EP456: Heterozygous deletion of the VEGFC gene in 4q34.3 is associated with Milroy-Like lymphedema: First prenatal case report

Abstract

Primary or congenital lymphedema occurs rarely on idiopathic or developmental abnormalities in the lymphatic system, especially hypoplasia or aplasia of lymphatics. Milroy disease (MIM #153100), an autosomal dominant congenital lymphedema, characterized by peripheral edema mainly of the lower extremities, is resulted from pathogenic variants in the vascular endothelial growth factor receptor 3 (VEGFR3) gene (MIM *136352). However, missense VEGFR3 variants were only identified in approximately 70% of the patients diagnosed with Milroy disease suggesting genetic heterogeneity of the condition. Recently, pathogenic variants in VEGFC gene (MIM *601528), encoding one of the VEGFR3 ligands, were associated with autosomal dominant Milroy-like primary lymphedema (MIM #615907), a rare autosomal dominant disorder, characterized by congenital isolated lymphedema. Hitherto, only twenty-six postnatal cases in six families world-wide with primary lymphedema harboring VEGFC single point pathogenic variants were recorded (Table 1). No prenatal cases as well as VEGFC deletions were reported. We report the three-generation family with Milroy-like disease. The proband is a 24+4-week female fetus. Ultrasonography at 23+5 weeks of gestation showed fetal edema of the feet, prefrontal edema and facial dysmorphism including broad nasal bridge, short philtrum, and full lower lip. The fetus’s mother was a 22-year-old female with occasional swelling of lower legs and ankles during pregnancy or warm weather. Dysplastic, upslanting and yellowish toenails were also observed. The fetus’s grandmother was a 40-year-old female and had a family history of lymphedema. Family history dates back to the fetus’s great-grandmother, maternal grand-aunt and two maternal cousins, they were all affected by edema. Congenital lymphedema of her feet progressed to legs but below the knees. Moreover, she also exhibited bilateral edema of the dorsi of both hands. Dysplastic and upslanting toenails, varicose, prominent veins and hyperkeratosis were also noted. Lymphoscintigraphy showed symmetrical tracer uptake, with a discrete reduction in uptake of tracer within the right groin lymph nodes. 180K aCGH analysis showed a 137 kb interstitial microdeletion within 4q34.3 region encompassing only VEGFC gene. Segregation analysis showed that the deletion was of maternal in origin. The fetus’s grandmother also carried the 4q34.3 deletion.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) To the best of our knowledge, this is the first prenatal report of VEGFC deletion. Our results reinforce that VEGFC haploinsufficiency is associated with primary Milroy-like lymphedema with incomplete penetrance, inter- and intra-familial variable expressivity, and contribute to add knowledge to the current literature with the description of the prenatal phenotype of Milroy-like disease. Our report also suggests that molecular VEGFC analysis should also be performed in VEGFR3-negative patients with congenital lymphedema.