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At a glance

A severe and characteristic syndrome of craniofacial malformations associated with neurological impairment.

Synonyms

Cornelia de Lange Syndrome; De Lange Syndrome; Typus Degenerativus Amstelodamensis; Amsterdam Dwarfism.

History

First described in 1916 by the German physician Winfried Robert Clemens Brachmann (1888-1969). In 1933, the Dutch pediatrician Cornelia Catharina de Lange (1871-1951) reported two more cases and named the disorder after the city (Amsterdam) in which she worked in “Typus degenerativus Amstelodamensis.”

Incidence

1:10,000 to 30,000 live births. It appears that all ethnic groups are similarly affected.

Genetic inheritance

Familial cases with dominant transmission have been described, but almost all cases are sporadic. The penetrance is almost complete and intra-familial phenotypic variability is high. Depending on the mutated gene, five types of BdLS are distinguished and several hundred different mutations are now known to cause BdLS. BdLS 1 refers to the most common mutations, which have been mapped to the NIPBL-gene (Nipped-B homolog, Drosophila) or Cohesin Loading Factor gene on chromosome 5p13.2 and accounts for approximately 80% of all patients. BdLS 2 is caused by mutations in the SMC1A gene (Structural Maintenance of Chromosomes 1A) located on chromosome Xp11.22 and are present in about 5% of cases. In BdLS 3, the responsible mutations affect the SMC3 (Structural Maintenance of Chromosomes 3) gene on chromosome 10q25.2. BdLS 4 has its origin in mutations in the RAD21 Cohesin Complex Component gene, which has been mapped to chromosome 8q24.11. Both, BdLS 3 and 4 are exquisitely rare. Finally, BdLS 5 shows mutations in the HDAC8 (Histone Deacetylase 8) gene on chromosome Xq13.1, which make up about 5% of cases. Inheritance for BdLS 1, 3, and 4 is autosomal dominant, whereas for BdLS 2 and 5 it is X-linked dominant. The clinical manifestations in BdLS 2 and 3 are generally milder when compared to classic BdLS (BdLS 1), particularly with regards to growth retardation and limb reduction defects. BdLS 4, too, is clinically milder than BdLS 1. While growth retardation, facial and minor skeletal anomalies are quite similar to BdLS 1, developmental delay and limb involvement are less severe. In addition to mild classic BdLS phenotype, BdLS 5 patients exhibit some additional atypical facial features (eg, large anterior fontanelle, hooded eyelids, broader nasal root), truncal obesity and a more pleasant personality. However, males are more severely affected than females (due to random X-chromosome inactivation). It is noteworthy that a significant number of patients test negative for any of these known mutations.

Pathophysiology

All five genes mentioned above encode components of cohesin. Cohesin is a multi-protein complex that is made up of four subunits. The mitotic and meiotic cell cycle each require DNA replication with duplication of the chromosomes and production of sister chromatids. Cohesin acts as a molecular glue in the process ...

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