Jawad Syndrome

A number sign (#) is used with this entry because of evidence that Jawad syndrome (microcephaly with mental retardation and digital anomalies) is caused by homozygous mutation in the RBBP8 gene (604124) on chromosome 18q11.2.

Seckel syndrome-2 (606744), a microcephaly syndrome involving growth retardation and a characteristic facial appearance, is also caused by mutation in the RBBP8 gene.

Clinical Features

Kelly et al. (1993) described 2 brothers with congenital microcephaly and moderately severe mental retardation. The presence of identical and symmetrical digital anomalies suggested a distinct entity. One brother had hallux valgus with complete syndactyly of toes 4 and 5. The fifth fingers were short with a single flexion crease, and the fourth finger lacked a distal interphalangeal crease. Precisely the same changes in the toes and fingers were found in an older brother with similar microcephaly. By x-ray, the hands showed a very short middle phalanx of the fifth finger. Although the phenotype showed similarities to Filippi syndrome (272440), Kelly et al. (1993) considered it distinct because the patients did not have cryptorchidism, striking physical retardation, or striking facial changes.

Hassan et al. (2008) reported a consanguineous Pakistani family with a syndromic form of congenital microcephaly. Clinical features of the 7 affected family members included congenital microcephaly with sharply sloping forehead, moderate to severe mental retardation, and anonychia congenita. Digital malformations of variable degree were present, including polydactyly and synpolydactyly, and white spots were observed on the skin of the hands and feet of all affected individuals.

For similar craniodigital syndromes, see 272440 and 615236.

Mapping

Hassan et al. (2008) performed linkage analysis in a consanguineous Pakistani family with syndromic microcephaly and mapped the phenotype to a 25.2-cM interval on chromosome 18p11.2-q12.3 between D18S1150 and D18S1100. The authors noted that a 15.33-cM (12.03-Mb) region of continuous homozygosity between D18S1150 and D18S997 represented the most likely candidate region; a maximum 2-point lod score of 3.03 was obtained at marker D18S1104.

Inheritance

Jawad syndrome is inherited in an autosomal recessive manner (Hassan et al., 2008; Qvist et al., 2011).

Molecular Genetics

In affected members of a consanguineous Pakistani family with syndromic microcephaly mapping to chromosome 18p11.22-q11.2, previously studied by Hassan et al. (2008), Qvist et al. (2011) identified homozygosity for a 2-bp deletion in the RBBP8 gene (604124.0003). The mutation was detected in heterozygosity in 2 obligate carriers and was not found in any controls.

Exclusion Studies

In a consanguineous Pakistani family with syndromic microcephaly mapping to chromosome 18p11.22-q11.2, Hassan et al. (2008) analyzed 6 candidate genes but identified no mutations.