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

Bi-allelic inactivation of FH (a truncating germline variant plus a second somatic variant) with fumarate accumulation in the parathyroid adenoma.

Between 60% and 85% of hereditary primary hyperparathyroidism cases lack an identifiable genetic aetiology. In an index patient with asymptomatic hypercalcaemia and a parathyroid adenoma, exome sequencing revealed two heterozygous FH variants: one germline (p.Gln376fs) and one somatic (p.Pro503_Lys504dup). Functional inactivation of FH was supported by diffuse nuclear and cytoplasmic 2-succinocysteine immunoreactivity and an elevated fumarate/malate ratio in tumour tissue, without classic HLRCC manifestations; preserved protein expression suggested residual enzymatic activity accounting for an attenuated phenotype. No additional bona fide FH-deficient parathyroid adenoma was found among 130 patients with hereditary primary hyperparathyroidism of unknown aetiology; conversely, among 11 patients with pheochromocytoma/paraganglioma syndrome carrying pathogenic germline FH variants, one woman (FH p.Thr234Ala) had multi-gland disease requiring parathyroidectomy at age 40. The authors suggest that parathyroid function surveillance may be worth considering in carriers of fumarate hydratase deficiency tumour predisposition syndromes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The mechanism is coherent and well documented at tissue level — a germline then somatic double hit, 2-succinocysteine staining, fumarate/malate ratio — which makes the association plausible beyond chance. But the demonstration rests on a single index case, and the absence of any further case among 130 unexplained hereditary hyperparathyroidism patients shows that the contribution of FH is at best very marginal. The suggestion of adding parathyroid surveillance for FH variant carriers deserves discussion, but with two observations in total it remains a working hypothesis.

Analysis by Dr Thibaut Benquey