Cornelia de Lange syndrome is a phenotypically heterogeneous multi-system disorder that is primarily recognized by the presence of distinct facial dysmorphia. CDLS4 affected individuals exhibit microcephaly, a long and smooth philtrum, thick arched eyebrows with synophrys, long eye lashes, a wide and broad nasal bridge and a thin upper lip. Other features include prenatal and post-natal growth retardation, mild to severe cognitive delay, cutis marmorata of the skin, cleft palate, gastroesophageal reflux and skeletal anomalies such as vertebral clefting, hemivertebrae, brachydactyly, syndactyly, radioulnar abnormalities and exostoses. The overall prevalence of CDLS is thought to be around 1 in 10,000-30,000 live births. As the condition is highly variable, the severity of symptoms differs even between family members. The CDLS4 subtype, associated with RAD21 gene mutations, is believed to be a milder form of the disorder compared to NIPBL-associated CDLS1. Life expectancy is not adversely affected in CDLS and most patients live well into adulthood.
The condition is thought to be underdiagnosed and frequently misdiagnosed, especially in patients with a milder phenotype. Hence molecular analysis of the RAD21 gene is beneficial in confirming a CDLS4 diagnosis. Treatment of the disorder is based on individual symptoms and requires a multi-disciplinary approach. Patients benefit from physical, occupational and speech therapy.
The disorder follows an autosomal dominant pattern of inheritance and is caused by heterozygous mutations in the RAD21 gene. This gene encodes a member of the cohesion complex, which is required for the cohesion of sister chromatids after DNA replication, as well as for double strand break repair, DNA recombination and the apoptotic process. At least 8 mutations in the gene have been associated with CDLS4, including missense variants and a large deletion that results in the absence of the gene.
Monies et al. (2017) described the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 4-month-old male, presented with overgrowth, macrocephaly, speech delay, moderate to severe intellectual disability, stereotypic behaviors, ataxia, hypospadias, kidney malformation, renal tubulopathy, ptosis, anorectal malformation and AML. Using a multigene panel for dysmorphology/skeletal dysplasia, a heterozygous mutation (c.68G>A, p.W23X) was identified in exon 2 of the patient’s RAD21 gene, associated with Cornelia de Lange Syndrome 4. Given the atypical presentation of the patient, this case helped in the phenotypic expansion of the disorder.
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