Meier-Gorlin Syndrome 2

A number sign (#) is used with this entry because of evidence that Meier-Gorlin syndrome-2 (MGORS2) is caused by homozygous or compound heterozygous mutation in the ORC4 gene (603056) on chromosome 2q23.

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

Clinical Features

Bongers et al. (2001) reported 5.25-year-old monozygotic twin sisters, born of consanguineous American parents of Acadian/French Creole ancestry, who had intrauterine growth retardation and were noted to be microcephalic at birth. Examination at 5 years of age showed height and weight below the 3rd centile for both girls, with head circumferences at the 3rd centile. Both had dolichocephaly, mild micrognathia, flat philtrum with small mouth, and slight hypoplasia of the nasal alae. They had microtia, with simple ears and relatively small external auditory meatuses. In both patients, the clitoris appeared prominent, probably because of mild hypoplasia of the labia majora. There was distal interphalangeal camptodactyly of the second, third, and fourth fingers, and on the fifth fingers there was proximal interphalangeal camptodactyly. Joints were hyperextensible, especially elbows and knees; patellae were present and appeared to be of normal size. Psychomotor development was normal, and they had high-pitched voices with articulate speech and alert and happy personalities.

Guernsey et al. (2011) described 1 male and 3 female patients with Meier-Gorlin syndrome-2, all of whom had pre- and postnatal growth retardation, microtia, extremely hypoplastic or absent patellae, and feeding difficulties with gastroesophageal reflux. Two of the patients had tracheomalacia, 1 of whom also had bronchomalacia and required aortopexy; another patient, who had a disproportionately narrow thoracic cage, had congenital emphysema of the right middle lobe and underwent lobectomy at 6 months of age. Two of the patients had unilateral clubfoot. Breast hypoplasia was present in the 2 postpubertal female patients, 1 of whom also displayed mildly hypoplastic labia majora.

Mapping

Using a whole-genome analysis tool, Guernsey et al. (2011) identified a haplotype on chromosome 2 shared by 4 genotyped individuals with Meier-Gorlin syndrome. The shared 5.4-Mb segment was bounded by SNPs rs6759621 and rs17398704.

Molecular Genetics

Bicknell et al. (2011) analyzed the ORC4 gene in patients with an established diagnosis of Meier-Gorlin syndrome and identified homozygosity for a missense mutation (Y174C; 603056.0001) in the monozygotic twin sisters previously reported by Bongers et al. (2001). Compound heterozygosity for Y174C and a frameshift mutation (603056.0002) was also identified in an unrelated 23-year-old American woman with Meier-Gorlin syndrome. In addition to microtia and absent patellae, the woman also had hypoplasia of the mammary glands.

In 2 patients with Meier-Gorlin syndrome mapping to chromosome 2, Guernsey et al. (2011) independently identified homozygosity for the Y174C mutation in the ORC4 gene, and in 2 more MGS patients, they identified compound heterozygosity for the Y174C mutation and another mutation in the ORC4 gene (603056.0002 and 603056.0003, respectively).