Megalocornea-Mental Retardation Syndrome

Clinical Features

Neuhauser et al. (1975) reported a family in which 3 sibs were affected with megalocornea, iris hypoplasia, severe mental retardation, hypotonia, seizures, and minor facial anomalies, including frontal bossing, downslanting palpebral fissures, epicanthal folds, and broad nasal base. Four sporadic cases were also reported. Neuhauser et al. (1975) suggested autosomal recessive inheritance.

Schmidt and Rapin (1981) reported 2 unrelated patients with megalocornea associated with mental retardation. Both patients had hypotonia and facial features similar to those reported by Neuhauser et al. (1975).

Del Giudice et al. (1987) reported 2 unrelated cases, one of which occurred in a girl whose parents were third cousins. Her parents noticed hypotonia, slow psychomotor development, and prominent eyes during her first months of life. Gronbech-Jensen (1989) described a case with short stature and mild malformation of the left auricle. Kimura et al. (1991) described a patient with Neuhauser syndrome who also had primary hypothyroidism and delayed myelination observed on brain magnetic resonance imaging (MRI).

Santolaya et al. (1992) reported an affected patient. Hypotonia was noted at birth, and developmental delay was apparent soon after. Facial features included a round face, low frontal hairline, mild frontal bossing, broad nasal bridge, large corneas, mild hypertelorism, long upper lip, high palate, and small chin. She also had poor coordination. Santolaya et al. (1992) concluded that hypotonia is a major feature of this syndrome.

Antinolo et al. (1994) reported an isolated case of megalocornea, mental retardation, and hypotonia.

Sarkozy et al. (2002) reported a child with megalocornea-mental retardation syndrome who had also had primary hypothyroidism, osteopenia, and hypercholesterolemia. They suggested that the latter 3 features, previously described in only one case each, may be distinct features of MMR.

Derbent et al. (2004) reported a male child with features of Neuhauser syndrome, including mental and motor retardation, megalocornea, and generalized hypotonia. He had characteristic facies with frontal bossing, hypertelorism, depressed and broad nasal root, long philtrum, micrognathia, and high-arched palate. Other features included bifid uvula and cerebral cortical atrophy.

Clinical Variability

Frydman et al. (1990) described 2 unrelated patients with mild mental retardation, megalocornea, and hypotonia suggestive of Neuhauser syndrome. However, they had additional features which were not consistent, including macrocephaly, swallowing difficulties, large, fleshy ears, and long fingers. One child was obese and the other had scoliosis.

Verloes et al. (1993) reported 4 unrelated cases of megalocornea and mental retardation associated with anomalies that the authors considered to be distinct from Neuhauser syndrome. The authors classified the megalocornea-mental retardation syndromes into 5 types: type 1 was Neuhauser syndrome, with iris hypoplasia and minor anomalies. Type 2 was a recessive form reported by Frank et al. (1973) and Temtamy et al. (1991), with camptodactyly, scoliosis, and growth retardation (see Frank-ter Haar syndrome; 249420). Type 3, including their 4 cases, included patients with normal irides, severe hypotonia, relative or absolute macrocephaly and minor anomalies. They suggested that the patients reported by Frydman et al. (1990) might comprise a fourth form, with normal irides, megalencephaly, and obesity. Type 5 included provisionally unclassifiable cases.

Nomenclature

Raas-Rothschild et al. (1988) noted that the clinical findings of mental retardation and megalocornea are nonspecific and suggested the eponym 'Neuhauser syndrome' to describe this disorder.

Molecular Genetics

In a 10-year-old boy with megalocornea, intellectual disability, facial dysmorphism, and a history of hypotonicity and seizures, Davidson et al. (2014) sequenced the CHRDL1 gene (300350) and identified a missense mutation that was also present in his unaffected mother. However, the authors stated that it was unlikely that his extraocular features were caused by the CHRDL1 mutation because no other patients with megalocornea due to CHRDL1 mutations (see 309300) exhibited developmental delay or any of the other extraocular phenotypes associated with MMR syndrome. Furthermore, his deceased maternal grandfather was reported to have had 'large eyes,' cataracts, and glaucoma, whereas 2 paternal half sibs had seizures and intellectual disability. Whole-exome sequencing in the patient revealed several plausible variants that might have caused his extraocular phenotype, but due to lack of familial DNA samples, the potential pathogenicity of those variants could not be tested. Davidson et al. (2014) suggested that MMR syndrome may be digenic or multigenic in some cases.