Cohen-Gibson Syndrome

A number sign (#) is used with this entry because of evidence that Cohen-Gibson syndrome (COGIS) is caused by heterozygous mutation in the EED gene (605984) on chromosome 11q14.

Description

Cohen-Gibson syndrome is an overgrowth disorder characterized by increased somatic parameters apparent from birth and associated with variable intellectual disability. Affected individuals have dysmorphic facial features, advanced bone age, and skeletal abnormalities, including flaring of the metaphyses of the long bones, large hands with long fingers and camptodactyly, and often scoliosis or cervical spine anomalies. Other features may include hypotonia, difficulty walking due to skeletal anomalies, and umbilical hernia (summary by Cooney et al., 2017).

Clinical Features

Cohen et al. (2015) reported a 27-year-old man, born of unrelated Turkish parents, with an overgrowth syndrome associated with intellectual disability. At birth, he had only mildly increased length and weight, and thereafter showed delayed psychomotor development with speech delay and poor fine motor skills. He developed seizures at 4.5 years of age. Dysmorphic features included macrocephaly, large ears, hypertelorism, downslanting palpebral fissures, and retrognathia with a prominent crease between the lower lip and the chin. Brain imaging was normal. At age 8 years, he was very tall (+4.6 SD), but his height leveled out in adulthood (+1.85). Additional features included myopia, cataracts, umbilical hernia, cryptorchidism, posttraumatic patellar dislocation, widely spaced nipples, pigmented nevi, and large hands with camptodactyly. Radiographic studies showed advanced bone age, scoliosis, abnormal flaring of the distal clavicles, distal ribs, and metaphyses of the distal radius, distal ulna, distal femur, and proximal tibia, as well as a flattened left acetabulum and femoral head.

Cohen and Gibson (2016) reported a second male patient, born of unrelated Caucasian parents, with COGIS. Somatic overgrowth was observed on prenatal ultrasound, and he had respiratory distress and mild jaundice soon after birth. He showed developmental delay in infancy, with walking at 24 months and poor speech acquisition; he also had an umbilical hernia. Throughout childhood and adulthood, he had hypotonia, stiffness of the joints and tendons, and biomechanical variations of the feet and knees, resulting in balance, coordination, and walking difficulties. Radiographic studies showed advanced bone age and scoliosis. Dysmorphic features included asymmetric skull, macrocephaly, round face, abnormal bite, retrognathia with a prominent crease between the lower lip and chin, deep-set eyes, almond-shaped palpebral fissures, large low-set ears, prominent nasal root and nasal bridge with bulbous nasal tip, and bifid uvula. He also had large hands with long slender fingers, large slender feet, numerous pigmented nevi, and C1-C2 spinal instability resulting in traumatic spinal cord compression. His growth slowed with age: at age 22 years, his height was above the 97th percentile and head circumference was above the 90th percentile. His stance remained slightly forward, with hips and knees flexed and restricted range of movement of certain large joints of the upper and lower limbs.

Cooney et al. (2017) reported a 16-year-old girl, born of unrelated Hispanic parents, with COGIS. She had increased birth weight (+4.2 SD), length (+2.6), and head circumference (+2.2). Dysmorphic features noted at birth included cleft palate, posterior ear pits, capillary hemangioma of the back, and umbilical hernia. She had hypotonia, poor feeding, and global developmental delay with moderate intellectual disability. She had multiple additional congenital anomalies, including nephromegaly, tracheomalacia, patent ductus arteriosus requiring coil occlusion, atrial septal defect, mitral regurgitation, and inguinal and femoral hernias. Brain imaging at age 2 years showed substantial white matter volume loss, particularly in the frontal lobe, and moderate to severe thinning of the corpus callosum. Skeletal anomalies included advanced bone age, cervical spine stenosis, small iliac wings, coxa valga, wide metaphyses, osteopenia, Achilles tendon and hamstring contractures, chondromalacia, recurrent dislocation and subluxation of the patellae, pes planovalgus, and camptodactyly. She had an abnormal gait due to her contractures. At age 16, her growth parameters were above the 95th percentile, and she had dysmorphic facial features, including broad face with short forehead, depression of the supraorbital ridges, long and low-set ears, thick eyebrows, hypertelorism, downslanting and almond-shaped palpebral fissures, wide and depressed nasal bridge, and broad neck. She also had visual disturbances due to exotropia, hyperopic astigmatism, and ptosis. Distal skeletal abnormalities included long, broad palms, long fingers, broad thumbs, camptodactyly, small nails, and joint laxity of the small joints of the hands.

Imagawa et al. (2017) reported a 5-year-old Japanese boy with COGIS. He had increased birth weight (+3.1 SD), length (+2.2 SD), and head circumference (+1.4 SD). Characteristic craniofacial features included macrocephaly, round face, broad forehead, hypertelorism, prominent long philtrum, retrognathia, low nasal bridge, large ears, and epicanthus. Brain imaging was normal. He had delayed psychomotor development, with walking at 23 months, speech delay, and low IQ (57 to 65). He had multiple skeletal abnormalities, including advanced bone age, flexion disorder of the metacarpophalangeal joints of the first and fifth fingers, and wide metaphyses of the femoral and tibial bones. He also had an umbilical hernia. At age 5.4 years, his height, weight, and head circumference were +4.5 SD, +3.8 SD, and +2.6 SD, respectively.

Molecular Genetics

In a 27-year-old man, born of unrelated Turkish parents, with COGIS, Cohen et al. (2015) identified a de novo heterozygous missense mutation in the EED gene (R302S; 605984.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.

In a 22-year-old man, born of unrelated Caucasian parents, with COGIS, Cohen and Gibson (2016) identified a de novo heterozygous missense mutation in the EED gene (H258Y; 605984.0002). The mutation was found by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.

In a 16-year-old girl, born of unrelated Hispanic parents, with COGIS, Cooney et al. (2017) identified a heterozygous missense mutation in the EED gene (R302G; 605984.0003). The mutation, which was found by whole-exome sequencing, was not present in the mother; the father was unavailable for testing. Functional studies of the variant and studies of patient cells were not performed.

In a 5-year-old Japanese boy with COGIS, Imagawa et al. (2017) identified a de novo heterozygous missense mutation in the EED gene (R236T; 605984.0004). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the R236T and R302S mutant proteins were associated with decreased levels of H3K27me3 compared to wildtype, and Western blot analysis of patient cells with the R236T mutation also showed loss of H3K27me3, consistent with loss of PRC2 activity and a loss of function.