Ayme-Gripp Syndrome

A number sign (#) is used with this entry because of evidence that Ayme-Gripp syndrome (AYGRP) is caused by heterozygous mutation in the MAF gene (177075) on chromosome 16q23.

Description

Ayme-Gripp syndrome is a clinically homogeneous phenotype characterized by congenital cataracts, sensorineural hearing loss, intellectual disability, seizures, brachycephaly, a distinctive flat facial appearance, and reduced growth (Niceta et al., 2015).

Clinical Features

Gripp et al. (1996) described 2 unrelated patients, a girl and a boy, with a seemingly previously unrecognized syndrome: congenital cataracts, sensorineural deafness, distinctive facial appearance, skeletal changes, postnatal short stature, and mental retardation. The parents were nonconsanguineous in each case. The appearance of the eyes was somewhat suggestive of Down syndrome. The philtrum was long, broad, and smooth and the face was generally flat. One of the patients had bilateral radioulnar synostosis; the other had idiopathic chondrolysis. The high-resolution karyotypes of the 2 patients were 46,XX and 46,XY, respectively. In the male patient, the authors found no microdeletions associated with either Smith-Magenis syndrome (182290) or Xp22.3.

Ayme and Philip (1996) observed a 20-year-old woman with a similar complex of abnormalities. They suggested that their patient had the same disorder (Fine-Lubinsky syndrome; 601353) as that reported by Fine and Lubinsky (1983).

Nakane et al. (2002) reported a Japanese boy who presented at 8 months of age with dysmorphic facies and mental retardation. He was brachycephalic, with prominent frontal bones and enlarged anterior fontanel. He also exhibited a remarkably flat face with shallow orbits, hypertelorism, low-set ears, and a small nose with depressed nasal bridge. His mouth was not small, but he could not open it widely. He had gross developmental delay and did not respond to sound. Auditory evoked responses suggested severe bilateral deafness, and ophthalmologic examination showed bilateral cataract. Nakane et al. (2002) noted that many of this patient's features were similar to those seen in the patient described by Ayme and Philip (1996); because his mouth was not small, Nakane et al. (2002) concluded that this patient represented a variant of Fine-Lubinsky syndrome.

Keppler-Noreuil et al. (2007) reported an unrelated boy and girl with a clinical phenotype most closely resembling that reported by Gripp et al. (1996). Common features included facial dysmorphism suggestive of Down syndrome, including flat nasal bridge, slanted palpebral fissures, epicanthal folds, low-set ears, and tented upper lip/thin vermilion border. Both patients had short stature, congenital cataracts, hearing loss, and delayed mental development. Microarray analysis in the boy revealed a subtelomeric 1.0- to 1.9-Mb deletion of chromosome 11q25; the same deletion was also found in his mother, who had short stature, mild facial dysmorphism, and mild mental retardation (IQ of 70), but no cataracts or hearing loss. The phenotype was distinct from that seen in Jacobsen syndrome (147791). Microarray analysis was normal in the girl. Keppler-Noreuil et al. (2007) postulated that patients with this novel syndrome may have a microdeletion of the chromosome 11q terminal region or haploinsufficiency of a gene within this region.

Molecular Genetics

In a 43-year-old woman with Ayme-Gripp syndrome, Niceta et al. (2015) performed whole-exome sequencing and identified heterozygosity for a de novo missense mutation in the MAF gene (S54L; 177075.0005). Sanger sequencing confirmed the mutation, which was not found in her parents. Analysis of the MAF gene in 12 additional probands with overlapping features revealed heterozygous missense mutations (177075.0005-177075.0010) in 7, including the patients reported by Ayme and Philip (1996), Gripp et al. (1996), and Keppler-Noreuil et al. (2007). Niceta et al. (2015) noted partial overlap between the clinical presentation of this syndrome and that of Fine-Lubinsky syndrome, and suggested the designation 'Ayme-Gripp syndrome' for the MAF-associated phenotype.