HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach?

Abstract

It is still debatable which is the best management to familial forms of hyperparathyroidism. Conservative, minimally invasive or aggressive surgical approaches have been proposed from different groups around the world. Our objective was to study the gene mutation, expression of HRPT2 and the clinical outcome after 32 years of follow-up in one Brazilian kindred with familial isolated hyperparathyroidism (FIHP). Clinical and biochemical data, direct sequencing of the HRPT2 gene, analysis of parafi bromin expression using RT-PCR, and immunohistochemistry were done. A nonsense mutation was found in exon 1 (c.96G>A)(p.Trp32X) in all affected members studied. Using RT-PCR, mRNA transcription was altered with complete absence of both transcripts in tumor tissue. Immunohistochemical analysis of tumors showed loss of parafi bromin immunoreactivity. In this kindred there was a high prevalence of recurrence (75%), or persistence after less than subtotal parathyroidectomy that led us to consider a more aggressive surgical approach should be discussed among the affected family members, once surgical criteria was met. We concluded that it is necessary to individualize the surgical approach for HRPT2-related hyperparathyroidism until we can gather a better phenotypegenotype correlation in larger series, to best defi ne their treatment. RESUMO Formas Familiares de Hiperparatireoidismo Relacionadas a Mutações no Gene HRPT2: Estudos Moleculares Poderiam Direcionar Procedimentos Cirúrgicos?A melhor conduta nas formas familiares de hiperparatireoidismo relacionadas a mutações no gene HRPT2 ainda é controvertida. Cirurgias conservadoras, minimamente invasivas ou mais agressivas já foram propostas por diferentes grupos. Objetivamos estudar a seqüência e a expressão do gene HRPT2, além do desfecho clínico, após seguimento de até 32 anos de uma família brasileira com hiperparatireodismo familiar isolado (FIHP). Utilizamos dados clínicos e bioquímicos, seqüenciamento direto do HRPT2 além de análise da expressão da parafi bromina através da RT-PCR e imunohistoquímica. Foi identifi cada mutação nonsense no éxon 1 (c.96G>A)(p.Trp32X) em todos os membros afetados que foram estudados. A análise do mRNA transcrito, através da RT-PCR, demonstrou ausência do transcrito no tecido tumoral. A imunohistoquímica também evidenciou ausência da parafi bromina. Nessa família houve alta (75%) prevalência de recorrência ou persistência da doença após paratireoidectomia parcial o que nos levou a considerar fundamental discutir uma abordagem cirúrgica mais agressiva com os outros familiares portadores da mutação caso critérios de indicação cirúrgica sejam atingidos. Dessa maneira, até que estudos mais amplos estabeleçam uma correlação genótipo-fenótipo no hiperparatireoidismo familiar relacionado a mutações no HRPT2, a abordagem cirúrgica deverá ser individualizada. Silveira et al. HRPT2 mutations in FIHP and surgery

Familial isolated primary hyperparathyroidism/hyperparathyroidism‐jaw tumour syndrome caused by germline gross deletion or point mutations of CDC73 gene in Chinese

“…It is notable that the three families with FIHP in the present study all carried mutations of the CDC73 gene. The same genetic background of FIHP and HPT‐JT supports the theory that a subset of patients with FIHP is a variant of HPT‐JT with incomplete penetrance . In previous studies, FIHP is associated with a high frequency of MEN1 mutations ranging between 22% and 57% .…”

“…The same genetic background of FIHP and HPT-JT supports the theory that a subset of patients with FIHP is a variant of HPT-JT with incomplete penetrance. 4,7,23,24 In previous studies, FIHP is associated with a high frequency of MEN1 mutations ranging between 22% and 57%. 8,25,26 However, MEN1 gene mutation has not been detected in our FIHP families.…”

Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features

“…Patients with confirmed HPT-JT syndrome have a very high risk of recurrence in the same or other glands, which is at least 25%, but which may occur in the majority of patients at follow-up extending to 30 years 6,8,9,38,40–43. Therefore, the diagnosis of parafibromin-deficient (HPT-JT type) parathyroid tumors should precipitate long-term follow-up for the possibility of late recurrence or metachronous disease, whether or not WHO criteria for malignancy are met.…”

Hyperparathyroidism-jaw tumor syndrome: Results of operative management

“…A recent study by Silveira and colleagues showed a high rate of recurrence (4/9) and/or persistent (2/9) PHPT. The authors speculated that aggressive treatment may be warranted and genotype-phenotype data may be able to direct the surgeon (18). The recurrence rate of PHPT in this cohort was 25.0%.…”