ESCO2 Spectrum Disorder

Excerpt

Clinical characteristics: ESCO2 spectrum disorder is characterized by mild-to-severe prenatal growth restriction, limb malformations (which can include bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening of the upper and/or lower limbs), hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia), flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus]), craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations), and ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal opacities). Intellectual disability (ranging from mild to severe) is common. Early mortality is common among severely affected infants; mildly affected individuals may survive to adulthood.

Diagnosis/testing: The diagnosis of ESCO2 spectrum disorder is established in a proband with suggestive clinical findings and either biallelic pathogenic variants in ESCO2 identified by molecular genetic testing or premature centromere separation identified by cytogenetic testing.

Management: Treatment of manifestations: Individualized treatment to improve quality of life; feeding and nutrition support; management of limb malformations through a multidisciplinary neuromuscular clinic including orthopedics, physical medicine, and physical and occupational therapy with adaptative devices, prostheses, therapy, stretching, night splints, and casts as needed; hand surgery as needed to facilitate early development of prehensile grasp and improve motor function; specialized bottle and surgery for cleft lip and/or palate; surgical treatment for craniosynostosis and micrognathia; treatment of ocular issues per ophthalmologist; developmental and educational support including speech therapy; standard treatment for ophthalmologic, cardiac, urogenital, and kidney abnormalities; prompt treatment of infection with management per infectious disease specialist; treatment of stroke per neurologist; treatment of malignancy per oncologist; family and social support.

Surveillance: Assess growth, limb mobility and function, development and educational needs, blood pressure, frequency of infections, and home adaptation needs at each visit; assessment of feeding, speech development, and hearing (in those with cleft lip and palate) per craniofacial team; kidney function tests annually; follow up for ophthalmologic and cardiac anomalies per treating physicians; physical examination including full skin and neurologic examination for evidence of malignancy annually; referral to neurologist including brain imaging for vascular anomalies and aneurysms in those with intellectual disability, corneal opacities, and/or heart defects; assess for clinical manifestations of aneurysms and vascular malformations annually starting in adolescence; serum immunoglobulin levels in infancy.

Genetic counseling: ESCO2 spectrum disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ESCO2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ESCO2 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. Prenatal testing for pregnancies at increased risk is also possible by cytogenetic testing of fetal cells obtained by amniocentesis or chorionic villus sampling in conjunction with ultrasound examination.