Main

Sir,

Increased homozygosity leads to the expression of recessive genes in the children of consanguineous unions. There is also the possibility of noninherited genetic disease in such patients, and this should not be overlooked.

Case report

An 11-month-old girl was initially referred to us in 1988 with nystagmus, recently noticed by her 35-year-old mother. She was systemically well as were her five elder siblings. Her parents are second cousins, but there was no family history of ocular or systemic pathology (Figure 1).

Figure 1
figure 1

Family tree demonstrating recessive allele transmission probabilities.

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Examination confirmed the presence of horizontal jerk nystagmus and revealed bilateral iris transillumination. Her family is of Pakistani origin, and her irides were a paler brown colour than might have been considered the usual norm. No hypopigmentation of her skin was noted.

She was followed up over the next few years and found to have hypoplastic maculae (Figure 2a).

Figure 2
figure 2

(a) Bilateral hypoplastic maculae. (b) Right posterior pole cataract.

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By the age of 3 she was noted to have developed a right posterior pole lens opacity (Figure 2b). The vision in each eye was 6/60 with a small hypermetropic astigmatic correction, achieving 6/36 binocularly, and it was felt that there would be no benefit to be gained from surgery for this cataract. A diagnosis of ocular albinism was made, presumed to be autosomal recessive, with a coincidental left lens opacity. We have not as yet been able to perform the visual evoked potential examination that would be necessary to demonstrate the abnormally increased decussation of retino-geniculate axons at the chiasm, which would be expected to confirm the clinical diagnosis of ocular albinism.

By the age of 8, systemic features brought her to the attention of the clinical genetics department with learning difficulties, height below the 1st centile, head circumference on the 10th centile, a single subcutaneous nodule on her chest wall, enlargement of her left labia majora and cutaneous lesions. These consisted of five raised, hairy lesions, 5–15 mm in diameter on her arms, with 10 small pale macules across her trunk and thighs, each 2–3 mm in diameter. She also had two larger pale patches on her buttocks, of 3–4 cm diameter.

The chest wall nodule was biopsied and found to be a plexiform neurofibroma, which led to neuro-axial MRI scans being performed. Bilateral acoustic neuromas and multiple spinal cord tumours were found, thus establishing the diagnosis of neurofibromatosis type 2 (NF2). Mutation screening for NF2 was performed and a mutation affecting the conserved splice donor site of intron 4 of the NF2 (schwannomin) gene, 447+2TC, was found. Although this is not a classic NF2 mutation, it was felt to account fully for the phenotype. The conjunction of clinical NF2 and ocular albinism raised the possibility of a chromosomal abnormality; the karyotype was normal however.

She is now 14 years old with stable visual acuities of 6/60 right eye, 6/36 left eye and persistent manifest horizontal jerk nystagmus. There has been no progression of the cataract. Her parents and siblings have been examined fully in the Ophthalmology Department and none of them have been found to show any signs of either NF2 or ocular albinism. Family interview revealed no history whatsoever of premature loss of hearing or any other neurological manifestations of NF2, nystagmus or poor vision.

Comment

The coincidence of autosomal recessive ocular albinism and NF2 in the same individual has not, to our knowledge, been described before. The clinical diagnosis of ocular albinism was made on the basis of the iris pallor and transillumination, nystagmus, hypopigmented fundus and hypoplastic maculae. Although autosomal recessive ocular albinism is rare, the consanguineous parentage would support this diagnosis.

Either parent in generation 1 could be carrying the recessive allele for ocular albinism (Figure 1). The probability of a recessive allele being expressed in subsequent children of this second-cousin marriage would be 0.5 × 0.5 × 0.5 × 0.5 × 0.5 × 0.5 × 0.5 = 1/128. The same would apply for any recessive allele from either parent in generation 1.

The NF2 is most likely a new mutation as 95% penetrance for bilateral vestibular schwannomas would be expected, and this would have almost certainly appeared phenotypically in the family history.1 Of the NF2 cases, 50% present with no antecedent family history, so it is not unusual to find this as a new mutation. Genetic counselling was therefore reassuring, as the risk of either conditions appearing in subsequent children is very low.

The first clinical manifestation of NF2 in our patient was the posterior subcapsular cataract, a finding in around 80% of cases of NF2.2 The subcutaneous plexiform neurofibroma found in this case is not typical of NF2, and does not carry the risk of malignant degeneration expected in similar lesions of NF1.3

Ocular abnormalities are often the first sign of NF2,4 the coincidence of the cataract and the ocular albinism perhaps leading to less attention being paid to the cataract than might otherwise have been the case.