Hennekam syndrome
Hennekam syndrome is an inherited disorder characterized by lymphatic system abnormalities, which can lead to fluid buildup, distinctive facial features, and intellectual disabilities.
Overview
Hennekam syndrome affects the lymphatic system, a network of vessels that transports lymph, white blood cells, nutrients, and proteins. In affected individuals, lymphatic vessels are often dilated (lymphangiectasia), causing them to leak or slow the flow of lymph. This results in puffiness or swelling (lymphedema) caused by fluid buildup in tissues.
Symptoms
The signs and symptoms of Hennekam syndrome vary widely, even within the same family:
- Lymphedema: Typically present at birth, often affecting the legs and genitalia. Severe cases may involve hydrops fetalis (extensive fluid buildup before birth).
- Internal Lymphangiectasia: Can affect the kidneys, lungs, heart, and intestines. Intestinal involvement may interfere with nutrient absorption and cause abdominal swelling (chylous ascites).
- Facial Features: Flattened mid-face and nasal bridge, puffy eyelids, widely spaced eyes, low-set ears, and a small mouth with gum overgrowth.
- Developmental and Neurological: Intellectual disabilities (ranging from mild to severe), seizures, and growth delays.
- Skeletal Abnormalities: Premature fusion of skull bones (craniosynostosis), permanently bent fingers and toes, fusion of skin between digits, inward- or upward-turning feet, and spinal curvature.
- Other Features: Heart, kidney, or genital abnormalities; umbilical hernia; hearing loss; and excessive body hair (hirsutism).
Causes
Hennekam syndrome is caused by pathogenic variants in the CCBE1, ADAMTS3, or FAT4 genes. The CCBE1 and ADAMTS3 proteins regulate the activity of vascular endothelial growth factor receptor 3 (VEGFR3), which is critical for lymphatic system development. The FAT4 protein is involved in cell positioning within tissues. Variants in these genes disrupt the development and maintenance of the lymphatic system.
Inheritance
This condition is inherited in an autosomal recessive pattern. This means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. Parents of an affected individual each carry one copy of the altered gene but typically do not show signs or symptoms of the condition.
