Coffin-Siris Syndrome

CLINICAL CHARACTERISTICS

Classically, Coffin-Siris syndrome (CSS) was characterized by specific dysmorphic features (coarse facies, sparse scalp hair, thick eyebrows with long lashes, wide nasal bridge with broad nasal tip, anteverted nares with thick ala nasi, wide mouth with thick, everted vermilion of the upper and lower lips, and hypertrichosis), the absence or underdevelopment of the fifth digit finger/toe or nail, learning and developmental differences, and various organ system-related anomalies. As genetic technology has evolved, more individuals with subtle physical exam findings are being diagnosed with CSS. The vast majority of affected individuals have developmental delay / intellectual disability, typically in the moderate-to-severe range, although those with mild cognitive impairment or even normal intelligence have more rarely been described. Most affected individuals have feeding difficulties (with ~25%-50% requiring a feeding tube in childhood, some of whom then outgrow it), hypotonia, and frequent infections. About half of affected individuals have epilepsy. Other findings may include skeletal features (joint laxity, scoliosis), hearing impairment (both conductive and sensorineural), eye issues (ptosis, strabismus), congenital heart defects, genitourinary malformations, and behavioral issues (including hyperactivity and/or aggressiveness).

DIAGNOSIS/TESTING: The diagnosis of CSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in one of the following 14 known genes identified by molecular genetic testing: , , , , , , , , , , , , , or S.

MANAGEMENT

Feeding therapy with consideration of placement of gastrostomy tube in those with persistent feeding issues. Standard treatment for developmental delay / intellectual disability, epilepsy, tics, sleep disturbance, scoliosis, joint laxity, knee subluxations, obesity, refractive error, strabismus, ptosis, hearing loss, congenital heart defects, undervirilization, inguinal hernia, frequent infections, and hepatoblastoma. : At each visit, measurement of growth parameters; evaluation of nutrition status and safety of oral intake; assessment for new neurologic manifestations, such as seizures or tics; monitoring of developmental progress and educational needs; behavioral assessment for anxiety, ADHD, ASD, aggression, & self-injury; monitoring for signs and symptoms of sleep disturbance; evaluation for mobility and self-help skills; and assessment for signs and symptoms of frequent infections. Annually or as clinically indicated, ophthalmology evaluation and vision assessment; audiology evaluation. At least every six months in those with teeth, dental evaluation. In those with -related CSS: serum AFP level (with consideration of liver ultrasound) every three months until age four years.

GENETIC COUNSELING

CSS is inherited in an autosomal dominant manner; however, most affected individuals have the disorder as the result of a CSS-causing pathogenic variant. If the CSS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.