Meier-Gorlin Syndrome 3

A number sign (#) is used with this entry because of evidence that Meier-Gorlin syndrome-3 (MGORS3) is caused by homozygous or compound heterozygous mutation in the ORC6 gene (607213) on chromosome 16q11.

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

Lacombe et al. (1994) reported 5 patients, including a brother and sister, who had short stature, very small external ears, cryptorchidism in males, and various bone defects including absent or nonossified patellae, femoral asymmetry, coxa valga, abnormal ribs, sacral hypoplasia, skull defect, and abnormal development of sternum. All of the patients had similar facies, with marked micrognathia. The sibs were born to second-cousin Turkish Kurd parents and had 1 healthy sib. At 7 years of age, the brother had marked growth retardation, whereas his 6-year-old sister had only mild growth retardation.

On follow-up of the Turkish Kurd family reported by Lacombe et al. (1994), Bicknell et al. (2011) noted that the brother and sister and another affected brother all had microtia, and the sister and 1 brother had abnormally formed ears; the sister and 1 brother had absent patellae, whereas the other brother had hypoplasia of the patellae. In addition, the sister had hypoplasia of the mammary glands.

Shalev (2007) described 3 fetuses from 3 consecutive pregnancies of first-cousin Ashkenazi Jewish parents. The fetuses exhibited abnormal nuchal translucency; growth restriction; small flat ears; dislocation of the knees, with patellar aplasia noted in 1; gracile bones; clubfeet; and abnormal growth of other skeletal components, in particular shortening of the femurs, small thorax, and hypoplastic mandible.

In 3 sibs with Meier-Gorlin syndrome from a consanguineous Turkish Kurd family reported by Lacombe et al. (1994), Bicknell et al. (2011) identified compound heterozygosity for a 2-bp deletion and a missense mutation in the ORC6 gene (607213.0001 and 607213.0002).

De Munnik et al. (2012) reported 4 patients with Meier-Gorlin syndrome who were compound heterozygous for a missense and a splice site mutation in the ORC6 gene (607213.0003-607213.0004). The authors noted that 1 of the patients had microtia and short stature but no patellar abnormalities, and 1 exhibited conductive hearing loss.

In 2 affected fetuses and 3 unaffected individuals from an Ashkenazi Jewish family originally described by Shalev (2007), Shalev et al. (2015) performed exome analysis and identified homozygosity for a 4-bp deletion in the ORC6 gene in the 2 patients (607213.0005). The mutation was present in heterozygosity in the first-cousin parents and in 2 healthy sisters, and was not found in the ExAC database. Shalev et al. (2015) noted that in contrast to the previously reported relatively mild ORC6-associated MGORS phenotype, these patients with homozygous null mutations in the ORC6 gene exhibited severely abnormal embryologic development, expanding the clinical phenotype and suggesting a genotype-phenotype correlation in this disease.