Three M Syndrome 2

A number sign (#) is used with this entry because of evidence that 3M syndrome-2 (3M2) is caused by homozygous or compound heterozygous mutation in the OBSL1 gene (610991) on chromosome 2q35.

Description

3M syndrome-2 (3M2) is characterized by low birth weight and short stature, relative macrocephaly, lumbar hyperlordosis, and prominent heels. Dysmorphic facial features include triangular face with frontal bossing and midface hypoplasia, anteverted nares with fleshy nasal tip, and full fleshy lips (Hanson et al., 2009).

For a general phenotypic description and a discussion of genetic heterogeneity of 3M syndrome, see 3M1 (273750).

Clinical Features

Temtamy et al. (2006) reported 2 Egyptian brothers and an unrelated Egyptian boy who exhibited the characteristic features and radiologic findings of 3M syndrome, including low birth weight, short stature, malar hypoplasia, anteverted nostrils with a fleshy nasal tip, long philtrum, pointed full chin, short broad neck, broad chest with transverse grooves of the anterior thorax, and hyperlordosis. Oral examination revealed prominent premaxilla, hypoplastic maxilla, thick patulous lips, high-arched palate, median fissured tongue, delayed eruption of teeth with enamel hypocalcification, and malocclusion. Radiographic studies showed slender long bones and ribs, a narrow pelvis, and foreshortened vertebral bodies.

Hanson et al. (2009) studied probands from 10 families with the 3M syndrome phenotype in which direct DNA sequencing failed to detect mutations in the CUL7 gene (609577), including an Egyptian family with 2 affected brothers originally reported by Temtamy et al. (2006). All patients had short stature, prominent heels, and a distinctive facial appearance with anteverted nares, fleshy tipped nose, frontal bossing, midface hypoplasia, and prominent heels, and were phenotypically indistinguishable from those with 3M syndrome-1.

Demir et al. (2013) described a 16.5-year-old Turkish boy, born of first-cousin parents, who had low birth weight, short stature, delayed bone age, slender long bones, lumbar lordosis, tall/foreshortened lumbar vertebrae, and prominent heels, who also exhibited facial dysmorphism consistent with 3M syndrome. Growth hormone treatment was instituted but discontinued due to inadequate height gain (3 cm) at the end of 1 year.

Keskin et al. (2017) reported a 16-month-old Turkish girl who had prenatal growth retardation with severe short stature and lumbar lordosis, as well as triangular face, long philtrum, fleshy nose tip, prominent mouth and lips, and pointed chin, suggesting 3M syndrome. Growth hormone treatment resulted in a 7-cm gain in height over a 6-month period.

Inheritance

Temtamy et al. (2006) reported 2 brothers and an unrelated boy with 3M syndrome, all offspring of healthy first-cousin Egyptian parents, consistent with an autosomal recessive pattern of inheritance.

Molecular Genetics

By genomewide linkage analysis, followed by candidate gene sequencing of 10 unrelated families with 3M syndrome-2, including the Egyptian family with 2 affected brothers originally reported by Temtamy et al. (2006), Hanson et al. (2009) identified homozygous or compound heterozygous mutations in the OBSL1 gene (see, e.g., 610991.0001-610991.0005) in affected individuals. All of the mutations were truncating mutations within the first 6 exons of the gene and affected all known isoforms, resulting in complete loss of OBSL1. Thus, 3M syndrome-2 represents the null phenotype of human OBSL1. Knockdown of OBSL1 via siRNAs in HEK cells led to a decrease in CUL7 levels, suggesting a role for OBSL1 in the maintenance of normal levels of CUL7. These findings suggested that the 2 proteins work in the same pathway that affects cell proliferation and human growth.

In a 16.5-year-old Turkish boy with 3M syndrome, who was negative for mutation in the CUL7 gene, Demir et al. (2013) identified homozygosity for a frameshift mutation in the OBSL1 gene (610991.0006).

In a 16-month-old Turkish girl with 3M syndrome, Keskin et al. (2017) identified homozygosity for the most prevalent mutation in the OBSL1 gene, a 1-bp duplication (610991.0001).