Oliver Owen, Britt Allison D, Borst Alexandra J, Goldmuntz Elizabeth, Bakeer Nihal, Lang Shih-Shan, Fuller Stephanie, Vossough Arastoo, Beslow Lauren A
Division of Neurology, Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.
Comprehensive Vascular Anomalies Program, Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.
J Clin Med. 2025 May 12;14(10):3359. doi: 10.3390/jcm14103359.
Pathogenic variants in the growth differentiation factor 2 () gene have been linked to a hereditary hemorrhagic telangiectasia (HHT)-like syndrome, yet their clinical significance remains under investigation. This study reports seven pediatric patients with variants from a single center. We identified children with pathogenic variants and variants of uncertain significance (VUS) from the Children's Hospital of Philadelphia Comprehensive HHT Program and cross-referenced the list with a full-text query by gene name on >53,000,000 visits to ensure complete ascertainment. Medical records were reviewed retrospectively, and variables of interest were abstracted. The median age at genetic testing was 12 years (range 1.75-16). Reasons for genetic testing included telangiectasias, pulmonary hypertension, familial testing, respiratory symptoms, seizures, developmental disabilities, and lung arteriovenous malformations (AVMs). Four patients had missense VUS, including two novel VUS (c.34C>G; p.Leu12Val, c.41C>T; p.Ser14Phe), while three had pathogenic deletions. All patients experienced epistaxis, starting at a median age of 6 years (range 2-12). Three had telangiectasias. One patient had both a VUS and a partial endoglin () gene deletion. While this patient's symptoms of HHT are likely related to her variant, synergy cannot be excluded, and two first-degree family members with clinically significant epistaxis also have the same VUS. Notably, two patients had visceral AVMs-one with a lung AVM and another with a vein of Galen malformation. Interpretation of VUS and their relationship to clinical symptoms is challenging given the rarity of these genetic variants and the inadequate diagnostic utility of the current clinical criteria for HHT in the pediatric population. Further research with larger cohorts is necessary to improve the genotype-phenotype correlation in -related HHT. Carefully collected clinical information with longitudinal follow-up may also assist in refining classification of VUS as benign or pathogenic in the future.
生长分化因子2（）基因的致病性变异与遗传性出血性毛细血管扩张症（HHT）样综合征有关，但其临床意义仍在研究中。本研究报告了来自单一中心的7例患有变异的儿科患者。我们从费城儿童医院综合HHT项目中识别出患有致病性变异和意义未明变异（VUS）的儿童，并通过在超过5300万次就诊记录中以基因名称进行全文查询来交叉核对名单，以确保全面确定。对病历进行回顾性审查，并提取感兴趣的变量。基因检测时的中位年龄为12岁（范围1.75 - 16岁）。基因检测的原因包括毛细血管扩张、肺动脉高压、家族检测、呼吸道症状、癫痫发作、发育障碍以及肺动静脉畸形（AVM）。4例患者有错义VUS，包括2个新的VUS（c.34C>G；p.Leu12Val，c.41C>T；p.Ser14Phe），而3例有致病性缺失。所有患者均有鼻出血，中位发病年龄为6岁（范围2 - 12岁）。3例有毛细血管扩张。1例患者既有VUS又有内皮糖蛋白（）基因部分缺失。虽然该患者的HHT症状可能与其变异有关，但不能排除协同作用，且两名有临床显著鼻出血的一级家庭成员也有相同的VUS。值得注意的是，2例患者有内脏AVM，1例有肺AVM，另1例有大脑大静脉畸形。鉴于这些基因变异的罕见性以及当前儿科人群中HHT临床标准的诊断效用不足，对VUS及其与临床症状的关系进行解读具有挑战性。需要对更大的队列进行进一步研究，以改善与相关的HHT中的基因型 - 表型相关性。仔细收集的临床信息及纵向随访未来也可能有助于完善VUS作为良性或致病性的分类。
