病例报告：同卵双胞胎LEOPARD综合征伴相同PTPN11 c.1391G>C（p.Gly464Ala）突变的心肌肥厚型心肌病表现不一致

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中文摘要

背景： LEOPARD综合征（LS；伴多发性雀斑的Noonan综合征）是一种罕见的常染色体显性RAS病，其中PTPN11突变导致心肌肥厚型心肌病（HCM），外显率高度可变。方法：我们报告一对青少年同卵双胞胎兄弟，携带相同的PTPN11 c.1391G>C（p.Gly464Ala）新发突变，尽管共享基因组及宫内和出生后环境，却出现不一致的心脏表型。结果：较年轻的孪生兄弟发生梗阻性HCM，伴二尖瓣收缩期前向运动及左心室流出道梗阻（静息峰值压差36 mmHg，Valsalva峰值压差61 mmHg），并伴漏斗胸和巨舌；较年长的孪生兄弟为非梗阻性HCM（最大室间隔厚度12 mm），伴卵圆孔未闭。两名孪生兄弟均有多个雀斑、面部畸形和需人工耳蜗植入的感音神经性听力损失。较年轻的孪生兄弟接受β受体阻滞剂和活动限制治疗，而较年长的孪生兄弟仅接受监测。结论：本病例表明，相同的RAS病突变可产生不同形式的HCM，支持非遗传修饰因素在心血管表型表达中的作用，并强调LS需要血流动力学指导的个体化心血管管理。

英文摘要

LEOPARD syndrome (LS; Noonan syndrome with multiple lentigines) is a rare autosomal dominant RASopathy in which PTPN11 mutations cause hypertrophic cardiomyopathy (HCM) with highly variable expressivity. We report adolescent monozygotic twin brothers carrying an identical PTPN11 c.1391G > C (p.Gly464Ala) mutation that arose de novo, who developed discordant cardiac phenotypes despite sharing a genome and an intrauterine and postnatal environment. The younger twin developed obstructive HCM with systolic anterior motion of the mitral valve and left ventricular outflow tract obstruction (peak resting gradient 36 mmHg, peak Valsalva gradient 61 mmHg), together with pectus excavatum and macroglossia; the older twin had non-obstructive HCM (maximal septal thickness 12 mm) with a patent foramen ovale. Both twins had multiple lentigines, facial dysmorphism, and sensorineural hearing loss requiring cochlear implantation. The younger twin was treated with a beta-blocker and activity restriction, whereas the older twin was managed with surveillance alone. This case demonstrates that an identical RASopathy mutation can produce divergent forms of HCM, supports a role for non-genetic modifiers in cardiovascular expression, and underscores the need for hemodynamics-guided, individualized cardiovascular management in LS.