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Abstract <p>A substantial fraction (60–85%) of hereditary primary hyperparathyroidism (hPHPT) lacks an identifiable genetic etiology. We describe fumarate hydratase (<i>FH</i>) mutations as a potential cause of hPHPT, expanding the phenotypic spectrum of FH deficiency tumor predisposition syndromes. In an index patient who presented with asymptomatic hypercalcemia and a chief-to-transitional cell-dominant parathyroid adenoma, whole-exome sequencing revealed two unique heterozygous <i>FH</i> variants (germline p.Gln376fs*2; somatic p.Pro503_Lys504dup). Functional inactivation of FH was supported by diffuse nuclear and cytoplasmic 2-succinocysteine immunoreactivity and elevated fumarate/malate ratio in tumor tissue. This individual did not show classic HLRCC manifestations. Preserved FH protein expression suggested residual enzymatic activity, which may account for an attenuated phenotype. To assess broader relevance, no additional patients with <i>bona fide</i> FH-deficient parathyroid adenoma were identified among 130 individuals with suspected hPHPT of unknown etiology evaluated at our institute. In a complementary cohort of 11 patients with pheochromocytoma/paraganglioma syndrome harboring pathogenic germline heterozygous <i>FH</i> variants, one female (<i>FH</i> p.Thr234Ala) presented with multi-gland disease requiring parathyroidectomy at age 40 years, features suspicious for hPHPT. These findings support fumarate hydratase deficiency as a plausible etiology for a subset of parathyroid adenomatous disease. Thus, consideration of parathyroid function surveillance in patients with fumarate hydratase deficiency tumor predisposition syndromes may be warranted.</p> Clinical Trial Number <p>NCT04969926.</p>

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Expansion of Germline Variants in Primary Hyperparathyroidism: Fumarate Hydratase Deficiency as a Cause of Parathyroid Adenomas

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Hussam Alkaissi,
  • Elias Chuki,
  • Yi Liu,
  • James Welch,
  • Lynn Bliss,
  • Niharika Shah,
  • Sunita K. Agarwal,
  • William F. Simonds,
  • Martha Quezado,
  • Sanaz Sakiani,
  • Thorkell Andresson,
  • Karel Pacak,
  • Naris Nilubol,
  • Lee S. Weinstein,
  • Christopher A. Febres-Aldana,
  • Smita Jha

摘要

Abstract

A substantial fraction (60–85%) of hereditary primary hyperparathyroidism (hPHPT) lacks an identifiable genetic etiology. We describe fumarate hydratase (FH) mutations as a potential cause of hPHPT, expanding the phenotypic spectrum of FH deficiency tumor predisposition syndromes. In an index patient who presented with asymptomatic hypercalcemia and a chief-to-transitional cell-dominant parathyroid adenoma, whole-exome sequencing revealed two unique heterozygous FH variants (germline p.Gln376fs*2; somatic p.Pro503_Lys504dup). Functional inactivation of FH was supported by diffuse nuclear and cytoplasmic 2-succinocysteine immunoreactivity and elevated fumarate/malate ratio in tumor tissue. This individual did not show classic HLRCC manifestations. Preserved FH protein expression suggested residual enzymatic activity, which may account for an attenuated phenotype. To assess broader relevance, no additional patients with bona fide FH-deficient parathyroid adenoma were identified among 130 individuals with suspected hPHPT of unknown etiology evaluated at our institute. In a complementary cohort of 11 patients with pheochromocytoma/paraganglioma syndrome harboring pathogenic germline heterozygous FH variants, one female (FH p.Thr234Ala) presented with multi-gland disease requiring parathyroidectomy at age 40 years, features suspicious for hPHPT. These findings support fumarate hydratase deficiency as a plausible etiology for a subset of parathyroid adenomatous disease. Thus, consideration of parathyroid function surveillance in patients with fumarate hydratase deficiency tumor predisposition syndromes may be warranted.

Clinical Trial Number

NCT04969926.