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Purpose <p>Multiple endocrine neoplasia type 2 (MEN2) is caused by germline pathogenic variants (PVs) in the <i>RET</i> proto-oncogene, leading to medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism (PHPT). <i>RET</i> p.Lys666Asn is a rare PV, but its clinical significance remains incompletely understood. The purpose of this study is to expand the clinical understanding of the <i>RET</i> Lys666Asn variant.</p> Methods <p>Index patients carrying the <i>RET</i> Lys666Asn variant were identified through clinical genetic testing in two referral medical centers. Comprehensive clinical evaluation, biochemical screening, and imaging studies were performed to assess the presence of MTC, pheochromocytoma, and PHPT of the index patients and carrier family members. We performed a literature search on Lys666Asn carriers and their clinical manifestations.</p> Results <p>Ten individuals from five families were identified as carriers of the <i>RET</i> Lys666Asn variant. The median age at diagnosis was 43.7&#xa0;years (range 2–75&#xa0;years). Only one individual presented with pheochromocytoma, diagnosed at age 54. The rate of MTC, pheochromocytoma, and PHPT was 0 (0–0.26), 0.1 (0.01–0.39), and 0 (0–0.26), respectively. In a pooled analysis of cases reported in the literature, MTC, pheochromocytoma, and PHPT rate are 0.42 (0.28–0.57), 0.11 (0.04–0.22), and 0.03 (0–0.12), respectively. MTC had a wide age range at presentation (20–70&#xa0;years).</p> Conclusion <p>The <i>RET</i> Lys666Asn variant is associated with lower event rate of MEN2-related tumors compared to classical MEN2 variants, particularly MTC and pheochromocytoma. Despite its rarity, pheochromocytoma cannot be excluded in carriers, underscoring the need for individualized screening protocols based on specific <i>RET</i> variants.</p>

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RET Lys666Asn has a low rate of MEN2-related tumors but may be associated with pheochromocytoma

  • 期刊论文

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  • 发表日期：

    2026年3月19日

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  • Reut Halperin,
  • Naama Peshes-Yaloz,
  • Amit Tirosh,
  • Orit Twito

摘要

Purpose

Multiple endocrine neoplasia type 2 (MEN2) is caused by germline pathogenic variants (PVs) in the RET proto-oncogene, leading to medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism (PHPT). RET p.Lys666Asn is a rare PV, but its clinical significance remains incompletely understood. The purpose of this study is to expand the clinical understanding of the RET Lys666Asn variant.

Methods

Index patients carrying the RET Lys666Asn variant were identified through clinical genetic testing in two referral medical centers. Comprehensive clinical evaluation, biochemical screening, and imaging studies were performed to assess the presence of MTC, pheochromocytoma, and PHPT of the index patients and carrier family members. We performed a literature search on Lys666Asn carriers and their clinical manifestations.

Results

Ten individuals from five families were identified as carriers of the RET Lys666Asn variant. The median age at diagnosis was 43.7 years (range 2–75 years). Only one individual presented with pheochromocytoma, diagnosed at age 54. The rate of MTC, pheochromocytoma, and PHPT was 0 (0–0.26), 0.1 (0.01–0.39), and 0 (0–0.26), respectively. In a pooled analysis of cases reported in the literature, MTC, pheochromocytoma, and PHPT rate are 0.42 (0.28–0.57), 0.11 (0.04–0.22), and 0.03 (0–0.12), respectively. MTC had a wide age range at presentation (20–70 years).

Conclusion

The RET Lys666Asn variant is associated with lower event rate of MEN2-related tumors compared to classical MEN2 variants, particularly MTC and pheochromocytoma. Despite its rarity, pheochromocytoma cannot be excluded in carriers, underscoring the need for individualized screening protocols based on specific RET variants.