Cornelia de Lange syndrome and genetics
Cornelia de Lange syndrome (CdLS) is a developmental disorder characterized by a range of physical and intellectual disabilities, with distinctive facial features and possible limb abnormalities. The condition is primarily linked to mutations in genes associated with the cohesin protein complex, which is essential for proper gene expression and chromosomal stability during cell division. CdLS primarily arises from spontaneous (de novo) mutations and can be inherited in an autosomal dominant or X-linked dominant pattern.
The NIPBL gene, located on chromosome 5, is a significant contributor, with about 60% of CdLS cases related to its mutations. Other genes, such as SMC1A and SMC3, also play a role in the syndrome, particularly in milder forms of CdLS. Characteristic symptoms include intellectual disabilities ranging from mild to severe, growth impairment, and various associated health issues like heart defects and hearing loss.
Diagnosis typically involves genetic testing following the identification of distinct physical features. While there is no cure for CdLS, treatments focus on managing symptoms and improving quality of life through surgical interventions and therapies. Early diagnosis and support can lead to better developmental outcomes, though the severity of the condition can vary widely among individuals.
Cornelia de Lange syndrome and genetics
ALSO KNOWN AS: Brachmann-de Lange syndrome; Amsterdam dwarfism; typus degenerativus amstelodamensis
DEFINITION Cornelia de Lange syndrome (CdLS) is a developmental disorder of variable severity. Mutations of genes associated with the cohesin protein complex are present in more than half of individuals with CdLS. Cohesin regulates gene expression. Changes in gene expression affect the developing embryo and are believed to underlie the deficits seen in CdLS.
Risk Factors
CdLS is mostly a sporadic disorder, the result of spontaneous (de novo) mutations. The syndrome is inherited in an autosomal dominant and X-linked dominant pattern. Mildly affected individuals can have children, but 50 percent of their offspring will have CdLS. Germline explains several affected children born to normal parents.
Etiology and Genetics
According to 2022 data from the US National Library of Medicine, CdLS is estimated to occur in 1 out of 10,000 to 30,000 live births, although it likely is not diagnosed in many cases. It is a cohesinopathy. Cohesin is a multiprotein complex that holds sister chromatids together after DNA replication. It is also involved in the repair of double-stranded DNA and plays a regulatory role in gene expression. Disruption of cohesin function interferes with the normal course of embryonic development. Alterations in three different proteins associated with cohesin’s ringlike structure have been found in CdLS.
Approximately 60 percent of individuals with CdLS have mutations in the Nipped-B-Like (NIPBL) gene. NIPBL is located on the long arm of chromosome 5. Its product, the NIPBL protein, also known as delangin, mediates the binding of cohesin to chromosomes. A variety of NIPBL mutations have been identified, ranging from point mutations to small insertions and deletions. Individuals with truncations and deletions are more profoundly affected than those with missense mutations.
Rare cases of CdLS have been associated with chromosomal rearrangements affecting the area on chromosome 5 where NIPBL is located.
The cohesion complex consists of four subunit proteins. Mutations in the structural maintenance of chromosome 1A and 3 (SMC1A and SMC3) have been linked to CdLS. Four percent of individuals with CdLS have mutations in the SMC1A gene. SMC1A is located on the short arms of the X chromosome. The gene is not subject to X inactivation, so both male and female patients can have SMC1A mutations. Individuals with SMC1A mutations tend to have a milder form of CdLS: Growth is less impaired, abnormalities of the arms and legs are rarely if at all present, and organ systems generally are spared. The principal finding in individuals with SMC1A mutations is intellectual disability, which does not tend to be severe.
SMC3 is located on the long arm of chromosome 10. Mutations in the SMC3 gene are infrequent and mainly associated with mild to moderate intellectual disability.
HDAC8, BRD4, ANKRD11, and RAD21 have also been found to contribute to the condition. Mechanisms other than gene mutations could hypothetically lead to the malfunction of NIPBL, SMC1A, and SMC3.
Symptoms
Characteristic facial features include arched, well-defined eyebrows, long eyelashes, and a short, upturned nose. The head is small, with low-set ears and an underdeveloped mandible. Hair growth often is abundant. Arm defects include absent forearms, single fingers, and small hands. Growth is impaired. Intellectual disability varies from mild to severe. Other potential findings include eye and kidney anomalies, hearing loss, heart malformations, a dysfunctional gastrointestinal tract, underdeveloped genitalia, autism, and self-destructive behavior.
Screening and Diagnosis
Pregnancy-associated plasma protein-A (PAPP-A) levels are low in early gestation. High-resolution ultrasound can reveal increased nuchal translucency (cystic hygroma), dysmorphic facial features, and organ and possibly limb anomalies in the fetus. Otherwise, at birth, the infant’s striking facial features and clinical findings will lead to the diagnosis of CdLS. The initial genetic evaluation consists of chromosomal analysis. When the results of this analysis are negative, mutational analysis of the NIPBL gene should be obtained. If there are no mutations in the NIPBL gene, then analysis of the SMC1A and SMC3 genes can be pursued.
Treatment and Therapy
Gastroesophageal reflux disease requires surgery when medical treatment has failed. Surgical correction is needed for intestinal malrotation. High-calorie formula and feeding tube placement will support weight gain. Surgery may be necessary to correct heart defects, cleft palate, and undescended testicles or to improve mobility of the limbs. Vesicoureteral reflux warrants prophylactic antibiotics. Regular hearing screens are needed as sensorineural hearing loss may develop over time. Visits with the ophthalmologist facilitate the detection and treatment of common problems such as narrowing of the tear ducts, myopia, and cataracts. Seizure disorders require medication. Early intervention directed at optimizing developmental outcome includes speech, occupational, and physical therapy.
Prevention and Outcomes
Screening may be conducted in families in which a parent or child has been diagnosed with CdLS, but it is a genetic condition and cannot be prevented. In early pregnancy, fetal cells obtained by chorionic villus sampling or amniocentesis can be analyzed for a known CdLS-causing mutation. High-resolution fetal scans during pregnancy will monitor growth and detect anomalies associated with CdLS in families with no identified mutation. Long-term survival is influenced by the severity of organ and system involvement.
Bibliography
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