Seckel Syndrome 2

A number sign (#) is used with this entry because of evidence that Seckel syndrome-2 (SCKL2) is caused by homozygous mutation in the RBBP8 gene (604124) on chromosome 18q11.

Jawad syndrome (251255), a microcephaly syndrome involving mental retardation and digital anomalies, is also caused by mutation in the RBBP8 gene.

Description

Seckel syndrome is a rare autosomal recessive disorder characterized by growth retardation, microcephaly with mental retardation, and a characteristic facial appearance (Borglum et al., 2001).

For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see SCKL1 (210600).

Clinical Features

Borglum et al. (2001) studied a consanguineous family of Iraqi descent with Seckel syndrome. The parents were first cousins and had 4 children who fulfilled the criteria for Seckel syndrome, as well as a younger healthy girl. Borglum et al. (2001) mapped the locus in this family to chromosome 18 and noted a number of distinct differences between this family and individuals in chromosome 3-linked families with Seckel syndrome (SCKL1; 210600). The mental and motor retardation in the chromosome 18-linked family was milder. The growth retardation of the chromosome 18-linked patients was proportionate, whereas in the chromosome 3-linked families, the heads were small relative to other parameters. All affected sibs in the chromosome 18-linked family had one or more small cafe-au-lait spots on the skin, a finding not previously reported in Seckel syndrome. This finding suggested to the authors that the underlying defect in these patients might involve DNA repair.

Shaheen et al. (2014) studied a 9-year-old Saudi Arabian girl with short stature (height -6.2 SD below mean) who was underweight (weight -4.2 SD below mean) and also had microcephaly (head circumference -4.1 SD below mean), microphthalmia, micrognathia, microglossia, small teeth, and limited supination of upper extremities. Brain MRI showed calcification of the bilateral basal ganglia and cerebellum.

Mapping

Borglum et al. (2001) studied a consanguineous family of Iraqi descent with Seckel syndrome. A maximum multipoint lod score of 3.1 was obtained to markers proximal on chromosome 18 and with a region of overlapping homozygosity in the 4 affected children between the markers D18S78 and D18S866, corresponding to an approximately 30-cM transcentromeric region, 18p11.31-q11.2.

Molecular Genetics

In a consanguineous Iraqi family with Seckel syndrome mapping to chromosome 18p11.31-q11.2, previously studied by Borglum et al. (2001), Qvist et al. (2011) sequenced the candidate gene RBBP8 and identified homozygosity for a splice site mutation (604124.0001) that segregated with the disease and was not found in 100 controls.

In a 9-year-old Saudi Arabian girl with Seckel syndrome, Shaheen et al. (2014) identified homozygosity for a missense mutation in the RBBP8 gene (R100W; 604124.0004).