Meier-Gorlin Syndrome 6

A number sign (#) is used with this entry because of evidence that Meier-Gorlin syndrome-6 (MGORS6) is caused by heterozygous mutation in the GMNN gene (602842) on chromosome 6p22.

For a general phenotypic description and a discussion of genetic heterogeneity of Meier-Gorlin syndrome, see 224690.

Clinical Features

Burrage et al. (2015) described 3 unrelated patients with primordial dwarfism, microtia, and absent patellae, fulfilling the clinical diagnostic criteria of Meier-Gorlin syndrome. Patient 1 was born at 32 weeks and 4 days' gestation. The pregnancy was complicated by twin gestation, placental insufficiency, and severe intrauterine growth restriction in the proband. The proband had feeding problems necessitating nasogastric tube feeding, and she was diagnosed with gastroesophageal reflux and failure to thrive. She had cochlear implants placed for conductive hearing loss secondary to aural atresia/microtia and was diagnosed with grade II subglottic stenosis, tracheomalacia, and bronchomalacia. She had delayed bone age (-3.5 SD from mean for age) with low IGF1 (147440) and normal IGFBP3 (146732). Brain MRI showed a mildly simplified gyral pattern with delayed myelination. Other distinct craniofacial findings included frontal bossing, downslanting palpebral fissures, bilateral entropion, upturned nose with hypoplastic nares, severe microtia with no external auditory canal openings, midface hypoplasia, full lips, and micrognathia. She also had absent patellae, midphalangeal hypoplasia of the fifth digit of the hands, single transverse palmar crease on the right hand, underdeveloped distal finger creases, sandal gap between first 2 toes bilaterally, a small umbilical hernia, and hypoplastic female genitalia. Patient 2, who was previously described by Bongers et al. (2001) (patient 2) and de Munnik et al. (2012) (patient 43), had growth hormone deficiency, delayed puberty, congenital emphysema, and an IQ of 61. Patient 3 had a birth weight of 2,750 g (Z score, -1.1), birth length of 45 cm (Z score, -2.2), cleft palate, and feeding difficulties necessitating nasogastric tube feeding. She also had congenital hip dysplasia, strabismus convergens, recurrent respiratory infections, mildly delayed psychomotor development that was particularly evident in speech, posteriorly rotated ears with a simple shape and narrow auditory canals, small nose with flat nasal bridge, aplastic patellae, planovalgus feet, and marked lumbar lordosis.

Inheritance

Meier-Gorlin syndrome-6 is an autosomal dominant disorder (Burrage et al., 2015).

Molecular Genetics

By whole-exome and/or Sanger sequencing in 3 unrelated patients with Meier-Gorlin syndrome in whom no mutations were found in previously identified MGORS-causing genes, Burrage et al. (2015) identified heterozygous de novo mutations in the 5-prime end of the GMNN gene (602842.0001-602842.0003). The mutations were not found in the 1000 Genomes Project or ExAC databases. Functional studies in patient lymphocyte-derived cell lines suggested a gain-of-function mechanism in which the mutation results in a protein lacking the destruction box and hence having increased stability and prolonged inhibition of replication.