Oculocutaneous Albinism with Melanosomal Abnormalities (See Table 645-1)

Hermansky-Pudlak syndrome is a collection of autosomal recessive genetic disorders characterized by oculocutaneous albinism, ceroid accumulation in lysosomes, and prolonged bleeding time. In mice, 16 distinct genetic loci that produce coat color mutant phenotypes associated with platelet deficiencies are recognized; eight have been identified in humans.

Chédiak-Higashi syndrome (CHS; Chapter 124) is another genetic abnormality associated with dysfunction of lysosome-related organelles. Patients with CHS have hypopigmentation of the skin, eyes, and hair; prolonged bleeding times and easy bruising; recurrent infections; abnormal natural killer cell function; and peripheral neuropathy. CHS is caused by mutations in the CHS1/LYST gene, which is a lysosomal trafficking regulatory gene.

Piebaldism

A congenital autosomal dominant disorder, piebaldism is characterized by sharply demarcated amelanotic patches that occur most frequently on the forehead, anterior scalp (producing a white forelock), ventral trunk, elbows, and knees. Islands of normal or darker than normal pigmentation may be present within the amelanotic areas (Fig. 645-2). The plaques are a result of a permanent localized absence of melanocytes. The pattern of depigmentation arises from defective melanoblast migration from the neural crest during development. The reason that piebaldism is a localized and not a generalized process remains unknown. Piebaldism must be differentiated from vitiligo, which may be progressive and is not usually congenital, nevus depigmentosus, and Waardenburg syndrome.

Figure 645-2 Depigmented macule with islands of hyperpigmentation in piebaldism.

Waardenburg Syndrome

Waardenburg syndrome also manifests at birth as localized areas of depigmented skin and hair. There are four types of Waardenburg syndrome. The hallmark of Waardenburg type 1 is the white forelock, which is seen in 20-60% of patients. Only 15% of patients have areas of depigmented skin. Deafness occurs in 9-37%, heterochromia irides in 20%, and unibrow (synophrys) in 17-69% of those affected. Dystopia canthorum (i.e., telecanthus) is seen in all patients with Waardenburg type 1. Waardenburg type 2 is similar to type 1, except that patients with type 2 lack dystopia canthorum, but they also have a higher incidence of deafness. Waardenburg type 3 is similar to Waardenburg type 1, except that patients also have limb abnormalities. It is also called the Klein-Waardenburg syndrome. Waardenburg type 4 is also called the Shah-Waardenburg syndrome. Patients with this type all have Hirschsprung disease. Dystopia canthorum is seldom seen in these patients.

Tuberous Sclerosis Complex (TSC1, TSC2 Genes)

See Chapter 589.2 for a discussion of this complex.

Hypomelanosis of Ito

Hypomelanosis of Ito is a congenital skin disorder affecting children of both sexes and frequently associated with defects in several organ systems. There is no evidence for genetic transmission; chromosomal mosaicism and chromosomal translocations have been reported. Hypomelanosis of Ito is currently a descriptive rather than definitive diagnosis. Blaschkoid hypomelanosis is a better descriptive term.

The skin lesions of hypomelanosis of Ito are generally present at birth but may be acquired in the first 2 years of life. The lesions are similar to a negative image of those present in incontinentia pigmenti, consisting of bizarre, patterned, hypopigmented macules arranged over the body surface in sharply demarcated whorls, streaks, and patches that follow the lines of Blaschko (Fig. 645-3). The palms, soles, and mucous membranes are spared. The hypopigmentation remains unchanged throughout childhood but fades during adulthood. The degree of depigmentation varies from hypopigmented to achromic. Neither inflammatory nor vesicular lesions precede the development of the pigmentary changes as in incontinentia pigmenti. The hypopigmented areas demonstrate fewer and smaller melanocytes and a decreased number of melanin granules in the basal cell layer than normal. Inflammatory cells and pigment incontinence are lacking.

Figure 645-3 Marbled hypopigmented streaks on the abdomen in hypomelanosis of Ito.

The most commonly associated abnormalities involve the nervous system, including mental retardation (70%), seizures (40%), microcephaly (25%), and muscular hypotonia (15%). The musculoskeletal system is the second most frequently involved system, affected by scoliosis and thoracic and limb deformities. Minor ophthalmologic defects (strabismus, nystagmus) are present in 25% of patients, and 10% have cardiac defects. These frequencies are likely to be overestimated because patients with isolated skin disease often do not seek further evaluation. The differential diagnosis includes systematized nevus depigmentosus, which is a stable leukoderma not associated with systemic manifestations. Differentiation from incontinentia pigmenti, particularly the hypopigmented fourth stage, is critical for genetic counseling because incontinentia pigmenti, unlike hypomelanosis of Ito, is inherited.

Vitiligo

Clinical Manifestations

There are two subtypes of vitiligo, generalized (nonsegmental) and segmental, which probably are distinctly different diseases (Table 645-2). Generalized vitiligo (85-90% of cases) may be divided into widespread (type A) and localized (type B). About 50% of all patients with vitiligo have onset before 18 yr of age, and 25% demonstrate depigmentation before age 8. Most children have the generalized form, but the segmental type is more common among children than among adults. Patients with the generalized form usually present with a remarkably symmetric pattern of white macules and patches (Fig. 645-4); the margins may be somewhat hyperpigmented. The patches tend to be acral and/or periorificial. Occasionally, almost the entire skin surface becomes depigmented.

Table 645-2 TYPICAL FEATURES OF SEGMENTAL AND NONSEGMENTAL VITILIGO

SEGMENTAL VITILIGO	NONSEGMENTAL VITILIGO
Often begins in childhood	Can begin in childhood, but later onset is more common
Has rapid onset and stabilizes	Is progressive, with flare-ups
Involves hair compartment soon after onset	Involves hair compartment in later stages
Is usually not accompanied by other autoimmune diseases	Is often associated with personal or family history of auto-immunity
Often occurs in the face	Commonly occurs at sites sensitive to pressure and friction and prone to trauma
Is usually responsive to autologous grafting, with stable repigmentation	Frequently relapses in situ after autologous grafting
Can be difficult to distinguish from nevus depigmentosus, especially in cases with early onset

From Taïeb A, Picardo M: Vitiligo, N Engl J Med 360:160–168, 2009.

Figure 645-4 Sharply demarcated, symmetric, depigmented areas of vitiligo.

There are several varieties of localized vitiligo. A form of localized vitiligo is the halo nevus phenomenon, whereby benign moles develop depigmented rings at the periphery. Premature graying of scalp hair (canities) has also been considered a form of localized vitiligo. In segmental vitiligo, depigmented areas are limited to a quasidermatomal distribution. This type of vitiligo has a rapid onset and progression in a localized area without the development of depigmentation in other areas.

A number of autoimmune diseases occur in patients with vitiligo, including Addison disease, Hashimoto thyroiditis, pernicious anemia, diabetes mellitus, hypoparathyroidism, and polyglandular autoimmune syndrome with selective immunoglobulin (Ig) A deficiency. In addition, other diseases with possible immune defects, such as alopecia areata and morphea, have been seen in patients with vitiligo.

Vogt-Koyanagi-Harada syndrome is vitiligo associated with uveitis, dysacusia, meningoencephalitis, and depigmentation of the skin, scalp hair, eyebrows, and eyelashes. In the Alezzandrini syndrome, vitiligo is associated with tapetoretinal degeneration and deafness.

Light microscopic examination of early lesions shows mild inflammatory change. Over time, degenerative changes occur in melanocytes, leading to their complete disappearance.

The differential diagnosis of vitiligo includes other causes of widespread acquired leukoderma. The two most common problem diagnoses are tinea versicolor and postinflammatory hypopigmentation.