Wohllk N.,University of Chile |
Schweizer H.,University Hospital Freiburg |
Erlic Z.,University Hospital Freiburg |
Erlic Z.,University of Zürich |
And 3 more authors.
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2010
Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant cancer syndrome with major components of medullary thyroid carcinoma (MTC), pheochromocytoma and hyperparathyroidism. The disease is caused by germline mutations of the RET proto-oncogene. Subtypes of MEN 2 include MEN 2A, MEN 2B and familial MTC (FMTC) which differ in pattern of additional lesions or - in FMTC - lack of pheochromocytoma. In 2009, after extensive review of the literature, the guidelines of the American Thyroid Association made several recommendations regarding clinical and genetic diagnostic testing and treatment options. In this article, the recently published literature is reviewed and concerns regarding future perspectives are added. In particular, a critical handling of rare DNA variants and double mutations is necessary. Up to now, mutation-specific risk profiles and mutation-associated treatment recommendations are unavailable. We emphasise the need for approved centres for treatment of patients affected by MEN 2, not only adults but young children as well. As a high level of skill is required for endoscopic adrenal-sparing surgery, surgeons should declare their expertise before operating such patients. Registry-based follow-up should be mandatory including documentation of short- and long-term outcome in order to provide valid data for future counselling of patients with MEN 2. © 2010 Elsevier Ltd. All rights reserved.
Frank-Raue K.,Molecular Laboratory |
Haag C.,Molecular Laboratory |
Schulze E.,Molecular Laboratory |
Keuser R.,Endocrine Practice |
And 3 more authors.
European Journal of Endocrinology | Year: 2011
Objective: Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is a rare autosomal dominant cause of benign and malignant parathyroid tumours, ossifying jaw tumours, various cystic and neoplastic renal abnormalities and benign and malignant uterine tumours. Disease-causing mutations have been localised in the tumour suppressor gene CDC73. There is limited information available on the mutations, and resulting phenotypes and long-term follow-up data are especially scarce. Design:We analysed the clinical data from 16 patients (including three families) carrying mutations in the CDC73 gene. We describe five new mutations/gene variants, the corresponding phenotypes of these carriers and the long-term follow-up. Methods: The 16 patients were evaluated at an endocrine outpatient clinic and at a surgical department. DNA samples were obtained for sequence analysis of the CDC73 gene. Results: Clinical features of HPT-JT syndrome were detected in 13 of the 15 carriers with germline CDC73 mutations. The major features were benign (n = 7; 47%) or cancerous (n = 3; 20%) HPT-JT was present in eight cases (53%). Most patients had severe hypercalcaemia, and median serum calcium levels were 3.36 mmol/l. A patient with non-secretory parathyroid carcinoma was included. HPT was diagnosed at a median age of 28.5 years. Mutational analysis of the CDC73 gene identified eight sequence changes, three of them have been reported previously, whereas five are novel: c.1346delG, c.88-94delTTCTCCT, the non-coding variants, c.307+5G>T and c.424-5T>C and c.*12C>A of unknown significance. Conclusions: This study significantly increases the information available on the mutations and phenotypes of HPT-JT syndrome. © 2011 European Society of Endocrinology.
Raue F.,Endocrine Practice |
Frank-Raue K.,Endokrinologische Gemeinschaftspraxis
Familial Cancer | Year: 2010
Multiple endocrine neoplasia type 2 (MEN2) is a autosomal dominat inherited tumour-syndrome caused by germline activating mutations of the RET proto-oncogene on chromosome 10. It is clinically characterized by the presence of medullary thyroid carcinoma (MTC), bilateral pheochromocytoma and primary hyperparathyroidism (MEN2A) within a single patient. Three distinct clinical forms have been described depending on the phenotype: the classical MEN 2A, MEN 2B, an association of MTC, pheochromocytoma and mucosal neuroma, (FMTC) familial MTC with a low incidence of other endocrinopathies. Each variant of MEN2 results from different RET gene mutation, with a good genotype phenotype correlation. Genetic testing detects nearly 100% of mutation carriers and is considered the standard of care for all first degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a classification into four risk levels utilizing the genotype-phenotype correlations. MEN 2 gives a unique model for early prevention and cure of cancer and for stratified roles of mutation-based diagnosis of carriers. © Springer Science+Business Media B.V. 2010.
Zoicas F.,Friedrich - Alexander - University, Erlangen - Nuremberg |
Droste M.,Endocrine Practice |
Mayr B.,Friedrich - Alexander - University, Erlangen - Nuremberg |
Buchfelder M.,Friedrich - Alexander - University, Erlangen - Nuremberg |
Schofl C.,Friedrich - Alexander - University, Erlangen - Nuremberg
European Journal of Endocrinology | Year: 2013
Background: Patients with hypothalamic pathology often develop morbid obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Glucagon-like peptide-1 (GLP-1) analogues improve glycaemic control in type 2 diabetic patients and cause weight loss in obese patients by yet unknown mechanisms. Here we tested whether GLP-1 analogues were also effective in the treatment of obesity and associated metabolic alterations in patients with hypothalamic disease. Methods: Nine patients (eight with type 2 diabetes mellitus) with moderate to severe hypothalamic obesity were treated with GLP-1 analogues for up to 51 months. Body weight, homeostasis model assessment - insulin resistance (HOMA-IR), HbA1c and lipids were assessed. Results: Eight patients experienced substantial weight loss (-13.1±5.1 kg (range -9 to -22)). Insulin resistance (HOMA-IR -3.2±3.5 (range -9.1 to 0.8)) and HbA1c values (-1.3±1.4% (range -4.5 to 0.0)) improved under treatment (24.3±18.9 months (range 6 to 51)). Five patients reported increased satiation in response to the treatment. Two of the eight patients complained about nausea and vomiting and one of them abandoned therapy because of sustained gastrointestinal discomfort after 6 months. One patient suffered from intolerable nausea and vomiting and discontinued treatment within 2 weeks. Conclusion: GLP-1 analogues can cause substantial and sustained weight loss in obese patients with hypothalamic disease. This offers a new approach for medical treatment of moderate to severe hypothalamic obesity and associated metabolic alterations. © 2013 European Society of Endocrinology.
Frank-Raue K.,Endocrine Practice |
Leidig-Bruckner G.,Endocrine Practice |
Haag C.,Endocrine Practice |
Schulze E.,Endocrine Practice |
And 3 more authors.
Clinical Endocrinology | Year: 2011
Objective Primary hyperparathyroidism (HPT) is characterised by autonomous secretion of PTH from enlarged parathyroid glands leading, in most patients, to asymptomatic hypercalcaemia. Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene; it is characterised by lifelong and usually asymptomatic hypercalcaemia. Establishing the correct diagnosis is important because surgery can be curative in HPT, but ineffective in FHH. There is overlap in the diagnostic criteria for the two disorders and some patients carrying inactivating mutations in the CaSR gene, which is suggestive of FHH, also have HPT with hyperplastic parathyroid glands or adenomas. Design and patients CaSR gene mutations were analysed and clinical and biochemical parameters evaluated in 139 consecutive outpatients presenting with hypercalcaemia and suspected of having HPT. Results Six different mutations of the CaSR gene were found in eight patients. In four patients, classical FHH was suspected based on clinical and biochemical results and was confirmed by the CaSR mutations. In the other four patients, HPT was diagnosed based on the biochemical profile or symptoms; in these four patients, the parathyroids were operated on and single adenomas were histologically confirmed. In all four patients, serum calcium decreased postoperatively; and in three patients, serum calcium normalised postoperatively. The CaSR mutations in these patients were R25X, E250K and Q926R. Conclusion The coexistence of HPT and FHH in four of 139 patients suggests a pathogenetic role of CaSR mutations in HPT. Despite also having a CaSR mutation, these patients benefited from parathyroid surgery. © 2011 Blackwell Publishing Ltd.
Diana T.,Johannes Gutenberg University Mainz |
Wuster C.,Endocrine Practice |
Kanitz M.,Johannes Gutenberg University Mainz |
Kahaly G.J.,Johannes Gutenberg University Mainz
Journal of Endocrinological Investigation | Year: 2016
Purpose: TSH-receptor (TSHR) antibodies (Ab) can be measured with binding or bio-assays. Sensitivity and specificity of five binding and two bio-assays were compared. Methods: TSHR-blocking (TBAb) and TSHR-stimulating (TSAb) Ab were measured with reporter bio-assays. Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bTSH alone. TSAb was reported as percentage of specimen-to-reference ratio (SRR%). TSHR-binding inhibitory immunoglobulins (TBII) were measured with Kronus, Dynex, Kryptor, Cobas, and Immulite. Results: Sixty patients with Graves’ disease (GD), 20 with Hashimoto’s thyroiditis (HT), and 20 healthy controls (C) were included. C tested negative in all assays (specificity 100 %) while all 60 hyperthyroid GD patients tested positive in the TSAb bio-assay (sensitivity 100 %). Among these 60 GD patients, 20 had low TSAb positivity (SRR% 140–279), but were TBII positive in only 20 (100 %), 7 (35 %), 9 (45 %), 11 (55 %), and 18 (90 %) using the Kronus, Dynex, Kryptor, Cobas, and Immulite, respectively. In 20 moderate TSAb-positive (SRR% 280–420) patients, TBII tested positive in 20 (100 %), 14 (70 %), 13 (65 %), 16 (80 %), and 19 (95 %), respectively. The high (SRR% > 420) TSAb-positive patients were all TBII positive. All 20 hypothyroid HT patients tested TBAb positive (sensitivity 100 %) in the bio-assay while they tested TBII positive in 20 (100 %), 18 (90 %), 20, 20, and 18, respectively. Results obtained with two luminometers correlated for TSAb positive (r = 0.99, p < 0.001), TBAb positive (r = 0.88, p < 0.001), and C (r = 0.86, p < 0.001). None of the binding assays differentiated between TSAb and TBAb. Conclusions: Sensitivity is highly variable between binding and bio-assays for TSHR-Abs. © 2016, Italian Society of Endocrinology (SIE).
Letz S.,Friedrich - Alexander - University, Erlangen - Nuremberg |
Rus R.,Friedrich - Alexander - University, Erlangen - Nuremberg |
Haag C.,Endocrine Practice |
Dorr H.-G.,Friedrich - Alexander - University, Erlangen - Nuremberg |
And 7 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010
Context and Objective: Activating mutations in the calcium-sensing receptor (CaSR) gene cause autosomal dominant hypocalcemia (ADH). The aims of the present study were the functional characterization of novel mutations of the CaSR found in patients, the comparison of in vitro receptor function with clinical parameters, and the effect of the allosteric calcilytic NPS-2143 on the signaling of mutant receptors as a potential new treatment for ADH patients. Methods: Wild-type and mutant CaSR (T151R, P221L, E767Q, G830S, and A844T) were expressed in human embryonic kidney cells (HEK 293T). Receptor signaling was studied by measuring intracellular free calcium in response to different concentrations of extracellular calcium ([Ca2+]o) in the presence or absence of NPS-2143. Results: All ADH patients hadl owered serum calcium ranging from 1.7 to 2.0 mM and inadequate intact PTH and urinary calcium excretion. In vitro testing of CaSR mutations from these patients revealed exaggerated [Ca2+]o-induced cytosolic Ca2+ responses with EC50 values for [Ca2+]o ranging from 1.56 to 3.15 mM, which was lower than for the wild-type receptor (4.27mM). The calcilytic NPS-2143 diminished the responsiveness to [Ca2+] o in the CaSR mutants T151R, E767Q, G830S, and A844T. The mutant P221L, however, was only responsive when coexpressed with the wild-type CaSR. Conclusion: Calcilytics might offer medical treatment for patients with autosomal dominant hypocalcemia caused by calcilytic-sensitive CaSR mutants. Copyright © 2010 by The Endocrine Society.
Raue F.,Endocrine Practice |
Frank-Raue K.,Endocrine Practice
Clinics | Year: 2012
Multiple endocrine neoplasia type 2 is an autosomal-dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the rearranged during transfection proto-oncogene, which encodes the receptor tyrosine kinase, on chromosome 10. It has a strong penetrance of medullary thyroid carcinomas and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Multiple endocrine neoplasia type 2 is divided into three varieties depending on its clinical features: multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma. The specific rearranged during transfection mutation may suggest a predilection toward a particular phenotype and clinical course of medullary thyroid carcinoma, with strong genotype-phenotype correlations. Offering rearranged during transfection testing is the best practice for the clinical management of patients at risk of developing multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2 has become a classic model for the integration of molecular medicine into patient care. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on the classification of rearranged during transfection mutations into risk levels according to genotype-phenotype correlations. Earlier identification of patients with hereditary medullary thyroid carcinoma can change the presentation from clinical tumor to preclinical disease, resulting in a high cure rate of affected patients and a much better prognoses. © 2012 CLINICS.
PubMed | Johannes Gutenberg University Mainz and Endocrine Practice
Type: Journal Article | Journal: Journal of endocrinological investigation | Year: 2016
TSH-receptor (TSHR) antibodies (Ab) can be measured with binding or bio-assays. Sensitivity and specificity of five binding and two bio-assays were compared.TSHR-blocking (TBAb) and TSHR-stimulating (TSAb) Ab were measured with reporter bio-assays. Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bTSH alone. TSAb was reported as percentage of specimen-to-reference ratio (SRR%). TSHR-binding inhibitory immunoglobulins (TBII) were measured with Kronus, Dynex, Kryptor, Cobas, and Immulite.Sixty patients with Graves disease (GD), 20 with Hashimotos thyroiditis (HT), and 20 healthy controls (C) were included. C tested negative in all assays (specificity 100%) while all 60 hyperthyroid GD patients tested positive in the TSAb bio-assay (sensitivity 100%). Among these 60 GD patients, 20 had low TSAb positivity (SRR% 140-279), but were TBII positive in only 20 (100%), 7 (35%), 9 (45%), 11 (55%), and 18 (90%) using the Kronus, Dynex, Kryptor, Cobas, and Immulite, respectively. In 20 moderate TSAb-positive (SRR% 280-420) patients, TBII tested positive in 20 (100%), 14 (70%), 13 (65%), 16 (80%), and 19 (95%), respectively. The high (SRR%>420) TSAb-positive patients were all TBII positive. All 20 hypothyroid HT patients tested TBAb positive (sensitivity 100%) in the bio-assay while they tested TBII positive in 20 (100%), 18 (90%), 20, 20, and 18, respectively. Results obtained with two luminometers correlated for TSAb positive (r=0.99, p<0.001), TBAb positive (r=0.88, p<0.001), and C (r=0.86, p<0.001). None of the binding assays differentiated between TSAb and TBAb.Sensitivity is highly variable between binding and bio-assays for TSHR-Abs.
News Article | November 28, 2016
MAYWOOD, IL - Osteoporosis is preventable and treatable, but only a small proportion of people at risk for fractures are evaluated and treated, according to new osteoporosis guidelines written by an expert panel headed by Loyola Medicine endocrinologist Pauline M. Camacho, MD, FACE. The guidelines recommend that all postmenopausal women aged 50 and older be evaluated for osteoporosis risk. Such evaluation should include a detailed history, physical exam and clinical fracture risk assessment. Dr. Camacho is first author of the guidelines, which were developed by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology and published in the journal Endocrine Practice. Dr. Camacho is president of the AACE, director of Loyola Medicine's Osteoporosis and Metabolic Bone Disease Center and a professor in the division of endocrinology of Loyola University Chicago Stritch School of Medicine. Osteoporosis is a silent skeletal disorder characterized by compromised bone strength that increases the risk of fracture. Bone strength has two main features: bone density and bone quality. The guidelines' recommendations are graded from A to D. Most recommendations, including the recommendation to evaluate all women 50 and older, are graded B, meaning they are based on at least one well-designed study. Recommendations with an A grade are based on the most convincing evidence from multiple gold-standard clinical trials. A-grade recommendations include: The initial therapy should be guided by the patient's fracture risk and the presence or absence of prior fragility fractures. For patients with moderate fracture risk, the guidelines recommend that stable patients take a "drug holiday" after taking an oral bisphosphonate for five years or an intravenous bisphosphonate for three years. Patients at higher fracture risk should continue oral therapy for up to 10 years and IV therapy for up to six years. During the drug holiday in these higher fracture risk patients, another drug such as raloxifene or teriparatide could be considered. The National Osteoporosis Foundation estimates that 10.2 million Americans have osteoporosis and an additional 43.4 million have low bone mass. More than two million osteoporosis-related fractures occur annually in the United States, and more than 70 percent of these occur in women. Among women aged 55 and older, the annual cost of caring for osteoporotic fractures exceeds the annual costs of caring for breast cancer, heart attacks and strokes. "Despite these significant costs, fewer than 1 in 4 women aged 67 years or older with an osteoporosis-related fracture undergoes bone density measurement or begins osteoporosis treatment," the guidelines state. Risk factors for osteoporosis include age 65 or older, low body weight, family history of osteoporosis or fractures, smoking, early menopause and excessive alcohol intake (three or more drinks per day). "Further study is needed to determine the most effective means of communicating benefit and risk in osteoporosis management," the guidelines state. "The best available evidence at this time suggests that communication skills can be learned, decision aids may be helpful and that shared decision-making may improve clinical outcomes." The guidelines are titled, "American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016."