54]. White skin patches are usually symmetrical, and there is a tendency for involvement of periorificial skin and bony prominences. In contrast with piebaldism, vitiligo is usually progressive and may be associated with other autoimmune disorders, such as alopecia areata, insulin-dependent diabetes mellitus, and pernicious anemia.

MANAGEMENT — Piebaldism is a benign condition with a stable course that poses mostly a cosmetic concern. All patients with piebaldism should be referred for genetic evaluation, testing (if molecular diagnosis is needed), and genetic counseling (see 'Genetic counseling' below). The majority of patients do not seek treatment of disease manifestations, except when the lesions are located on the face. Light therapy and corticosteroids have no role in treatment. Limited therapeutic options to address the skin and hair depigmentation include:

●Cosmetic camouflage and hair dye may provide emotional benefit and improve quality of life [55,56]. In light-skinned patients, diligent sun protection may provide camouflage by preventing tanning of surrounding skin.

●Temporary pigmented agents, such as the tanning product dihydroxyacetone, may be used on the depigmented patches [57].

●Several surgical methods have been tried with variable success, including the transfer of melanocytes using full- or partial-thickness skin graft, mini-grafts, or suction blistering grafts [58-60]. Treatments with a combination of dermabrasion and grafting or a combination of carbon dioxide (CO₂) laser ablation and autologous noncultured cell suspension transplantation have been described in a few patients [61,62]. The noncultured epidermal cell suspension grafting technique allows for the treatment of larger areas by using only a small sample of autologous donor skin [62].

Sun protection, including the use of broad-spectrum sunscreens, is recommended to prevent sunburns and to reduce risk for skin cancer. (See "Selection of sunscreen and sun-protective measures".)

Differences that affect appearance can have a deep impact on the patient and family. Behavioral health referral can help individuals with coping strategies, if needed.

GENETIC COUNSELING — Piebaldism is an autosomal dominant disorder with variable penetrance [63]. The children of a person with piebaldism have a 50 percent chance of inheriting a disease-causing gene. There are rare reports in the literature of a more severe form of piebaldism with additional anomalies appearing in offspring of two piebald-affected parents. Genetics referral can be considered, especially prior to reproductive age for affected individuals so they can better understand their reproductive risk.

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Piebaldism is a rare, autosomal dominant disorder of melanocyte development and migration caused in most cases by mutations in the tyrosine kinase domain of the KIT proto-oncogene, resulting in patchy depigmentation of hair and skin. Affected individuals have white patches of skin (leukoderma) and/or hair (poliosis), most commonly located near the front hairline. (See 'Pathogenesis' above.)

●Clinical presentation – The "white forelock," a triangular or diamond-shaped, midline area of white hair on the frontal scalp, is the most distinctive clinical manifestation of piebaldism and is present in the vast majority of affected individuals (picture 1C). White patches of irregular shape and size may be observed on the face, trunk, and extremities (picture 1A-B). The depigmentation is typically stable over time. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of piebaldism can be made clinically in many cases, based on the finding of a white forelock and/or stable, midline, depigmented patches on the forehead, chest, abdomen, and extremities that are present since birth (picture 1A-C). Molecular testing for KIT, SNAI2, and other genes associated with congenital hypopigmentation may be needed for confirmation of diagnosis, especially in cases of negative family history or unexpected associated clinical findings. It is recommended that children with clinical features of piebaldism undergo a careful ocular examination for retinal or iris pigment alterations and hearing evaluation to rule out Waardenburg syndrome. (See 'Diagnosis and evaluation' above and 'Waardenburg syndrome' above.)

●Management – Piebaldism is a benign, nonprogressive disorder of pigmentation that does not require treatment. However, some patients may seek treatment because of cosmetic concerns. Cosmetic camouflage techniques and hair dying can provide emotional benefit and improve quality of life. For more severe cases, several surgical methods for treatment of leukoderma (including skin grafting, mini-grafting, or suction blister grafting) have been described in a few patients with variable results. Sun protection, including the use of broad-spectrum sunscreens, is recommended to prevent sunburns and to reduce risk for skin cancer. (See 'Management' above.)