CTCF-related neurodevelopmental disorder (ORPHA:363611)
A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, borderline to severe intellectual disability, feeding difficulties, behavioral anomalies, vision anomalies and mild facial dysmorphism. Other associated features may include microcephaly, short stature, urogenital or palatal anomalies (e.g. cleft palate), minor cardiac defects, recurrent infections or hearing loss.
Epidemiology
Up to date, 47 individuals worldwide are reported in the literature.
Clinical description
Affected individuals usually present with variable developmental delay or intellectual disability, ranging from learning difficulties with normal intellect to severe cognitive impairment. Developmental delay usually becomes evident in childhood with walking age ranging from 12 months to 3 years and language abilities varying from first words at 12 months to absent speech at 12 years of age. Intrauterine growth retardation during pregnancy or low birth measurements are observed in about one third of the reported cases. Feeding difficulties and failure to thrive are common in infants, sometimes requiring temporary tube feeding. Behavioral anomalies are common and include autistic features, hyperactivity, attention deficit or aggressivity. Further frequent and variable clinical aspects include vision anomalies, sensorineural and/or conductive hearing loss, recurrent infections and minor facial dysmorphism such as a long face with a prominent forehead, long palpebral fissures or a bulbous nasal tip. Microcephaly, cardiac defects and palatal anomalies such as high or cleft palate are present in about 30% of patients. Most of the reported individuals show a body height within the normal range, but short stature and less frequently tall stature has been reported. Febrile seizures or epilepsy occur in few individuals as well as nonspecific MRI and minor skeletal anomalies.
Etiology
The disorder is caused by heterozygous, pathogenic variants (larger deletions, truncating variants or missense variants within the zinc-finger domains) in the CTCF-gene on chromosome 16q22.1, which encodes for an important chromatin organizer.
Diagnostic methods
Diagnosis is confirmed by genetic testing, usually by non-targeted approaches such as multigene panel or exome sequencing.
Differential diagnosis
The differential diagnosis includes 22q11.2 deletion syndrome and a number of other neurodevelopmental disorders associated with feeding difficulties, mild developmental delay and variable anomalies.
Antenatal diagnosis
Prenatal diagnosis is possible when the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal dominant. Most cases result from a de novo pathogenic variant. Two inherited cases have been reported, where the variant was transmitted from a mildly affected or presumably healthy parent to the affected child, and genetic counseling should be offered in such cases.
Management and treatment
Affected individuals benefit from early developmental support including occupational therapy and special education where needed. Regular evaluation of growth parameters and for vision and hearing anomalies is recommended. If urogenital, cardiac or other anomalies are present or suspected, patients should be referred to the appropriate specialists.
Prognosis
The prognosis is usually good, but depends on severity of the disease and organ involvement. Affected individuals may require life-long support from their caregivers.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Pr Christiane ZWEIER