Cornelia de Lange syndrome

Key points

• Rare congenital multisystem disorder characterised by distinctive facial features, growth restriction, limb anomalies, and intellectual disability
• Most commonly caused by mutations in NIPBL gene (>50% of cases) - cohesin complex pathway
• Prenatal US may show symmetrical IUGR, limb defects, and facial dysmorphism
• Limb anomalies range from subtle (small hands, clinodactyly) to severe (oligodactyly, phocomelia)
• Also known as Brachmann-de Lange syndrome

Epidemiology & risk factors

• Incidence: ~1 in 10,000-30,000 live births
• Most cases are de novo mutations; autosomal dominant (NIPBL, SMC3, RAD21) or X-linked (HDAC8, SMC1A)
• No sex predilection overall, though X-linked forms preferentially affect males more severely
• Recurrence risk low for de novo mutations (~1.5% due to gonadal mosaicism)

Pathophysiology

• Mutations affect the cohesin complex, essential for chromatid cohesion, gene regulation, and DNA repair
• NIPBL (Nipped-B-like) is the most commonly mutated gene - acts as a cohesin loading factor
• Disrupted cohesin function leads to dysregulation of developmental gene expression rather than chromosomal instability
• Genotype-phenotype correlation: NIPBL mutations tend to produce more severe phenotypes than SMC1A/SMC3 mutations

Clinical features

• Craniofacial: synophrys (confluent eyebrows), long philtrum, thin downturned lips, micrognathia, low-set ears, microcephaly
• Limbs: upper limb reduction defects (oligodactyly, absent forearm/phocomelia in severe cases), small hands/feet, proximal placement of thumbs, clinodactyly of 5th finger
• Growth: prenatal and postnatal growth restriction, symmetrical IUGR
• GI: gastro-oesophageal reflux (common and often severe), intestinal malrotation, diaphragmatic hernia (CDH)
• Cardiac: CHD in ~25% - VSD, ASD, pulmonary stenosis
• GU: cryptorchidism, hypospadias, renal anomalies
• Neurological: intellectual disability (variable severity), seizures, sensorineural hearing loss
• Behavioural: self-injurious behaviour, autistic features

Imaging / investigations

Prenatal US

• Symmetrical IUGR with normal amniotic fluid
• Limb anomalies - absent/hypoplastic forearms, oligodactyly, clinodactyly
• Facial features may be visible: micrognathia, prominent philtrum
• CDH if present
• Cardiac anomalies on fetal echo

Radiographs

• Upper limb reduction defects - ranging from absent radius/ulna to subtle phalangeal hypoplasia
• Small first metacarpal, proximal thumb placement
• Clinodactyly of 5th finger
• Microcephaly on skull films

MRI (brain)

• Non-specific findings: small brainstem, cerebellar hypoplasia
• Simplified gyral pattern in severe cases

Genetic testing

• NIPBL sequencing is first-line (>50% detection rate)
• Panel testing for cohesin complex genes (SMC1A, SMC3, RAD21, HDAC8)

Differentials

• Foetal alcohol syndrome - growth restriction and facial features overlap but no limb reduction defects; maternal history
• Roberts syndrome - limb reduction with facial clefting; AR inheritance; premature centromere separation on cytogenetics
• Phocomelia-thrombocytopenia (TAR syndrome) - bilateral absent radii but thumbs present; thrombocytopenia
• Trisomy 18 (Edwards syndrome) - overlapping digits, IUGR, cardiac defects; karyotype diagnostic
• Fanconi anaemia - radial ray anomalies with pancytopenia; chromosome breakage studies positive

Management

• Multidisciplinary approach: genetics, paediatrics, orthopaedics, ENT, cardiology, GI
• Aggressive management of GOR (major cause of morbidity - risk of aspiration, Barrett's)
• Cardiac and renal anomaly screening
• Hearing assessment and early intervention
• Behavioural and developmental support
• Surgical correction of limb/GI/cardiac anomalies as indicated
• Genetic counselling for recurrence risk