A number sign (#) is used with this entry because of evidence that lymphatic malformation-7 (LMPHM7) is caused by heterozygous mutation in the EPHB4 gene (600011) on chromosome 7q22.

LMPHM7 is an autosomal dominant disorder with variable expressivity. Some patients may develop severe nonimmune lymphatic-related hydrops fetalis (LRHF) in utero, resulting in early death, whereas others may have milder manifestations, such as atrial septal defect (ASD) or varicose veins as adults. The hydrops and/or swelling improves spontaneously in those who survive the neonatal period (summary by Martin-Almedina et al., 2016).

For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.

Martin-Almedina et al. (2016) reported 2 unrelated families from the United Kingdom and Norway, respectively, with an inherited disorder characterized mainly by LRHF and/or ASD. The first family had 7 affected members spanning 3 generations. Four patients had LRHF of variable severity that improved spontaneously over time in those who survived the neonatal period, and 1 affected fetus died in utero. Atrial septal defect was found in 2 of those with LRHF and in 3 patients without LRHF. One older patient, who did not have LRHF, had persistent varicose veins and peripheral edema. One patient with LRHF and ASD also had a diaphragmatic hernia and cystic hygroma at birth. The Norwegian family contained 2 monozygotic twin sisters, each of whom had an affected son. This family had a high number of first-trimester miscarriages. The 2 sisters had subcutaneous edema at birth that resolved in infancy, although 1 required ventilation and thoracentesis for bilateral chylothoraces. Both sisters had varicose veins as adults. Both sons had LRHF and ASD. In both families, features associated with LRHF included pericardial and pleural effusions, ascites, chylothoraces, and subcutaneous edema. Two adults, 1 from each family, showed impaired lymph drainage in the lower limbs without clinical evidence of lymphedema.

Li et al. (2018) reported a large 4-generation family in which the proband, who had fetal hydrops, exhibited near-complete opacification of his lungs at birth and required ventilatory support for 4 weeks. He had recurrent pleural effusions, and lung biopsy at age 4 months showed histologically abnormal large lymphatic structures, consistent with pulmonary lymphangiomatosis. He also experienced diarrhea with fat-rich foods. At 11 years of age, 2 liters of chylous effusion was drained from his right chest, which reaccumulated within 12 hours. Lymphangiography at that time revealed retrograde flow of contrast agent from lymphatics into the retroperitoneum, abdomen, neck, mediastinum, and possibly bronchi. In his teenage years, the proband developed prominent veins on his lower extremities, which progressively worsened. Magnetic resonance (MR) lymphangiography at age 24 years showed abnormal central lymphatic anatomy, suggestive of absent or dysfunctional lymphatic valves, with proliferation of lymphatic channels in the retroperitoneum, around the spine, and in the lungs; those channels were also dysfunctional and showed abnormal flow. Maximal intensity projection of dynamic contrast MR lymphangiography showed retroperitoneal masses and dilated and tortuous thoracic duct with retrograde perfusion of the right lung. The authors thought that this represented a channel-type lymphatic malformation, which they designated 'central conducting lymphatic anomaly.' Affected family members showed variability in age of onset and severity of symptoms, with some affected individuals remaining asymptomatic until adolescence. The proband's mother and multiple maternal relatives experienced edema of the lower extremities, with venous stasis and superficial clots. His mother and a maternal aunt, uncle, and cousin also had abdominal distention with edema. In addition, one of his mother's sibs was stillborn with hydrops fetalis. Echocardiogram in the proband was normal.

The transmission pattern of LMPHM7 in the families reported by Martin-Almedina et al. (2016) was consistent with autosomal dominant inheritance with variable expressivity.

In 11 patients from 2 unrelated families with nonimmune hydrops fetalis, lymphedema, and central conduction lymphatic anomalies, Martin-Almedina et al. (2016) identified different heterozygous missense mutations in the EPHB4 gene (600011.0001 and 600011.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, although there was variable expressivity of the phenotype. Both mutations occurred at highly conserved residues in the tyrosine kinase domain, and in vitro functional expression studies in HEK293 cells and lymphatic endothelial cells showed that the mutant proteins were devoid of tyrosine kinase activity, suggesting altered EPHB4 signaling. The findings indicated that the mutations had a negative effect on receptor activity after ligand stimulation. There was no evidence of a dominant-negative effect.

In a large 4-generation family with hydrops fetalis, lymphedema, and central conduction lymphatic anomalies, Li et al. (2018) performed whole-exome sequencing and identified heterozygosity for a splice site mutation in the EPHB4 gene (600011.0013) that segregated fully with disease in the family and was not found in in-house control samples or in public variant databases.

Martin-Almedina et al. (2016) found that deletion of the EphB4 gene specifically in the lymphatic vasculature of embryonic mice between days E10 to E12 resulted in subcutaneous edema and abnormal lymphatic development. Tissue from mutant mice showed tortuous and dilated dermal lymphatic vessels associated with defective formation of lymphovenous valves.