Explore the vast range of titles available.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited disease, characterized by germ-line variants in RET proto-oncogene. Variants are frequently located in the RET extracellular cysteine-rich region domain, mainly affecting cysteines which are replaced by an alternative amino acid, resulting in a mispaired cysteine and the generation of RET dimers. We describe a novel c.1765A > T variant of RET proto-oncogene in a family with medullary thyroid carcinoma (MTC) that predicts the creation of an additional cysteine p.(Ser589Cys) in the cysteine-rich domain. In this site only three other punctual variants have been described, giving rise to extra cysteines. We have characterized the clinical phenotype of this family. The index case was a 79-year-old woman with MTC in both thyroid lobes. This variant co-segregates in this family in four affected members. One member was operated on at 31 years of age and already presented MTC, indicating that prophylactic thyroidectomy was appropriated. Variants predicting additional cysteines are not frequent in RET, and when present, they allow us to understand their implication in the disease. According to clinical data obtained in this family, this variant could be categorized as a moderate-risk of the disease.

Diabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle. We have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from obese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TR(alpha1). This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR( alpha1) and to T(3)-responsive promoters, as shown by ChIP assays. T(3) stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related. Our data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes. This finding may be of relevance for the alterations in muscle function associated with this disease.

To evaluate the effect of the 4G/5G PAI-1 gene polymorphism on the development of organ failure and outcome in critically ill patients with septic syndromes. Prospective, observational study in a medical intensive care unit of a university hospital. 224 consecutively admitted patients. Epidemiological data, severity scores, and the primary site of infection were recorded. DNA genotyping of the PAI-1, TNF-beta, and IL1-ra genes, and measurement of plasma PAI-1 antigen and D-dimer were carried out. The primary outcome variables were organ dysfunction and mortality. Eighty-eight subjects had septic shock at ICU entry or within 48 h from admission. Homozygotes for the 4G allele exhibited higher plasma concentrations of PAI-1 antigen and D-dimer than 4G/5G and 5G/5G subjects). ICU mortality was 44.0% in patients with 4G/4G, 23.4% in 4G/5G and 12.5% in 5G/5G, mainly due to multiorgan failure. After adjusting for SAPS II at admission the genotypes independently associated with ICU mortality in septic shock were TNF-B2/B2 (OR 2.83, 1.04-7.67) and 4G/4G of PAI-1 (OR 2.23, 1.02-4.85). The PAI-1 genotype did not determine susceptibility to infection or the outcome in nonseptic systemic inflammatory response syndrome, sepsis, severe sepsis, and nosocomial septic shock. Homozygosity for 4G of the PAI-1 gene confers an increase in the risk of mortality in adult patients with septic shock due to a greater organ failure.

BackgroundIt has long been observed that there are families in which non-medullary thyroid cancer (NMTC) occurs, but few syndromes and genes have been described to date. Proteins in the shelterin complex have been implied in cancer. Here, we have studied shelterin genes in families affected by NMTC (FNMTC).MethodsWe performed whole-exome sequencing (WES) in 10 affected individuals from four families with at least three affected members. Polymerase chain reaction (PCR) and Sanger sequencing were performed to search for variants in the TINF2 gene in 40 FNMTC families. TINF2 transcripts and loss of heterozygosity (LOH) were studied in several affected patients of one family.ResultsWe found the c.507G>T variant in heterozygosis in the TINF2 gene in one family, co-segregating in all five affected members. This variant affects the normal splicing. LOH was not observed.ConclusionsOur results reinforce the TINF2 gene as a susceptibility cause of FNMTC suggesting the importance of location of frameshift variants in TINF2. According to our data and previous literature, TINF2 pathogenic variants appear to be a significant risk factor for the development of NMTC and/or melanoma.

Abstract Glucocorticoid resistance syndrome is a rare genetic condition characterized by generalized or partial target-tissue insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic-pituitary-adrenal axis. Clinical manifestations may include mineralocorticoid and/or androgen excess without manifestations of Cushing syndrome. At a cellular level, glucocorticoid actions are mediated by the nuclear glucocorticoid receptor encoded by the NR3C1 gene. To date, only 33 glucocorticoid receptor loss-of-function pathogenic variants have been associated with glucocorticoid resistance syndrome. The NR3C1 gene has 2 known disease-causing mechanisms: haploinsufficiency and negative dominance. We describe a mother and her son with a mild hyperandrogenic phenotype and a novel genetic variant of the NR3C1 gene predicting a truncated protein and causing glucocorticoid resistance syndrome. To date, no accurate genotype-phenotype correlation has been found.

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension and is associated with a higher cardiometabolic risk than essential hypertension. The aim of this consensus is to provide practical clinical recommendations for its surgical and medical treatment, pathology study and biochemical and clinical follow-up, as well as for the approach in special situations like advanced age, pregnancy and chronic kidney disease, from a multidisciplinary perspective, in a nominal group consensus approach of experts from the Spanish Society of Endocrinology and Nutrition (SEEN), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN), Spanish Society of Internal Medicine (SEMI), Spanish Radiology Society (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Society of Laboratory Medicine (SEQC(ML)), Spanish Society of Anatomic-Pathology and Spanish Association of Surgeons (AEC). Keypoints The treatment of choice for PA is medical therapy with mineralocorticoid receptor blockade for bilateral cases and unilateral adrenalectomy for unilateral PA. The goals of PA treatment are to normalize blood pressure (BP) and excessive aldosterone production, with the final aim of improving associated comorbidities and reducing mortality. Spironolactone is usually the mineralocorticoid receptor antagonist (MRA) of choice for medical treatment of PA. However, eplerenone has a similar efficacy to that of spironolactone when used in doses 2–3 times higher than the latter and administered 2–3 times a day. Eplerenone has the advantage of not inducing the anti-androgenic side effects commonly seen with spironolactone. Adrenalectomy is the gold standard procedure used to remove the aldosterone-hypersecreting adrenal tissue. The Primary Aldosteronism Outcome (PASO) group criteria are recommended for defining the control objectives of biochemical and clinical response to treatment.

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension (HT), and is associated with a higher cardiometabolic risk than essential HT. However, PA remains underdiagnosed, probably due to several difficulties clinicians usually find in performing its diagnosis and subtype classification. The aim of this consensus is to provide practical recommendations focused on the prevalence and the diagnosis of PA and the clinical implications of aldosterone excess, from a multidisciplinary perspective, in a nominal group consensus approach by experts from the Spanish Society of Endocrinology and Nutrition (SEEN), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN), Spanish Society of Internal Medicine (SEMI), Spanish Radiology Society (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Society of Laboratory Medicine (SEQC(ML)), Spanish Society of Anatomic-Pathology, Spanish Association of Surgeons (AEC). Highlights Following a positive screening test, no further studies are needed for diagnosis of PA if a plasma aldosterone concentration (PAC) > 20 ng/dL and a low circulating direct renin or plasma renin activity (PRA) are detected in a patient with spontaneous hypokalemia. In all other patients, one (or more) of four different tests is (are) currently recommended: the fludrocortisone suppression test, the oral salt loading test, the intravenous saline test, and/or the captopril challenge test. In all cases, hypokalemia must be corrected prior to testing. Interfering medication must be progressively withdrawn before testing, while introducing alpha-1 adrenergic blockers, long-acting non-dihydropyridine calcium antagonists, and/or hydralazine as needed for control of hypertension. All but the captopril challenge test run the risk of inducing hypokalemia, fluid overload, and a worsening of hypertension. In the case of borderline results, the initial test employed can be repeated, or a second test performed. Patients with both a negative saline infusion and captopril challenge test appear to be at a low risk for harboring unilateral disease, whereas those positive for both are more likely to exhibit unilateral aldosterone secretion than when tests render conflicting results. Patients showing a positive screening aldosterone to renin ratio (ARR) with normal/high PAC and a low renin/PRA, yet with negative diagnostic testing, presenting mild hyperaldosteronism, can benefit from targeted therapy of hypertension with mineralocorticoid receptor antagonists.

Objective Biochemical suspicion of familial hypocalciuric hypercalcemia (FHH) might provide with a negative (FHH-negative) or positive (FHH-positive) genetic result. Understanding the differences between both groups may refine the identification of those with a positive genetic evaluation, aid management decisions and prospective surveillance. We aimed to compare FHH-positive and FHH-negative patients, and to identify predictive variables for FHH-positive cases. Design Retrospective, national multi-centre study of patients with suspected FHH and genetic testing of the CASR , AP2S1 and GNA11 genes. Methods Clinical, biochemical, radiological and treatment data were collected. We established a prediction model for the identification of FHH-positive cases by logistic regression analysis and area under the ROC curve (AUROC) was estimated. Results We included 66 index cases, of which 30 (45.5%) had a pathogenic variant. FHH-positive cases were younger ( p  = 0.029), reported more frequently a positive family history ( p  < 0.001), presented higher magnesium ( p  < 0.001) and lower parathormone levels ( p  < 0.001) and were less often treated for hypercalcemia ( p  = 0.017) in comparison to FHH-negative cases. Magnesium levels showed the highest AUROC (0.825, 95%CI: 0.709–0.941). The multivariate analysis revealed that family history and magnesium levels were independent predictors of a positive genetic result. The predictive model showed an AUROC of 0.909 (95%CI: 0.826–0.991). Conclusions The combination of magnesium and a positive family history offered a good diagnostic accuracy to predict a positive genetic result. Therefore, the inclusion of magnesium measurement in the routine evaluation of patients with suspected FHH might provide insight into the identification of a positive genetic result of any of the CaSR-related genes.

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with a significant percentage of germline pathogenic variants (GPVs). Unlike in the United States, routine universal genetic testing is not performed in Europe. The aim of the study is to evaluate the diagnostic yield of germline genetic testing in all patients with PDAC. Methods: Individuals with newly diagnosed PDAC from three Spanish hospitals were enrolled, regardless of family history. Thirteen known susceptibility genes for PDAC were studied using a multigene panel or whole-exome sequencing. Results: One hundred seventy-nine PDAC patients underwent genetic testing. Fourteen (7.8%) had a GPV or likely pathogenic variant In the genes studied: six in ATM, six in BRCA2, one in PALB2, and one in TP53. Of these, seven (50%) did not meet the clinical criteria for genetic study and would have been classified as sporadic PDAC. Presenting with a personal history of any other neoplasm was associated with some GPV, with an odds ratio (OR) of 3.5 (1.1–11.5). A family history of PDAC and breast cancer was also associated with some GPV, with oRs of 3.7 (1.08–13.6) and 8.5 (2.6–26.6), respectively. None of the patients over 60 years without a relevant family history of malignancies presented a GPV associated with PDAC. Conclusions: In our PDAC cohort, a noteworthy number of GPVs were identified, and half of these patients would have been classified as sporadic based solely on clinical criteria. Genetic testing should always be considered, particularly in patients under 60 years or those with a history of other malignancies, especially where economic resources need optimization.

Nonsyndromic familial non-medullary thyroid cancer (FNMTC) represents 3–9% of thyroid cancers, but the susceptibility gene(s) remain unknown. We designed this multicenter study to analyze families with nonsyndromic FNMTC and identify candidate susceptibility genes. We performed exome sequencing of DNA from four affected individuals from one kindred, with five cases of nonsyndromic FNMTC. Single Nucleotide Variants, and insertions and deletions that segregated with all the affected members, were analyzed by Sanger sequencing in 44 additional families with FNMTC (37 with two affected members, and seven with three or more affected members), as well as in an independent control group of 100 subjects. We identified the germline variant p. Asp31His in NOP53 gene (rs78530808, MAF 1.8%) present in all affected members in three families with nonsyndromic FNMTC, and not present in unaffected spouses. Our functional studies of NOP53 in thyroid cancer cell lines showed an oncogenic function. Immunohistochemistry exhibited increased NOP53 protein expression in tumor samples from affected family members, compared with normal adjacent thyroid tissue. Given the relatively high frequency of the variant in the general population, these findings suggest that instead of a causative gene, NOP53 is likely a low-penetrant gene implicated in FNMTC, possibly a modifier.