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The article presents a draft of clinical recommendations for the diagnosis and treatment of primary hyperparathyroidism in adult patients, which provides a modern examination algorithm, discusses the basic principles of laboratory, instrumental diagnostics and treatment approaches.

Disclaimer. The EAC Guidelines represent the views of the EAC, and were produced after careful consideration of the scientific and medical knowledge, and the evidence available at the time of their publication. The EAC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the EAC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the EAC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic, or therapeutic medical strategies; however, the EAC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the EAC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

Phosphaturic mesenchymal tumor can cause osteomalacia due to excessive secretion of fibroblast growth factor 23 (FGF23), which disrupts the metabolism of phosphate and vitamin D. These tumors are predominantly benign, but less than 5% of them are malignant forms. This article presents the first clinical case in the Russian Federation of a 69-year-old patient with severe hypophosphatemia due to metastatic prostate cancer. Increased secretion of FGF23 are described in the androgen-resistent prostate cancer, which led to pronounced disorders of mineral metabolism, accompanied by a clinical symptom of weakness, pain in the bones, immobilization of the patient. The condition was regarded as worsening against the background of the progression of the disease. However, symptomatic therapy aimed at increasing the level of phosphate significantly improved the patient’s general condition. The medical community should be aware of the possibility of developing hypophosphatemia in patients with weakness and bone pain, which are not always associated with the progression of metastatic prostate cancer.

AIM: To determine significant factors affecting the survival of patients with ectopic ACTH syndrome (EAS).MATERIALS AND METHODS: A multi-center, observational study with a retrospective analysis of patients with EAS. The end point of the study was the fatal outcome of patients from various causes. In order to identify predictors of survival or mortality, univariate and multifactorial Cox regression analyses were carried out. ROC-analysis was used to determine the prognostic threshold values of individual predictors. The survival analysis was carried out using the Kaplan-Mayer method. Statistical data processing was carried out by using IBM SPSS Statistics 23.RESULTS: The age of patients at the time of diagnosis ranged from 12 to 76 years (Me 40 years [28;54]). The age of the studied population was 55 years [38; 64] for women and 42 years [32; 54] for men. The median period of observation was 50 months [13;91], with a maximum follow-up of 382 months. 92 patients (60,9%) had bronchopulmonary NET, 17 (11,3%) — thymic carcinoid, 8 — pancreatic NET, 5 –pheochromocytoma, 1– cecum NET, 1– appendix carcinoid tumor, 1 — medullary thyroid cancer and 26 (17,2%) patients had an occult NET. The primary tumor was removed in 101 patients (66,9%). Bilateral adrenalectomy was performed in 42 (27,8%) cases. Metastases were revealed in 23,2% (n=35) of patients. Relapse of the disease was observed in 24,4%, long-term remission was preserved in 64 patients (74,4%). Death occurred in 42 patients (28%). The average age of survivors was 47,0±15,2 versus 53,5±15,6 years for the deceased (p=0,022). The average survival time from diagnosis for the deceased was 32 months, Me 16,5 months [7;54]. Multivariate analysis revealed that the following factors have a direct impact on survival: age of diagnosis ≥51 years (OR 4,493; 95% CI 2,056–9,818, pCONCLUSION: The prognosis of patients with EAS is influenced by the age of diagnosis, NET localization, distant metastases and level of LNSC. The most common cause of ectopic ACTH syndrome was bronchopulmonary NET which was associated with the best survival rate.

This draft clinical practice guideline for the diagnosis, treatment and prevention of vitamin D deficiency is an update from a previous 2016 document. An analysis of the relevant literature data was carried out, with particular attention to meta-­analyzes, randomized clinical trials and systematic reviews published over the past 5 years. The updated recommendations were discussed and revised by the leading endocrinologists of the Russian Federation, who have expert status in this issue.The classification of 25(OH)D levels has been revised (in particular, the target range of 25(OH)D values has been specified), recommendations have been developed for screening of the disorders associated with vitamin D deficiency. The concept of vitamin D-associated toxicity and recommendations for its diagnosis and prevention have been introduced. Also, indications for the assessment of other vitamin D metabolites besides 25(OH)D, the main marker of vitamin D status, have been indicated.The section regarding treatment of vitamin D deficiency has been expanded and corrected. The major additions concerned the replenishment of the vitamin D deficiency and insufficiency in certain categories of patients (particularly, in the presence of the chronic kidney disease and autoimmune diseases, as well as in pregnant women) and monitoring of the effectiveness and safety of the therapy. The indications for prescribing active metabolites of vitamin D have been adjusted. Recommendations for the prevention of vitamin D deficiency in the general population have also been revised, taking into account large randomized clinical trials, meta-analyzes and systematic reviews of recent years.This publication is an expanded version of the federal guidelines.

BACKGROUND: The Department of Thoracic Surgery of the National Medical Research Center of Surgery named after A. V. Vishnevsky has been dealing with the problem of surgical treatment of patients with neuroendocrine lung tumors for more than 20 years. This article presents the experience of treating patients with ectopic ACTH syndrome over the past 15 years.AIM: To study the features of preparation, surgical aspects of treatment and delayed results in patients with ACTH-producing tumors of bronchopulmonary localization.MATERIALS AND METHODS: The study included 55 patients who underwent surgical treatment of ACTH-producing neuroendocrine tumor of bronchopulmonary localization in the period from 2005 to 2020. In order to systematize the approach to surgical treatment and the choice of the type of operation, a point analysis of the patient’s severity has been developed. Demographic information about patients, anamnesis data, results of hormonal and instrumental studies at pre- and postoperative stages and long-term treatment results were analyzed. The control period of observation of patients after surgery ranged from 6 months to 5 years.RESULTS: The age of the patients ranged from 18 to 72 years (36±15). According to the MSCT results of the chest, neoplasms in the lungs ranging in size from 5 to 25 mm were detected. Patients who scored from 18 to 23 points had lung resection due to the severity of the condition. With a total score from 14 to 18, segmentectomy with lymph node dissection was performed. When the total score was less than 14, a lobectomy with lymph node dissection was performed. During the planned histological examination, lung neuroendocrine tumor of various differentiation degree was confirmed in all patients. The results of treatment were followed in the period from 6 to 60 months, with a median of 19 months [10;24]. Regression of clinical manifestations of hypercortisolism after 1 year of dynamic follow-up period was detected in 83% of patients. After 60 months of follow-up 10 patients (71.4%) had a persistent clinical effect after surgical treatment with complete regression of hypercortisolism symptoms.CONCLUSION: The analysis of the results of surgical treatment, according to the proposed methodological aspects, with dynamic control after 6, 12 and 36 months showed the effectiveness of such surgical intervention with results comparable to the world indicators of leading clinics.

McCune Albright syndrome (MAS) is a rare disorder caused by a sporadic postzygotic mutation in the GNAS gene, which encodes the alpha subunit of the Gs signaling protein.Permanent activation of the Gs protein leads to uncontrolled production of intracellular cAMP, and autonomic hyperfunction of target organs. Estimated prevalence of the disease – 1\100000 to 1\1000000. For the first time, MAS syndrome was described in 1936 as a triad of symptoms – fibrous dysplasia of bones (FD), spots on the skin of the color of «coffee with milk» and premature sexual development. However, it is now known, that the phenotype of the disease is much more complex. This is primarily due to the mosaic type of mutation in the GNAS gene, which determines a wide range of clinical manifestations, and presents certain difficulties in the diagnosis of this syndrome. Various endocrinopathies can be manifestations of MAS like an acromegaly, a hyperthyroidism, Cushing’s syndrome, hypophospatemic osteomalacia as well as damage to other organs and systems, namely the pathology of the gastrointestinal tract, hepato-biliary cardiovascular systems. This article presents three late diagnosed clinical cases of MAS in patients with coffee-milk spots and FD, multinodular goiter; in two cases in combination with acromegaly. We have demonstrated the possibilities of drug therapy for acromegaly in MAS, as well as the experience of using bisphosphonate for the treatment of FD.The knowledge of clinical manifestations of the MAS, early diagnostics and possibilities of drug therapy in the management of these patients have the important prognostic value for improving the quality of patient’s life.

BACKGROUND: Vitamin D (25-hydroxyvitamin D [25(ОН)D]) deficiency (AIM: The aim of this study is to estimate the vitamin D metabolites and their relationship with the main parameters of phosphorus-calcium metabolism in patients with PHPT at baseline and on the background of a single dose of cholecalciferol 150,000 IU.MATERIALS AND METHODS: A single-center interventional, dynamic, prospective, comparative study has been carried out. The study included 54 participants, divided into two groups: the 1st group included 27 patients with confirmed PHPT, the 2nd control group (n = 27), matched on gender (p = 0.062). The study included 4 visits; the baseline laboratory examination and a bolus dose of cholecalciferol were performed at the visit 1, the subsequent visits included a dynamic laboratory examination.RESULTS: Vitamin D deficiency (2 D3 with albumin-corrected and ionized calcium, as well as between the 25(OH)D3 /24.25(OH)2 D3 ratio with PTH and magnesium. After taking of cholecalciferol, the levels of 1.25(OH)2 D3 and 25(OH)D3 /24.25(OH)2 D3 were significantly increased, and the levels of 25(OH)D3 /1.25(OH)2 D3 were significantly declined at all visits among patients with PHPT. The common 25(OH)D level was comparable to the control group, however the levels of 1,25(OH)2 D3 in patients with PHPT were 55% higher at baseline, and after taking of cholecalciferol 150,000 IU. They remained increased by 3–7 days by an additional 23–36%, significantly higher than those in the control group: 44%, 74% and 65%, at visits 2, 3 and 4, respectively (pCONCLUSION: The completely comprehensive assessment of vitamin D metabolites was carried out for the first time in patients with PHPT before and after using a bolus dose of cholecalciferol. The results confirmed the differences of vitamin D metabolism in chronic excessive secretion of PTH compared to control group, which is new data in the pathogenesis of the disease, and can be used to develop optimal regimens for cholecalciferol taking in this population.

[English] Due to continuous aging of population and increase in the number of elderly people, osteoporosis became socially significant disease leading to disability, increasing mortality and thereby putting an additional burden on the public healthcare system. Screening to identify groups with a high probability of fracture is recommended using the FRAX® Tool for all postmenopausal women and men over 50 years old (А1). In the presense of major pathological fractures (hip, spine, multiple fractures) it is recommended to diagnose osteoporosis and prescribe treatment regardless of the results of spine and hip double X-ray absorptiometry (DXA) or FRAX® (B2). It is recommended to evaluate C-terminal telopeptide when prescribing antiresorptive therapy and procollagen type 1 N-terminal propeptide (P1NP) when prescribing anabolic therapy to patients receiving osteoporosis treatment at baseline and 3 months after the start of therapy in order to assess the effectiveness of treatment early and adherence to the therapy (А2). It is recommended to diagnose osteoporosis and prescribe treatment to patients with high individual 10-year probability of major pathological fractures (FRAX®) regardless of the results of spine and hip DXA (В3). It is recommended to diagnose osteoporosis and prescribe treatment with a decrease in BMD, measured by DXA, by 2.5 or more T-score standard deviations in femoral neck, and/or in total hip, and/or in lumbar vertebrae, in postmenopausal women and men over 50 years old (А2). It is recommended to prescribe bisphosphonates, denosumab or teriparatide to prevent pathological fractures and increase BMD in patients with postmenopausal osteoporosis, osteoporosis in men, glucocorticoid-induced osteoporosis (А2). When the clinical effect of therapy in osteoporotic patients without pathological fractures is achieved (BMD T-score > -2.0 SD in femoral neck and absence of new fractures), it is recommended to interrupt bisphosphonates therapy for 1-2 years with subsequent follow-up (B2). In patients with vertebral fractures, hip fractures or multiple fractures, it is recommended to continue ceaseless long-term treatment of osteoporosis (В3). All drugs for the treatment of osteoporosis are recommended to be prescribed in combination with calcium and cholecalciferol (А2). In order to reduce the risk of recurrent fractures by prescribing osteoporosis therapy timely and maintaining long-term follow-up of patients over 50 years old with pathological fractures, it is recommended to create Fracture Liaison Services (В2). [Русский] В связи с непрерывным старением населения и увеличением количества лиц старшего и пожилого возраста остеопороз стал социально значимым заболеванием, приводя к инвалидности, повышая уровень смертности и создавая тем самым дополнительную нагрузку на систему здравоохранения. Скрининг для выявления групп с высокой вероятностью переломов рекомендован с использованием Алгоритма FRAX® среди всех женщин в постменопаузе и мужчин старше 50 лет (А1). При наличии патологических переломов крупных костей скелета (бедренной кости, тел(а) позвонков(-а), множественных переломов) в анамнезе рекомендовано устанавливать диагноз остеопороза и назначать лечение независимо от результатов рентгеноденситометрии поясничного отдела позвоночника и проксимального отдела бедренной кости или FRAX® (B2). Рекомендуется определение С-концевого телопептида при назначении антирезорбтивной терапии и исследование уровня N-терминального пропептида проколлагена 1-го типа (P1NP) при назначении анаболической терапии пациентам, получающим лечение остеопороза, исходно и через 3 месяца от начала терапии с целью ранней оценки эффективности лечения и приверженности к терапии (А2). Рекомендовано устанавливать диагноз остеопороза и назначать лечение пациентам c высокой индивидуальной 10-летней вероятностью основных патологических переломов (FRAX®) независимо от показателя рентгеноденситометрии поясничного отдела позвоночника и проксимального отдела бедренной кости (В3). Рекомендовано устанавливать диагноз «остеопороз» и назначать терапию при снижении МПК, измеренной при DXA, на 2,5 и более стандартных отклонения по Т-критерию в шейке бедренной кости, и/или в целом в проксимальном отделе бедренной кости, и/или в поясничных позвонках у женщин в постменопаузе и у мужчин старше 50 лет (А2). Для предупреждения патологических переломов и повышения МПК у пациентов с постменопаузальным остеопорозом, остеопорозом у мужчин, глюкокортикоидным остеопорозом рекомендуется прием бисфосфонатов, деносумаба или терипаратида (А2). Пациентам с остеопорозом без патологических переломов при достижении клинического эффекта терапии (МПК до -2,0 SD по Т-критерию в шейке бедренной кости и отсутствие новых переломов) рекомендовано на 1-2 года прекратить терапию бисфосфонатами с последующим динамическим наблюдением (B2). Пациентам с переломами тел позвонков, бедренной кости или множественными переломами в анамнезе рекомендуется продолжать непрерывное длительное лечение остеопороза (В3). Все препараты для лечения остеопороза рекомендуется назначать в сочетании с препаратами кальция и колекальциферола (А2). С целью своевременного назначения терапии остеопороза и обеспечения длительного наблюдения за пациентами в возрасте 50 лет и старше с патологическими переломами для снижения риска повторных переломов рекомендуется создавать Службы профилактики повторных переломов (В2).

Primary hyperparathyroidism (PHPT) is an endocrine disorder of parathyroid glands characterized by excessive secretion of parathyroid hormone (PTH) with an upper normal or elevated blood calcium level. Classical PHPT refers to a symptomatic, multi-system disorder, wich can lead to a significant decrease in the quality of life, disability of patients, and even an increased risk of premature death. Hypercalcemia and the catabolic effect of PTH on various cells are considered as the main pathogenetic mechanisms of the PHPT associated complications. In the last two decades, there has been an increase in the incidence of PHPT, mainly due to the mild forms of the disease, primarily due to the routine calcium screening in North America, Western Europe and, Asia. High prevalence of the disease, as well as the variety of clinical manifestations, cause the attention of different specialists - physicians, rheumatologists, urologists, nephrologists, cardiologists and other doctors. This review cover the main issues of Russian guidelines for the management of PHPT, approved in 2020, including laboratory and instrumental methods, differential diagnosis, surgical and conservative approach, short-term and long-term follow-up. This guidelines also include the recommendations for special groups of patients with hereditary forms of PHPT, parathyroid carcinoma, PHPT during pregnancy.

Multiple endocrine neoplasia syndrome type 1 (MEN1, Wermer's syndrome) is a group of heterogeneous inherited diseases, with its pathogenesis related to hyperplasia or neoplasms of several endocrine glands. This syndrome is characterized by autosomal dominant mode of inheritance, high penetrance and similar prevalence among males and females. Prevalence of MEN1 is estimated to be 1:100,000 of the population. An interesting feature of the presented clinical case is a relapse and transformation of pituitary tumor from a prolactin-secreting into the mixed one, with distinct compartments of ACTH- and prolactin-secreting, in a female patient with a family MEN1 syndrome, with involvement of the pancreas, parathyroid and pituitary glands. Her brother had a synchronous manifestation of the same types of tumors, except corticotropinoma. The presented clinical case highlights the necessity of a comprehensive and life-long follow-up of MEN1 patients for a timely detection of neoplasms and appropriate treatment.

Background: Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is a type hypercorticism caused by ectopic production of ACTH and/or its precursors by neuroendocrine tumors (NET) of various localization, such as lung and thymus carcinoids, less frequently those of pancreas and gastrointestinal tract, medullary thyroid cancer, pheochromocytoma, small cell lung cancer, as well as some other tumor types. The wide spectrum of tumors associated with the ectopic ACTH syndrome (EAS) makes their diagnosis and treatment a complicated issue. Materials and methods : The study was done with surgical and diagnostic biopsy samples from 60 patients who had tumors with EAS, 36 (60%) of them being bronchopulmonary carcinoids, 10 (16.7%) thymus carcinoids, 5 (8.3%) pancreatic NETs, 3 (5%) medullary thyroid cancers, 3 (5%) NETs of unknown primary localization, and NET of appendix, cecum and pheochromocytoma (one case of each, i.e. 1.7%, 1.7%, 1.7%). There were 38 female and 22 male patients (1.72:1), with their mean age of 39 ± 14 years (range, 16 to 77 years). We analyzed their clinical data, as well as the results of morphological and immunohistochemical examination of the tumors. Results : According to the World Health Organization classification (2015), typical carcinoids (TC) of the lung were found in 77.8% (28/36) of the bronchopulmonary tumors. 22.2% (8/36) of the bronchopulmonary tumors and all thymus tumors (100%, n = 10) were classified as atypical carcinoids (ATC). Four pancreatic NETs were classified as Grade 2 (G2), 1 as G3, and NETs of the cecum and appendix as G1 and G2, respectively. At present, 29 (48%) patients are living with no relapse (mean age 39 ± 13.5 years), whereas 22 (37%) of patients developed a relapse (mean age 35 ± 13 years), and 15 (25%) of them died, regardless of the age of the patients The history of the disease was not traced in 4 cases. 5-year relapse-free survival of patients with TC of the lung was 85.7% (24/28), of those with ATC 25% (2/8), with ATC of the thymus and medullary thyroid cancer 0%. Mortality from to TC of the lung for the entire follow-up period was 3.6% (1/28), to ATC 12.5% (1/8), to ATC of the thymus and for medullary thyroid cancer 62.5% and 100%, respectively. The patients with NET of the cecum, appendix and pheochromocytoma are alive without progression for 4, 5 and 6 years, respectively. Therefore, the lowest 5-year survival of patients with EAS was observed in medullary thyroid cancer, pancreatic NET and thymus carcinoids: in 100% (3/3), 75% (3/4), and 57.1% (4/7), respectively. Conclusion: The most unfavorable prognostic factors in the EAS are the localization of tumors in the thymus, pancreas and thyroid gland. This indicates the necessity of a differentiated treatment approaches to patients with this syndrome.

A review of the literature is devoted to the issue of secondary hyperparathyroidism (SHPT) with underlying chronic renal failure. Initial manifestations of the disease can be observed even with a minimal decrease in the rate of glomerular filtration and are pathophysiologically associated with violations of normal metabolism of vitamin D with its conversion into D-hormone. SHPT pathogenesis is based on the D-hormone deprivation and triggering of pathophysiology mechanisms of bone remodelling, increased FRP-23, PTH, changes in the serum levels of calcium and phosphorus, which may further lead to significant changes in the bone tissue structure and cardiovascular complications. Active metabolites of vitamin D and vitamin D analogues (Paricalcitol) were developed for the replacement of active forms of vitamin D in conditions of D-hormone deficiency. Due to its chemical structure and pharmacokinetics, Paricalcitol is able to block the synthesis of parathyroid hormone to a greater extent and increase the absorption of calcium and phosphorus in the intestine to a lesser extent, which gives it advantages over pre-existing active metabolites

Myokines are hormone-like acting molecules produced in skeletal muscles during and immediately after exercise. They affect both paracrine (inside the muscles themselves) and endocrine manner (in adipose tissue, liver, endothelium, skin, mucosa etc.) implementing different effects on target tissues, mainly through regulation of metabolic processes (such as glucose and lipid metabolism, growth and division of neurons and endothelial cells and others). The examination of myokines is of great interest for researchers of different medicine departments, particularly for endocrinologists, because of myokines’ involvement in pathogenesis of abdominal and visceral obesity, diabetes mellitus type 2 and cardiovascular diseases that are all the components of metabolic syndrome. The most important issue for clinicians is a possibility of future therapeutic implication of the myokine’s signal pathways in treatment of widespread metabolic disorders.

Представлено краткое изложение клинических рекомендаций по диагностике и лечению остеопороза, разработанных членами Российской ассоциации эндокринологов при участии членов Российской ассоциации по остеопорозу (ревматологов, травматологов, терапевтов, гинекологов-эндокринологов). Рекомендации разработаны с позиций доказательной медицины, в соответствии с требованиями к составлению клинических рекомендаций Минздрава России, опубликованными в 2016 г. Значительное место в изложении отведено диагностике остеопороза у взрослых, дифференциальной диагностике с другими метаболическими заболеваниями скелета, а также принципам патогенетического лечения остеопороза. Клинические рекомендации полезны будут как врачам общей практики, так и специалистам, прежде всего эндокринологам, ревматологам, травматологам-ортопедам, гинекологам, нефрологам, гастроэнднрологам и неврологам, так как остеопороз является мультифакториальным и мультидисциплинарным заболеванием

The review of literature details the issues of genetics, the specific features of inheritance, the clinical picture and treatment of pseudohypoparathyroidisms (PHPT). In practice, clinicians more frequently deal with type 1 PHPT and the diagnosis of this type creates no significant problems. However, despite the low prevalence of the other types of PHPT - 1b, 1c, and 2, the diseases may run with noticeably clinical symptoms and present a significant problem in the context of diagnosis and treatment. This review may be of concern to both clinicians and geneticists who are interested in this problem.В обзоре литературы подробно освещены вопросы генетики, особенностей наследования, клинической картины и лечения заболеваний группы псевдогипопаратиреоза (ПГПТ). В практической деятельности клиницисты чаще имеют дело с типом 1а ПГПТ, и диагностика этого типа не вызывает значительных сложностей. Однако, несмотря на малую распространенность остальных типов ПГПТ - 1b, 1с и 2, заболевания могут протекать с выраженной клинической симптоматикой и представлять значительную проблему в плане диагностики и лечения. Данный обзор может представлять интерес как для клиницистов, так и для генетиков, интересующихся этой проблемой.

The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific - Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.Представлено описание двух клинических случаев первичного гиперпаратиреоза (ПГПТ) тяжелого течения у молодых больных раком околощитовидной железы, которым проведено молекулярно-генетическое исследование для исключения наследственных форм ПГПТ. Методом высокопроизводительного параллельного секвенирования на полупроводниковом секвенаторе Ion Torrent Personal Genome Machine (Thermo Fisher Scientific - Life Technologies, США) у обеих пациенток выявлены герминальные гетерозиготные нонсенс-мутации в гене - супрессоре опухолевого роста CDC73, кодирующем белок парафибромин: p.R91X и p.Q166X. В России мутации в указанном гене описываются впервые, одна из мутаций описывается впервые в мире. Выявление герминальных мутаций в гене CDC73 у пациентов с ПГПТ требует пожизненного регулярного профилактического обследования для ранней диагностики компонентов синдрома гиперпаратиреоза с опухолью челюсти (hyperparathyroidism-jaw tumor syndrome - HPT-JT), рецидива ПГПТ после хирургического вмешательства, в том числе вследствие рака околощитовидной железы, а также позволяет выявить носителей мутаций среди родственников первой линии родства.Представлено описание двух клинических случаев первичного гиперпаратиреоза (ПГПТ) тяжелого течения у молодых больных раком околощитовидной железы, которым проведено молекулярно-генетическое исследование для исключения наследственных форм ПГПТ. Методом высокопроизводительного параллельного секвенирования на полупроводниковом секвенаторе Ion Torrent Personal Genome Machine (Thermo Fisher Scientific — Life Technologies, США) у обеих пациенток выявлены герминальные гетерозиготные нонсенс-мутации в гене — супрессоре опухолевого роста CDC73, кодирующем белок парафибромин: p.R91X и p.Q166X. В России мутации в указанном гене описываются впервые, одна из мутаций описывается впервые в мире. Выявление герминальных мутаций в гене CDC73 у пациентов с ПГПТ требует пожизненного регулярного профилактического обследования для ранней диагностики компонентов синдрома гиперпаратиреоза с опухолью челюсти (hyperparathyroidism-jaw tumor syndrome — HPT-JT), рецидива ПГПТ после хирургического вмешательства, в том числе вследствие рака околощитовидной железы, а также позволяет выявить носителей мутаций среди родственников первой линии родства.

Microribonucleic acids (miRNAs) are a class of noncoding RNAs that regulate posttranscriptional gene expression. These molecules are regulators of cell proliferation, metabolism, apoptosis, and differentiation. MiRNAs are not degraded by RNAases and their concentrations can be measured in different body fluids, including serum. The expression of miRNAs varies in intact tissues and tumors, including pituitary adenomas. Pituitary tumors are encountered in 22.5% of the population and, in a number of cases, may be asymptomatic, but in case of invasion or/and hormone overproduction, their clinical presentation is severe with multiple symptoms leading to disability and even death. The mechanisms for the development and progression of pituitary tumors and the markers for remission and recurrence have not been adequately investigated. This literature review discusses the biological significance of miRNAs in pituitary tumors and the potential value of circulating miRNAs as biomarkers.Микрорибонуклеиновые кислоты (микроРНК) - класс некодирующих РНК, которые регулируют посттранскрипционную экспрессию генов. Эти молекулы являются регуляторами, контролирующими пролиферацию, метаболизм, апоптоз и дифференцировку. МикроРНК не подвержены разрушению РНКазами и их концентрация может быть измерена в различных биологических жидкостях, в том числе сыворотке крови. Экспрессия микроРНК в опухолях и здоровых тканях, в том числе в аденомах гипофиза, различна. Опухоли гипофиза встречаются у 22,5% населения и в ряде случаев могут протекать бессимптомно, но при их инвазивном росте и/или гормональной активности новообразования развиваются тяжелые многосимптомные заболевания, приводящие к инвалидности и смерти. Механизмы возникновения и прогрессирования опухолей гипофиза, маркеры ремиссии и рецидива не достаточно изучены. В настоящем обзоре литературы обсуждается биологическое значение микроРНК в опухолях гипофиза и потенциальное значение циркулирующих микроРНК как биологических маркеров.

Clinical symptoms of vitamin D deficiency may be quite misleading and masked as rare hereditary syndromes. We describe a family, sister and brother presented with the pain in lower extremities at the age of 14 and 16years accordingly, with severe vitamin D deficiency that was misdiagnosed in the course of the disease with pseudohypoparathyroidism and 1-alpha-hydroxylase deficiency. They benefited from treatment with alfacalcidol and ossein-hydroxyapatite complex supplement which were further discontinued due to socioeconomic factors. At presentation after 2 years without treatment extremely low 25(OH)D levels were revealed. The patients' family history was remarkable for the same clinical features in mother and her Indian ancestry. Thus we describe an uncommon manifestation of severe vitamin D deficiency in a familial setting which emphasizes the necessity of vitamin D testing in calcium or parathyroid disorders.

This review discusses the recent evidence showing that the skeleton itself produces at least two hormones: fibroblast growth factor 23 (FGF23) and osteocalcin. FGF23 is secreted by osteocytes in bone and acts on the kidney to inhibit 1-alpha-hydroxilation ofvitamin D and promote phosphorous excretion. The affinity of FGF23 to FGF receptor is low, but FGF23 binds to FGF receptor-Klotho complex with more affinity. Therefore, Klotho determines the kidney-specific action of FGF23. Increase in FGF23 or Klotho levels due to genetic defects or ectopic production results in low serum phosphorous levels in humans. Contrary to this, low FGF23 or Klotho levels lead to hypophosphatemia and ectopic calcification. Mouse genetics studies revealed that osteoblast product, osteocalcin, in its undercarboxylated stage acts on the pancreatic beta-cells to enhance insulin production and on peripheral tissues to increase glucose utilization as a result of increased insulin sensitivity and to reduce visceral fat. In addition to this, undercarboxylated osteocalcin may also have another hormonal role, this time as a mediator of testosterone secretion. Osteocalcin was shown to induce testosterone production in Leydig cells of the testes both in ex vivo and in vivo studies. In both localizations, at the pancreas and at the testes osteocalcin acts through the GPCR6A receptor, this activates the cAMP response element-binding protein signaling pathway. Thus, this review reports the recent studies indicating bone ’s role as an endocrine organ.

Objective - to evaluate the value of trabecular bone score and risk factors of fractures in patients with Cushing’s syndrome (CS). Material and methods. One hundred eighty two patients with laboratory-confirmed Cushing’s syndrome were enrolled. All patients underwent measurement of bone mineral density (BMD) at the lumbar spine (LI-LIV), femoral neck and total hip using DXA Prodigy (GEHC Lunar, Madison, WI, USA). Trabecular bone score (TBS) was assessed retrospectively on the basis of already existing DXA images using software TBS iNsight software v2.1 (Medimaps, Merignac, France). Each patient was interviewed for the presence of low-traumatic fractures during the active stage of the disease. A lateral X-ray of the thoracic and lumbar spine ThIV-LV was performed to estimate vertebral fractures. Twenty-four hours urinary free cortisol (24hUFC) was measured by imunochemiluminescence assay VITROS ECi with the preliminary extraction with diethyl ether (reference values 60-413 nmol/24 h). Results. Among 182 patients with CS (149 women, 33 men), Cushing’s disease was confirmed in 151 cases, 9 patients diagnosed with benign adrenal tumor and 22 - ACTH-ectopic syndrome. The median of age - 35 (Q25-Q75 27-49) years, body mass index - 29 (26-33) kg/m2, 24hUFC - 1760 (985-2971) nmol/24h. Fractures were confirmed in 80 (44%) cases, 70 patients suffered from vertebral fractures, which were multiple in 53 cases; 23 patients had non-vertebral fractures. Median of trabecular bone score was 1.205 (1.102-1.307), which is much lower than expected in healthy volunteers (>1.350), while the decrease in bone mineral density (BMD) did not correspond to the severity and prevalence of osteoporosis fractures: LI-LIV Z-score - 1.7 (2.5-0.73); femoral neck Z-score - 1 (-1.6- -0.4). However, when using binary logistic regression analysis (adjusted for sex, age, body mass index, bone mineral density, trabecular bone score and 24hUFC) revealed that the most significant predictor of fracture is high levels of 24hUFC (p=0.001) . The high prevalence of vertebral fractures in patients with CS most likely influenced the results of trabecular bone score and its ability to predict fractures. Conclusion. Patients with active CS have low trabecular bone score, rather than bone mineral density, which reflects deterioration in bone microarchitecture. The low-traumatic fracture occurrence depends on the severity of CS reflected in 24hUFC levels.

В статье представлен обзор современной литературы и результаты наших исследований, обобщающие экспериментальные и клинические данные о влиянии цинакалцета на гормонально-биохимические показатели фосфорно-кальциевого обмена, на маркеры костного метаболизма, минеральную плотность костей, также на гистоморфометрические показатели почечной остеодистрофии у гемодиализных пациентов с вторичным гиперпаратиреозом

The Wnt/β signaling pathway (Wnt-SP) is a phylogenetically ancient mechanism that regulates development and maintains tissue homeostasis through the control of cell proliferation, differentiation, migration, and apoptosis. The accurate regulation of the canonical Wnt/β-catenin signaling pathway (Wnt-SP) is critical for embryogenesis and postnatal development; and impaired signal transduction at one of its stages leads to various diseases, including organ malformations, cancers, metabolic and neurodegenerative disorders. The literature review discusses the biological role of the canonical Wnt-SP in the development of the skeleton and in the remodeling of bone tissue. The Wnt signal transmission changes observed during genetic mutations cause various human skeletal diseases. Understanding the functional mechanism involved in the development of bone abnormality could open new horizons in the treatment of osteoporosis, by affecting the Wnt-SP. The design of antibodies to sclerostin, a Wnt-SP inhibitor, is most promising now. The paper summarizes the studies that have investigated the canonical Wnt-SP and designed drugs to treat osteoporosis.Сигнальный путь Wnt (СП-Wnt) - филогенетически древний механизм регуляции развития и поддержания гомеостаза тканей за счет контроля пролиферации, дифференциации, миграции и апоптоза клеток. Точность регуляции канонического сигнального пути Wnt/β-катенин (далее в тексте сигнальный путь Wnt - СП-Wnt) имеет решающее значение в эмбриогенезе и постнатальном развитии, а нарушение проведения сигналов на одном из его этапов приводит к различным заболеваниям, включая пороки развития органов, раковые заболевания, метаболические и нейродегенеративные расстройства. Обзор литературы посвящен обсуждению биологической роли канонического СП-Wnt в развитии скелета и ремоделировании костной ткани. Изменения в передаче сигнала Wnt, наблюдаемые при генетических мутациях, вызывают различные заболевания скелета человека. Понимание функциональных механизмов развития патологии костной ткани позволило открыть новые горизонты в лечении остеопороза за счет влияния на СП-Wnt. Наиболее перспективным в настоящее время является разработка антител к склеростину - ингибитору СП-Wnt. Статья обобщает исследования, посвященные каноническому СП-Wnt и разработке лекарственных препаратов для лечения остеопороза.

Постепенное увеличение продолжительности жизни человека, стремление к улучшению ее качества требует улучшения результатов профилактики и лечения остеопороза. Основную часть лиц, подверженных ОП, составляют женщины в менопаузе. Разносторонний подход к проблеме восстановления баланса костного метаболизма привел к внедрению в практику препаратов с различными механизмами действия. В последнее время крайне важным аспектом является повышение приверженности к лечению пациентов, получающих многолетнее лечение остеопороза. Инновационным шагом является внедрение в практику применения нового препарата моноклонального человеческого антитела к лиганду RANK деносумаб. В обзоре представлены результаты сравнительных многоцентровых слепых рандомизированных исследований эффективности деносумаба и пероральных бисфосфонатов. Показано более выраженное достоверно влияние деносумаба (подкожно 60 мг 1 раз в 6 мес.) на прирост МПК во всех отделах скелета (как богатых трабекулярной, так и кортикальной костной тканью), значимое снижение риска переломов при хорошей переносимости лечения.

In this critical review, we have summarized the specific evidence on ibandronic acid (Bonviva) efficacy, tolerability, feasibility and safety acquired from randomized controlled clinical trials, meta-analyses, bridging trials, long-term extension studies, observational studies and clinical experience. We have paid special attention to reviewing the surrogate endpoints, which are routinely used in clinical practice to estimate the treatment efficacy as well as those high technology methods that are currently used in research centers to predict anti-fracture efficacy. Although the only registered indication for Bonviva in Russia is for postmenopausal osteoporosis, we have reviewed the available clinical trials on the efficacy of ibandronic acid to prevent postmenopausal osteoporosis, to treat low bone mass in males, to treat and prevent glucocorticoid induced osteoporosis and other types of secondary osteoporosis and, in particular, in patients after organ transplantation. In addition to this, we have extensively discussed the currently available data on the safety of pharmacologic treatment for osteoporosis.

Multiple endocrine neoplasia syndrome type 1 (MEN1, Wermer syndrome) – group o а heterogeneous inherited deseases, caused by hyperlasia or neoplasia of several endocrine glands. The phenotype of MEN1 is broad, and over 20 different combinations of endocrine and non-endocrine metabolic manifestations have been described. This case demonstrates multiple formations of endocrine organs, starting non-classical with macroprolactonoma resistant to dopamine agonists therapy, other endocrine disorders developed gradually eventually: hyperparathyreoidism and hypoglycemia caused by pancreas lesions, produced proinsulin in high levels.

The authors review the current literature data on the pathogenesis, clinical manifestations and treatment of glucocorticoid induced osteoporosis in patients with endogenous hypercortisolism. High levels of glucocorticoids lead to bone loss, bone quality deterioration and low traumatic fractures as a consequence of reduced bone formation. In addition to this, muscle weakness and sex steroids hormone abnormalities increase the risk of falls and fractures. The new available data on possible mechanisms of these changes including the involvement of RANKL/RANK/OPG, Wnt-betacatenin signaling pathway and pathogenesis of myopathy are discussed. This review also outlines the practical recommendation and new questions that should be evaluated in future research.

The article briefly reviews the specific features of target-organ lesions in multiple endocrine neoplasia type 1 (MEN1) syndrome and a clinical case of genetically confirmed MEN1 syndrome in a young female patient. Despite the relative rarity of this disease, timely diagnosis, treatment and screening for its main components are very important for the overall prognosis of patients with MEN1 and their first-degree relatives who are MEN1 gene mutation carriers. The described case is noteworthy for a number of specific features. The authors could find no account of optic chiasm glioma within the framework of MEN1 in the literature. Moreover, therapy-resistant somatoprolactinoma engages attention, which points to its aggressive nature with pituitary adenoma that is not been clearly visualized on magnetic resonance imaging. Of interest is the order of detection of neoplasms, in particular the manifestation of hypoglycemic episodes as a sign of organic hyperinsulinism. which have been initially regarded as epileptic seizures, after the use of sustained-release somatostatin analogues for the treatment of acromegaly.Представлены краткий обзор особенностей поражения органов-мишеней при синдроме множественных эндокринных неоплазий 1-го типа (МЭН-1) и клиническое наблюдение генетически подтвержденного синдрома МЭН-1 у молодой пациентки. Несмотря на относительную редкость этого заболевания, своевременная диагностика, лечение и скрининг основных его компонентов крайне важны для общего прогноза у пациентов с МЭН-1 и их родственников первой линии родства - носителей мутации в гене MEN1. Представленный случай примечателен рядом особенностей. В литературе мы не встретили описания глиомы хиазмы в рамках МЭН-1. Кроме того, обращает внимание резистентность соматопролактиномы к терапии, что указывает на ее агрессивный характер, в отсутствие четкой визуализации аденомы гипофиза по данным магнитно-резонансной томографии. Интересна и последовательность выявления новообразований, в частности проявление эпизодов гипогликемии как признака органического гиперинсулинизма, первоначально расцененных как эпилептические припадки, после назначения аналогов соматостатина длительного действия по поводу акромегалии.

The main manifestations of central diabetes insipidus (CDI), a disease of absolute deficiency of hypothalamic hormone vasopressin, are severe thirst and polyuria, which severely interferes with normal life of patients. In some cases CDI may be the first sign of wide spread metastatic process, appearing many years after successful treatment of oncological diseases.

Обзор литературы посвящён патогенетической обоснованности, эффективности и безопасности применения деносумаба в терапии постменопаузального остеопороза. Обсуждается механизм действия препарата, сходства и отличия по отношению к другим препаратам для лечения остеопороза. Подробно представлены результаты II и III фаз клинических исследований деносумаба, в том числе в сравнении с алендроновой кислотой и возможности назначения деносумаба после лечения бисфосфонатами. Отдельное внимание уделяется безопасности и практическим аспектам терапии деносумабом

Primary hyperparathyroidism (PHPT) is a common endocrine disorder that affects bones, urinary tract, cardiovascular system, gastrointestinal tract, and another organs and tissues. The most cases of PHPT are mild forms and those patients have nonspecific symptoms, which require careful diagnostic considerations and choice of treatment. There is not enough data about prevalence of PHPT, especially it's mild forms, in Russian Federation, and future epidemiological research needs to be done. Present literature review includes information about etiology, pathogenesis, clinical findings, diagnostic and differential diagnostic, indication for surgery and medical treatment of PHPT. The review is based on data of studies from the different countries and few studies from Endocrine science center.

The reported clinical case represents an example of characteristic traits in lipid metabolism and fat tissue deposition in hypercorticosolism. Probable causes for fat mass expansion in glucocorticosteroid excess, its distinctive cushingoid distribution, role of 11β-HSD1 and glucocorticoid receptors and reversibility of specific abnormalities after correction of hypercortisolism are discussed in the context of physiological and pathological aspects of glucocorticosteroid action.

This paper reports two clinical cases of ACTH-dependent hypercorticism. Difficulties encountered in differential diagnosis of this condition were due to poor informative value of routine diagnostic methods. The use of selective blood collection from the inferior petrosal sinuses (for the first time in Russia) greatly facilitated the choice of the adequate treatment strategy. A detailed description of clinical features of ACTH-dependent hypercorticism in two young women is presented along with the results of laboratory and instrumental studies. Technical aspects of selective blood collection from the inferior petrosal sinuses in conjunction with the desmopressin stimulation protocol are considered. Indications for the use of this diagnostic method under real clinical conditions are proposed. Results of the study are discussed with reference to the treatment strategy chosen for the management of ACTH-dependent hypercorticism and the outcome of surgical intervention.

The cardiovascular system was analyzed in patients with symptomatic (n = 31) and mild primary hyperparathyroidism (n = 34) whose mean age was 54.6 years; 95% females). In the patients with symptomatic primary hyperparathyroidism, the PQ interval was longer and the QT interval was significantly shorter than those in patients with mild hyperparathyroidism. Left ventricular hypertrophy was noted in 45.2% of patients with symptomatic and in 15.2% of those with mild hyperparathyroidism (p = 0.013). Left ventricular diastolic dysfunction was also more common in the group of symptomatic hyperparathyroidism. There was a statistically significant correlation between the levels of parathyroid hormone, total and ionized calcium and the duration of QT interval and the determinants of diastolic function and left ventricular hypertrophy. The revealed cardiovascular disorders in patients with primary hyperparathyroidism are presumed to depend on the increase rate of parathyroid hormone and total and ionized calcium.

Central diabetes insipidus is a rare pituitary disease due to impairment of synthesis or/and secretion of vasopressin (AVP), characterized by polyuria, polydipsia, low urine osmolality and hyperosmolality of plasma. Main therapy for CDI is substitutive therapy with desmopressin. Lately, it has been shown that AVP stimulates bone formation through the induction of PG synthesis in mesangial cells, contributing to prevent osteoporosis. Pivonello et al. (1998) found that patients with CDI even on nasal desmopessin therapy had a significant impairment in BMD and serum osteocalcin. The aim of this study was to assess the biochemical parameters of bone metabolism and the bone mineral density (BMD) in patients with idiopathic variant of CDI, treated with oral desmopressin. In 24 patients with idiopathic CDI, treated with oral desmopressin and 24 healthy controls we evaluated BMD (analyzer Prodigy, Lunar, DXA), serum osteocalcin (OK) and C-terminal telopeptide of type I collagen (CTx), (ECLIA, Roche Elecsys 1010/2010) as well as calcium total, ionized calcium and alkaline phosphatase (analyzer Hitachi 912, commercial kits Roche). Anterior pituitary dysfunction and concomitant conditions associated with osteoporosis were eliminated on clinical and laboratory basis. The results showed no significant differences between study groups with the exception for ionized calcium which was higher in the group of CDI (p=0,02). We were not able to confirm detrimental effects of idiopathic CDI on BMD and biochemical markers of bone metabolism.

Приведены 2 клинических случая поздней диагностики тяжелых форм первичного гиперпаратиреоза. повлекшие за собой неоправданные врачебные манипуляции, и развитие тяжелых осложнений заболевания. В первом случае из-за ошибочного диагноза остео... и нерасп ПГПТ пациентки подверглись многократным операциям на нижней челюсти. Во втором случае поздний диагноз ПГПТ у молодого пациента, несмотря на успешное хирургическое вмешательство привел к прогрессирующей ХПН и развитию вторичного гиперпаратиреоза.

For many years, hyperparathyroidism, including primary, primarily associated with severe pathology of the osseous system and kidneys, was considered a rare disease. The widespread introduction into the clinical practice of the determination in the blood of calcium, and then parathyroid hormone, and osteodensitometry made it possible to recognize this disease more often and at earlier stages and to treat it more successfully. By now, the specific gravity of mild and asymptomatic forms of hyperparathyroidism has increased from 10-15% in the 1980s to 80%. Conservative management of these forms of hyperparathyroidism requires more thorough research on the prognosis of survival, duration and quality of life, and the risk of developing associated diseases in these patients.

The purpose of the study was to define indications for surgical treatment and its scope in patients with secondary hyperparathyroidism in the presence of end-stage chronic renalfailure. The authors examined 80 patients who had a history of long-term procedures of hemo- or peritoneal dialysis. The patients’ mean age was 47±3.2 years. Measurements of the levels of alkaline phosphatase, ionized and total calcium, phosphorus, parathyroid hormone, ultrasound of the parathyroid glands, densitometry and X-ray study were made in all the patients. All the patients received alfacalcidole therapy during different periods of time. Clinical, laboratory, and morphological correlations were made to establish indications for surgical treatment. The sensitivity ofpreoperative ultrasonography was 72.5% and that of intraoperative ultrasound study was as high as 98.4%. The sensitivity of intraoperative revision was 75%. Sixteen of the 20 patients operated on underwent total parathyroidectomy by autografting a fragment of one of the least glands into the muscle. Subtotal parathyroidectomy was made in 3 patients; 3 parathyroid glands were removed in 1. Emergency and planned studies were performed in all the patients. The duration of the patients operated on averaged 14 months. Three patients undergone total parathyroidectomy with autografiing developed signs of hyperparathyroidism following 6, 12, and 13 months, in this connection graft resection was made in these patients. In the follow-up periods of 3 to 6 months, the level of parathyroid hormone became normal after resurgery in 2 of these patients, hypoparathyroidism developed in one patient. Two months after surgery, recurrent secondary hyperthyroidism was detected in 2 of the 3 patients who had undergone subtotal parathyroidectomy (4 and 7 months after the occurrence of signs of transient hypoparathyroidism) and in 1 patient in whom 3 parathyroid glands had been removed. Four of the 20 patients operated on were observed to have hypoparathyroidism that was compensated by calcium preparations and active forms of vitamin D3. Thus, a good result was noted in 70% of the patients after surgical treatment.

The article devoted to the secondary hyperparathyroidism in patients with end-stage chronic renal failure

The article is devoted to the study of the complete form of the testicular feminization syndrome with dysherminoma in one testicle combiner with prolactinoma.

Deficiency of Р450с17 (17a-hydroxylase/17,20-liase) is а rare hereditary steroidogenesis defects disordering the synthesis of sex steroids and leading to excessive production of mineralocorticoid production. Clinical findings and results of molecular and hormonal studies in 6patients with P450cl7 deficiency are presented. All patients were born with female phenotype, 5 with male karyotype and 1 with female karyotype. Testicular feminization was erroneously diagnosed in all genetic men, and the genetic woman was treated for ovarian in sufficiency. Five of 6 patients suffered from severe arterial hypertension (up to 100/130 mm Hg). Hypopotassemia was observed in 3 patients. P450cl7 deficiency was diagnosed on the basis of increased serum corticosterone level, and in 4 patients it was confirmed by multisteroid analysis. Amplification and subsequent direct sequencing of CYP17gene revealed homozygotic mutation in exon 1 (R96Q) in 1 patient. The same mutations in exon 6 (V360L) were detected in 2 unrelated families (4 patients). Constituent heterozygosis by 2 mutations, in exon 6 (R347C) and exon 8 (R416C), was detected in 1 patient. These findings evidence the need in differential diagnosis of P450cl7 deficiency and the testicular feminization syndrome.