Hennekam syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Hennekam syndrome is an inherited disorder that is characterized by abnormalities of the lymphatic system, which is part of both the circulatory system and the immune system. The lymphatic system is a network of vessels that transport white blood cells (lymphocytes), nutrients, and proteins in a fluid called lymph. In people with Hennekam syndrome, the lymphatic vessels are often dilated (lymphangiectasia), which can slow down the flow of lymph and cause the vessels to leak. As a result, people with this condition experience puffiness or swelling that is caused by a buildup of fluid within certain tissues (lymphedema). The affected vessels may also break open (rupture).

The lymphedema in people with Hennekam syndrome is typically present at birth and often affects the legs and genitalia. Severely affected infants may have extensive swelling caused by fluid buildup before birth (hydrops fetalis).

People with Hennekam syndrome may have lymphangiectasia in the kidneys, lungs, and the membrane covering the heart (pericardium). Many affected infants have intestinal lymphangiectasia, which affects the vessels that transport lymph to and from the intestines. This can cause lymph to leak into the intestines, which can interfere with the absorption of proteins and other nutrients. Affected individuals may also have a buildup of lymph in the abdomen, which can cause swelling (chylous ascites). The lymphedema that is seen in individuals with Hennekam syndrome may affect one side of the body more severely than the other.

Distinctive facial features are common among people with Hennekam syndrome. Affected individuals often have a flattened appearance to the middle of the face and the bridge of the nose, puffy eyelids, widely spaced eyes (hypertelorism), low-set ears, and a small mouth with overgrowth of the gums (gingival hypertrophy). Some individuals with Hennekam syndrome have intellectual disabilities, and these can range from mild to severe. Seizures and growth delays may also occur.

The skeletal abnormalities that can be seen in people with Hennekam syndrome include a premature fusion of the skull bones (craniosynostosis), permanently bent fingers and toes (camptodactyly), and a fusion of the skin between the fingers and toes (cutaneous syndactyly). Affected individuals may also have inward- and upward-turning feet (clubfeet), a narrow upper chest that may have a sunken appearance (pectus excavatum), and an abnormal side-to-side curvature of the spine (scoliosis).

Additional features can include structural abnormalities of the heart, kidneys, or genitals; a soft out-pouching around the belly-button (umbilical hernia); hearing loss; and excessive body hair (hirsutism).

The signs and symptoms of Hennekam syndrome vary widely, even among members of the same family. Because of the potentially serious complications, the life expectancy of individuals with Hennekam syndrome also varies.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the CCBE1, ADAMTS3, or FAT4 gene cause Hennekam syndrome.

The CCBE1 and ADAMTS3 genes provide instructions for making proteins that are found in the extracellular matrix, which is the intricate lattice of proteins and other molecules that forms in the spaces between cells. The CCBE1 and ADAMTS3 proteins work together to help regulate the activity of another protein called vascular endothelial growth factor receptor 3 (VEGFR3). This protein plays an important role in the development and maintenance of the lymphatic system.

The CCBE1 and ADAMTS3 gene variants that cause Hennekam syndrome reduce the amount of functional protein that is available to help regulate the activity of VEGFR3. A disruption in VEGFR3 activity impairs the development of the lymphatic system and contributes to the lymphangiectasia and lymphedema seen in people with Hennekam syndrome. Since the lymphatic system extends throughout the body, a disruption in its early development may change the balance of fluids and impair the normal development of other structures.

Research suggests that the protein produced from the FAT4 gene is involved in determining the position of cells and their components within various tissues. Proper cell positioning within a tissue allows cells to coordinate their activity and plays an important role in tissue structure and function. The FAT4 gene variants that cause Hennekam syndrome interfere with the proper positioning of cells within the developing lymphatic vessels, which contributes to the lymphangiectasia and lymphedema seen in affected individuals.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Hennekam syndrome is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Hennekam syndrome is rare, although the exact prevalence is not known. At least 100 cases of Hennekam syndrome have been reported worldwide.

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.

Abnormal dental morphology · Very frequent (99-80%)

An abnormality of the morphology of the tooth.

Abnormal facial shape · Very frequent (99-80%)

An abnormal morphology (form) of the face or its components.

Abnormal pinna morphology · Very frequent (99-80%)

An abnormality of the pinna, which is also referred to as the auricle or external ear.

Decreased circulating antibody level · Very frequent (99-80%)

An abnormally decreased level of immunoglobulin in blood.

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.

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

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

Flat face · Very frequent (99-80%)

Absence of concavity or convexity of the face when viewed in profile.

Hypertelorism · Very frequent (99-80%)

Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).

Other findings in the same source

From: Orphanet

Additional reported features include Intellectual disability (Very frequent (99-80%)); Low-set ears (Very frequent (99-80%)); Lymphangioma (Very frequent (99-80%)); Lymphedema (Very frequent (99-80%)); Lymphopenia (Very frequent (99-80%)); Malabsorption (Very frequent (99-80%)); Mild postnatal growth retardation (Very frequent (99-80%)); Supernumerary tooth (Very frequent (99-80%)); Tooth agenesis (Very frequent (99-80%)); Wide nasal bridge (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 Hennekam 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 Hennekam 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.