目的:为了证明侧向过度生长(LO)的高产量分子诊断工作流程,身体部位异常增大的先天性疾病,并通过分子遗传学对其进行分类。和研究设计:我们将2003年至2023年之间诊断为LO的186例回顾性病例分类为可疑的Beckwith-Wiedemann谱(BWSp),PIK3CA相关过度生长谱(PROS),血管过度生长(VO),或孤立(ILO),根据初步的临床评估,确定合适的第一层分子测试和组织进行分析。患者接受了PI3K/AKT/mTOR相关基因的11p15表观遗传异常或体细胞变异检测,血管增生,和RAS-MAPK级联使用血液或皮肤DNA。对于初始测试为阴性的情况,采用序贯级联分子方法来提高诊断率.
结果:这种方法导致54%的病例进行了分子诊断,89%的病例与最初的临床怀疑一致,11%的病例重新分类。BWSp是最常见的原因,43%的病例表现出11p15异常。PROS的确认率最高,74%的临床诊断患者显示PIK3CA变异。VO与其他综合征表现出显著的临床重叠。国际劳工组织的分子诊断被证明具有挑战性,只有21%的病例可以归类为特定条件。
结论:尽管,从分子角度来看,LO未被诊断,迄今为止还没有诊断指南,这对于解决潜在的癌症易感性至关重要,实现精准医学治疗,或指导管理。本研究揭示了LO的分子病因,强调量身定制的诊断方法和选择适当的测试以实现最高诊断产量的重要性。
OBJECTIVE: To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics.
METHODS: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum, PIK3CA-related overgrowth spectrum (PROS), vascular overgrowth, or isolated LO, based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield.
RESULTS: This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions, and 11% reclassified. Beckwith-Wiedemann spectrum was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PIK3CA-related overgrowth spectrum had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. Vascular overgrowth demonstrated significant clinical overlap with other syndromes. A molecular diagnosis of isolated LO proved challenging, with only 21% of cases classifiable into a specific condition.
CONCLUSIONS: LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which is crucial for addressing potential cancer predisposition, enabling precision medicine treatments, and guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of a tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.