USD Genetica Medica, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.
Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Am J Med Genet C Semin Med Genet. 2023 Jun;193(2):160-166. doi: 10.1002/ajmg.c.32034. Epub 2023 Feb 3.
Gain of function pathogenic variants in MRAS have been found in a small subset of pediatric subjects presenting with Noonan syndrome (NS) associated with hypertrophic cardiomyopathy (HCM) and moderate to severe intellectual disability. These variants are considered to confer a high-risk for the development of severe HCM with poor prognosis and fatal outcome. We report on the natural history of the first adult subject with NS carrying the recurrent pathogenic p.Thr68Ile amino acid substitution. Different from what had previously been observed, he presented with a mild, late-onset left ventricular hypertrophy, and a constellation of additional symptoms rarely seen in NS. The present case provides evidence that HCM does not represent an obligatory, early-onset and severe complication in subjects with MRAS variants. It also adds new data about late-onset features suggesting that other unexpected complications might be observed in adult subjects providing anticipatory guidance for individuals of all age.
已在一小部分表现为肥厚型心肌病（HCM）和中度至重度智力残疾的伴有 NS 的儿科患者中发现 MRAS 的致病性功能获得变异。这些变异被认为是导致严重 HCM 的高风险，预后不良，且结局致命。我们报告了首例携带反复出现的致病性 p.Thr68Ile 氨基酸取代的 NS 成年患者的自然病史。与之前观察到的不同，他表现为轻度、迟发性左心室肥厚，以及一组在 NS 中很少见的其他症状。本病例提供了证据表明，HCM 并非 MRAS 变异患者的强制性、早发和严重并发症。它还增加了关于迟发特征的新数据，表明在成年患者中可能会观察到其他意外并发症，为所有年龄段的个体提供了预期指导。
