Genetic analysis of the MEN1 gene and HPRT2 locus in two Italian kindreds with familial isolated hyperparathyroidism

Cetani, Filomena; Pardi, Elena; Giovannetti, Anna; Vignali, Edda; Borsari, Simona; Golia, F.; Cianferotti, Luisella; Viacava, Paolo; Miccoli, Paolo; Gasperi, Maurizio; Pinchera, Aldo; Marcocci, Claudio

doi:10.1046/j.1365-2265.2002.01502.x

Cited by 34 publications

(33 citation statements)

References 19 publications

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“…The majority of FIHP with MEN 1 mutations presented with mild hypercalcemia and multiglandular disease or parathyroid hyperplasia, similar to what is usually seen in MEN1 (8)(9)(10)(11)(12)(13). On the other hand, in FIHP families where HRPT2 gene mutations have been detected, the clinical presentation is more severe and in all cases the histopathological diagnosis was parathyroid carcinoma or adenoma, frequently associated with atypical or cystic features similar to those seen in HPT-JT syndrome (13)(14)(15).…”

Section: Introductionmentioning

confidence: 94%

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

Silveira

Dias²,

Marinho³

et al. 2008

Arq Bras Endocrinol Metab

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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

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Section: Introductionmentioning

confidence: 94%

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

Silveira

Dias²,

Marinho³

et al. 2008

Arq Bras Endocrinol Metab

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“…The proband of HPT-JT family (A) had the typical jaw tumor, and her sister had cystic kidney lesions. One FIHP kindred (D) has been previously linked to the HRPT2 locus (14). Subjects III-5 and III-6 of family D underwent parathyroidectomy elsewhere for PHPT and did not agree to participate in the study.…”

Section: Familial Casesmentioning

confidence: 99%

“…FIHP may be due to an incomplete expression of these syndromic forms or to other entities. Indeed, abnormalities of MEN1 (11)(12)(13)(14)(15)(16)(17), HRPT2 (7, 8, 18 -20), and calcium-sensing receptor (CASR) (19 -21) genes have all been reported in a minority of FIHP kindreds. However, the majority of FIHP cases have currently unrecognized causes.…”

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confidence: 99%

Genetic Analyses of theHRPT2Gene in Primary Hyperparathyroidism: Germline and Somatic Mutations in Familial and Sporadic Parathyroid Tumors

Cetani

Pardi

Borsari

et al. 2004

The Journal of Clinical Endocrinology & Metabolism

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We investigated the involvement of the HRPT2 gene by loss of heterozygosity analysis and direct sequencing in a kindred with hyperparathyroidism-jaw tumor syndrome (HPT-JT) and three kindreds with familial isolated primary hyperparathyroidism (FIHP). Seven patients with sporadic parathyroid cancers and 35 with parathyroid adenomas with no family history of primary hyperparathyroidism or HPT-JT were also studied. A germline heterozygous substitution G to A was found in the donor splice site of intron 1 in one of the three FIHP families. No mutations were identified in the HPT-JT kindred. A somatic HRPT2 mutation was found in four of seven patients with parathyroid cancers, two of which were unreported frameshift mutations (195insT and 195insA) in exon 2. Consistent with recent findings, two of seven patients with sporadic parathyroid cancer had germline mutations. Four adenomas showed loss of heterozygosity at HRPT2, whereas a somatic HRPT2 mutation was found in one. In conclusion, we provide additional evidence for a strong association between HRPT2 gene mutations and sporadic parathyroid cancer. The finding that two of the seven patients with sporadic parathyroid cancer carried an HRPT2 germline mutation suggests that they might have occult HPT-JT. Our results also confirm the need for testing HRPT2 gene in FIHP families.

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“…Das Syn drom wur de bis her 2 Chro mo som loka li sa tio nen zu ge ord net, 1q25-q31 und 11q13 [9,55]. Dies legt nahe, dass die Gene MEN 1 bzw.…”

Section: Fa MI Li äRer Iso Lier Ter Hy Per Para Thyreo Idis Musunclassified

Das familiäre Nebenschilddrüsenkarzinom

Gimm

Lorenz²,

Thanh³

et al. 2006

Chirurg

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In contrast to primary hyperparathyroidism, parathyroid carcinoma is a rare disease. In patients with hyperparathyroidism jaw tumor (HPT-JT) syndrome, caused by germline mutations in HRPT2, the development of parathyroid carcinoma is estimated to be 10-15%. This review summarizes the clinical and molecular genetic data of about 100 patients in the literature and three of our own cases. Unfortunately, osteofibromas, which might enable timely diagnosis of HPT-JT syndrome, occur in only about 30% of patients; about 80% have uniglandular disease. Based on the current data, a general recommendation to perform prophylactic parathyroidectomy cannot be given. However, thorough screening of patients at risk is mandatory. Of note in patients thought to have sporadic parathyroid carcinoma, germline HRPT2 mutations are found in up to 20%. Hence, any patient with parathyroid carcinoma should undergo HRPT2 mutation analysis.

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Genetic analysis of the MEN1 gene and HPRT2 locus in two Italian kindreds with familial isolated hyperparathyroidism

Cited by 34 publications

References 19 publications

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

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

Genetic Analyses of theHRPT2Gene in Primary Hyperparathyroidism: Germline and Somatic Mutations in Familial and Sporadic Parathyroid Tumors

Das familiäre Nebenschilddrüsenkarzinom

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