MEN1 – Familial Isolated Hyperparathyroidism

Familial isolated hyperparathyroidism (FIHP) is an autosomal dominant disorder characterized by primary hyperparathyroidism in the absence of other endocrine neoplasias. Multiple independent kindreds with FIHP harbor heterozygous germline MEN1 mutations, demonstrating that FIHP represents an allelic variant of multiple endocrine neoplasia type 1 (MONDO:0007540).

Genetic evidence from case reports and series shows at least 32 affected individuals across five unrelated families carrying MEN1 variants. In a Japanese kindred, three members had a missense mutation c.914G>A (p.Gly305Asp) segregating with disease, with two additional asymptomatic carriers at advanced ages (PMID:10664521). In seven FIHP families, four germline mutations—including two 4-bp deletions and two missense changes (p.Asp153Val, p.Ala411Pro)—were found in 17 affected members, and loss of the wild-type allele was demonstrated in parathyroid tumors (PMID:12699448). An intronic splice-site variant c.1350+1G>A co-segregated with FIHP in 12 relatives and produced an aberrantly spliced transcript in vitro and in patient blood (PMID:15292357).

The variant spectrum in FIHP includes missense, splice-site, and small deletion/insertion mutations distributed throughout MEN1. Recurrent AD variants such as p.Arg527Ter and p.Pro277His have been identified in multiple small families, some later manifesting full MEN1 features (PMID:12016470). Penetrance is reduced and age-dependent, with late‐onset hyperparathyroidism in several carriers.

Functional studies support a tumor suppressor mechanism: loss of heterozygosity in parathyroid adenomas confirms a two‐hit inactivation, while minigene and RT-PCR assays of the IVS9+1G>A allele reveal intron retention predicting truncated menin with loss of function. Menin’s role in transcriptional regulation and genome stability underscores haploinsufficiency as the pathogenic mechanism.

Minor conflicting evidence arises from small FIHP cohorts lacking MEN1 mutations, indicating genetic heterogeneity and suggesting additional FIHP genes. However, MEN1‐positive families consistently show segregation, LOH, and functional concordance.

Integration and Conclusion

The accumulation of >30 FIHP probands with segregating MEN1 mutations, corroborated by LOH and splicing assays, yields a Strong clinical validity classification. Genetic evidence is Strong (32 affected individuals; multi‐family segregation), and experimental evidence is Moderate (LOH studies; splicing assays). FIHP due to MEN1 mutations benefits from germline testing to guide surveillance and parathyroid management. Key Take‐home: MEN1 testing should be included in FIHP workups to enable early detection and tailored surgical planning.

References

• European journal of endocrinology • 2000 • A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism. PMID:10664521
• Clinical endocrinology • 2003 • Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. PMID:12699448
• The Journal of clinical endocrinology and metabolism • 2004 • Novel intronic mutation of MEN1 gene causing familial isolated primary hyperparathyroidism. PMID:15292357
• World journal of surgery • 2002 • Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism. PMID:12016470

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