Advanced bilateral persistent fetal vasculature associated with a novel mutation in the Norrie gene

Unilateral cases of persistent fetal vasculature (PFV) are sporadic,¹ while bilateral cases may be associated with X linked Norrie disease.² Associated sensorineural deafness and mental retardation in males³ may be absent,⁴ and genetic testing can be useful in separating sporadic PFV from Norrie disease as the following report illustrates.

Case report

A male proband (III:1, fig 1), the first child of healthy non‐consanguineous white parents, was born by normal vaginal delivery, at term, following normal pregnancy and weighed 3.64 kg. Bilateral PFV was noted (fig 2) with a normal systemic examination including hearing test. During bilateral vitreo‐lensectomy, severe retinal and optic nerve dysplasia was found. The four generation family history was negative for eye problems. Development at 15 months was normal. The karyotype was normal. A missense mutation in the Norrie disease gene (NDP) was identified in the proband. This was 123G>T, leading to an amino acid substitution of arginine to serine at codon 41 (R41S), which is a non‐conservative change. As this sequence change had not been previously reported in Norrie disease, it was unclear whether it was a pathogenic mutation or a polymorphism in the gene, unrelated to the patient's phenotype. Genetic testing of the mother (II:2, fig 1) identified the same mutation in the heterozygous form, indicating that it had not arisen de novo in the proband. In the absence of signs of PFV in the mother, genetic testing of other family members was performed. The mutation was absent from the proband's maternal grandparents, indicating that it had probably arisen on one of the maternal X chromosomes. It is therefore highly likely to be a pathogenic mutation.

Figure 1 Three generation pedigree. Males are shown as squares and females as circles. The proband is indicated with an arrow. The solid symbols represent affected individuals and open symbols represent unaffected individuals. A dot in the centre of a symbol represents an unaffected carrier.

Figure 2 Lenticular vascularisation of the left eye.

Comment

Norrie disease is an X linked disease causing bilateral blindness as a result of the primitive hyaloid failing to regress. The Norrie disease gene (NDP) maps to Xp11.3⁵,⁶ and has two coding exons. Multiple pathogenic mutations have been reported with no strong genotype‐phenotype correlation, although there is evidence that mutations at the 3′ end of the gene lead to a milder phenotype.⁷ In addition, intrafamilial variability of the ocular phenotype has been described.⁸ The sequence change in the Norrie gene detected in this family led to a non‐conservative amino acid change (R41S), but it was not certain that this variant would have a functional effect since it had not been reported previously. Family studies have, however, demonstrated that it is a de novo change, probably arising in the grandparental germline, and is therefore likely to be pathogenic. The proband's mother was 24 weeks' pregnant and the study suggested a low recurrence risk for isolated PFV, but a one in two chance that future sons would have Norrie disease, and a one in two chance that any future daughters would be carriers. Prenatal testing was declined, but this could be offered in future pregnancies. The proband's maternal aunt can be offered carrier testing because although the mutation most likely arose de novo in the proband's mother, the possibility that one of the proband's maternal grandparents might carry the mutation in a mosaic form cannot be excluded.