Hennekam syndrome is an inherited disorder resulting from malformation of the lymphatic system, which is part of both the circulatory system and immune system. The lymphatic system consists of a network of vessels that transport lymph fluid and immune cells throughout the body.

The characteristic signs and symptoms of Hennekam syndrome are lymphatic vessels that are abnormally expanded (lymphangiectasia), particularly the vessels that transport lymph fluid to and from the intestines; puffiness or swelling caused by a buildup of fluid (lymphedema); and unusual facial features.

Lymphangiectasia often impedes the flow of lymph fluid and can cause the affected vessels to break open (rupture). In the intestines, ruptured vessels can lead to accumulation of lymph fluid, which interferes with the absorption of nutrients, fats, and proteins. Accumulation of lymph fluid in the abdomen can cause swelling (chylous ascites). Lymphangiectasia can also affect the kidneys, thyroid gland, the outer covering of the lungs (the pleura), the membrane covering the heart (pericardium), or the skin.

The lymphedema in Hennekam syndrome is often noticeable at birth and usually affects the face and limbs. Severely affected infants may have extensive swelling caused by fluid accumulation before birth (hydrops fetalis). The lymphedema usually affects one side of the body more severely than the other (asymmetric) and slowly worsens over time.

Facial features of people with Hennekam syndrome may include a flattened appearance to the middle of the face and the bridge of the nose, puffy eyelids, widely spaced eyes (hypertelorism), small ears, and a small mouth with overgrowth of the gums (gingival hypertrophy). Affected individuals may also have an unusually small head (microcephaly) and premature fusion of the skull bones (craniosynostosis).

Individuals with Hennekam syndrome often have intellectual disability that ranges from mild to severe, although most are on the mild end of the range and some have normal intellect. Many individuals with Hennekam syndrome have growth delay, respiratory problems, permanently bent fingers and toes (camptodactyly), or fusion of the skin between the fingers and toes (cutaneous syndactyly).

Abnormalities found in a few individuals with Hennekam syndrome include a moderate to severe shortage of red blood cells (anemia) resulting from an inadequate amount (deficiency) of iron in the bloodstream, multiple spleens (polysplenia), misplaced kidneys, genital anomalies, a soft out-pouching around the belly-button (umbilical hernia), heart abnormalities, hearing loss, excessive body hair growth (hirsutism), a narrow upper chest that may have a sunken appearance (pectus excavatum), an abnormal side-to-side curvature of the spine (scoliosis), and inward- and upward-turning feet (clubfeet).

The signs and symptoms of Hennekam syndrome vary widely among affected individuals, even those within the same family. Life expectancy depends on the severity of the condition and can vary from death in childhood to survival into adulthood.

Mutations in the CCBE1 or FAT4 gene can cause Hennekam syndrome.

The CCBE1 gene provides instructions for making a protein that is found in the lattice of proteins and other molecules outside the cell (extracellular matrix). The CCBE1 protein is involved in the maturation (differentiation) and movement (migration) of immature cells called lymphangioblasts that will eventually form the lining (epithelium) of lymphatic vessels.

The function of the protein produced from the FAT4 gene is largely unknown. Research shows that the FAT4 protein may be involved in determining the position of various components within cells (cell polarity).

CCBE1 gene mutations that cause Hennekam syndrome change the three-dimensional shape of the protein and severely decrease its function. The abnormal protein cannot play its role in the formation of the lymphatic vessel epithelium. The resulting malformation of lymphatic vessels leads to lymphangiectasia, lymphedema, and other features of Hennekam syndrome. Since the lymphatic system extends throughout the body, a disruption to the vessels can affect almost any organ. Altered lymphatic development before birth may change the balance of fluids and impair normal development, contributing to many of the other signs of Hennekam syndrome such as unusual facial features.

FAT4 gene mutations that cause Hennekam syndrome result in a FAT4 protein with decreased function. Reduced FAT4 protein activity seems to impair normal development of the lymphatic system, but the mechanism is unknown.

Together, mutations in the CCBE1 and FAT4 genes are responsible for approximately half of all Hennekam syndrome cases. The cause of the remaining cases is unknown.

Normal Function

The CCBE1 gene provides instructions for making a protein that is found in the lattice of proteins and other molecules outside the cell (extracellular matrix). The CCBE1 protein is involved in the formation of the lymphatic system, which consists of a network of vessels that transport lymph fluid and immune cells throughout the body. Specifically, the CCBE1 protein helps guide maturation (differentiation) and movement (migration) of immature cells called lymphangioblasts that will eventually form the lining (epithelium) of lymphatic vessels.

Health Conditions Related to Genetic Changes

Hennekam syndrome

At least 13 mutations in the CCBE1 gene have been found to cause Hennekam syndrome, an inherited disorder resulting from malformation of the lymphatic system. Most CCBE1 gene mutations change single protein building blocks (amino acids) in the CCBE1 protein leading to a change in the three-dimensional shape of the protein. The abnormal protein cannot play its role in the formation of the lymphatic vessel epithelium. A poorly formed lymphatic system leads to lymphatic vessels that are abnormally expanded (lymphangiectasia) and are prone to break open (rupture), puffiness or swelling caused by a buildup of fluid (lymphedema), and other features of Hennekam syndrome. CCBE1 gene mutations account for about 25 percent of all cases of Hennekam syndrome.

Other Names for This Gene

• collagen and calcium-binding EGF domain-containing protein 1
• FLJ30681
• full of fluid protein homolog
• KIAA1983

Genomic Location

Normal Function

The FAT4 gene provides instructions for making a protein that is found in most tissues. The protein spans the membrane surrounding cells so that part of the protein is outside the cell and part of the protein is inside the cell. The precise function of the FAT4 protein is largely unknown; however, research shows that the FAT4 protein is likely involved in determining the position of various components within cells (cell polarity). The FAT4 protein is also thought to function as a tumor suppressor, which means that it keeps cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Hennekam syndrome

At least seven mutations in the FAT4 gene have been found to cause Hennekam syndrome, an inherited disorder resulting from malformation of the lymphatic system, which consists of a network of vessels that transport lymph fluid and immune cells throughout the body. The FAT4 gene mutations that cause Hennekam syndrome reduce the activity of the FAT4 protein, which seems to impair normal development of the lymphatic system. However, the mechanism is unknown. A poorly formed lymphatic system leads to lymphatic vessels that are abnormally expanded (lymphangiectasia) and are prone to break open (rupture), puffiness or swelling caused by a buildup of fluid (lymphedema), and other features of Hennekam syndrome. FAT4 gene mutations account for about 25 percent of all cases of Hennekam syndrome.

Other disorders

Mutations in the FAT4 gene have also been found in individuals who have van Maldergem syndrome, a condition characterized by intellectual disability, hearing loss, skeletal abnormalities, and a brain malformation called periventricular heterotopia. The FAT4 gene mutations that cause van Maldergem syndrome lead to a decrease in FAT4 protein function. It is thought that a decrease in FAT4 protein activity in the brain disrupts the polarity of nerve cells in the brain, which leads to periventricular heterotopia.

It is unknown how mutations in the FAT4 gene can cause the signs and symptoms of van Maldergem syndrome in some people but lead to different signs and symptoms in those with Hennekam syndrome (described above). One mutation that replaces the protein building block (amino acid) glutamic acid with the amino acid lysine at position 2375 in the FAT4 protein (written as Glu2375Lys or E2375K) has been found in both individuals with van Maldergem syndrome and those with Hennekam syndrome.

FAT4 gene mutations have also been found in many types of cancers, including a type of skin cancer called head and neck squamous cell carcinoma, an aggressive form of skin cancer called melanoma, a liver cancer called hepatocellular carcinoma, stomach (gastric) cancer, and pancreatic cancer. The FAT4 gene mutations involved in these cancers are different from the ones that cause van Maldergem syndrome and Hennekam syndrome (described above).

The FAT4 gene mutations associated with cancers are called somatic mutations; they are found only in cells that become cancerous and are not inherited. It is likely that these mutations prevent the FAT4 protein from acting as a tumor suppressor, contributing to the uncontrollable growth and division of cells that is characteristic of cancer. People with van Maldergem syndrome and Hennekam syndrome are not thought to have an increased risk of developing cancer.

Other Names for This Gene

• cadherin family member 14
• cadherin-related family member 11
• CDHF14
• CDHR11
• FAT tumor suppressor homolog 4
• FAT-J
• fat-like cadherin protein FAT-J
• FAT4_HUMAN
• FATJ
• NBLA00548
• protocadherin Fat 4
• VMLDS2

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

At least 50 cases of Hennekam syndrome have been reported worldwide.