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BACKGROUND/AIM Familial multiple endocrine neoplasia type 1 (MEN1) is a rare disorder mostly associated with germline MEN1 mutations. MATERIALS AND METHODS Genotyping of the MEN1, cyclin-dependent kinase inhibitor 1B (CDKN1B) and aryl hydrocarbon receptor-interacting protein (AIP) genes using Sanger sequencing was carried out in a family with MEN1 and the resulting germline variants genotyped in an additional 95 ethnically matched controls. RESULTS A missense variant in AIP (p.Arg16His) gene and a truncating mutation (p.Gly111fs*8) in MEN1 gene were both detected in the proband and his father, showing limited co-segregation with phenotype. p.Arg16His AIP missense variant was detected in one control. CONCLUSION There are conflicting data regarding the functional effects of AIP p.Arg16His and its role in disease development. We demonstrated the co-occurrence of p.Arg16His AIP missense variant in a patient with a bona fide MEN1 mutation. Our finding of p.Arg16His AIP in one of the 95 controls and its co-occurrence with MEN1 in a patient suggests that it is more likely that this variant is a rare polymorphism, unrelated to MEN1 pathogenesis.

Familial multiple endocrine neoplasia type 1 (MEN1) is a rare disorder mostly associated with germline MEN1 mutations.Genotyping of the MEN1, cyclin-dependent kinase inhibitor 1B (CDKN1B) and aryl hydrocarbon receptor-interacting protein (AIP) genes using Sanger sequencing was carried out in a family with MEN1 and the resulting germline variants genotyped in an additional 95 ethnically matched controls.A missense variant in AIP (p.Arg16His) gene and a truncating mutation (p.Gly111fs*8) in MEN1 gene were both detected in the proband and his father, showing limited co-segregation with phenotype. p.Arg16His AIP missense variant was detected in one control.There are conflicting data regarding the functional effects of AIP p.Arg16His and its role in disease development. We demonstrated the co-occurrence of p.Arg16His AIP missense variant in a patient with a bona fide MEN1 mutation. Our finding of p.Arg16His AIP in one of the 95 controls and its co-occurrence with MEN1 in a patient suggests that it is more likely that this variant is a rare polymorphism, unrelated to MEN1 pathogenesis.

Adenomas hipofisários são tumores intracranianos comuns que ocorrem de forma esporádica. Em alguns casos raros, esta doença é identificada em grupos familiares e não tem envolvimento com outros tumores endócrinos, uma condição identificada como adenomas de hipófise familiais isolados (FIPA). O desenvolvimento de FIPA tem sido associado a anormalidades genéticas, especialmente no gene AIP, no qual mutações germinativas foram relatadas em aproximadamente 30% dos casos. Mutações no gene MEN1 foram descritas em famílias com adenoma de hipófise, mas com fenótipo específico para neoplasia endócrina múltipla tipo 1. Mutações no receptor de prolactina (PRLR) também têm sido associadas ao desenvolvimento de adenoma hipofisário em modelos animais. Assim, na maioria dos casos de FIPA o defeito genético exato que leva ao desenvolvimento da doença permanece desconhecido. Portanto, o objetivo deste trabalho é determinar a base genética de FIPA em uma família brasileira. A família estudada é composta por três irmãos diagnosticados com adenoma hipofisário secretor de prolactina através de testes clínicos, bioquímicos e de imagem. O sequenciamento Sanger foi utilizado para genotipagem dos genes candidatos AIP, MEN1 e PRLR. Além disso, uma pesquisa por novas mutações foi realizada utilizando-se a técnica de sequenciamento de todo exoma. Uma análise in silico e algoritmos de previsão foram aplicados para priorizar variantes provavelmente patogênicas. Nenhuma mutação foi identificada na região codificadora e reguladora de MEN1, AIP e PRLR. O exoma revelou variantes novas e provavelmente patogênicas em três genes diferentes: RXRG, REXO4 e TH. As variantes em RXRG e TH podem estar associadas ao prolactinoma isolado na família estudada e a possível contribuição desses genes para outras famílias FIPA devem ser exploradas. Pituitary adenomas are common intracranial tumors that occur sporadically. In some rare cases this condition is identified in familial clusters and has no involvement with other endocrine tumors, a disorder identified as Familial Isolated Pituitary Adenoma (FIPA). FIPA development has been associated with genetic abnormalities, especially in AIP gene, where germline mutations have been reported in approximately 20% of cases. Mutations in the MEN1 gene have been described in a subset of pituitary adenoma families, but with bona fide multiple endocrine neoplasia type 1 feature. Mutations in prolactin receptor (PRLR) have also been associated to pituitary adenoma in animal models. Thus, in most FIPA cases the exact genetic defect that lead to disease development remains unknown. Therefore, the aim of this work is to determine the genetic basis of FIPA in a Brazilian family. The studied family is composed of three siblings presented with isolated prolactinsecreting pituitary adenoma diagnosed through clinical, biochemical and imaging testing. Sanger sequencing was used to genotype candidate genes AIP, MEN1 and PRLR. Further mutation screening was performed using whole-exome sequencing. In silico analysis and additional predictive algorithms were applied to prioritize likely pathogenic variants. No mutations in the coding and flanking intronic regions in the MEN1, AIP and PRLR genes were detected. Whole-exome sequencing revealed novel, predicted damaging, heterozygous variants in three different genes: RXRG, REXO4 and TH. The RXRG and TH possibly pathogenic variants may be associated with isolated prolactinoma in the studied family and the possible contribution of these genes to additional FIPA families should be explored.

Adenomas de hipófise são neoplasias benignas que ocorrem a partir da expansão de células específicas da adenohipófise. Estes tumores compreendem 10 a 15% de todos os tumores intracranianos. Os mecanismos patogênicos destes podem ocorrer em função de alterações genéticas ou epigenéticas, que resultam na desregulação do ciclo celular, alteração da sinalização intracelular ou perda de fatores supressores de tumor. O prolactinoma é o adenoma hipofisário mais frequente e pode causar infertilidade. No entanto, casos familiais da doença são raros e pouco entendidos. Portanto, a proposta deste trabalho foi realizar caracterizações moleculares de duas famílias com histórico de prolactinoma: a família 1, identificada como prolactinoma familial isolado, e a família 2, um caso de neoplasia endócrina múltipla tipo 1 (MEN1). Para isso, foram pesquisadas mutações em dois genes supressores de tumor, AIP e MEN1. DNA genômico foi extraído de integrantes hígidos e afetados das duas fam ílias estudadas. O sequenciamento foi realizado para os 9 exons codificantes de MEN1, e os 6 exons de AIP. Nenhuma variante foi detectada no gene MEN1 nas amostras testadas de ambas as famílias. Também não foram detectadas mutações em AIP nos pacientes da família 1, mas o paciente portador de MEN1 apresentou a variante p.R16H. De acordo com os resultados desse trabalho, não há correlações entre mutações nos genes MEN1 e AIP e o desenvolvimento de prolactinoma na família 1. O papel da variante p.R16H na progressão de MEN1 no paciente da família 2 necessita de maiores investigações. Pituitary adenomas are benign neoplasms that arise from the expansion of single cells from the adeno-pituitary. These tumors comprise 10 to 15% of all intracranial tumors. The pathogenic mechanisms of these tumors can be either genetic or epigenetic changes, resulting in the deregulation of cell cycle, signaling defects or loss of tumor suppressor factors. The prolactinoma is the most frequent pituitary adenoma, and may cause infertility. However, familial cases are rare and poorly characterized. Therefore, the propose of this work is to perform molecular characterization of two families that carry prolactinoma: family 1, which harbors familial isolated prolactinoma, and family 2, a familial multiple endocrine neoplasia type 1 case. We surveyed mutations in two tumor suppressor genes, AIP and MEN1. For this study, genomic DNA was extracted from affected as well as healthy members of both families. Sequencing was performed for the 9 coding exons of MEN1, and the 6 exons of AIP. Significant variants were not detected in MEN1 for neither tested samples from both families. Unexpectedly, there were no mutations on AIP in family 1, but the multiple endocrine neoplasia type 1 patient has the genetic variation p.R16H in exon 1 of AIP. Considering the related results, no correlations were detected between mutations in the selected genes and prolactinoma development in family 1. The rule of p.R16H variant in pituitary adenoma development in family 2 patient needs further investigation.