Cornelia de Lange syndrome (CdLS) is a rare, multisystem developmental disorder characterized by prenatal and postnatal growth failure, intellectual disability, behavioral differences, and a distinctive craniofacial appearance. The syndrome encompasses a broad clinical spectrum, ranging from mild presentations with subtle features to a severe classic form with significant structural anomalies and profound intellectual disability. Published prevalence estimates range from 1 in 10,000 to 1 in 100,000 individuals; data from the EUROCAT registry place the prevalence of the classic form at approximately 1 in 50,000, while milder presentations are likely underrepresented in that figure. Based on data in the GeneReviews chapter for this condition, the syndrome is associated with pathogenic variants in genes encoding components of the cohesin complex and its regulators, including NIPBL, SMC1A, SMC3, HDAC8, RAD21, and BRD4. Approximately 99% of cases arise from de novo pathogenic variants; affected individuals rarely have an affected parent. Onset is congenital, with prenatal growth failure identifiable in a majority of cases. Six molecularly defined subtypes—Cornelia de Lange syndrome 1 through 6—correspond to pathogenic variants in each of these genes.

The clinical features of Cornelia de Lange syndrome span multiple organ systems and vary in severity across the clinical spectrum. Synophrys—fusion or near-fusion of the eyebrows—is among the most frequently documented features, present in approximately 98% of individuals with classic presentations. Growth failure, feeding difficulties, and intellectual disability are each reported in approximately 95% of affected individuals; growth failure begins prenatally and persists throughout life in those with classic CdLS, with mean height and weight below the fifth centile. Intellectual disability ranges broadly, with reported IQ values spanning below 30 to 102 and an average of approximately 53 in surveyed cohorts; those with classic features are more likely to have severe-to-profound intellectual disability.

Additional craniofacial features include microbrachycephaly, long eyelashes, thin upper lip vermilion border, downturned corners of the mouth, micrognathia, highly arched palate with or without clefting, and small widely spaced teeth. Hypertrichosis—involving the face, ears, back, and arms—occurs in approximately 80% of individuals. Hearing loss, including sensorineural hearing loss, is documented in approximately 80%; gastroesophageal reflux disease in approximately 75%; and nasolacrimal duct obstruction in approximately 70%. Ptosis is present in approximately 60%.

Congenital heart defects occur in approximately 30% of individuals, most commonly pulmonary or peripheral pulmonary stenosis, ventricular septal defect, or atrial septal defect. Seizures are documented in approximately 25%. Limb abnormalities range from mild variants (small hands, fifth-digit clinodactyly, proximally placed thumb) to severe reduction defects involving the forearms or complete absence. Self-injurious behavior is documented in approximately 56% of individuals; behavioral features also include sleep difficulties, anxiety, attention deficits, and characteristics consistent with autism spectrum disorder.

Cornelia de Lange syndrome arises from pathogenic variants in genes encoding components of the cohesin complex or its regulators, based on GeneReviews data for this condition. Pathogenic variants in NIPBL—encoding the cohesin loader Nipped-B homolog—account for the majority of molecularly confirmed cases. NIPBL, SMC3, RAD21, and BRD4 variants are associated with autosomal dominant inheritance, while variants in SMC1A and HDAC8 are associated with X-linked inheritance. Across all genetic forms, approximately 99% of cases result from de novo pathogenic variants not inherited from either parent; fewer than 1% of individuals have an affected parent.

Genotype-phenotype correlations are documented: individuals with NIPBL missense variants or in-frame deletions exhibit milder growth failure, less severe intellectual disability, and fewer structural anomalies compared to those with NIPBL loss-of-function variants. Loss-of-function variants in SMC1A are associated with a distinct early-infantile epileptic encephalopathy rather than the classic CdLS phenotype. SMC1A pathogenic variants causing a CdLS phenotype are typically missense. The frequency of parental germline mosaicism is estimated at approximately 1.5% to 5.4% in enriched cohorts, which carries implications for recurrence risk in subsequent pregnancies even when neither parent is clinically affected.

The diagnosis of Cornelia de Lange syndrome is established through a combination of clinical evaluation and molecular genetic testing. An international consensus statement defines both cardinal and suggestive clinical features, along with a scoring system to differentiate classic from non-classic presentations.

Clinical features supporting the diagnosis include a distinctive craniofacial appearance (synophrys, microcephaly, long eyelashes, short nasal bridge, anteverted nares, thin upper lip, micrognathia), prenatal or postnatal growth failure, developmental delay or intellectual disability, limb abnormalities of varying severity, and hypertrichosis. Radiographic identification of a short first metacarpal resulting in a proximally placed thumb may assist diagnosis in individuals without frank limb deficiencies.

Molecular confirmation is achieved through a multigene panel encompassing at least NIPBL, SMC1A, HDAC8, SMC3, RAD21, and BRD4, along with additional genes associated with overlapping phenotypes such as AFF4, ANKRD11, CREBBP, and EP300. Comprehensive genomic testing—exome sequencing, exome array, or genome sequencing—is employed when the clinical presentation is atypical or the diagnosis has not initially been considered. Following diagnosis, multisystem evaluations are undertaken across neurologic, developmental, gastrointestinal, cardiac, ophthalmologic, audiologic, genitourinary, musculoskeletal, and immunologic domains to establish the full extent of disease.

Management of Cornelia de Lange syndrome is multidisciplinary, addressing manifestations across the affected organ systems. Feeding difficulties and failure to thrive are managed through feeding therapy; gastrostomy tube placement is used when dysphagia or aspiration risk is persistent. Gastroesophageal reflux disease is managed with medical therapy and postprandial positioning; fundoplication is employed in severe or refractory cases. Malrotation, when present, is corrected surgically.

Seizures are managed with antiseizure medications administered under the supervision of an experienced neurologist; no specific antiseizure medication has been demonstrated to be uniquely effective for CdLS. Developmental delay and intellectual disability are addressed through early intervention programs incorporating physical therapy, occupational therapy, and speech-language therapy. Early augmentative and alternative communication approaches are documented in the literature as associated with improved functional communication outcomes. Hearing aids are utilized in individuals with hearing loss. Ophthalmologic care is provided for ptosis, strabismus, nasolacrimal duct obstruction, and vision impairment. Cleft palate and congenital heart defects are managed by the relevant specialty teams. Behavioral concerns—including anxiety, attention deficits, and self-injurious behavior—are assessed by neuropsychiatric specialists. No disease-specific approved pharmaceutical therapies are identified in this packet.

The clinical course of Cornelia de Lange syndrome reflects the broad spectrum of severity. Growth failure persists throughout life in those with classic presentations; milder phenotypes experience less severe growth impairment. Intellectual disability ranges from mild to profound; those with classic CdLS features are more likely to have severe-to-profound intellectual disability. Motor and adaptive skill development proceed along slower trajectories: approximately half of affected children walk independently by 24 months and 95% by age 10; approximately half can self-feed by age 3 and 95% by age 10. Expressive language is typically more impaired than receptive language, and receptive language more impaired than overall cognition. Early augmentative communication interventions are documented as effective for improving communication outcomes. Hearing loss may improve over time in some individuals. Overall prognosis is substantially influenced by the degree of intellectual disability, the presence of structural cardiac or other organ anomalies, seizure burden, and the severity of behavioral challenges.

Six active clinical trials are registered for Cornelia de Lange syndrome. A Phase 2 study at Johns Hopkins University (NCT04381897) is examining N-acetylcysteine for repetitive and self-injurious behaviors, with a scheduled start in August 2026. A Phase 2 trial sponsored by the University of Milan (NCT06789783) is evaluating the effects of lithium treatment and is currently recruiting. A behavioral assessment and treatment study for problem behavior in children with CdLS is recruiting at Kennedy Krieger Institute (NCT05829668). A physical activity and community empowerment project is recruiting at the University of North Carolina (NCT06740162). A long-term natural history registry at Sanford Health (NCT01793168) continues to collect longitudinal data. A longitudinal growth and development study examining children with rare genetic syndromes (NCT04463316) is also recruiting. The broader research landscape includes 111 classified publications; basic science and preclinical research represents the dominant type, with gene therapy and biomarker-related publications identified alongside case reports and reviews.