Deardorff et al. (2012) reported 2 unrelated patients, a boy and a girl, with a phenotype suggestive of Cornelia de Lange syndrome. Both had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, long or ... Deardorff et al. (2012) reported 2 unrelated patients, a boy and a girl, with a phenotype suggestive of Cornelia de Lange syndrome. Both had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, long or prominent eyelashes, broad nasal bridge, smooth philtrum, and thin upper lip. The boy had ptosis and an upturned nasal tip, whereas the girl had upslanted palpebral fissures and a short nose. The boy had a number of additional congenital anomalies, including poor dental enamel, submucosal cleft palate, stapes fixation, thin fingers, left radioulnar synostosis, delayed skeletal age, vertebral clefting, pectus carinatum, short femoral neck, tetralogy of Fallot, intestinal malrotation, and gastroesophageal reflux. He also had severe cognitive delay and attention deficit-hyperactivity disorder. The girl had short fingers, fifth finger clinodactyly, small prominent first toe, long fourth metacarpal, cutis marmorata, and mild neurodevelopmental defects.
In 2 unrelated patients with Cornelia de Lange syndrome-4, Deardorff et al. (2012) identified different de novo heterozygous mutations in the RAD21 gene (P376R; 606462.0001 and C585R; 606462.0002). These mutations were identified by screening of the RAD21 gene ... In 2 unrelated patients with Cornelia de Lange syndrome-4, Deardorff et al. (2012) identified different de novo heterozygous mutations in the RAD21 gene (P376R; 606462.0001 and C585R; 606462.0002). These mutations were identified by screening of the RAD21 gene in 258 individuals with a CDLS-like phenotype after genomewide copy-number analysis had identified a different patient with a de novo deletion of chromosome 8q24.1 that included RAD21. In vitro studies showed that the P376R mutation resulted in altered activity of the mutant protein rather than a loss of function. Patient cells showed decreased sister chromatid separation, increased aneuploidy, and defective DNA repair, as well as abnormal transcriptional activity in a zebrafish model. The boy with the P376R mutation had a more severe phenotype than the girl with the C585R mutation. Functional studies of the C585R mutation suggested a loss of function, similar to patients with deletion of the RAD21 gene. Deardorff et al. (2012) concluded that dominant RAD21 mutations result in more severe functional defects and a worse phenotype than loss-of-function mutations or deletions. Deardorff et al. (2012) also noted that RAD21 lies between TRPS1 and EXT1, and would thus be deleted in persons with Langer-Giedion syndrome. The mild facial and cognitive involvement seen in individuals with RAD21 heterozygous loss-of-function mutations may cause many individuals to go clinically unnoticed.