Robinow Syndrome, Autosomal Recessive 2

A number sign (#) is used with this entry because of evidence that autosomal recessive Robinow syndrome-2 (RRS2) is caused by homozygous or compound heterozygous mutation in the NXN gene (612895) on chromosome 17p13.

Description

Autosomal recessive Robinow syndrome-2 is a skeletal dysplasia characterized by postnatal mesomelic short stature and relative macrocephaly as well as dysmorphic facial features, including frontal bossing, hypertelorism, prominent eyes, wide short nose with anteverted nares, and triangular mouth. Variable other congenital anomalies may be present, including omphalocele, ventral hernia, and cardiac anomalies (White et al., 2018).

For a discussion of genetic heterogeneity of autosomal recessive Robinow syndrome, see RRS1 (268310).

Clinical Features

White et al. (2018) studied 2 sisters (BAB9844 and BAB9847, from family HOU3634), ages 3 years and 6 months, respectively, and an unrelated 5-year-old Turkish girl (BAB8841, from family HOU3189), who exhibited features of autosomal recessive Robinow syndrome. All 3 had short stature and relative macrocephaly, and shared dysmorphic features including high forehead, hypertelorism, low-set posteriorly rotated ears with dysmorphic helices, prominent eyes, broad and low nasal bridge, broad nasal tip with anteverted nares, and micrognathia. Skeletal anomalies included mesomelia and brachydactyly, as well as broad thumbs and first toes. The Turkish girl exhibited other congenital anomalies including omphalocele and ventral hernia, bicuspid aortic valve with dilation of the ascending aorta, and aberrant right coronary artery. She also had developmental delay, not walking until 36 months of age and only putting words into phrases at age 5 years. Development appeared to be normal in the sisters.

Molecular Genetics

In a 5-year-old Turkish girl with autosomal recessive Robinow syndrome, who was negative for mutation in the ROR2 gene (602337), White et al. (2018) performed exome sequencing and identified homozygosity for a nonsense mutation in the NXN gene (R209X; 612895.0001) that segregated with disease in the family. Using GeneMatcher, the authors identified a second family in which 2 similarly affected sisters were compound heterozygous for mutations in NXN, a 3-bp deletion (612895.0002) and an intragenic 84-bp deletion (612895.0003). Their unaffected parents were each heterozygous for 1 of the mutations.