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

Abstract

BackgroundCapillary malformation‐arteriovenous malformation (CM‐AVM) is characterized by multifocal fast‐flow capillary malformations, sometimes with arteriovenous malformations/fistulas, skeletal/soft tissue overgrowth, telangiectasias, or Bier spots. Lymphatic abnormalities are infrequently reported. We describe seven patients with CM‐AVM and lymphatic anomalies.MethodsFollowing IRB approval, we identified patients with CM‐AVM and lymphatic anomalies seen at the Vascular Anomalies Center at Boston Children's Hospital from 2003 to 2023. We retrospectively reviewed records for clinical, genetic, laboratory, and imaging findings.ResultsWe found seven patients with CM‐AVM and lymphatic abnormalities. Five patients were diagnosed prenatally: four with pleural effusions (including one suspected chylothorax) and one with ascites. Pleural effusions resolved after neonatal drainage in three patients and fetal thoracentesis in the fourth; however, fluid rapidly reaccumulated in this fetus causing hydrops. Ascites resolved after neonatal paracentesis, recurred at 2 months, and spontaneously resolved at 5 years; magnetic resonance lymphangiography for recurrence at age 19 years suggested a central conducting lymphatic anomaly (CCLA), and at age 20 years a right spermatic cord/scrotal lymphatic malformation (LM) was detected. Chylous pericardial effusion presented in a sixth patient at 2 months and disappeared after pericardiocentesis. A seventh patient was diagnosed with a left lower extremity LM at 16 months.Six patients underwent genetic testing, and all had RASA1 mutation. RASA1 variant was novel in three patients (c.1495delinsCTACC, c.434_451delinsA, c.2648del), previously reported in two (c.2603+1G>A, c.475_476del), and unavailable in another. Median follow‐up age was 5.8 years (4 months–20 years).ConclusionCM‐AVM may be associated with lymphatic anomalies, including pericardial/pleural effusions, ascites, CCLA, and LM.

Central conducting lymphatic anomaly: from bench to bedside

“…These techniques have allowed researchers to identify single-gene disorders causing CCLA ( Table 1 ). Mosaic and germline RASopathies due to pathogenic variants that result in upregulation of the RAS/MAPK signaling pathway are the most common causes of CCLA ( Figure 1B ) ( 48 , 61 , 80 – 88 ). Specifically, somatic pathogenic variants in ARAF , BRAF , KRAS , and MAP2K1 resulting in isolated lymphatic as well as syndromic presentations have been identified ( 48 , 61 , 82 , 85 ).…”

“…Specifically, somatic pathogenic variants in ARAF , BRAF , KRAS , and MAP2K1 resulting in isolated lymphatic as well as syndromic presentations have been identified ( 48 , 61 , 82 , 85 ). Germline monoallelic pathogenic variants in PTPN11 , KRAS , HRAS , BRAF , RAF1 , RIT1 , SOS1 , SOS2 , and RASA1 have been identified in individuals with CCLA and Noonan syndrome, CCLA and Costello syndrome, CCLA and cardiofaciocutaneous syndrome, or CCLA and capillary malformation-arteriovenous malformation syndrome ( 48 , 61 , 80 – 88 ). Interestingly, the phenotypic heterogeneity may be due to second hits, as has been demonstrated in RASA1 disorders ( 89 – 93 ).…”