A number sign (#) is used with this entry because of evidence that lymphatic malformation-8 (LMPHM8) is caused by homozygous mutation in the CALCRL gene (114190) on chromosome 2q32. One such family has been reported.

Lymphatic malformation-8 (LMPHM8) is an autosomal recessive disorder in which affected fetuses die in utero due to nonimmune hydrops fetalis (NIHF). The fetus and placenta are edematous with interstitial accumulation of fluid and abnormally shaped vessels. The disorder results from impaired lymphangiogenesis. Carrier females have reduced fertility and recurrent miscarriages likely due to NIHF (summary by Mackie et al., 2018).

For a discussion of genetic heterogeneity of lymphatic malformation, see LMPHM1 (153100).

Mackie et al. (2018) reported a 22-week-old fetus, of consanguineous Arab parents, with hydrops fetalis. Family history showed that the maternal grandmother of the fetus and 2 of her daughters, one of which was the mother of the fetus, had subfertility and experienced recurrent spontaneous miscarriages, confirmed in some cases to be due to nonimmune hydrops fetalis. Prenatal ultrasound of affected fetuses showed abnormal accumulation of interstitial fluid in extravascular compartments, polyhydramnios, marked pleural effusion and reduced lung size, skin edema, and pericardial effusion. The affected placentas were large and edematous with severe edema of the chorionic villae, abnormally shaped and compressed vessels, likely due to the edema, and scattered Hofbauer cells.

The transmission pattern of LMPHM8 in the family reported by Mackie et al. (2018) was consistent with autosomal recessive inheritance.

In a 22-week-old male fetus, conceived of consanguineous parents, with hydrops fetalis due to LMPHM8, Mackie et al. (2018) identified a homozygous in-frame deletion in the CALCRL gene (Val205del; 114190.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Three female mutation carriers in the family had a total of 8 miscarriages; 2 of the 8 were confirmed to be due to hydrops fetalis, but DNA from the other likely affected fetuses was not available. The variant was not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases. In vitro functional expression studies in HEK293 cells showed that the mutant CALCRL protein had reduced association with RAMP2 (605154), reduced translocation to the plasma membrane, and impaired signaling activity compared to wildtype. The findings were consistent with a specific loss-of-function effect targeting the CALCRL-RAMP2-ADM (103275) signaling pathway, which is essential for normal lymphangiogenesis. The fetus was also homozygous for a missense R349G variant in the ASAH1 gene (613468), which is associated with Farber lipogranulomatosis (FRBRL; 228000). FRBRL can sometimes present with antenatal hydrops fetalis; however, other clinical manifestations of FRBRL were not present in the fetus or in other nongenotyped family members.

Mackie et al. (2018) found that global deletion of the Calcrl gene in mice resulted in mid-gestation embryonic lethality with profound interstitial edema due to arrested lymphangiogenesis. The placentas from Calcrl-null mice showed marked interstitial edema within the labyrinth and enlarged junctional zone. Targeted deletion of the Calcrl gene in lymphatic endothelial cells also caused embryonic lethality with profound interstitial and subcutaneous edema. Histologic analysis showed small lymphatic vessels that were developmentally arrested, as well as dilated and malformed lymphatic capillaries compared to controls. The phenotype was similar to that observed in both Adm-null and Ramp2-null mice, confirming that the CALCRL-RAMP2-ADM signaling pathway is essential for normal lymphangiogenesis.