Piebaldism: A brief report and review of the literature.

Piebaldism is a rare autosomal dominant disorder of melanocyte development characterized by a congenital white forelock and multiple symmetrical stable hypopigmented or depigmented macules. We report a family with piebaldism affecting three successive generations and also review the literature.

INTRODUCTION

Piebaldism is a rare autosomal dominant disorder characterized by the congenital absence of melanocytes in affected areas of the skin and hair due to mutations of the c-kit gene, which affects the differentiation and migration of melanoblasts from the neural crest during the embryonic life. Affected individuals present at birth with a white forelock and relatively stable, persistent depigmentation of skin with a characteristic distribution.

CASE REPORT

Parents of a five-year-old boy and 21-month-old girl complained of white patches in both their children since birth. The patches were asymptomatic and had remained stable since their appearance. The examination of both children revealed large depigmented macules over the ventral part of the mid-trunk and over mid-portions of the lower extremities on the anterior aspect [Figure 1]. The shape of the depigmented macules was rhomboid. Leucotrichia was associated with the depigmented macules. Discrete, 5-15-mm, skin-colored and hyperpigmented macules were interspersed within the depigmented macules on the trunk and lower extremity (darker in the elder child). The entire back, hands and feet, upper extremity and mucosae were completely spared. A well-circumscribed white forelock in the mid-frontal region with a depigmented macule on the middle of the forehead was also seen in both children [Figure 2]. The hairs of the eyebrows at the medial aspect were also depigmented in the younger child. The children had no obvious ocular, hearing or neurological defects. The physical and mental development was normal. There was no history of consanguinity amongst the parents. The audiograms of both the children were normal. Routine biochemical tests were also normal.

Figure 1

Depigmentation on the trunk and mid-portion of lower extremities in two siblings. Note the islands of hyperpigmented macules within depigmentation

Figure 2

White forelock and depigmented macule on mid-forehead. Also note the whitening of hair of the medial one-third of eyebrows

A similar pattern of depigmentation was seen in the father. There was a history of similar depigmented patches in the grandfather [Figure 3]. The rest of the family members were not involved. Both, father and grandfather had depigmented macules with leucotrichia on the lower extremity and trunk with almost similar distribution of lesions as seen in the children. White forelock in frontal region was also present. There was a history of spontaneous repigmentation (to some extent) of depigmented macules with the age in both father and grandfather.

Figure 3

Pedigree chart depicting the pattern of inheritance (black color represents members having piebaldism)

DISCUSSION

Piebaldism is a rare autosomal dominant disorder characterized by the congenital absence of melanocytes in affected areas of the skin and hair due to mutations of the c-kit gene, located on Chromosome 4q12, which affects the differentiation and migration of melanoblasts from the neural crest during the embryonic life. The c-kit gene encodes the cell-surface receptor transmembrane tyrosine kinase for the steel factor, an embryonic growth factor.[1] The literature contains 14 point mutations, nine deletions, two nucleotide splice mutations, and three insertions of the c-kit gene, all causing piebaldism with a range of phenotypes.[2] In a study of 26 unrelated patients with a piebaldism-like depigmentation, 17 patients had classic lesions, five had atypical clinical features or family histories, and four had other disorders. Pathologic mutations or deletions of the kit gene were found in 10 (59%) of the typical patients and in two (40%) of the atypical patients. None of the patients without c-kit mutations had apparent abnormalities of the steel factor gene.[3]

Clinical manifestations and phenotypic severity of piebaldism strongly correlate with the site of the mutation within the c-kit gene. Dominant negative missense mutations of the intracellular tyrosine kinase domain appear to yield the most severe phenotypes, while mutations in the amino terminal extracellular ligand-binding domain result in haplo insufficiency and are associated with the mildest forms of piebaldism.[2] Intermediate phenotypes are seen with mutations near the transmembrane region. The classic type of static piebaldism is due to c-kit gene mutations in the vicinity of codon 620.

The incidence of piebaldism is estimated to be less than 1:20000. Both males and females are equally affected, and no race is spared.[4] Affected individuals present at birth with a relatively stable and persistent depigmentation of the hair and skin, although in a number of patients, repigmentation may occur spontaneously, either partially or completely, especially after injury.[5] A white forelock of hair arising from a triangular, elongated or diamond-shaped, midline, depigmented macule on the forehead may be the only manifestation in 80-90% of cases.[6] Eyebrows and eyelashes may also be affected. The characteristic distribution of depigmented macules includes central macule on forehead with white forelock, anterior abdomen extending to the chest, the lateral trunk sparing the dorsal spine, the mid-arms and legs sparing the hands, and feet.[4] Depigmented macules are rectangular, rhomboid or irregular in shape and usually have a symmetrical distribution. Typically, islands of hyperpigmentation are present within and at the border of depigmented areas.[4]

Melanocytes are absent or considerably reduced in depigmented patches histologically and ultrastructurally. They are normal in number in the hyperpigmented areas. Other conditions characterized by depigmentation of hair and skin need to be considered, in particular albinism and vitiligo, which may be congenital [Table 1]. Albinism is another congenital genetically inherited disorder, but is characterized by partial or complete absence of melanin production in the skin, hair and eyes. Vitiligo may rarely be present at birth, but is usually acquired later in life, is unstable and is not genetically inherited, although it may run in some families. The appearance of depigmented macules since birth, presence of white forelock in the frontal region, typical distribution of depigmented macules, their relative stability since the time of appearance and presence of a similar pattern of depigmented macules in other family members make the diagnosis of piebaldism easier.

Table 1

Comparative features of Piebaldism, Vitiligo, Albinism and Waardenburg's syndrome

Pigmentary anomalies in piebaldism are typically restricted to the hair and skin. However, rare associations have been reported with piebaldism, in particular Hirschprung's disease or aganglionic megacolon, supporting evidence of a network of interacting genes and proteins for the regulation of melanocytes and enteric plexus neurons during their development at the time of embryogenesis.[7] Neurofibromatosis Type I was associated with piebaldism on a few occasions.[89] A piebald patient with congenital dyserythropoietic anemia Type II (HEMPAS) and a patient with Diamond-Blackfan anemia have been reported.[1011] Grover's Disease or transient acantholytic dermatosis limited to the depigmented macules in a piebaldism patient has been described.[12]

A number of syndromes associate piebald-like hypopigmentation of the skin and hair with other anomalies, but are not associated with anomalies of the kit gene. Waardenburg's syndrome, an autosomal dominant disorder is characterized by a congenital white forelock, lateral displacement of the medial canthi, a hypertrophic nasal root, partial or total heterochromia of the iris and sensorineural deafness [Table 1]. All anomalies of Waardenburg's syndrome involve the neural crest from which are derived not only melanocytes, but also gut enteric plexus ganglion cells and other neural tissue as well as connective tissue of the head and neck.[1314] Ziprkowski and Margolis in 1962 described an X-linked recessive disorder characterized by hypomelanosis, deafness and mutism in a Jewish Israeli family of Sephardic origin.[15] It has now been included in the albinism-deafness syndrome (ADFN) and the gene has been localized to Xq24-q26 but not identified.[16] Woolf first reported piebaldism, in association with congenital deafness, in 1965 in two Hopi Indian brothers in Arizona.[17] The Tietz syndrome was first described as a congenital generalized depigmentation and profound congenital sensorineural deafness, transmitted as an autosomal dominant trait with full penetrance, and attributed to a mutation in the micropthalmia-associated transcription factor (MITF) gene in descendants of the same family.[18]

Treatment is a challenge. A combination of dermabrasion and grafting of pigmented skin into depigmented areas, with or without phototherapy, may be worthwhile in selected patients. Depigmented areas may be treated with thin split-thickness grafts and minigrafting or with in vitro cultured epidermis and suction epidermal grafting with additional minigrafting.[19] All patients with piebaldism had excellent repigmentation with transplantation. Grafts of epidermal sheets were found to be technically easier and to yield the best results, except on the elbow and arms. Phototherapy alone has little effect, but is helpful after transplantation. Recently, transplant of autologous melanocytes obtained through the culture of melanocytes or of melanocytes and keratinocytes has been described as a safe and effective treatment for patients with piebaldism.[2021] This induced scarless repigmentation using a small donor site. After these procedures, phototherapy can be used.