Short Stature, Rhizomelic, With Microcephaly, Micrognathia, And Developmental Delay

A number sign (#) is used with this entry because of evidence that rhizomelic short stature with microcephaly, micrognathia, and developmental delay (SRMMD) is caused by heterozygous mutation in the ARCN1 gene (600820) on chromosome 11q23.

Clinical Features

Izumi et al. (2016) studied 4 individuals from 3 unrelated families who exhibited rhizomelic short stature as well as microcephaly, micrognathia, laxity of the small joints, and developmental delay. Other variable features included posterior cataract, cleft palate, ventricular septal defect, cryptorchidism, seizures, and autism. Two of the patients were a father and daughter; the father had previously been described by Verloes et al. (1997).

Molecular Genetics

By whole-exome sequencing in 4 patients who had rhizomelic short stature with microcephaly, micrognathia, and developmental delay, Izumi et al. (2016) identified heterozygosity for truncating mutations in the ARCN1 gene (600820.0001-600820.0003). One of the probands (see 600820.0003) was also heterozygous for a missense mutation in the SYT1 gene (D233N; see 185605), which Izumi et al. (2016) suggested might have contributed to the additional feature of seizures in that patient; however, given that all 4 patients with ARCN1 mutations exhibited comparable degrees of developmental delay and intellectual disability, the authors concluded that the ARCN1 mutations likely play a major role in the neurologic features observed in this syndrome, and that ARCN1 is probably required for normal brain growth and cognitive development.