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Abstract：
PIK3CA-related overgrowth spectrum (PROS) is an umbrella term referring to various clinical entities, which share the same pathogenetic mechanism. These conditions are caused by somatic gain-of-function mutations in PIK3CA, which encodes the 110-kD catalytic α subunit of PI3K (p110α). These PIK3CA mutations occur as post-zygotic events and lead to a gain of function of PI3K, with consequent constitutional activation of the downstream cascades (e.g., AKT/mTOR pathway), involved in cellular proliferation, survival and growth, as well as in vascular development in the embryonic stage. PIK3CA-related cancers and PROS share almost the same PIK3CA mutational profile, with about 80% of mutations occurring at three hotspots, E542, E545, and H1047. These hotspot mutations show the most potent effect on enzymatic activation of PI3K and consequent downstream biological responses. If present at the germinal level, these gain-of-function mutations would be lethal to the embryo, therefore we only see them in the mosaic state. The common clinical denominator of PROS disorders is that they are sporadic conditions, presenting with congenital or early childhood onset overgrowth with a typical mosaic distribution. However, the severity of PROS is highly variable, ranging from localized and apparently isolate overgrowth to progressive and extensive lipomatous overgrowth associated with life-threatening vascular malformations, as seen in CLOVES syndrome. Traditional therapeutic approaches, such as sclerotherapy and surgical debulking, are often not curative in PROS patients, leading to a recrudescence of the overgrowth in the treated area. Specific attention has been recently paid to molecules that are used and studied in the oncogenic setting and that are targeted on specific alterations of the pathway PI3K/AKT/mTOR. In June 2018, Venot et al. showed the effect of Alpelisib (BYL719), a specific inhibitor for the p110α subunit of PI3K, in patients with PROS disorders who had severe or life-threatening complications and were not sensitive to any other treatment. In these cases, dramatic anatomical and functional improvements occurred in all patients across many types of affected organ. Molecular testing in PROS patients is a crucial step in providing the conclusive diagnosis and then the opportunity for tailored therapy. The somatic nature of this group of diseases makes challenging to reach a molecular diagnosis, requiring deep sequencing methods that have to be performed on DNA extracted from affected tissue. Moreover, even analyzing the DNA extracted from affected tissue there is no guarantee to succeed in detection of the casual somatic mutation, since the affected tissue itself is highly heterogeneous and biopsy approaches can be burdened by incorrect sampling or inadequate tissue sample. We present an 8-year-old girl with CLOVES syndrome, born with a large cystic lymphangioma involving the left hemithorax and flank, multiple lipomas, and hypertrophy of the left foot and leg. She developed severe scoliosis. Many therapeutic approaches have been attempted, including Sildenafil treatment, scleroembolization, laser therapy, and multiple debulking surgeries, but none of these were of benefit to our patient\'s clinical status. She then started treatment with Rapamycin from May 2019, without significant improvement in both vascular malformation and leg hypertrophy. A high-coverage Whole Exome Sequencing analysis performed on DNA extracted from a skin sample showed a mosaic gain-of-function variant in the PIK3CA gene (p.H1047R, 11% of variant allele frequency). Once molecular confirmation of our clinical suspicion was obtained, after a multidisciplinary evaluation, we decided to discontinue Sirolimus and start targeted therapy with Alpelisib (50 mg/day). We noticed a decrease in fibroadipose overgrowth at the dorsal level, an improvement in in posture and excellent tolerability. The treatment is still ongoing.
摘要：
PIK3CA相关的过度生长谱（PROS）是一个笼统的术语，指的是各种临床实体，具有相同的致病机制。这些情况是由PIK3CA中的体细胞功能获得性突变引起的，其编码PI3K的110-kD催化α亚基(p110α)。这些PIK3CA突变作为合子后事件发生，并导致PI3K功能的获得，随之而来的下游级联的宪法激活(例如，AKT/mTOR通路)，参与细胞增殖，生存和成长，以及在胚胎阶段的血管发育。PIK3CA相关癌症和PROS共享几乎相同的PIK3CA突变谱，大约80%的突变发生在三个热点，E542、E545和H1047。这些热点突变对PI3K的酶活化和随后的下游生物反应显示出最有效的作用。如果存在于生发水平，这些功能获得突变对胚胎是致命的，因此，我们只看到他们在马赛克状态。PROS疾病的共同临床分母是它们是偶发性疾病，表现为先天性或儿童早期发病的过度生长，具有典型的马赛克分布。然而,PROS的严重性是高度可变的，从局部和明显孤立的过度生长到与危及生命的血管畸形相关的进行性和广泛的脂肪瘤过度生长，如在CLOVES综合征中所见。传统的治疗方法，比如硬化治疗和手术减瘤,在PROS患者中通常无法治愈，导致处理区域过度生长的复发。最近已经特别关注在致癌环境中使用和研究的分子,其靶向途径PI3K/AKT/mTOR的特异性改变。2018年6月，Venot等人。显示了Alpelisib（BYL719）的效果，PI3K的p110α亚基的特异性抑制剂，患有严重或危及生命的并发症且对任何其他治疗均不敏感的PROS疾病患者。在这些情况下,在许多类型的受影响器官中,所有患者的解剖结构和功能均有显著改善.PROS患者的分子检测是提供结论性诊断的关键步骤，然后是定制治疗的机会。这组疾病的躯体性质使得很难进行分子诊断，需要对从受影响组织提取的DNA进行深度测序方法。此外，即使分析从受影响的组织中提取的DNA，也不能保证成功检测到偶然的体细胞突变，因为受影响的组织本身是高度异质的，活检方法可能是由不正确的采样或不充分的组织样本负担。我们介绍了一个患有CLOVES综合征的8岁女孩，出生时患有累及左半胸部和侧腹的大型囊性淋巴管瘤，多发性脂肪瘤,左脚和腿肥大。她出现了严重的脊柱侧弯。已经尝试了许多治疗方法，包括西地那非治疗,硬化栓塞,激光治疗,和多次切除手术，但这些都没有对我们患者的临床状况有益。然后，她从2019年5月开始接受雷帕霉素治疗，血管畸形和腿部肥大没有明显改善。对从皮肤样品中提取的DNA进行的高覆盖率全外显子组测序分析显示，PIK3CA基因中存在镶嵌功能增益变体（p。H1047R,11%的变异等位基因频率)。一旦获得我们临床怀疑的分子确认，经过多学科评估，我们决定停用西罗莫司,开始使用Alpelisib(50mg/d)进行靶向治疗.我们注意到背侧的纤维脂肪过度生长减少，姿势的改善和出色的耐受性。治疗仍在进行中。
