Cornelia de Lange Syndrome

Definition

The diagnosis of CdLS is clinical; gene testing is available to support the clinical diagnosis, but not all individuals with CdLS will have a known genetic mutation. Individuals affected with classic CdLS have distinct craniofacial abnormalities including high arched palate, microbrachycephaly, and micrognathia. In addition, hirsutism, including synophrys, hirsute ears, and long, coarse eyelashes are noted in most individuals. Prenatal growth failure continuing throughout life is identified in greater than 95% of affected individuals, as are severe to profound mental retardation and upper limb abnormalities. Genetic testing can be helpful in determining which subtype of CdLS the individual has, the cause of the syndrome, and the risk to other family members.

Prevalence and Epidemiology

The incidence of classic CdLS is 1 : 100,000 to 1 : 10,000. It is thought that a large proportion of individuals with mild CdLS are not diagnosed, and the prevalence may be much higher than these estimates suggest. CdLS affects all ethnic groups and can be found equally in males and females.

Etiology and Pathophysiology

Several genes have been associated with CdLS. Approximately 60% of individuals with this condition have been found to have heterozygous alterations in the NIPBL gene, another 5% of individuals with CdLS have been found to have mutations in the SMC1A gene, 4% have mutations within the HDAC8 gene, 1%–2% have mutations in the SMC3 gene, and <1% have alterations within the RAD21 gene. No genetic abnormalities are identified in approximately 30% of affected individuals. For “mutation-negative” patients with CdLS, deeper sequencing from multiple tissues may lend a genetic diagnosis.

NIPBL mutations are associated with the CdLS1subtype. Although the exact function of the NIPBL protein, delangin, is unknown, it is thought that it is important in proper sister chromatid cohesion. Individuals with CdLS1 may display the classic signs of this syndrome or may display milder manifestations, although most individuals with more severe manifestations of CdLS have mutations in the NIPBL gene. In most cases, these NIPBL gene alterations are de novo , although autosomal dominant transmission has been reported in several families.

Mutations in the SMC1A and SMC3 genes have been identified in only a few affected individuals, and genotype-phenotype associations are not well established, although individuals with mutations in these genes appear to have milder manifestations of the syndrome than individuals with NIPBL mutations. The limb and other structural defects seen in individuals with CdLS are rarely found in individuals with mutations in these genes. The SMC1A and SMC3 proteins are components of the cohesin complex. Similar to the NIPBL protein, they are thought to be important in cohesion of sister chromatids. For this reason, CdLS is thought to be a cohesinopathy. SMC1A mutations can cause CdLS in males or females. CdLS2 is thought to be X-linked dominant. SMC3 mutations are associated with the CdLS3 subtype and are typically de novo but can be associated with autosomal dominant transmission.