Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder due to defects in the cohesin complex that regulates sister chromatid cohesion and gene expression. Incidence is about 1 in 10,000 to 30,000. Causative genes: NIPBL (about 60%; autosomal dominant, mostly de novo, with the most severe phenotype), SMC1A (X-linked, about 5%), SMC3, RAD21, and HDAC8 (X-linked), BRD4. Mosaic NIPBL variants occur and may need testing from buccal mucosa or other tissues if blood tests are negative.

• Characteristic facies: synophrys with arched, thick eyebrows, long curly eyelashes, short upturned nose with depressed bridge, long smooth philtrum, thin downturned upper lip, low set posteriorly rotated ears, and micrognathia
• Prenatal and postnatal growth retardation, microcephaly, and hirsutism
• Upper limb malformations: small hands, proximal thumbs, fifth finger clinodactyly, oligodactyly, and in severe cases reduction defects (absent forearms)
• Gastrointestinal: gastro oesophageal reflux (up to 90%, often severe and causing aspiration, oesophagitis and Barrett oesophagus), intestinal malrotation with volvulus, feeding difficulty, constipation
• Neurodevelopmental: moderate to profound intellectual disability, limited speech, autism spectrum features, self-injury, anxiety, and sleep problems
• Congenital heart defects (about 25%), renal anomalies, cryptorchidism, hearing loss (about 60%; conductive and sensorineural), myopia and ptosis, seizures (about 25%), dental anomalies, cleft palate, and congenital diaphragmatic hernia

• Clinical diagnosis uses a consensus scoring scheme with cardinal features (characteristic facies, hirsutism, upper limb anomalies, feeding difficulty, developmental delay). Confirmation is by multigene panel or exome sequencing (NIPBL, SMC1A, SMC3, RAD21, HDAC8, BRD4), with testing of a second tissue (buccal cells or saliva) when blood is negative but suspicion is high. Baseline workup: echocardiography, renal ultrasound, hearing test (auditory brainstem response), ophthalmology, upper gastrointestinal contrast study or pH monitoring where reflux is symptomatic, and developmental assessment.

• Gastro oesophageal reflux (key to morbidity and behaviour): proton pump inhibitor (omeprazole 1 to 2 mg/kg/day or lansoprazole), prokinetics, thickened feeds, and surgical fundoplication or gastrojejunal feeding if refractory; exclude malrotation before surgery and when there is persistent bilious vomiting. Unexplained irritability, self-injury or food refusal should prompt investigation for reflux, constipation, dental problems, otitis, and pain.
• Feeding and nutrition: high calorie feeds, gastrostomy when needed, and dietetic follow up.
• Surveillance and management of heart, kidney and eye disease; early hearing amplification (hearing aids, grommets).
• Behaviour: behavioural interventions, communication training with sign language or devices, and SSRIs, risperidone or aripiprazole for self-injury or severe aggression.
• Seizures: standard antiepileptic drugs.
• Orthopaedics: monitor for scoliosis, hip dislocation and limb deformities; upper limb surgery or prostheses.
• Cryptorchidism: orchidopexy.
• Anaesthesia: take care with micrognathia, difficult airway, and gastric aspiration risk.
• Genetic counselling: recurrence risk is low (about 1 to 2%) for sporadic cases because of germline mosaicism; 50% if a parent is affected, and X-linked inheritance patterns apply to SMC1A and HDAC8.