Cornelia de Lange syndrome

Most cases (approximately 60%) of Cornelia de Lange syndrome (CdLS) are caused by changes (mutations) in the NIPBL gene. About 10% of people affected by the condition have mutations in one of four known genes ( SMC1A, SMC3, HDAC8 and RAD21). Many of the genes associated with CdLS encode proteins that play an important role in human development before birth. Mutations in these genes may result in an abnormal protein that is not able to carry out its normal function. This is thought to interfere with early development leading to the many signs and symptoms of CdLS.

In the remaining 30% of people with CdLS, the underlying genetic cause of the condition is unknown.

The diagnosis is suspected when the following signs and symptoms are present:

• Head and face appearance ( >95%): Very small and flat head (microbrachycephaly), unibrow (synophrys) and highly arched eyebrows (in 98% of the cases), long and thick eyelashes, low-set abnormally placed ears with a thick helix (curve of the outer ear), short nose with upturned tip with nares that are easily seeing from the front (anteverted nares), long space between the nose and the superior lip, thin downturned lips, high and arched palate with clefts (30% of the cases), very small jaw (micrognathia) in 80% of the cases, with spurs (42% of the cases), and short neck.
• Growth failure ( >95%): Growth failure that starts while the baby is growing inside the womb, resulting in a very low height and weight throughout life, and failure to thrive secondary to gastroesophageal reflux and other issues with feeding.
• Intellectual disability ( >95%) Severe-to-profound developmental delay
• Limb abnormalities ( >95%). Small or absent forearms and missing fingers in about 30% of the cases. Some people do not have limb deficiencies but have micromelia (small hands), abnormal placed thumbs, and an abnormal curvature of the fifth finger (clinodactyly). A fusion of the bones of the forearm (radioulnar synostosis) is common and may result in a defect of the elbows. Small feet and joined toes (syndactyly) in more than 80% of the cases.
• Excess of hair in the face, back and arms (hirsutism) in more than 80% of the cases.

People with the milder syndrome usually have many of the characteristic facial features but with less severe cognitive and upper extremities defects, and mild intellectual disability (intelligence is normal in some cases). A milder syndrome is more common in people with variants in the SMC3, RAD21, HDAC8 or SMC1A genes.

The diagnosis of CdLS is established with the presence of the clinical features and/or by the genetic test showing a variation in any of the genes associated with the syndrome. However, about 30% of the people affected by the syndrome do not have any known cause.

Depending on the mutated gene, Cornelia de Lange syndrome (CdLS) can be inherited in an autosomal dominant manner, when it is caused by variations in the NIPBL , SMC2 , or RAD21 genes, or it can have an X-linked inheritance when it is caused by variations in the SMC1A or HDAC8 genes. However, most cases (more than 99%) result from new ( de novo) mutations, which means that are not inherited from the parents and occur in people with no family history of the condition.

Intellectual disability is a common feature of Cornelia de Lange syndrome, occurring in more than 95 percent of people with this condition. The IQ test is one tool for measuring intelligence, and a score below 70 indicates that a person has intellectual disability. IQ scores in people with Cornelia de Lange syndrome range from 30 to 102, so there have been some people with IQ scores in the normal range. The average IQ score for people with Cornelia de Lange is 53.

Visit our Organizations Web page to find a list of groups dedicated to Cornelia de Lange syndrome. You can contact these organizations to get in touch with other families.

Life expectancy is relatively normal for people with Cornelia de Lange syndrome and most affected children live well into adulthood. For example, one article mentioned a woman with Cornelia de Lange syndrome who lived to age 61 and an affected man who lived to age 54. However, certain features of this condition, particularly severe malformations of the heart or throat, may decrease life expectancy in some affected people.

Because Cornelia de Lange syndrome (CdLS) affects many different systems of the body, medical management is often provided by a team of doctors and other healthcare professionals. Treatment for this condition varies based on the signs and symptoms present in each person. It may include:

• Supplemental formulas and/or gastrostomy tube placement to meet nutritional needs and improve the growth delay
• Ongoing physical, occupational, and speech therapies
• Surgery to treat skeletal abnormalities, gastrointestinal problems, congenital heart defects and other health problems
• Medications to prevent or control seizures.

The CdLS foundation's Web site offers more specific information about the treatment and management of CdLS. Please click on the link to access this resource.