Ritscher-Schinzel Syndrome 2

A number sign (#) is used with this entry because of evidence that Ritscher-Schinzel syndrome-2 (RTSC2) is caused by mutation in the CCDC22 gene (300859) on chromosome Xp11.

Description

Ritscher-Schinzel syndrome-2 is an X-linked recessive syndromic form of intellectual disability associated with posterior fossa defects, cardiac malformations, and minor abnormalities of the face and distal extremities (summary by Kolanczyk et al., 2015).

For a discussion of genetic heterogeneity of Ritscher-Schinzel syndrome, see RTSC1 (220210).

Clinical Features

Voineagu et al. (2012) reported a large family (IGOLD #586) in which 6 males spanning 3 generations had syndromic X-linked intellectual disability. One patient was deceased; clinical information was available for 5 patients, but the information given in a table was somewhat variable and unclear as to which individual had which features. Features included intellectual disability (in 3 of 5 patients), defects of the posterior fossa, including Dandy-Walker malformation, cerebellar hypoplasia, and arachnoid cyst (in 1 of 5), cardiac defects, including atrial and ventricular septal defects, patent ductus arteriosus, and hypoplastic right pulmonary artery (in 1 of 5), and distal skeletal abnormalities. Several patients had dysmorphic facial features, including hypertelorism, beaked nose and broad nasal tip, ear abnormalities, and high-arched palate. Other features included undescended testes (in 3 of 5), hypoplastic lung (in 2 of 5), intestinal malrotation (in 1 of 5), and absent kidney (in 1 of 5). Kolanczyk et al. (2015) concluded that the phenotypic features reported by Voineagu et al. (2012) were consistent with RTSC.

Kolanczyk et al. (2015) reported 8- and 15-year-old brothers, born of unrelated Austrian parents, with a syndromic form of X-linked mental retardation similar to Ritscher-Schinzel syndrome. Both had large anterior fontanels, postnatal growth delay, hypotonia, and delayed psychomotor development with poor speech. Both also had Dandy-Walker malformation and cardiac ventricular septal defects. Dysmorphic facial features included relatively large head, broad forehead, upslanting palpebral fissures, wide-set eyes, short philtrum, large protruding tongue, and broad neck with low posterior hairline. They also had camptodactyly, clinodactyly, hypoplastic fingernails, and broad halluces with overriding fifth toes. One had cryptorchidism.

Inheritance

The transmission pattern of RTSC2 in the family reported by Kolanczyk et al. (2015) was consistent with X-linked recessive inheritance.

Molecular Genetics

In affected members of a family (IGOLD #586) with syndromic X-linked intellectual disability, Voineagu et al. (2012) identified a hemizygous splice site mutation in the CCDC22 gene (300859.0001). Patient cells showed a 5-fold decrease in mRNA levels, and increased levels of abnormally spliced transcripts retaining intron 1. The proband was 1 of 208 patients who underwent X-chromosome resequencing and had previously been part of a large cohort studied by Tarpey et al. (2009).

In 2 brothers, born of unrelated Austrian parents, with Ritscher-Schinzel syndrome-2, Kolanczyk et al. (2015) identified a hemizygous missense mutation in the CCDC22 gene (300859.0002). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Lymphocytes from 1 of the patients showed a 50% decrease in CCDC22 protein levels compared to controls, and there was increased abundance of the WASH1 (613632) protein. Kolanczyk et al. (2015) noted that RTSC1 (220210) is caused by mutation in the gene encoding strumpellin (KIAA0196; 610657), which is part of the WASH complex.