A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-6 (CSS6) is caused by heterozygous mutation in the ARID2 gene (609539) on chromosome 12q12.

Coffin-Siris syndrome-6 (CSS6) is characterized by short stature, sparse hair, mildly to severely impaired intellectual development, coarse facial features, and variable behavioral anomalies. Some patients have fifth digit clinodactyly with small nails. Other congenital anomalies and seizures may be present (summary by Shang et al., 2015; Van Paemel et al., 2017; Bramswig et al., 2017).

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

Shang et al. (2015) reported 4 unrelated patients, aged 6 to 15 years, with intellectual disability, variable behavioral anomalies, short stature, and dysmorphic facial features. All patients developed failure to thrive postnatally. Gastroesophageal reflux and constipation were common. Two of the patients had wormian bones of the skull, one of whom also had plagiocephaly. One patient had mild pectus excavatum, and another had kyphoscoliosis and conductive hearing loss. MRI of the brain, performed in 2 patients, demonstrated mild periventricular leukomalacia in one and a small arachnoid cyst with prominent lateral ventricles in the other. All patients had micrognathia or retrognathia, low-set or posteriorly rotated ears, epicanthal folds, downslanting palpebral fissures, high-arched palate, and frontal bossing. One patient had a cleft palate, diaphragmatic eventration, and atrial septal defect. The developmental quotient or IQ ranged from 50 to 89. Variable behavioral issues included attention deficit-hyperactivity disorder (ADHD), tics, anxiety, obsessions, repetitive behaviors, and sensitivity to loud noises and certain food textures. Seizures were not observed.

Bramswig et al. (2017) reported 2 patients with a CSS-like phenotype. Patient 1 had normal birth parameters but required surgery for bilateral inguinal hernias and unilateral testicular torsion as a neonate. By 20 months of age, his height and weight were low (-2.21 SD and -2.84 SD, respectively); he had severe hypotonia and showed delayed development. He had delayed dental eruption with yellow-brown teeth. He developed seizures at age 14 months, with infantile spasms that evolved to different seizure types. MRI showed a Dandy-Walker malformation and a thin corpus callosum. He required shunting. He had a tall forehead, slightly coarse facial features, hypertelorism, depressed nasal root and short nose, prominent long philtrum, and thin upper lip. At age 7 years, he remained small with average head circumference. He had severe intellectual disability with absent speech and inability to sit independently. Hand anomalies included a single palmar crease, small hands with tapering fingers, small feet, and nail hypoplasia of the fifth finger and toenails. Patient 2 had normal birth parameters, but showed developmental delay. At age 22 months, he was short (-2.2 SD) with a normal head circumference. He had coarse facial features with midface hypoplasia, normal eye spacing, horizontal palpebral fissures, small upturned nose, a cupid bow, and full lower lip. He had generalized mild hypotonia, but no speech. With age, his facial features continued to coarsen. He had tapered fingers bilaterally, normal palmar creases, small nails, and bilateral fifth finger clinodactyly. X-ray of the left hand showed hypoplastic distal phalanges. He had small toenails, especially of the fifth toes that also showed clinodactyly.

Van Paemel et al. (2017) reported a girl who presented at age 3 years 11 months with short stature and neuromotor delay. The child had been noted at 34 weeks' gestation to have intrauterine growth retardation and placental calcification. Her birth parameters were low (-2.2 SD) and she exhibited left-sided clubfoot and bilateral hip dysplasia. Postnatally, her growth parameters further deteriorated to -3.3 and -4.0 SD, and she had feeding difficulties. Her development was initially normal but later showed delay; she started walking at age 27 months, spoke her first words at about age 2 years, and talked in simple 3-word sentences at age 3 years. She manifested a 50-db hearing loss even after placement of tympanostomy tubes and adenoidectomy. Physical examination showed stiff and bitemporal sparse scalp hair, high frontal hairline, prominent forehead, and coarse facial features, including an open and wide mouth with full lips, pronounced nasolabial folds, a prominent philtrum, and retrognathia. She had hypoplasia of the fifth ray of the toenails, and brachymesophalangy and clinodactyly of the fifth rays of both hands. She showed aggression and had ADHD and sensitivity to loud noises.

Most of the heterozygous mutations in the ARID2 gene that were identified in patients with CSS6 by Shang et al. (2015), Bramswig et al. (2017), and Van Paemel et al. (2017) were confirmed to be de novo.

In 4 unrelated patients with Coffin-Siris syndrome (CSS6; 617808), Shang et al. (2015) identified heterozygous frameshift or nonsense mutations in the ARID2 gene (609539.0001-609539.0004). The mutations were confirmed to be de novo in 3 of the families; in the fourth family, the parents were unavailable for testing. The mutations were identified by whole-exome sequencing of 970 patients with intellectual disability. None of the mutations were found in public variant databases.

In 2 unrelated patients with CSS6, Bramswig et al. (2017) identified de novo heterozygous frameshift mutations in the ARID2 gene (609539.0005-609539.0006).

In a 4-year-old girl with CSS6, Van Paemel et al. (2017) identified a de novo heterozygous deletion in the ARID2 gene (609539.0007).