CORNELIA DE LANGE SYNDROME

Cornelia de Lange syndrome (CdLS) is a malformation-retardation syndrome with characteristic craniofacial dysmorphia, growth retardation, hypertrichosis, and intellectual disability. Pathogenic variants in six genes are known, with 60% of cases attributable to the NIPBL gene. In some patients, NIPBL variants are not detectable in peripheral lymphocytes because they occur in other tissues in the mosaic.

Symptoms

Typical symptoms of CdLS include:

• Characteristic craniofacial dysmorphia
• Prenatal growth retardation
• Hypertrichosis
• Synophrys
• Reduction malformations of the upper extremities
• Intelligence impairment (average IQ: 53)

In addition, heart defects and gastrointestinal disturbances are frequently found.

In milder forms, which probably affect the majority of patients, the facial dysmorphia dysmorphic features are also less pronounced than in the classic form; the cognitive impairment and limb defects are also less severe.

Causes

To date, pathogenic variants have been identified in six genes, with variants in the NIPBL gene accounting for the largest proportion (60%). In approximately 15–20% of patients with classic CdLS, NIPBL variants cannot be detected in peripheral lymphocytes because they are present in mosaic form in other tissues. In addition, variants in mosaic form have also been described in rare cases in the SMC3, RAD21, and SMC1A genes.

References

Kline et al. 2019, Am J Med Genet 179A:1080 / Kline et al. 2018, Nat Rev Genet 19:649 / Dangiolo et al. 2015, Am J Med Genet A167:3161 / Kaiser et al. 2014, Hum Mol Genet 23:2888 / Minor et al. 2014, Gene 537:279 / Kline et al. 2007, Am J Med Genet C Semin Med Genet 145C:248 / Bhuiyan et al. 2006, J Med Genet 43:568