Romain Martineau, Constance Wells, Florent Fuchs, Sophie Collardeau‐Frachon, Valentin Ruault, Sophie Colomb, Jean‐Michel Faure, Caroline Bartholmot, Marie Vincenti, Benjamin Ganne, Marjolaine Willems
University Hospital of Montpellier and Montpellier University. CESP Center for Research in Epidemiology and Population Health. Hospices Civils de Lyon & Université Claude Bernard.
France
Prenatal Diagnosis
Prenat Diagn 2026;
DOI: 10.1002/pd.70134
Abstract
Noonan syndrome (NS) is a rare multisystemic condition among the RASopathy group, characterized by a broad phenotypic spectrum and genetic variability. It results from pathogenic variants in genes regulating the RAS/MAPK pathway, affecting cell proliferation and differentiation. While the PTPN11 gene accounts for approximately 50% of cases, other genes, including MRAS, have been implicated. NS presents with features such as facial dysmorphism, short stature, and cardiac anomalies. Hypertrophic cardiomyopathy (HCM) is a major contributor to mortality, with specific variants conferring higher risk. This article includes a review of the literature on NS with pathogenic MRAS variants and describes an eighth case, the first documented with early and severe antenatal manifestations. The fetus exhibited increased nuchal translucency, agenesis of the ductus venosus, pulmonary lymphangiectasia, and complex hepatic vascular anomalies. A cesarean section was performed at 33 weeks’ gestation due to worsening fetal pleural effusions and maternal intolerance to polyhydramnios. Despite intensive postnatal care, the newborn died from refractory shock and multi-organ failure. Histopathology revealed HCM, obliterative portal venopathy and lymphangiectasia, consistent with NS pathology. These findings suggest that pathogenic MRAS variants confer a high risk of severe HCM (100% of cases). Moreover, emerging targeted therapies, such as MEK inhibitors, offer potential for treatment.
Category
Primary Pulmonary Lymphatic Disease
Genetic Factors Associated with Pulmonary Vascular Disease
Review Articles Concerning Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes