Hennekam syndrome

Overview

Hennekam syndrome is a rare genetic disorder characterized by a combination of lymphatic system abnormalities, distinctive facial features, and varying degrees of intellectual disability. First described in 1989 by Dutch pediatrician Raoul Hennekam, the syndrome is classified as a type of primary lymphedema and falls under the broader category of lymphatic dysplasia disorders. The most prominent features include generalized or localized lymphedema, intestinal lymphangiectasia (abnormal dilation of intestinal lymph vessels), facial dysmorphism, and developmental delay.

Causes

Hennekam syndrome is primarily caused by genetic mutations that affect lymphatic development. The most commonly implicated genes include:

• CCBE1 gene: Associated with Hennekam syndrome type 1 (autosomal recessive inheritance)

• FAT4 gene: Linked to Hennekam syndrome type 2 (autosomal recessive)

• ADAMTS3 gene: Recently associated with a variant form of the syndrome

These genes are involved in the regulation of lymphangiogenesis (formation of lymphatic vessels). Inherited mutations in these genes disrupt normal lymphatic vessel formation and function, leading to fluid accumulation and other systemic features.

Symptoms

The clinical features of Hennekam syndrome can vary in severity but typically include:

• Lymphedema: Swelling in the face, limbs, or genitalia due to lymphatic fluid accumulation

• Intestinal lymphangiectasia: Causes protein-losing enteropathy, leading to low serum protein levels, diarrhea, and swelling

• Facial abnormalities: Including a flat nasal bridge, hypertelorism (widely spaced eyes), a wide mouth, and low-set ears

• Intellectual disability: Ranging from mild to severe developmental delay

• Growth delay: Poor weight gain and short stature

• Hypotonia: Low muscle tone

• Dental abnormalities and delayed eruption of teeth

• Seizures or behavioral issues in some cases

Not all patients will exhibit every symptom, and the presentation may vary even among affected siblings.

Diagnosis

Diagnosis of Hennekam syndrome is based on clinical evaluation and confirmed through genetic testing. Diagnostic steps may include:

• Physical examination: Noting characteristic facial features and lymphedema

• Imaging studies: Lymphoscintigraphy or MRI to assess lymphatic vessel abnormalities

• Endoscopy or biopsy: To confirm intestinal lymphangiectasia

• Blood tests: To check for protein loss and low albumin levels

• Genetic testing: Identification of mutations in CCBE1, FAT4, or ADAMTS3 genes

Differential diagnosis includes other genetic syndromes with lymphedema or facial dysmorphism, such as Noonan syndrome or Milroy disease.

Treatment

There is no cure for Hennekam syndrome, and treatment focuses on managing symptoms and preventing complications. A multidisciplinary approach is often necessary. Management may include:

• Compression therapy: To reduce lymphedema in affected limbs

• Low-fat, high-protein diet: Especially in cases of intestinal lymphangiectasia, often with medium-chain triglycerides (MCTs)

• Nutritional supplements: To replace lost proteins and fat-soluble vitamins

• Physical and occupational therapy: For developmental and motor support

• Speech and cognitive therapy: To assist with communication and learning delays

• Surgical interventions: May be required for severe lymphatic obstructions or cosmetic concerns

Regular monitoring by specialists in genetics, gastroenterology, neurology, and lymphatic disorders is essential for comprehensive care.

Prognosis

The prognosis of Hennekam syndrome depends on the severity of symptoms and the effectiveness of symptom management. While the condition is chronic, many individuals can achieve improved quality of life with appropriate therapy and nutritional support. Intellectual and physical disabilities may limit independence in some cases, but early intervention and supportive services can significantly enhance developmental outcomes. Lifelong follow-up and tailored care are essential to address evolving medical needs.