Pathogenic variants (PVs) in the SDHD gene increase risk for paragangliomas (PGL)/pheochromocytomas, renal cell carcinomas, and gastrointestinal stromal tumors. Penetrance in individuals with SDHD PVs varies in reported research from 40–70%, and there is limited evidence of specific genotype risks. This study aims to characterize a multi-generational family with SDHD p.Trp43* PVs and potential genotype–phenotype considerations for surveillance. Individuals with a paternally inherited SDHD p.Trp43*(c.129G > A) PV were identified. Genetic, medical and family histories were abstracted, including clinical characteristics, tumor histories, and treatment approaches. Eleven individuals with the SDHD PV in the same kindred were diagnosed with 41 SDHx-related tumors across all family members. Eight individuals developed 27 head and neck PGL of varying origins, and seven individuals developed tumors outside of the head and neck region. Many individuals had multiple tumors, and age of first tumor diagnosis ranged from age 10 to age 45 years old. Individuals with SDHD p.Trp43* variants may have higher risks for SDHx related tumors than other SDHD variants. Prioritizing identification of at-risk individuals and initiating surveillance tailored to family history is recommended given the rate of multiple tumors found in one familial branch of individuals under 18 years old. Individuals with strong family histories of PGL at young ages with this PV will benefit from tailored surveillance recommendations.

SDHD基因中的致病变异 (PV)会增加副神经节瘤 (PGL)/嗜铬细胞瘤、肾细胞癌和胃肠道间质瘤的风险。SDHD PVs个体的外显率在报告的研究中从 40-70% 不等，并且特定基因型风险的证据有限。本研究旨在描述具有SDHD p.Trp43* PV 和潜在基因型-表型监测注意事项的多代家庭。鉴定出具有父亲遗传的SDHD p.Trp43*(c.129G > A) PV 的个体。提取了遗传、医学和家族史，包括临床特征、肿瘤病史和治疗方法。11 名患有SDHD的人同一家族中的 PV 在所有家庭成员中被诊断出患有 41 种SDHx相关肿瘤。8 个人发展了 27 个不同来源的头颈部 PGL，7 个人发展了头颈部区域以外的肿瘤。许多人患有多个肿瘤，首次诊断出肿瘤的年龄在 10 岁到 45 岁之间。与其他SDHD相比，具有SDHD p.Trp43* 变异体的个体患SDHx相关肿瘤的风险可能更高变体。鉴于在 18 岁以下个体的一个家族分支中发现的多发肿瘤的发生率，建议优先识别高危个体并启动针对家族史的监测。具有这种 PV 的年轻 PGL 家族史的个体将受益于量身定制的监测建议。