Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a rare genetic condition that affects growth and development and can range from mild to severe. A child’s growth before and after birth is often slower, and they may have short stature. Children with this condition may also have moderate to severe intellectual disability, behavior problems, and autism. People with CdLS often have distinct facial features and abnormalities in the hands, arms, and fingers. CdLS is one of a group of conditions called cohesinopathies, which are caused by changes in specific genes before birth.

Cornelia de Lange syndrome causes particular facial features, the slowing of body growth, cognitive issues, and other abnormalities. Symptoms may include:

• Malformations of the hands and arms
• Microcephaly
• Seizures
• Gastrointestinal problems such as gastroesophageal reflux (GERD)
• Autism spectrum disorders
• Underdevelopment of the sexual organs
• Cleft palate
• Heart defects
• Failure of the testes to descend into the scrotum (cryptorchidism)
• High, arched eyebrows, or eyebrows that meet in the midline
• Widely spaced teeth or eyes
• Hearing loss
• Excessive hair growth
• Myopia
• Dental abnormalities

In mild Cornelia de Lange syndrome cases, some of the symptoms above may be less serious or even absent.

Cornelia de Lange syndrome is genetic condition that is caused by mutations in at least five genes (NIPBL, RAD21, SMC3, HDAC8, and SMC1A). The severity of the condition can vary greatly depending on the type of mutation and which gene is affected. More than half of people with CdLS have mutations in the NIPBL gene. This is also associated with more severe disease.

Cornelia de Lange syndrome is rarely inherited. Rather, it usually happens sporadically, with no family history of the disease. This happens because of de novo, or new, mutations.

The HDAC8 and SMC1A genes are found on one of the sex chromosomes, specifically the X chromosome. Only one copy of the mutated gene is necessary to cause the disorder, and it affects both females and males. This differs from many other X-linked disorders, where males are mostly affected. The NIPBL, RAD21, and SMC3 genes are found on autosomes, or the non-sex chromosomes, and only one copy of the mutated gene is necessary to cause the disorder.

The five genes associated with CdLS produce proteins that are involved with development before birth. Specifically, the proteins are responsible for guiding the development of the face, limbs, and other parts the body.

To diagnose CdLS, your doctor will review your child’s medical history and perform a physical examination. Your doctor may also order genetic testing to test for the specific mutations in the five genes associated with CdLS (NIPBL, RAD21, SMC3, HDAC8, and SMC1A) and other genes of interest.

Your child’s doctor may recommend treatments for gastrointestinal issues. Gastroesophageal reflux (GERD) occurs when stomach acid flows back into the esophagus. Treatment for GERD varies by age but can include medication to reduce stomach acid or make the stomach empty faster. Your doctor may also recommend surgery in more severe cases or if the intestines are twisted. If nutritional needs are not being met, your doctor may prescribe supplemental formula or an intervention to deliver nutrition directly into the stomach.

Your doctor may prescribe medications to treat seizures. Hearing loss may be treated with hearing aids or cochlear implants. Your doctor may also recommend surgery or other treatments for heart defects or to improve mobility of the hands, arms, legs, or feet.

Your child may also need physical therapy, speech therapy, or occupational therapy to improve development and long-term prognosis. Your doctor may also suggest alternative methods of communication, such as sign language, if your child’s verbal skills are lacking.

The Cornelia de Lange Syndrome and Related Disorders Clinic at Boston Children’s Hospital is dedicated to the comprehensive care of children and adolescents who have CdLS or related conditions known as cohesinopathies.