Genetic testing for familial hyperparathyroidism: clinical-genetic profile in a Mediterranean cohort.

Background: Approximately 10% of primary hyperparathyroidism cases are hereditary, due to germline mutations in certain genes. Although clinically relevant, a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate. Methods: A customized gene panel (AIP, AP2S1, CASR, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, GCM2, GNA11, MEN1, PTH, RET, and TRPV6) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age, family history, high-risk histology, associated tumour, multiglandular disease, or recurrent hyperparathyroidism). We aimed to determine the prevalence of germline variants in these patients, to clinically characterize the probands and their relatives, and to compare disease severity in carriers versus those with a negative genetic test. Results: Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4), 1 novel variant of uncertain significance of CDKN2C, 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of TRPV6. Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands. Conclusion: The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features.

Response to initial therapy of differentiated thyroid cancer predicts the long-term outcome better than classical risk stratification systems.

Objective. Although differentiated thyroid cancer (DTC) usually has an indolent course, some cases show a poor prognosis; therefore, risk stratification is required. The objective of this study is to compare the predictive ability of classical risk stratification systems proposed by the European Thyroid Association (ETA) and American Thyroid Association (ATA) with the system proposed by Tuttle et al. in 2010, based on the response to initial therapy (RIT). Methods. We retrospectively reviewed 176 cases of DTC with a median follow-up period of 7.0 years. Each patient was stratified using ETA, ATA, and RIT systems. Negative predictive value (NPV) and positive predictive value (PPV) were determined. The area under receiver operating characteristic (ROC) curve was calculated in order to compare the predictive ability. Results. RIT showed a NPV of 97.7%, better than NPV of ETA and ATA systems (93.9% and 94.9%, resp.). ETA and ATA systems showed poor PPV (40.3% and 41%, resp.), while RIT showed a PPV of 70.8%. The area under ROC curve was 0.7535 for ETA, 0.7876 for ATA, and 0.9112 for RIT, showing statistical significant differences (P < 0.05). Conclusions. RIT predicts the long-term outcome of DTC better than ETA/ATA systems, becoming a useful system to adapt management strategies.