CTCF-Related Disorder

Clinical characteristics: CTCF-related disorder is characterized by developmental delay / intellectual disability (ranging from mild to severe), with both speech and motor delays being common; feeding difficulties, including dysphagia, and other gastrointestinal issues (gastroesophageal reflux disease and/or irritable bowel syndrome) that can lead to growth deficiency; hypotonia; eye anomalies (strabismus and/or refractive errors); scoliosis; nonspecific dysmorphic features; sleep disturbance; tooth anomalies (crowded teeth and/or abnormal decay); and, less commonly, other congenital anomalies (cleft palate, gastrointestinal malrotation, genitourinary anomalies, and congenital heart defects, including aortic ectasia). Short stature, seizures, hearing loss, recurrent infections, microcephaly, and autistic features have also been described in a minority of affected individuals. At least four reported individuals with CTCF-related disorder developed Wilms tumor, one of whom had bilateral Wilms tumor. However, there is no clear evidence of a significant predisposition for the development of cancer in individuals with CTCF-related disorder at this time.

Diagnosis/testing: The diagnosis of CTCF-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in CTCF identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy with a low threshold for clinical feeding evaluation and/or radiographic swallowing study for those with clinical signs or symptoms of dysphagia; gastrostomy tube placement may be required for persistent feeding issues. Stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation. Conductive hearing loss may respond to placement of PET; hearing aids may be helpful per otolaryngologist. Standard treatment for developmental delay / intellectual disability, neurobehavioral issues, gastroesophageal reflux disease, strabismus, refractive errors, ptosis, cleft palate, dental anomalies, scoliosis, hip dysplasia, ankle/foot anomalies, sleep disturbance, recurrent infections, renal anomalies, anomalies of the genitalia, congenital heart defects, seizures, and Wilms tumor.

Surveillance: At each visit: measure growth parameters and evaluate nutritional status and safety of oral intake; monitor for gastroesophageal reflux disease and/or constipation; assess for new manifestations such as seizures or changes in tone; monitor developmental progress and educational needs; assess for behavioral issues or changes in behavior; monitor for signs/symptoms of sleep disturbance; assess for frequent infections. Assess for signs and symptoms of scoliosis at least annually until skeletal maturity. Dental and ophthalmology evaluations at least annually or as clinically indicated. Annual audiology evaluation through childhood or as clinically indicated. No tumor screening protocol for individuals with CTCF-related disorder has been developed.

Pregnancy management: In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to or during pregnancy may be possible.

Genetic counseling: CTCF-related disorder is inherited in an autosomal dominant manner. Approximately 80% of individuals with CTCF-related disorder whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CTCF pathogenic variant. If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the CTCF pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.