Coffin-Siris Syndrome 9

A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-9 (CSS9) is caused by heterozygous mutation in the SOX11 gene (600898) on chromosome 2p25.

Description

Coffin-Siris syndrome 9 is characterized by mild intellectual disability, dysmorphic facial features, hypertrichosis, microcephaly, growth deficiency, and hypoplastic fifth toenails (Tsurusaki et al., 2014).

For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).

Clinical Features

Tsurusaki et al. (2014) applied whole-exome sequencing to 92 patients meeting the diagnostic criteria for Coffin-Siris syndrome (CSS; 135900) and identified 2 de novo SOX11 mutations in 2 unrelated female patients. Both patients showed dysmorphic facial features, microcephaly, growth deficiency, hypoplastic fifth toenails, and mild intellectual disability. The observed clinical features in both patients were classified as being at the mild end of CSS, as the first patient began speaking early for CSS, and the second patient had a relatively high IQ. The first patient had midface hypoplasia, while the second did not. Although the first patient was Japanese and the second Indian, they shared common features, including hypertrichosis, arched eyebrows, low-set and posteriorly rotated ears, and full cheeks. At 3 years of age, the first patient had a developmental quotient of 57 on the Kyoto scale. Her left kidney was slightly small, and she had distinctive facial features characterized by midface hypoplasia, short palpebral fissures, long eyelashes, a low nasal root, shortened nose with upturned nostrils, short philtrum, open mouth, full lips, and low-set ears. She had hypoplastic distal phalanges with nail hypoplasia, especially of the fifth digits. At 4 years 8 months of age, she was short (-2.9 SD) but had no evidence of growth hormone deficiency. When she was 10 years of age, her height was -2.8 SD, with a head circumference of -3.3 SD. The second patient was a 16-year-old Indian female with proportionate short stature and an IQ in the range of 70 to 80. Her chin was small, and she had supraorbital ridges that were hypoplastic with no ptosis. Her nose was long and her alae nasi hypoplastic, with overhanging columella. She had thick, rough hair with some thinning on her scalp and increased hair on her back. Her fourth and fifth toes were short, fingers were thin and tapered, and all nails were hypoplastic. Skeletal survey showed normal results. No secondary sexual characteristics were recognized until menarche at 17 years of age.

Molecular Genetics

In 2 unrelated female patients with MRD27, Tsurusaki et al. (2014) identified 2 de novo missense mutations in the SOX11 gene (Y116C, 600898.0001 and S60P, 600898.0002). The mutations occurred at evolutionarily highly conserved residues in the HMG domain and were shown to decrease transcriptional activity compared to wildtype.