HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach? / Formas familiares de hiperparatireoidismo relacionadas a mutações no gene HRPT2: estudos moleculares poderiam direcionar procedimentos cirúrgicos?

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 parafibromin 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 parafibromin immunoreactivity. In this kindred there was a high prevalence of recurrence (75 percent), 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 phenotype-genotype correlation in larger series, to best define their treatment.

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 parafibromina através da RT-PCR e imunohistoquímica. Foi identificada 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 parafibromina. Nessa família houve alta (75 por cento) 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.

No evidence for oncogenic mutations in guanine nucleotilde-binding proteins of endocrine tumors

In recent years, the application of DNA technology has led to significant advances in the elucidation of the somatic defects which can occur in several tumors, including oncogene expression, allelic loss and inappropriate gene transcription and translation. Normal cell growth is regulated by many proto-oncogenes encoding proteins and specific mutations can convert these genes in oncogenes, leading to abnormal protein products that are responsible for the growth of malignant cells. Mutations that inhibit GTPase activity of the a subunit of the stimulatory G protein (Gsa) have been demonstrated in approximately a thrid of GH-secreting tumors, in 10 percent of functionless pituitary tumors, and also in corticotropinomas although with far less frequency. These mutations -gsp mutations - stabilize the Gsa in the active state (GTP-bound state), resulting in the permanent activation of adenylyl cyclase, leading to tumorigenesis. In addition, mutations in the a subunit of the inhibitory GTP-binding protein gene (Gi2a), or gip mutations, have been found in a subset of adrenocortical and ovarian tumors. In the present work, using the polymerase chain reaction and denaturing gradient gel electrophoresis, we investigated the existence of gsp and gip mutations in twenty three different endocrine tumors.