Hennekam Lymphangiectasia-Lymphedema Syndrome 2

A number sign (#) is used with this entry because Hennekam lymphangiectasia-lymphedema syndrome-2 (HKLLS2) is caused by homozygous or compound heterozygous mutation in the FAT4 gene (612411) on chromosome 4q28.

Biallelic mutation in the FAT4 gene can also cause Van Maldergem syndrome-2 (VMLDS2; 615546), a distinct disorder that shows overlapping features with HKLLS.

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).

For a discussion of genetic heterogeneity of Hennekam lymphangiectasia-lymphedema syndrome, see HKLLS1 (235510).

Clinical Features

Hennekam et al. (1989) described a syndrome of intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia, and face, and severe mental retardation. Intestinal lymphangiectasia was accompanied by the usual hypoproteinemia, hypogammaglobulinemia, and lymphocytopenia. Facial anomalies included flat face, flat nasal bridge, hypertelorism, epicanthal folds, small mouth, tooth anomalies, and ear defects. The facial appearance was Oriental. Down syndrome had been suspected in some of the patients. The patients had seizures. Erysipelas was a problem complicating the edema of the legs. Autosomal recessive inheritance was strongly supported by the occurrence of the disorder in 2 males and 2 females of 2 sibships from parents who shared a common ancestral couple. Hennekam et al. (1989) reviewed genetic syndromes with lymphangiectasia and lymphedema as features.

Alders et al. (2014) reported 9 patients from 5 unrelated families with Hennekam lymphangiectasia-lymphedema syndrome. Two of the families had previously been reported by Hennekam et al. (1989) and Al-Gazali et al. (2003). All patients had an unusual facial appearance, with flat face, flat nasal bridge, hypertelorism, epicanthus, blepharophimosis, small ears, small mouth, and irregular dentition. Two sibs had hearing loss. Most had poor overall growth, but only 1 had microcephaly. All had lymphedema of the limbs, and all but 1 had lymphangiectasia variably affecting the gut, pericardium, lungs, kidneys, and genitalia. Other features included camptodactyly and rare syndactyly. Borderline to mild cognitive impairment was common, although 2 sibs apparently had normal cognition. Alders et al. (2014) noted that the facial appearance was remarkably similar to that of Van Maldergem syndrome.

Inheritance

The transmission pattern of HKLLS2 in the families reported by Alders et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 5 unrelated families with Hennekam lymphangiectasia-lymphedema syndrome-2, Alders et al. (2014) identified homozygous or compound heterozygous mutations in the FAT4 gene (see, e.g., 612411.0003; 612411.0007-612411.0010). The mutation in the first family was found using a combination of homozygosity mapping and whole-exome sequencing. Subsequent mutations were identified in 4 of 24 Hennekam syndrome patients who underwent direct sequencing of the FAT4 gene. Overall, FAT4 mutations were present in 5 (20%) of 25 families with the disorder. One of the homozygous mutations (E2375K; 612411.0003) was identified in 3 affected members of the original family with Hennekam syndrome reported by Hennekam et al. (1989). Functional studies of the FAT4 variants were not performed.