Cornelia de Lange syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Cornelia de Lange syndrome is a developmental disorder that affects many parts of the body. The features of this disorder vary widely among affected individuals and range from relatively mild to severe.

Cornelia de Lange syndrome is characterized by slow growth before and after birth leading to short stature; intellectual disability that is usually moderate to severe; and abnormalities of bones in the arms, hands, and fingers. Most people with Cornelia de Lange syndrome also have distinctive facial features, including arched eyebrows that often meet in the middle (synophrys), long eyelashes, low-set ears, small and widely spaced teeth, and a small and upturned nose. Many affected individuals also have features similar to autism spectrum disorder, a developmental condition that affects communication and social interaction.

Additional signs and symptoms of Cornelia de Lange syndrome can include excessive body hair (hypertrichosis), an unusually small head (microcephaly), hearing loss, and problems with the digestive tract. Some people with this condition are born with an opening in the roof of the mouth called a cleft palate. Seizures, heart defects, and eye problems have also been reported in people with this condition.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Cornelia de Lange syndrome can result from variants (also called mutations) in one of several genes. Variants in the NIPBL gene have been identified in more than half of all people with this condition. Variants in other genes, including SMC1A, HDAC8, RAD21, SMC3, and others, are much less common.

The proteins produced from most of the genes involved in Cornelia de Lange syndrome contribute to the structure or function of the cohesin complex, a group of proteins with an important role in directing development before birth. Within cells, the cohesin complex helps regulate the structure and organization of chromosomes, stabilize cells' genetic information, and repair damaged DNA. The cohesin complex also regulates the activity of certain genes that guide the development of the face, limbs, and other parts of the body. Other genes that are involved in rare cases of Cornelia de Lange syndrome also control gene activity and are likely important during development.

Variants in the NIPBL, SMC1A, HDAC8, RAD21, and SMC3 genes cause Cornelia de Lange syndrome by impairing the function of the cohesin complex, which disrupts gene regulation during critical stages of early development. Variants in other genes are also thought to disrupt the regulation of genes important for development.

The features of Cornelia de Lange syndrome vary widely, and the severity of the disorder can differ even in individuals with the same gene variant. Researchers suspect that additional genetic or environmental factors may be important for determining the specific signs and symptoms in each individual. In general, SMC1A, RAD21, and SMC3 gene variants cause milder signs and symptoms than NIPBL gene variants. Variants in the HDAC8 gene cause a somewhat different set of features, including delayed closure of the "soft spot" on the head (the anterior fontanelle) in infancy, widely spaced eyes, and dental abnormalities. Like affected individuals with NIPBL gene variants, those with HDAC8 gene variants may have significant intellectual disability.

In about 15 percent of cases, the cause of Cornelia de Lange syndrome is unknown. Researchers are looking for additional changes in the known genes, as well as variants in other genes, that may cause this condition.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

When Cornelia de Lange syndrome is caused by variants in the NIPBL, RAD21, or SMC3 gene, the condition is considered to have an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new gene variants and occur in people with no history of the condition in their family.

When Cornelia de Lange syndrome is caused by variants in the HDAC8 or SMC1A gene, the condition has an X-linked dominant pattern of inheritance. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. Studies of X-linked Cornelia de Lange syndrome indicate that one copy of the altered gene in each cell may be sufficient to cause the condition. Affected females, who have two X chromosomes, may have milder signs and symptoms than affected males, who have only one X chromosome. Most X-linked cases result from new variants in the HDAC8 or SMC1A gene and occur in people with no history of the condition in their family.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Although the exact incidence is unknown, Cornelia de Lange syndrome likely affects 1 in 10,000 to 30,000 newborns. The condition is probably underdiagnosed because affected individuals with mild or uncommon features may never be recognized as having Cornelia de Lange syndrome.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormally low-pitched voice · Very frequent (99-80%)

A persistent (minutes to hours) abnormal decrease in the pitch of the voice for the context or social situation or significantly different from the baseline of the individual.

Anteverted nares · Very frequent (99-80%)

Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).

Atresia of the external auditory canal · Very frequent (99-80%)

Absence or failure to form of the external auditory canal.

Brachycephaly · Very frequent (99-80%)

An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.

Curly eyelashes · Very frequent (99-80%)

Abnormally curly or curved eyelashes.

Delayed eruption of teeth · Very frequent (99-80%)

Delayed tooth eruption, which can be defined as tooth eruption more than 2 SD beyond the mean eruption age.

Delayed skeletal maturation · Very frequent (99-80%)

A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.

Depressed nasal bridge · Very frequent (99-80%)

Posterior positioning of the nasal root in relation to the overall facial profile for age.

Other findings in the same source

From: Orphanet

Additional reported features include Downturned corners of mouth (Very frequent (99-80%)); Gastroesophageal reflux (Very frequent (99-80%)); Generalized hirsutism (Very frequent (99-80%)); High palate (Very frequent (99-80%)); Highly arched eyebrow (Very frequent (99-80%)); Hypertonia (Very frequent (99-80%)); Intellectual disability (Very frequent (99-80%)); Intellectual disability, severe (Very frequent (99-80%)); Long eyelashes (Very frequent (99-80%)); Long philtrum (Very frequent (99-80%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Cornelia de Lange syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Cornelia de Lange syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.