Caracterización clínica y molecular de un grupo de pacientes españoles y alemanes con rasopatías

Laburpena

Introduction. RASopathies are a group of diseases due to variants in genes that encode components or regulators of the RAS/MAPK pathway. They represent one of the most prevalent groups of multiple congenital anomalies, including Noonan syndrome (NS), Noonan syndrome-like disorder with loose anagen hair (NSLH), Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL), Noonan syndrome with multiple lentigines (NSML), Cardiofaciocutaneous syndrome (CFC), Costello syndrome (CS), Neurofibromatosis-Noonan syndrome (NFNS) and Legius syndrome (LGSS). Objective. Clinical and molecular characterization of patients from Murcia and Essen (Germany) with RASopathies, and comparison with the literature. Estimation of their prevalence in Murcia, analysis of genotype-phenotype correlation, and of the adequacy of the follow-up to the clinical guidelines. Material and methods. Retrospective, descriptive and international collaborative study between the Medical Genetics Section, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain, and the Institut für Humangenetik, Universitätsklinikum, Essen, Germany. Review of medical records of patients with prenatal/postnatal diagnosis of a molecularly confirmed RASopathy, between 1994-2012 in Essen and 2002-2018 in Murcia. Collection of clinical, phenotypic data (Face2gene facial recognition program) and genotype, with statistical analysis. Results. 139 cases of RASopathy (3 prenatal; 118 Spain/21 Germany), with NS being the most common (65%). Main referral units: General Pediatrics, Medical Genetics and Pediatric Cardiology. Most common reasons for referral: dysmorphic features and heart disease. Mean age at referral: 12.45 years. Estimated prevalence for NS in Murcia: 1/6054 live newborns. Main findings in NS: heart defects (76%), short stature (53%), microcephaly (40%), intellectual disability (ID) (35%) and juvenile myelomonocytic leukemia (4%). 2 deceased patients (2.3%). Association between prenatal lymphatic abnormalities and pterygium colli. All those classified as typical met van der Burgt diagnostic criteria compared to 75% of the atypical ones (p = 0.003). Association between low weight, short stature, microcephaly, motor delay and cardiac surgery with ID, also between central nervous system abnormalities and seizures. 7% had no cardiac evaluation, 30% abdominal ultrasound, 24% ophthalmological evaluation, 36% hearing evaluation and 41% coagulation study. In NFNS and NSML particular features were overlapping with those of NS, with less frequency of hypertelorism and greater frequency of pigmented lesions. All CFC and CS were de novo and presented with a classic phenotype. In NS, NFNS and NSML the majority of cases were de novo, with the highest percentage of inherited cases in LGSS. PTPN11 was the most frequently mutated gene in NS (74%). 3 new variants were identified in SOS1, RAF1 and LZTR1, 5 in NF1 and 2 in SPRED1. Genotype-phenotype correlation: higher percentage of microcephaly in PTPN11 and HCM in RAF1. Neurodevelopment and height were less affected in SOS1. Conclusions. We present a wide series of RASopathy cases with clinical manifestations, mostly, in accordance with what has been published. In NS there is a large prevalence of microcephaly, higher in PTPN11, associated with ID and behavioral alteration, not previously reported. There appears to be greater severity of systemic involvement accompanying the severity of the craniofacial phenotype. The lack of complementary examinations constitutes a point of improvement. The mutational spectrum is similar to that described, with a higher percentage in NS of pathogenic variants in PTPN11, probably due to the increased accessibility to its study and its correlation with a more classic phenotype. The description of 10 new variants contributes to the expansion of molecular knowledge, and the results of the genotype-phenotype correlation to the improvement of prognostic information. The estimated prevalence in Murcia is lower than what has been reported, consequently the development of strategies to improve detection being necessary. Since main referral units are pediatrics, greater awareness of adult specialties towards this group of diseases is necessary. Key words: RASopathies, RAS/MAPK pathway, Noonan syndrome (NS), Noonan syndrome-like disorder with loose anagen hair (NSLH), Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL), Noonan syndrome with multiple lentigines (NSML), Cardiofaciocutaneous syndrome (CFC), Costello syndrome (CS), Neurofibromatosis-Noonan syndrome (NFNS), Legius syndrome (LGSS), PTPN11, SOS1, RAF1, RIT1, KRAS, NRAS, SHOC2, CBL, LZTR1, BRAF, MAP2K1, HRAS, NF1 and SPRED1.