Hennekam Lymphangiectasia-Lymphedema Syndrome1Q82.0

Hennekam's lymphangiectasia-lymphoedema syndrome is an autosomal recessive disorder characterized by generalized lymphoid dysplasia affecting multiple organs, including the intestinal tract, pericardium, and limbs. Other features of the disorder include facial dysmorphism and cognitive impairment (Alders et al. 2014).

Hennekam lymphangiectasia-lymphoedema syndrome-1 (HKLLS1) is caused by a homozygous or compound heterozygous mutation in the CCBE1 gene (612753) on chromosome 18q21.

The phenotype "Hennekam's lymphangiectasia lymphedema syndrome" is characterized by genetic heterogeneity.

• Mutations in the CCBE1 gene cause Hennekam's lymphangiectasia lymphedema syndrome type1 (HKLL type1).
• Mutation in the FAT4 gene (612411; chromosome 4q28) cause HKLLS type2 (616006).
• Mutation in ADAMTS3 gene (605011) on chromosome 4q13 cause HKLLS type3 (618154).

Connell et al (2010) reported on a 6-year-old British girl with generalized lymphedema. Her prenatal course was complicated by hydrops with pleural effusions and ascites, which required a peritoneal shunt at 33 weeks' gestation. At birth, she was edematous and required ventilation. At 1 month of age, she developed severe diarrhea while on a medium-chain triglyceride (MCT) diet. Intestinal histology showed lymphatic dilatation and inflammation. At 6 years of age, she continued to suffer from widespread generalized edema with recurrent ascites and persistently low serum albumin. She had a dysmorphic face with epicanthal folds and a depressed nasal bridge, suggestive of edema in utero. The patient was born to unaffected, nonrelated parents and was the oldest of 8 living siblings; an older brother with lymphedema had died at 5 months of age, and a male fetus with severe hydrops died at 17 weeks' gestation.

1. Al-Gazali LI et al. (2003) Further delineation of Hennekam syndrome. Clin Dysmorph 12: 227-232.
2. Alders M et al. (2014) Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Hum Genet 133: 1161-1167.
3. Alders M et al (2009) Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nature Genet 41: 1272-1274.
4. Connell F et al (2010) Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia. Hum Genet 127: 231-241.
5. Hennekam RCM et al (1989) Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet 34: 593-600.