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Paolo Beck-Peccoz and Luca Persani

Beck-Peccoz P, Persani L. Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol 1994;131:331–40. ISSN 0804–4643

Thyroid-stimulating hormone (TSH), like the other pituitary glycoprotein hormones, is produced and secreted as a mixture of isoforms, the majority of which represent differences in oligosaccharide structure and possess different bioactivity. When samples are quantified simultaneously by immunometric assay and bioassay, the ratio between bioactivity (B) and immunoreactivity (I) may serve as an index of the overall potency of TSH. Variations of the TSH B/I ratio have been documented in both physiological and pathological conditions associated with alteration of the two most important mechanisms controlling TSH synthesis and secretion, i.e. TRH release and the thyroid hormone feedback system. Major examples of this assumption are the low TSH bioactivity found in samples from patients lacking TRH and thus bearing a hypothalamic hypothyroidism, and the enhanced bioactivity that is invariably found in TSH from patients with thyroid hormone resistance. Moreover, variations of TSH bioactivity have been recorded in normal subjects during the nocturnal TSH surge, in normal fetuses during the last trimester of pregnancy, in patients with primary hypothyroidism and in patients with TSH-secreting pituitary adenoma and non-thyroidal illness. In conclusion, the secretion of TSH molecules with altered bioactivity plays an important pathogenetic role in various thyroid disorders, while in some particular physiological conditions the bioactivity of TSH may vary in order to adjust thyroid hormone secretion to temporary needs.

Paolo Beck-Peccoz, Istituto di Scienze Endocrine, Ospedale Maggiore IRCCS, Via F. Sforza 35, 1-20122 Milano, Italy

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Luca Persani, Tiziana de Filippis, Carla Colombo and Davide Gentilini

The technological advancements in genetics produced a profound impact on the research and diagnostics of non-communicable diseases. The availability of next-generation sequencing (NGS) allowed the identification of novel candidate genes but also an in-depth modification of the understanding of the architecture of several endocrine diseases. Several different NGS approaches are available allowing the sequencing of several regions of interest or the whole exome or genome (WGS, WES or targeted NGS), with highly variable costs, potentials and limitations that should be clearly known before designing the experiment. Here, we illustrate the NGS scenario, describe the advantages and limitations of the different protocols and review some of the NGS results obtained in different endocrine conditions. We finally give insights on the terminology and requirements for the implementation of NGS in research and diagnostic labs.

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Marcello Filopanti, Uberta Verga, Federica Ermetici, Luca Olgiati, Cristina Eller-Vainicher, Sabrina Corbetta, Luca Persani, Paolo Beck-Peccoz and Anna Spada

Objective

Primary hyperparathyroidism (PHPT) is a challenging problem in type 1 multiple endocrine neoplasia (MEN1) due to the high postsurgery recurrence rate. The aim was to evaluate the efficacy of cinacalcet in MEN1 patients in comparison with patients with sporadic PHPT (sPHPT) and the effect of Arg990Gly calcium-sensing receptor (CASR) polymorphism on the response to treatment.

Design

This is a randomized, crossover, double-blind study carried out in the University Hospitals.

Methods

Fifteen MEN1 patients with PHPT were randomized to two groups, one administered with 30 mg daily cinacalcet, titrated until calcium normalization, and one with placebo. After 3 months, patients were reassessed and after washout switched to the other treatment. For comparison, 20 sPHPT patients with similar calcium levels were administered with cinacalcet for 3 months. Ionized and total calcium, phosphate, and parathyroid hormone (PTH) were evaluated. CASR Arg990Gly was genotyped on blood DNA by direct sequencing.

Results

Cinacalcet normalized calcium, increased phosphate, and reduced PTH levels in all patients. Cinacalcet dosage required to normalize calcium in MEN1 and sPHPT was not significantly different (45±21 vs 54±25 mg/day). Few mild adverse events, not requiring drug withdrawal, were observed in both the groups. No association between Arg990Gly CASR polymorphism and response to cinacalcet was found.

Conclusions

This short-term prospective study demonstrated that the efficacy profile of cinacalcet in patients with MEN1-related PHPT and in those with sPHPT was similar and was not influenced by the 990 CASR variant. Although long-term safety and efficacy data are required, cinacalcet might be considered a treatment option in MEN1 patients who have contraindications to surgery or persistent PHPT after surgery.

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Giovanna Mantovani, Ernesto De Menis, Giorgio Borretta, Giorgio Radetti, Sara Bondioni, Anna Spada, Luca Persani and Paolo Beck-Peccoz

Objective: Mutations in the gene coding for the orphan nuclear receptor DAX1 cause X-linked adrenal hypoplasia congenita (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development due to hypogonadotropic hypogonadism becomes manifest at the time of puberty. Moreover, evidence from Dax1 knockout mice and a limited number of patients with AHC, suggests that mutations in DAX1 may directly cause abnormalities in spermatogenesis. The aim of this study was to characterize clinically and genetically five patients with AHC.

Design: DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1-year follow-up after gonadotropin treatment.

Methods: We report on five men with classic AHC manifestations. Genomic DNA was extracted from patients’ peripheral blood leukocytes and the coding region, splice sites, and promoter (−240 bp) region of DAX1 were directly sequenced.

Results: Three known and two novel mutations were detected in the DAX1 coding sequence in these patients. Semen analysis was performed in four of the five patients and showed azoospermia. Twelvemonth treatment with gonadotropins did not restore fertility in these patients. All patients showed a normal testicular Doppler ultrasound, in contrast with that observed in Dax1-deficient mice, which display abnormalities in the rete testis.

Conclusions: These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease.

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Daniela Preziati, Luigi La Rosa, Giovanni Covini, Rosaria Marcelli, Stefania Rescalli, Luca Persani, Ersilio Del Ninno, Pier Luigi Meroni, Massimo Colombo and Paolo Beck-Peccoz

Preziati D, La Rosa L, Covini G, Marcelli R, Rescalli S, Persani L, Del Ninno E, Meroni PL, Colombo M, Beck-Peccoz P. Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a. Eur J Endocrinol 1995;132:587–93. ISSN 0804–4643

The occurrence of thyroid abnormalities and the appearance of organ- and non-organ-specific autoantibodies during long-term recombinant interferon alpha-2a (IFN-α) therapy were studied in 86 and 51 consecutive outpatients with hepatitis C and B virus-related chronic active hepatitis (CAH-HCV and CAH-HBV), respectively. Most patients had longstanding community-acquired hepatitis. At baseline, 9.3% of CAH-HCV and 3.9% of CAH-HBV patients showed clinical and/or biochemical signs of thyroid dysfunction. The remaining patients were euthyroid, although anti-thyroid autoantibodies were found in 33/78 (42.3%) of CAH-HCV and in 5/49 (10.2%) of CAH-HBV patients. During IFN-α treatment, increased anti-thyroid autoantibody levels were seen in 40% of CAH-HCV initially negative patients, while they became detectable in no more than 10% of CAH-HBV patients. Interferon-α-induced hypo- or hyperthyroidism was recorded in 12 of 35 CAH-HCV patients treated for 12 months (34.3%). Only one CAH-HBV patient developed hyperthyroidism. High titers of anti-nuclear auto-antibodies (ANA) were recorded at enrolment in 5/36 (13.8%) of CAH-HCV and in 3/16 (18.7%) of CAH-HBV patients. Only one CAH-HCV patient displayed anti-parietal cell antibodies (PCA). After IFN-α treatment, ANA were found in 10/28 (35.7%) and PCA in 2/28 (7.1%) of CAH-HCV patients, while an additional CAH-HBV patient developed PCA, but not ANA. However, no signs of systemic autoimmune disease were recorded. In conclusion, more than half of the patients with chronic active hepatitis C, but only one-tenth of those with hepatitis B, displayed thyroid- and/or non-organ-specific autoantibodies prior to or during treatment with IFN-α. As most of the antibody-positive patients developed permanent thyroid disorders during IFN-α therapy, the risk of development of organ-specific autoimmunity should be assessed carefully and incorporated in the cost/effectiveness analysis in patients with longstanding hepatitis who are candidates for IFN-α treatment.

Paolo Beck-Peccoz, Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, Padiglione Granelli, Via F. Sforza 35, 20122-Milano, Italy

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Marina Muzza, Daniela Cordella, Johny Bombled, Brigitte Bressac-de Paillerets, Fabiana Guizzardi, Zelia Francis, Paolo Beck-Peccoz, Martin Schlumberger, Luca Persani and Laura Fugazzola

Context

Most germline-activating mutations of the RET proto-oncogene associated with inherited medullary thyroid cancer (MTC) are localized in exons 10, 11 and 13–15. Four novel RET variants, located in the extracellular domain (p.A510V, p.E511K and p.C531R) coded by exon 8 and in the intracellular juxtamembrane region (p.K666N) coded by exon 11, were identified on the leukocyte DNA from apparently sporadic cases.

Methods

Plasmids carrying Ret9-wild-type (Ret9-WT), Ret9-C634R and all Ret9 variants were transfected, and the phosphorylation levels of RET and ERK were evaluated by western blot analyses. The transforming potentials were assessed by the focus formation assay.

Results

The p.A510V, p.E511K and p.C531R variants were found to generate RET and ERK phosphorylation levels and to have a transforming activity higher than that of Ret9-WT variant, but lower than that of Ret9-C634R variant. Differently, the p.K666N variant, located immediately downstream of the transmembrane domain, and involving a conserved residue, displayed high kinase and transforming activities. Computational analysis predicted non-conservative alterations in the mutant proteins consistent with putative modifications of the receptor conformation.

Conclusions

The molecular analyses revealed an oncogenic potential for all the novel germline RET variants. Therefore, the prevalence of exon 8 genomic variations with an oncogenic potential may be higher than previously thought, and the analysis of this exon should be considered after the exclusion of mutations in the classical hotspots. In addition, on the basis of these functional data, it is advisable to extend the genetic screening to all the first-degree relatives of the MTC patients, and to perform a strict follow-up of familial carriers.

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Silvia Dossena, Antonella Maccagni, Valeria Vezzoli, Claudia Bazzini, Maria Lisa Garavaglia, Giuliano Meyer, Johannes Fürst, Markus Ritter, Laura Fugazzola, Luca Persani, Patrick Zorowka, Carlo Storelli, Paolo Beck-Peccoz, Guido Bottà and Markus Paulmichl

Objective: The SLC26A4 protein (pendrin) seems to be involved in the exchange of chloride with other anions, therefore being responsible for iodide organification in the thyroid gland and the conditioning of the endolymphatic fluid in the inner ear. Malfunction of SLC26A4 leads to Pendred syndrome, characterized by mild thyroid dysfunction often associated with goiter and/or prelingual deafness. The precise function of the SLC26A4 protein, however, is still elusive. An open question is still whether the SLC26A4-induced ion exchange mechanism is electrogenic or electroneutral. Recently, it has been shown that human pendrin expressed in monkey cells leads to chloride currents.

Methods: We overexpressed the human SLC26A4 isoform in HEK293 Phoenix cells and measured cationic and anionic currents by the patch-clamp technique in whole cell configuration.

Results: Here we show that human pendrin expressed in human cells does not lead to the activation of chloride currents, but, in contrast, leads to an increase of cationic currents.

Conclusion: Our experiments suggest that the SLC26A4-induced chloride transport is electroneutral when expressed in human cellular systems.

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Cristina Romei, Stefano Mariotti, Laura Fugazzola, Augusto Taccaliti, Furio Pacini, Giuseppe Opocher, Caterina Mian, Maurizio Castellano, Ettore degli Uberti, Isabella Ceccherini, Nadia Cremonini, Ettore Seregni, Fabio Orlandi, Piero Ferolla, Efisio Puxeddu, Francesco Giorgino, Annamaria Colao, Paola Loli, Fabio Bondi, Barbara Cosci, Valeria Bottici, Antonello Cappai, Giovanni Pinna, Luca Persani, Verga Uberta, Marco Boscaro, Maria Grazia Castagna, Carlo Cappelli, Maria Chiara Zatelli, Antongiulio Faggiano, Giuseppe Francia, Maria Luisa Brandi, Alberto Falchetti, Aldo Pinchera, Rossella Elisei and The ItaMEN network

Objective

Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population.

Methods

We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres.

Results and conclusions

The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001).

Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.

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Cristina Romei, Stefano Mariotti, Laura Fugazzola, Augusto Taccaliti, Furio Pacini, Giuseppe Opocher, Caterina Mian, Maurizio Castellano, Ettore degli Uberti, Isabella Ceccherini, Nadia Cremonini, Ettore Seregni, Fabio Orlandi, Piero Ferolla, Efisio Puxeddu, Francesco Giorgino, Annamaria Colao, Paola Loli, Fabio Bondi, Barbara Cosci, Valeria Bottici, Antonello Cappai, Giovanni Pinna, Luca Persani, Verga Uberta, Marco Boscaro, Maria Grazia Castagna, Carlo Cappelli, Maria Chiara Zatelli, Antongiulio Faggiano, Giuseppe Francia, Maria Luisa Brandi, Alberto Falchetti, Aldo Pinchera, Rossella Elisei and The ItaMEN network

The journal and the authors apologise for an error in the name of one of the authors (appears as Verga Uberta) of this article published in the European Journal of Endocrinology Vol 163 301–308. The correct name of the author should be Uberta Verga and not as published.

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Marco Bonomi, Valeria Vezzoli, Csilla Krausz, Fabiana Guizzardi, Silvia Vezzani, Manuela Simoni, Ivan Bassi, Paolo Duminuco, Natascia Di Iorgi, Claudia Giavoli, Alessandro Pizzocaro, Gianni Russo, Mirella Moro, Letizia Fatti, Alberto Ferlin, Laura Mazzanti, Maria Chiara Zatelli, Salvo Cannavò, Andrea M Isidori, Angela Ida Pincelli, Flavia Prodam, Antonio Mancini, Paolo Limone, Maria Laura Tanda, Rossella Gaudino, Mariacarolina Salerno, Pregnolato Francesca, Mohamad Maghnie, Mario Maggi, Luca Persani and Italian Network on Central Hypogonadism

Objective

Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation.

Design

Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals.

Methods

We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8).

Results

90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH.

Conclusions

Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.