Hennekam Lymphangiectasia-Lymphedema Syndrome 1

A number sign (#) is used with this entry because of evidence that Hennekam lymphangiectasia-lymphedema syndrome-1 (HKLLS1) is caused by homozygous or compound heterozygous mutation in the CCBE1 gene (612753) on chromosome 18q21.

Description

Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. Additional features of the disorder include facial dysmorphism and cognitive impairment (summary by Alders et al., 2014).

Genetic Heterogeneity of Hennekam Lymphangiectasia-Lymphedema Syndrome

See also HKLLS2 (616006), caused by mutation in the FAT4 gene (612411) on chromosome 4q28, and HKLLS3 (618154), caused by mutation in the ADAMTS3 gene (605011) on chromosome 4q13.

Clinical Features

Gabrielli et al. (1991) reported a male, born of second-cousin parents, with facial anomalies, syndactyly of the fingers, equinovarus feet, and cryptorchidism present at birth. He had had soft and abundant feces most of his life. He was first hospitalized at age 4 for leg edema and was found to have hypoalbuminemia, hypogammaglobulinemia, and lymphopenia. Conductive hearing loss was demonstrated at age 9 years. Gabrielli et al. (1991) provided photographs of the patient at age 14 years. The typical face was characterized by flat midface, flat nasal bridge, hypertelorism, epicanthal folds, small mouth, tooth anomalies, and small ears. The hand showed cutaneous syndactyly and camptodactyly. Seizures were thought to be related to hypocalcemia; however, it would seem that the ionized calcium may be normal. Pachygyria was demonstrated that may account for mental retardation and seizures.

Yasunaga et al. (1993) described the case of a 7-year-old boy with protein-losing gastroenteropathy. He had a face typical of Hennekam syndrome, including flat nasal bridge, hypertelorism, small mouth and tooth anomalies, but did not have mental retardation or severe lymphedema. Yasunaga et al. (1993) suggested that the child had a mild form of Hennekam syndrome. Study of the family in 3 generations suggested that heterozygotes may have some of the facial features.

Cormier-Daire et al. (1995) described a girl with intestinal lymphangiectasia, severe lymphedema of the limbs, seizures, mild mental retardation, and facial anomalies consistent with the diagnosis of Hennekam syndrome. In addition, she had an ectopic kidney and craniosynostosis of the coronal suture, 2 manifestations not previously reported in this disorder.

Scarcella et al. (2000) described 2 sisters with facial anomalies, protein-losing enteropathy, and intestinal lymphangiectasia consistent with the diagnosis of Hennekam syndrome. Both had a number of other anomalies not previously described in this disorder: primary hypothyroidism, hypertrophic pyloric stenosis, and an early fatal outcome at 8 and 3 months, respectively. Polyhydramnios complicated each pregnancy in the third trimester. At birth the older sister had flat face with flat and broad nasal bridge, short philtrum, hypertelorism, gingival hypertrophy, and mild retrognathia; the younger sister had similar features. Hepatosplenomegaly and lymphedema of the limbs developed in the first month of life in the first born. She died from a severe septic event at 8 months of age, after having recurrent gastroenteric and respiratory infections associated with severe hypogammaglobulinemia. Autopsy showed extensive lymphangiomatosis of the mediastinum, pleura and peritoneum, and intestinal lymphangiectasia. Fetal hepatomegaly was detected in the second born, who died at 3 months of age from cardiac failure due to severe refractory hypoproteinemia.

Forzano et al. (2002) reported an Italian patient with severe lymphedema of the lower limbs, genitalia, and face, intestinal lymphangiectasia, seizures, and moderate mental retardation. He had a flat face, depressed nasal bridge, and hypertelorism. Forzano et al. (2002) proposed that the patient had a severe form of Hennekam syndrome.

Van Balkom et al. (2002) reported 8 patients with Hennekam syndrome and compared their findings with those of the 16 previously reported cases. Lymphedema was usually congenital, sometimes markedly asymmetric, and often gradually progressive. Complications, such as erysipelas, were common. Lymphangiectasias were found in the intestines and occasionally in the pleura, pericardium, thyroid gland, and kidney. Several patients demonstrated congenital cardiac and blood vessel anomalies, suggesting a disturbance in angiogenesis. Typical facial features included flat face, flat and broad nasal bridge, and hypertelorism, but the features were variable and thought to mirror the extent of intrauterine facial lymphedema. Other anomalies included glaucoma, dental anomalies, hearing loss, and renal anomalies. Psychomotor development varied widely, even within a single family, from almost normal development to severe mental retardation. Convulsions were common. The existence of 10 familial cases, equal sex ratio, increased parental consanguinity rate, and absence of vertical transmission were consistent with an autosomal recessive pattern of inheritance.

Bellini et al. (2003) described a female infant with congenital lymphedema, facial anomalies, and intestinal lymphangiectasia consistent with a diagnosis of Hennekam syndrome. At birth, the patient presented with severe respiratory distress due to nonimmune hydrops fetalis, a congenital chylothorax, and pulmonary lymphangiectasia.

Al-Gazali et al. (2003) reported 4 children from 4 inbred Arab families with varying manifestations of Hennekam syndrome as well as additional features, including abnormalities of the middle ear, anomalous pulmonary venous drainage, interrupted inferior vena cava, polysplenia, crossed renal ectopia, median position of the liver, and multiple cavernous haemangiomas. Since anomalies of the veins and the consequent developmental abnormalities of the lymphatics might lead to alterations in the fluid balance of the embryo, Al-Gazali et al. (2003) hypothesized that altered fluid dynamics due to defective vascular and lymphatic development might disrupt critical events in craniofacial morphogenesis, resulting in Hennekam syndrome.

Connell et al. (2010) reported a 6-year-old British girl with generalized lymphedema. Her prenatal course was complicated by hydrops, with pleural effusions and ascites requiring peritoneal shunt at 33 weeks' gestation. At birth, she was edematous and required ventilation and inotropic support. At 1 month of age, she developed severe diarrhea on a medium chain triglyceride (MCT) diet, and began total parenteral nutrition and albumin infusions. Bowel histology showed lymphatic dilatation and inflammation. At 6 years of age, she continued to have widespread, generalized edema, with recurrent ascites and persistently low serum albumin, and was on an MCT diet; she also took thyroid replacement therapy for hypothyroidism. She had dysmorphic facies consistent with a history of in utero edema, with epicanthic folds and depressed nasal bridge. The patient, born of unaffected nonconsanguineous parents, was the oldest of 8 living sibs; an older brother with lymphedema had died at 5 months of age, and a male fetus with severe hydrops had miscarried at 17 weeks' gestation.

Mapping

In a large consanguineous Dutch pedigree with Hennekam syndrome, Alders et al. (2009) performed homozygosity mapping and identified a 5.7-Mb homozygous region on chromosome 18q21; additional homozygosity mapping in 2 unrelated probands with Hennekam syndrome from consanguineous families revealed several stretches of homozygosity, including an overlapping 0.5-Mb interval on 18q21 containing 4 genes.

In a British family in which 3 sibs had generalized lymphatic dysplasia, Connell et al. (2010) performed genomewide analysis and homozygosity mapping and identified a candidate region on chromosome 18q shared by the 3 affected sibs.

Molecular Genetics

In 5 affected individuals from consanguineous families with Hennekam syndrome, including 3 patients from a Dutch pedigree, 1 Omani patient, and 1 Iraqi patient, Alders et al. (2009) sequenced the candidate gene CCBE1 (612753) and identified homozygosity for missense mutations in all 5 patients (612753.0001-612753.0003, respectively). Analysis of CCBE1 in 19 additional families with Hennekam syndrome identified 2 unrelated probands who were compound heterozygotes for a nonsense mutation (612753.0004) and another missense mutation (612753.0005 and 612753.0006, respectively). Unaffected parents were heterozygous for the mutations, which were not found in 100 western European or 97 Arabic controls. Alders et al. (2009) noted that mutations were detected in only 5 (23%) of 22 families with Hennekam syndrome, indicating genetic heterogeneity.

In a 6-year-old British girl with generalized lymphatic dysplasia and 2 deceased male sibs with lymphedema and severe fetal hydrops, respectively, Connell et al. (2010) identified homozygosity for a missense mutation in the CCBE1 gene (612753.0001). The same mutation had been identified in a Dutch family with lymphedema by Alders et al. (2009).