Hennekam Lymphangiectasia-Lymphedema Syndrome 3

A number sign (#) is used with this entry because of evidence that Hennekam lymphangiectasia-lymphedema syndrome-3 (HKLLS3) is caused by homozygous or compound heterozygous mutation in the ADAMTS3 gene (605011) on chromosome 4q13.

Description

Hennekam lymphangiectasia-lymphedema syndrome-3 (HKKLLS3) is characterized by widespread congenital edema that is more severe in more dependent areas of the body. Associated features include facial dysmorphism and protein-losing enteropathy of variable severity (Brouillard et al., 2017).

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

Clinical Features

Brouillard et al. (2017) reported a sister and brother of western European origin born with congenital lymphedema of the lower extremities. Both pregnancies were complicated by polyhydramnios, and the boy also had hydroceles at birth. The lymphedema was widespread, but was more severe in more dependent areas of the body, and was worse in the left leg than the right in both children. Facial edema was minimal; dysmorphic features included flat face, synophrys, hypertelorism, strabismus, upslanting palpebral fissures, and anteverted peaked nostrils. Both had protein-losing enteropathy, for which the girl required gastrostomy tube feedings; she also had growth hormone (139250) deficiency, which responded well to replacement therapy. An unusual feature of the disorder was the nearly complete resolution of lymphedema during febrile illnesses. Neither patient exhibited developmental delay, hepatosplenomegaly, or major skeletal defects.

Scheuerle et al. (2018) reported a male born at 32 weeks' gestation following prenatal identification of hydrops fetalis. The parents denied consanguinity, but were from the same area of Mexico. A previous pregnancy had resulted in a stillbirth due to fetal hydrops. At birth, the infant was large for gestational age and hydropic, with dysmorphic facial features, a small omphalocele, and pitting edema. The infant had wide-set eyes with short palpebral fissures and epicanthal folds, low-set ears, a small nose, long philtrum, prominent upper lip, micrognathia, widely spaced nipples, and tetramelic brachydactyly. Umbilical hernia was also present. An echocardiogram showed a small secundum atrial septal defect, a patent ductus arteriosus, and a patent foramen ovale. At age 17 weeks, the infant had respiratory decompensation and died after removal of support. Autopsy showed diffuse lymphatic malformation with tortuous thick-walled lymphatic channels in the bowel mesentery as well as dilated hilar lymphatics of the kidney.

Molecular Genetics

By whole-exome sequencing in a nonconsanguineous family of western European origin in which 2 sibs had congenital lymphedema, Brouillard et al. (2017) identified compound heterozygosity for missense mutations in the ADAMTS3 gene (L168P, 605011.0001; I291T, 605011.0002). Their parents were each heterozygous for one of the mutations, neither of which was found in an internal cohort of 645 sequenced samples. The I291T variant was not present in public variant databases, whereas the L168P variant was found once in the gnomAD database.

In a male infant with Hennekam lymphangiectasia-lymphedema syndrome-3, Scheuerle et al. (2018) identified a homozygous nonsense mutation in the ADAMTS3 gene (R94X; 605011.0003). The mutation, which was found by whole-exome sequencing, was present in heterozygosity in his parents.