CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.A PI3KCA inhibitor reverses symptoms in a mouse model of PROS/CLOVES syndrome, which results from gain-of-function mutations in PI3KCA, and produces improvements in patients with PROS/CLOVES syndrome.

中文翻译：

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PIK3CA 相关过度生长综合征患者的靶向治疗

CLOVES 综合征（先天性脂肪瘤过度生长、血管畸形、表皮痣、脊柱侧弯/骨骼和脊柱综合征）是一种遗传性疾病，由 PIK3CA 基因的体细胞、马赛克功能获得性突变引起，属于 PIK3CA 相关谱系过度生长综合征（PROS）。这种罕见的疾病没有特殊的治疗方法，存活率很低。在这里，我们描述了 PROS/CLOVES 的出生后小鼠模型，该模型部分地概括了人类疾病，并证明了 PIK3CA 抑制剂 BYL719 在预防和改善器官功能障碍方面的功效。基于这些结果，我们使用 BYL719 治疗了 19 名 PROS 患者。该药物改善了所有患者的疾病症状。以前难治的血管肿瘤变小，充血性心力衰竭得到改善，偏侧肥大减少，脊柱侧弯减轻。该治疗与任何实质性副作用无关。总之，这项研究提供了第一个直接证据，支持 PIK3CA 抑制作为 PROS 患者的一种有前景的治疗策略。PI3KCA 抑制剂可以逆转 PROS/CLOVES 综合征小鼠模型的症状，这是由 PI3KCA 功能获得性突变引起的，并对 PROS/CLOVES 综合征患者产生改善。