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The eyes are not notably small although several patients have been reported to have significant hyperopia. Vision can be impaired and some individuals have early-onset nystagmus. The ERG responses are attenuated and may be absent. The retina is dysplastic with multiple atrophic punched-out lesions, attenuated retinal vessels, and sparse pigmentation. Large retinal folds have been described and one patient developed a retinal detachment. Optic atrophy was noted in one individual.
Microcephaly of 3-4 standard deviations below normal is a constant feature. Motor and language abilities can be mildly delayed and several patients have had mild learning difficulties. Brain imaging has been normal in most individuals but a shortened and thin corpus callosum was present in one patient.
Family and genetic evidence suggest autosomal recessive inheritance. Compound heterozygous mutations in the TUBGCP4 gene (15q15.3) is part of a protein complex involved in microtubule organization.
Low vision aids may be helpful in selected patients.
Abnormal retinal angiogenesis with retinal ischemia is the development defect that leads to the clinical features of the familial exudative vitreoretinopathies. It is usually bilateral. There is considerable clinical heterogeneity in the appearance of both the retina and the vitreous but common to all is the presence of peripheral areas of avascularity in the retina that may be seen in newborns. This may only be visible using fluorescein angiography in mild cases. The vessels may be hyperpermeable resulting in patchy exudates in the retina. Neovascularization often develops with retinal and vitreous bleeding and eventually retinal traction resulting in retinal folds and detachments. Severe disease with early onset may result in blindness in infants but milder disease may be asymptomatic even as adults. Cataracts may result.
The ocular disease may be confused with retinal dysplasia (as seen in pseudogliomas and Norrie disease) or retinopathy of prematurity.
No systemic features have been reported in EVR3.
This is likely an autosomal dominant disorder based on pedigree evidence but no specific mutation has been found. A disease locus at 11p13-p12 has been identified by linkage studies, located near the FZD4 gene containing the mutation responsible for EVR1.
Appropriate vitreoretinal surgery to release vitreous traction and to repair retinal detachments should be considered. Cataract removal may be beneficial. Low vision aids could be helpful in milder cases with residual vision.
The congenital lymphedema results in thickened and ptotic eyelids with prominent epicanthal folds. Congenital ptosis is not uncommon in the general population in the absence of lymphedema so that this feature by itself is insufficient to diagnose this syndrome. Retinal folds with variable degrees of pigmentary changes are often present. Narrowed retinal vessels, atrophic nerve heads and progressive chorioretinopathy have been reported. Visual acuity is often reduced, sometimes severely, and nystagmus may be present.
Coarse hair follicles over the dorsum of the hands and feet and white nails when combined with the thickened, ptotic eyelids suggest the presence of lymphedema. The hair pattern is often altered on the arms, nape of the neck, and the back. White lines in the palms are also suggestive. The ‘facial phenotype’ includes full cheeks, flat nasal bridge and underdeveloped supraorbital ridges, up slanting palpebral fissures, broad nose with rounded tip, anteverted nares, and a long philtrum, thin upper lip, and sometimes micrognathia. The ears may appear large. Children with this syndrome are often hypotonic during the newborn period but this feature is less evident later in childhood and improves more rapidly than the resolution of the lymphedema. The lymphedema usually improves during early childhood and is often confined to the dorsum of the hands and feet at that time. Psychomotor development is variably delayed and some but not all patients are mentally retarded. Microcephaly is a consistent feature.
Not all features are present in all patients and, specifically, there are often microcephalic relatives who lack other signs.
This is an autosomal dominant disorder may consist of more than one entity but at least some cases result from heterozygous mutations in KIF11 (10q23.33). The gene encodes a member of the kinesin family of proteins responsible for cytoplasmic mechanisms that are essential for spindle assembly and function as well as transportation of other intracellular organelles. Mutations in this gene have also been implicated in familial exudative vitreoretinopathy (FEVR) and there is phenotypic overlap with the condition described here.
It is not unusual for microcephalic individuals to also have chorioretinal dysplasia and/or pigmentary retinopathy. See microcephaly, chorioretinal dysplasia, mental retardation (156590), for a somewhat similar autosomal dominant condition, as well as microcephaly with chorioretinopathy, AR (251270) for an autosomal recessive condition with this combination. Neither of these conditions is associated with congenital lymphedema, however.
No treatment is known.
The ocular phenotype has not been well defined in this condition since few families have been reported. Microphthalmia is present in some patients. The corneas may be small and there is often some conjunctival growth over the limbus.
The retinal features consist of lacunar depigmentation of the RPE and in some cases resemble the lesions of congenital toxoplasmosis. Eighty to 90 per cent of patients have areas of atrophic and dysplastic-appearing lesions of the retina and choroid with vascular attenuation. The edges of lacunae may have patchy hyperpigmentation. These lesions are usually static but may show mild progression. Visual acuity is generally stable or only mildly progressive. However, other patients have a severe reduction in acuity. ERG responses are reduced.
The amount of microcephaly may be minimal and at least some patients have ‘bulging’ foreheads. The amount of mental deficiency varies from mild to severe. IQ levels are generally in the range of 60-70. Hypotonia has been reported in more severe cases. Skull size is usually 2-3 standard deviations below the mean and generally has some frontal prominence.
This seems to be an autosomal dominant disorder although no loci or mutations have been identified. It is likely that the category of disease known as microphthalmia-chorioretinal syndrome consists of a heterogeneous group of disorders. No locus or specific mutation has been identified.
It differs from the microcephaly, lymphedema, chorioretinopathy syndrome (152950) in which retinal folds, ptosis and lymphedema are associated with a typical facial phenotype. For other disorders in this database having a somewhat similar phenotype see: chorioretinopahty and microcephaly type 1 ((251270) and type 2 (616171).
Treatment is supportive. Low vision aids may be helpful.