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Etiology

image Prader–Willi and Angelman syndromes, whose clinical manifestations are described later but which can include cutaneous hypopigmentation, are associated with paternal or maternal, respectively, deletions of regions of the long arm of chromosome 15 containing a portion of the P gene. Hypopigmentation in these patients, who remain hemizygous for the P gene in the context of their large 15q deletion, suggests that there may be other genetic determinants of pigmentation in the chromosome 15 region of the P gene. Less commonly, these syndromes are associated with chromosome 15q uniparental disomy, or the exclusive presence of two copies of 15q from one parent, with maternal disomy associated with Prader–Willi's syndrome and paternal disomy associated with Angelman's syndrome.3 In addition, Prader–Willi's syndrome or Angelman's syndrome patients with OCA2 have been described with a typical deletion of one homolog of the P gene in the context of Prader–Willi's syndrome or Angelman's syndrome and inheritance of a mutation on the another homolog.61

Clinical Features

image Prader–Willi's syndrome is a developmental syndrome that includes neonatal hypotonia, hyperphagia and obesity, hypogonadism, small hands and feet, and mental retardation associated with characteristic behavior. Many individuals with Prader–Willi's syndrome are hypopigmented but do not have the typical ocular features of albinism; however, individuals with Prader–Willi's syndrome can have typical features of OCA. For those without OCA, the hypopigmentation is characterized by hair and skin that are lighter than unaffected family members. Childhood nystagmus and strabismus are common but often do not persist into adult life. The irides are pigmented with some translucency on globe transillumination, and retinal pigment is reduced in amount. Foveal hypoplasia usually is not present, but the fovea may not appear entirely normal. Visual evoked potential studies have revealed optic tract misrouting similar to that found in albinism in some individuals with Prader–Willi's syndrome and hypopigmentation, but this is not a universal finding. Some individuals with Prader–Willi's syndrome have typical OCA2 with cutaneous hypopigmentation and all ocular features of albinism.

image Angelman's syndrome is a complex developmental disorder with developmental delay and severe mental retardation, microcephaly, neonatal hypotonia, ataxic movements, and inappropriate laughter. In Angelman's syndrome, the hypopigmentation is characterized by light skin and hair. Nystagmus or strabismus may be present early in life, and iris translucency and reduced retinal pigment may be present. No analysis of optic nerve formation is available. As in Prader–Willi's syndrome, individuals with Angelman's syndrome who have typical OCA2 features have been described.62

Oculocutaneous Albinism Type 3

Mutations in the TYRP1 gene result in OCA3 (OMIM #203290). The first described mutation was in an African-American newborn twin initially classified clinically as brown OCA. Mutation analysis revealed a single-base deletion at codon 368 producing a frameshift and premature stop codon in exon 6 and a slightly truncated TYRP1 molecule.63 This mutation is shared by a substantial proportion of the rufous (“red”) OCA population in southern Africa.64 Rufous OCA is a distinct OCA phenotype in which the skin color is a mahogany brown with a slight reddish hue, and the hair color varies from deep mahogany to sandy red.2,64 Additional OCA3-associated TYRP1 mutations include a single-base substitution at codon 166, resulting in the alteration of a serine to a premature stop codon in exon 3 and a truncated TYRP1 molecule,64 also identified in the rufous OCA population; and, in a Pakistani kindred, individuals homozygous for a distinct premature termination mutation.65 A Caucasian male was compound heterozygous for a missense mutation in TYRP1 located in the second copper-binding domain, inherited from the patient's mother, and a stop codon, which apparently occurred spontaneously.66 Interestingly, the p.S166X mutation in TYRP1 previously associated with rufous OCA64 was found to modify an OCA2 phenotype to a red-haired variant.67

OCA3 has presented with both the brown OCA and the rufous OCA phenotypes in the African and African-American populations. In the two cases of individuals with OCA3 mutations only, not of African descent, the phenotype has been that of a tyrosinase-positive albinism, such as OCA1B or OCA2. As additional examples of OCA3 are characterized, genotype–phenotype correlation should become clearer.

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