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In Europe, the prevalence at birth of Cornelia de Lange syndrome (CdLS) is estimated at 1/80,000.

Distinctive facial features include: well-defined arched eyebrows, synophrys, long eyelashes, short nose, concave nasal ridge, anteverted nares, micrognathia, long smooth philtrum, and downturned corners of the mouth with a thin upper lip. Feeding difficulties and failure to thrive are frequently complicated by gastroesophageal reflux. Global developmental delay, in particular speech delay evolves towards intellectual disability ranging from mild to profound. Various behavioral disorders have been reported (anxiety, autistic traits/autism, shyness, compulsive obsessional disorder, self-injurious behavior, psychiatric disorders). Hearing loss is possible as well as various cardiac, renal, skeletal, gastrointestinal, and genital malformations.

Causative pathogenic variants in six genes involved in structural or regulatory components of the cohesin complex have been identified. NIPBL variants (5p13.2) are the most common cause (70% of patients). Less frequently involved genes include: SMC1A (Xp11.22-p11.21) associated with an X-linked form of CdLS, SMC3 (10q25) missense variants associated with a non-classical phenotype, RAD21 (8q24.11) mainly non-classical phenotype, HDAC8 (Xq13.1) implicated in an X-linked CdLS with some distinctive features, and BRD4 (19p13.12) recently associated with non-classical or mild CdLS. Genotype-phenotype correlations can be made to a certain extent, severe forms are more frequently associated with NIPBL.

Diagnosis is often suspected on clinical presentation and a clinical diagnosis can be confirmed for the classical phenotype if full criteria are met. The diagnosis is confirmed by genetic testing for up to 70% of patients presenting a classical phenotype. Gene panels should at least include the causal genes as wells as genes from differential diagnoses (e.g. ANKRD11). Somatic mosaicism occurs quite frequently in CdLS (15%) and saliva or buccal cell swabs should be considered as preferred sample for genetic testing.

Hypertrichosis is common in other syndromes that affect chromatin/transcription regulation genes such as Coffin Siris Syndrome, Wiedemann Steiner Syndrome, Rubinstein Taybi syndrome, CHOPS syndrome, etc. Other differential diagnoses include mucopolysaccharidosis, fetal alcohol syndrome, and Smith Lemli Opitz syndrome among others. There are overlapping features between KBG syndrome and mild or atypical CdLS.

Prenatal ultrasound examination may show IUGR, organ malformations (diaphragmatic hernia, limb defects), increased nuchal thickness, and abnormal facial profile. Prenatal genetic testing can be proposed when the pathogenic variant has been previously identified in a family member.

Most cases are sporadic. Occasionally, familial transmission occurs, following an autosomal dominant pattern. Genetic counseling can be difficult in milder forms given some inter-individual variability. Germline mosaicism explains recurrence cases when the pathogenic variant is not detected in parents. X-linked forms (SMC1A, HDAC8) require specific genetic counseling.

There is no cure for the disorder but psychoeducational care is necessary. Failure to thrive and gastroesophageal reflux require specific care: tube feeding, gastrotomy and Nissen anti-reflux intervention. Screening for multi-visceral or sensorineural complications helps to improve quality of life.

Life expectancy with appropriate care is typically unaltered but follow-up data is lacking. Life expectancy can be reduced in case of severe or untreated organ malformations. Quality of life is mostly altered by severe limb defects, behavioral disorders and psychiatric disorders. Hearing impairment can be difficult to diagnose and has been reported to improve with time in some adults.