Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
Orphanet J Rare Dis. 2019 Feb 7;14(1):29. doi: 10.1186/s13023-019-1010-z.
The RASopathies are a class of developmental disorders caused by germline mutations in the RAS-mitogen-activated protein kinase (MAPK) pathway. Hypertrophic cardiomyopathy (HCM) has been frequently described in children with RASopathy, but only a minority of patients have received formal genotyping. The purpose of this study was to evaluate the genetic basis and clinical outcome of pediatric patients with RASopathy-associated HCM.
We retrospectively reviewed the mutation spectrum and clinical outcome of all the patients with RASopathy derived from 168 pediatric HCM cases referred to our institution between January 2012 and July 2018.
A heterozygous missense mutation in one of known RASopathy genes was identified in 46 unrelated children with HCM. Mutations in the PTPN11 gene were the most prevalent (19/46); this was followed by mutations in RAF1 (11/46), KRAS (5/46), RIT1 (4/46), BRAF (3/46), SOS1 (2/46), HRAS (1/46), and SHOC2 (1/46). Moreover, two compound heterozygous missense mutations in the LZTR1 gene were identified in one patient with the Noonan syndrome phenotype and HCM. The median age at the diagnosis of HCM was 3.0 months (range 0 months to 8.1 years). Twenty-one of the patients had significant left ventricular outflow tract obstruction and 32 had concomitant congenital heart disease. Three patients with a mutation in exon 13 of the PTPN11 gene died of cardiac failure at the ages of 3.0, 3.5, and 6.0 months. The remaining 44 patients were alive after an average follow-up time of 3.9 years (0.5 to 17.1 years, median 2.9 years) from the initial diagnosis of HCM, including 5 patients with spontaneous regression of their cardiac hypertrophy.
RASopathy-associated HCM is a heterogeneous genetic condition characterized by early-onset cardiac hypertrophy and a high prevalence of co-existing congenital heart disease, which is most frequently related to specific mutations in the PTPN11 gene. Rapidly progressive HCM, resulting in an early death, is uncommon in RASopathy patients except those with specific mutations in exon 13 of the PTPN11 gene.
RAS 病是一类由 RAS-丝裂原活化蛋白激酶（MAPK）通路种系突变引起的发育障碍疾病。肥厚型心肌病（HCM）在患有 RAS 病的儿童中经常被描述，但只有少数患者接受了正式的基因分型。本研究旨在评估与 RAS 病相关的 HCM 患儿的遗传基础和临床结局。
我们回顾性分析了 2012 年 1 月至 2018 年 7 月我院收治的 168 例儿科 HCM 患者中所有源自 RAS 病的患者的突变谱和临床结局。
在 46 例 HCM 无关联儿童中发现了一个已知 RAS 病基因中的杂合错义突变。PTPN11 基因突变最为常见（19/46）；其次是 RAF1（11/46）、KRAS（5/46）、RIT1（4/46）、BRAF（3/46）、SOS1（2/46）、HRAS（1/46）和 SHOC2（1/46）。此外，在一名具有 Noonan 综合征表型和 HCM 的患者中发现了 LZTR1 基因的两个复合杂合错义突变。HCM 的中位诊断年龄为 3.0 个月（范围 0 个月至 8.1 岁）。21 例患者存在明显的左心室流出道梗阻，32 例患者伴有先天性心脏病。3 例 PTPN11 基因外显子 13 突变的患者分别在 3.0、3.5 和 6.0 个月时因心力衰竭死亡。其余 44 例患者在 HCM 初始诊断后平均随访 3.9 年（0.5 至 17.1 年，中位 2.9 年）后存活，其中 5 例患者的心脏肥大自发性消退。
与 RAS 病相关的 HCM 是一种异质性遗传疾病，其特征为早发的心脏肥大和高发性共存先天性心脏病，这与 PTPN11 基因的特定突变最相关。除了 PTPN11 基因外显子 13 中的特定突变外，RAS 病患者中很少出现导致早期死亡的快速进展性 HCM。
