A case report of RASA1-associated inherited lymphoedema with recurrent life-threatening lymphangitis

Abstract

Background Most cases of lymphoedema are secondary to other causes, while cases of primary lymphoedema, in particular that of congenital origin, are uncommon. Limited genetic disorders are so far known to be associated with lymphatic malformation including mutations in RASA1. This clinical case highlights the possible complications of RASA1-associated lymphatic malformation in a female suffering from recurrent life-threatening septic lymphangitis. Case summary A 23-year-old female patient presented with congenital lymphoedema of the lower right extremity. At the age of eight, she first suffered from an episode of lymphangitis. Thereafter, she developed recurrent episodes of lymphangitis predominately occurring during menstruation and culminating into severe and life-threatening septicaemias. Due to the menstrual association, endometriosis was suspected but could not be confirmed. Furthermore, angiography could not detect any sign of arteriovenous fistula. Single-Photon-Emission-Computed-Tomography confirmed absent major lymphatics of the right leg with severely impaired and prolonged dermal lymphatic backflow. Genetic testing identified a disease-causing variant in the RASA1 gene. Discussion To our knowledge, this is the first case of recurrent septic lymphangitis with close relation to menstruation in a female with RASA1-associated lymphatic malformation. Due to the possible de novo or somatic origin of a pathogenic variant, a genetic disease should be considered in spite of an unremarkable family history or a localized lymphoedema. Although there is no curative therapy available yet, the knowledge of the underlying genetic defect is important for interdisciplinary patient care and might be crucial for individual molecular therapies in the future.

EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans

“…For EPHB4 , these include lymphatic-related hydrops fetalis (LRHF, accumulation of fluid in the fetus because of lymphatic dysfunction), central conducting lymphatic anomaly (a lymphatic vessel flow disorder) and lymphedema (tissue edema consequent to lymphatic dysfunction) [ 35 , 36 , 37 , 38 ]. Similarly, germline inactivating RASA1 mutations have been reported in LRHF and lymphedema [ 39 , 40 ].…”

Spectrum of lymphatic anomalies in patients with RASA1‐related CM‐AVM

“…Prior reports of lymphatic abnormalities in 29 pediatric patients with CM-AVM include: NIHF (n = 17), pleural effusion (n = 10, including 5 chylothorax), LM (n = 6), polyhydramnios (n = 6), ascites (n = 5), pericardial effusion (n = 2), CCLA (n = 1), and lymphedema (n = 1). [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] The incidence of lymphatic abnormalities in CM-AVM is likely underreported in the literature, as they often present prenatally RASA1 is required for endothelial cell survival during developmental angiogenesis. Without it, collagen IV folding within endothelial cells is impaired, leading to retained collagen in the endoplasmic reticulum and cell death.…”

“…3 Lymphatic abnormalities have been reported in 29 patients across 19 case reports or series. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Lymphatic abnormalities also occur in RASA1 and EPHB4 knockout mice. 12,21 We describe seven patients with CM-AVM and lymphatic anomalies to highlight their phenotypic variability and associated morbidity.…”

“…2 CMs can be accompanied by intra-and extracranial arteriovenous malformations (AVMs) or arteriovenous fistulas, skeletal/soft tissue overgrowth, telangiectasias, or Bier spots (hypovascular macules). 3 Lymphatic abnormalities have been reported in 29 patients across 19 case reports or series. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Lymphatic abnormalities also occur in RASA1 and EPHB4 knockout mice.…”

“…Lymphatic abnormalities have been reported in 29 patients across 19 case reports or series 3–21 . Lymphatic abnormalities also occur in RASA1 and EPHB4 knockout mice 12,21 .…”