Vitreous

Clinical and histologic findings

Norrie disease is an X-linked recessive disorder associated with disease-causing variants in the NDP gene. Affected males are blind at birth or in early infancy due to bilateral retinal dysplasia. Some affected males are developmentally delayed and about one-third later develop cochlear deafness, usually starting in late teenage years. Other medical problems may become apparent over time, including seizure disorders, autism, and peripheral vascular disease. A more severe systemic phenotype is seen in patients with large chromosomal deletions encompassing the Norrie gene locus. Ocular findings include bilateral cataracts, bilateral retinal folds, retinal detachment, vitreous hemorrhage, and bilateral vitreoretinal dysplasia ( Fig. 41.3 ). The retinal detachments are usually present at birth and have been observed in utero by ultrasonography. Most cases progress to an extensive vitreoretinal mass and bilateral blindness. Angle closure glaucoma may develop; this is best managed by lensectomy. Late signs include corneal opacification, band keratopathy, and phthisis bulbi (see Fig. 41.3 ).

Carrier females do not usually show any ocular abnormality or electroretinography abnormalities, but symptomatic carriers have been rarely reported. One affected female born to a carrier mother had a retrolental mass in the right eye and a retinal fold with a tractional retinal detachment in the left. Molecular genetic testing confirmed that she was a manifesting heterozygote. She had skewed X-inactivation in her peripheral blood lymphocytes, suggesting non-random X inactivation, with inactivation occurring more frequently in the normal rather than the mutant X chromosome. A female with Norrie disease with an X autosome translocation has also been described.

Molecular genetics and pathogenesis

More than 100 disease-causing variants have been identified in the Norrie disease gene NDP . A variety of variants have been reported including missense, splice site, nonsense, and deletions. There is no clear genotype–phenotype correlation for intragenic variants, but patients with contiguous gene deletions have a more severe extraocular phenotype. The encoded protein, Norrin, is a key component of the Wnt signaling pathway which plays an important role in the development of the anterior and posterior segment and is especially important in retinal vascular development ; abnormal Wnt signaling may result in other retinal disorders including familial exudative vitreoretinopathy and the osteoporosis–pseudoglioma syndrome (see later sections). The association of Norrie disease with peripheral vascular disease is evidence for a role of the NDP gene in extraocular angiogenesis.

Missense variants in NDP are associated with another rare vitreoretinal disorder, X-linked familial exudative vitreoretinopathy (see below). There is also evidence that Coats disease may be caused by a somatic variant in NDP in the retina of affected eyes, resulting in a deficiency of Norrin, with consequent abnormal retinal vascular development, the hallmark of Coats disease (see Chapter 48 ).

The role of NDP in retinopathy of prematurity (ROP) is controversial. Some case–control studies have suggested that sequence variants in NDP may predispose to stage 5 ROP; other studies have been negative. These studies have involved small numbers of subjects and the controversy will not be resolved until larger studies have been performed.

Ndp knock-out mouse models have a similar ocular phenotype to humans, with fibrous masses in the vitreous cavities, disorganization of retinal ganglion cells, and sporadic degeneration of other retinal cell types. The mouse model shows early abnormalities in retinal vascular development. This is further evidence for disordered retinal vascular development being the primary cause of the retinal detachment in Norrie disease. As in humans, these mice have progressive hearing loss leading to profound deafness, with abnormal vasculature and eventual loss of most of the vessels in the stria vascularis (the main vasculature of the cochlea), suggesting a principal function of Norrin in regulating the interaction of the cochlea with its vasculature.

Management

In most cases of Norrie disease, affected males have bilateral total retinal detachment from birth and vitreoretinal surgery is not indicated. Lensectomy may be indicated when there is shallowing of the anterior chamber and a risk of pupil-block glaucoma. It is important that children and their families have good educational and social support, and are referred for genetic counseling to discuss the risk of further affected pregnancies. Molecular diagnosis is possible in the majority of cases and prenatal or pre-implantation diagnosis is possible where the causative sequence variant is known. Early delivery of a fetus known to carry a Norrin variant followed by antivascular endothelial growth factor (VEGF) and laser treatment of the retina was shown to result in a good outcome with normal foveal structure. This suggests that in some families who choose this option, prenatal diagnosis, preterm delivery, and prompt laser treatment may prevent retinal detachment.

Clinical findings

The acronym “HARD ± E” stands for hydrocephalus, agyria, retinal dysplasia, with or without encephalocele ( Fig. 41.4 ). This autosomal recessive syndrome is characterized by type II lissencephaly, retinal dysplasia, cerebellar malformation, and congenital muscular dystrophy. Hydrocephalus is common. Other variable features of the Walker–Warburg syndrome (WWS) include Dandy–Walker malformation and encephalocele. Neonatal death is common and survivors are severely developmentally delayed. The ocular features in this disorder are variable and include microphthalmia, Peters anomaly, cataract, retinal coloboma, incomplete retinal vascularization, and retinal dysplasia.

Other rare autosomal recessive disorders characterized by the combination of congenital muscular dystrophy and brain malformations include muscle–eye–brain (MEB) disease and Fukuyama congenital muscular dystrophy (FCMD). Ocular abnormalities are a constant feature in MEB and WWS, but not in FCMD.

Molecular genetics and pathogenesis

Next generation sequencing has revolutionized the molecular diagnosis of WWS and related phenotypes; the disorders are highly heterogeneous with biallelic disease-causing variants in 18 genes identified to date. Variants in these genes result in defective α-dystroglycan, a key protein in muscle structure and also in neuronal migration in brain development.

Clinical findings

This autosomal recessive syndrome is characterized by osteoporosis, severe learning difficulties, and vitreoretinal dysplasia ( Fig. 41.5 ). Multiple fractures, often after minor trauma, are commonplace. Affected children present in infancy with bilateral nystagmus and severe visual impairment; the systemic features occur in later infancy and childhood. Ocular features include vitreoretinal dysplasia with retrolental masses, microphthalmia, anterior chamber anomalies, cataract, and phthisis bulbi. Most patients are blind from birth, but a few patients have useful vision into their teenage years. Referral to a bone specialist is essential as early treatment with bisphosphonates can increase bone density and possibly reduce the frequency of fractures.

Molecular genetics and pathogenesis

OPS is associated with disease-causing variants in the gene encoding the low-density lipoprotein receptor-related protein 5 ( LRP5 ). Variants in LRP5 have also been implicated in both autosomal recessive and autosomal dominant familial exudative vitreoretinopathy (FEVR). These patients have also been shown to have reduced bone mineral density, suggesting that osteoporosis–pseudoglioma syndrome and LRP5 -associated FEVR are part of a single phenotypic spectrum with both ocular and bone manifestations.

Studies of LRP5 indicate that it affects bone accrual during growth by regulating osteoblastic proliferation. Furthermore, LRP5 is a component of the Wnt signaling pathway, regulating retinal development and angiogenesis. Disease-causing variants in this gene result in disordered retinal vascularization.