The term albinism describes a heterogenous group of genetic disorders of pigmentation that affect the eyes and visual system and, in some cases, hair and skin. The principal ocular features include nystagmus, iris transillumination defects, fundal hypopigmentation, photophobia, and hypoplasia of the fovea and optic nerve head. Visual acuity is usually reduced. Albinism can be classified into two major categories: oculocutaneous albinism (OCA) in which the hypopigmentation involves the skin, hair, and eyes; and ocular albinism (OA) with clinical involvement limited to the eye and visual system. OCA is inherited in an autosomal recessive pattern; autosomal dominant inheritance has been described rarely.1 Although autosomal recessive inheritance has been documented,2 OA is usually inherited in an X-linked recessive manner. Albinoidism is a term that has been used to describe a condition of ocular hypopigmentation without nystagmus associated with good visual acuity3 and does not refer to a single genetic disorder. It is used to describe the hypopigmentation associated with syndromes such as Prader-Willi or with Menkes disease.4 Albinoidism, unassociated with a syndrome, has been reported as an autosomal dominant trait in a small number of families.5,6
In individuals born of parents with dark skin, the presence of OCA is readily apparent on the basis of skin pigmentation. However, in individuals born of parents with light skin, the diagnosis may be difficult because of normal variability of pigmentation; an ocular examination is often useful for diagnosis. Traditionally, the ocular features considered necessary for this diagnosis include nystagmus, iris transillumination defects, and optic nerve head and foveal hypoplasia. As iris transillumination defects and optic nerve head size and coloration vary considerably within the population, and foveal hypoplasia is an imprecise determination, the presence of nystagmus has been an essential criterion for diagnosis.
We present a sibship of a boy with little or no skin pigmentation who was given the diagnosis of OCA on the basis of nystagmus, extensive iris transillumination defects, and hypoplasia of the optic nerves and foveae, and his similarly pigmented sister who had no nystagmus, but whose iris and fundus examination showed the classical features of albinism.
The proband is a 4V2-year-old boy who was noted to have nystagmus at 5 months of age and was given the diagnosis of OCA at 6 months. At the age of 11 months, he was evaluated by the UCLA Vision Genetics Center. He developed an exotropia at 2V2 years of age and underwent surgery. His mother indicated that he did not tan in the sun and that he was not Photophobie. On physical examination, he had white hair and unpigmented skin (Fig 1).
On ocular examination, visual acuity was 20/80 in each eye; a fine, horizontal, pendular nystagmus was noted. Extensive transillumination defects were evident at the base of the iris for 360° (Fig 2A); slit-lamp biomicroscopy was otherwise normal. Refraction following atropine cycloplegia showed +2.50 diopters in the right eye and + 1.50 D in the left. On ophthalmoscopy, he was found to have a very blond fundus with optic nerve and foveal hypoplasia (Fig 3A).
FIGURE 1: Face of the proband showing white hair and unpigmented skin; his sister's pigmentation was similar.
Because of the possibility of recurrence in future offspring, the family was evaluated at the UCLA Genetics Center. His sister, aged 2V2 years, was reported to have no visual problems; the mother indicated that she did not tan. Neither nystagmus nor photophobia had been noted.
On physical examination, she had white hair and a complexion very similar to her brother's; a pink nevus on the right forearm was noted. On ocular examination, she had a best corrected visual acuity in each eye of 20/40 by E game. There was no clinically detectable nystagmus. An exophoria was evident when viewing distant targets. She had multiple iris transillumination defects (Fig 2B); slitlamp biomicroscopy was otherwise normal. Refraction by retinoscopy after instillation of phenylephrine (2^2%) and cyclopentolate (%%) showed +1.50/+1.0O × 90.00 D in the right eye and + 0.50/ + 2.00 × 90.00 D in the left. On ophthalmoscopy, she had optic nerve and foveal hypoplasia with a blond fundus bilaterally (Fig 3B).
The mother of the children was examined for evidence of the carrier status of X-linked ocular albinism. On physical examination, she was fair skinned, with light brown hair. On ocular examination, she had normal visual acuity (20/20) in each eye; no nystagmus or iris transillumination defects were evident. Slit-lamp biomicroscopy was normal. Refraction was - 2.50 D in each eye. TTiere was no evidence of mottling of the choroid or retinal pigment epithelium in either eye; the optic nerves and maculae were normal.
There is no known parental consanguinity.
MATERIALS AND METHODS
Pattern visual evoked response (VER) was tested in each child using a method described by Creel and colleagues.7 The hair bulbs of the proband were examined by standard electron microscopy without dopa incubation for giant melanosomes. Each of the five exons of the tyrosinase gene was separately amplified from genomic DNA from the proband by polymerase chain reaction (PCR), and directly sequenced by the dideoxy chain termination technique, using a Taq DNA polymerase sequencing kit (US Biochemical Corp, Cleveland, Ohio).8,9
Using Creel's method of monocular stimulation in each eye with an on-off checkerboard pattern stimulus, we were unable to generate sufficient wave forms to demonstrate an asymmetry between the two eyes in each child.
Electron microscopy of the hairbulbs of the proband did not show evidence of macromelanosomes. Melanocyte and melanosome architecture was normal and stage II and III premelanosomes, but no fully melanized melanosomes (stage W), were present (Fig 4).
No alteration in the base sequence was found within the coding regions of the five exons of the tyrosinase gene of the proband.
OCA and OA are a heterogenous group of genetic diseases that have a common spectrum of phenotypic expression; specific diagnosis may be difficult. Visual acuity ranges from 20/30 to 20/400 and may correlate with the level of nystagmus which has been considered to be a consistent feature. Other nonspecific findings include iris transillumination defects, fundus hypopigmentation, and hypoplasia of the fovea and the optic nerve head. Although iris transillumination defects are a useful criterion for diagnosis in all forms, approximately 10% of normal individuals exhibit this finding.10 Furthermore, lightlypigmented fundi may be seen in normal individuals.
In addition to the ocular features, a clinical diagnosis of OCA is based on skin pigmentation. Hypopigmentation of hair and skin is variable, particularly in the tyrosinaserelated form of OCA, and often overlaps with what is considered normal variation in the population.3,4 Skin and hair pigmentation is clinically normal in X-linked OA; abnormal giant melanosomes are evident by electron microscopy in both hair and skin in affected individuals and carriers.2
Evidence of misrouted visual pathways has been demonstrated by VER studies in both OCA and OA11 and also may be useful for diagnostic purposes. Unlike normal humans where 45% to 50% of optic nerve fibers (mainly those from the temporal retina) remain uncrossed in the chiasm, anatomic studies in a man with OCA12 and other animals13,14 have shown that the majority of these fibers decussate at the optic chiasm. Creel and colleagues7,15 have demonstrated an asymmetrical response to monocular stimulation of each optic nerve with pattern appearancedisappearance stimuli in over 90% of albinos (OCA and OA); other authors have confirmed these findings.16
FIGURE 2: Retroillumination of the right eyes in the (A) proband and (B) his sister showing transillumination defects of the irides.
FIGURE 3: Right fundus of (A) the proband and (B) his sister showing hypopigmentation of the fundi with foveal and optic nerve head hypoplasia. Note retinal vessels through maculae.
The tyrosinase gene has been isolated and sequenced recently.17,18 Giebel and coworkers19 used the polymerase chain reaction (PCR) to amplify the gene in individuals with type IA OCA and found a mutation in codon 81 (exon 1) in 6 out of 30 OCA alleles. This mutation is the basis of some forms of clinically-diagnosed type IA OCA and sequencing of this gene in an affected individual should permit accurate diagnosis. The specific gene(s) responsible for type II OCA has (have) not been identified.
The proband reported herein has a form of albinism based on the nystagmus, decreased visual acuity, iris transillumination defects, fundus hypopigmentation, and optic and foveal hypoplasia; his sister is similarly affected based on the ocular hypopigmentation and optic and foveal hypoplasia. If X-linked ocular albinism was the basis of the disease, one could postulate uneven lyonization to explain the findings in the sister. However, OA is unlikely because of the absence of giant melanosomes in the hairbulbs of the proband and the absence of carrier findings in the mother. Furthermore, the cutaneous pigmentation, namely, fair hair and skin coloration, combined with the iris transillumination defects and fundus findings in both brother and sister support the diagnosis of OCA. We were unable to demonstrate asymmetry in the monocularly stimulated pattern VERs from each eye in the proband and his sister and believe this may be due to the patients' ages and relative inability to cooperate. The melanocyte structure is normal and stage I, II, and III premelanosomes are found, but fully melanized stage PV melanosomes are lacking. The clinical and the ultrastuctural studies do not indicate the specific type of OCA.
FIGURE 4: Electron photomicrograph ofhairbulb of melanocyte of proband showing stage II (solid arrow) and III (open arrow) premelanosomes (× 37 000).
Nystagmus is often identified as a consistent feature in all forms of albinism and may be the most reliable sign in a fair or blond individual. Although the amplitude of nystagmus probably correlates to some extent with visual acuity, the relationship is unclear. The cause of the nystagmus in hypopigmentation syndromes is unknown but may be related to the decussation abnormalities in the chiasm or hypoplasia of the fovea and/or optic nerve. Despite the extensive literature on albinism, individuals without nystagmus rarely have been given the diagnosis.20·21 The presence of nystagmus in the proband in our study contrasts sharply with its absence in his sister. The identical fundus findings, and skin and hair coloration suggest that they have the identical gene defect and demonstrate significant intrafamilial variability with respect to nystagmus. The identification of these siblings who have the identical gene defect provides important information regarding the variability of nystagmus in the clinical spectrum of the albinism.
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