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[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).

Functioning gonadotroph adenomas are rare pituitary tumors secreting one or two gonadotropins (follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH)), which are hormonally active. In the majority of cases, gonadotroph tumors are endocrinologically “silent” and make up more than a half of non-functioning pituitary adenomas. In this article we describe a rare clinical case of LH/FSH-secreting pituitary macroadenoma with bitemporal hemianopsia in a 62-year-old man. The patient underwent transnasal transsphenoidal adenomectomy, leading to remission. The distinctive feature of this case is the presence of secondary erythrocytosis due to endogenous hyperandrogenism, which required several blood exfusions to normaliza the level of hematocrit before surgery. It is noteworthy that clinical signs of erythrocytosis were present long before visual impairment. This clinical case demonstrates difficulties in the early diagnosis of functioning gonadotroph adenomas.

Background: Denosumab is a highly effective and safe first-line treatment for osteoporosis. Primary hyperparathyroidism is a prevalent condition found in patients with osteoporosis. However, data regarding effectiveness of denosumab treatment in patients with PHPT are scarce. Aims: To estimate the comparative effects of denosumab to treat postmenopausal osteoporosis (PMO) and osteoporosis caused by primary hyperparathyroidism (PHPT) or glucocorticoid-induced osteoporosis (GIOP) in postmenopausal women in routine clinical practice. Materials and methods: Retrospective study based on the medical card records. Patients over 50 years of age with verified osteoporosis (based on bone mineral density (BMD) T-score ≤ -2.5 SD and/or low-trauma fracture), who had at least 3 denosumab injections were included in the study. Results: 162 patients were included and divided into three groups according to the etiology of osteoporosis. The first group consisted of postmenopausal women with osteoporosis (PMO) [(n=85); median age 70 [64;78]]. Patients with glucocorticoid-induced osteoporosis (GIOP) were enrolled in the second group [(n=16); male to female ratio =1:15; median age 60 [57,8; 66,3]]. The third group consisted of patients with PHPT and osteoporosis [(n=61); male to female=2:59; median age 68 [63; 75]]. Among all patients, denosumab treatment significantly increased BMD and decreased serum levels of calcium and CTx compared with baseline. PMO: the median increase in BMD according to the T-score was L1-L4 0,6 (pConclusion: Denosumab treatment is similarly effective for increasing BMD and decreasing bone turnover markers in patients with PMO and PHPT among postmenopausal women. The hypocalciemic effect of denosumab is most significant in subjects with PHPT.

Osteopetrosis is a rare hereditary disease that develops as a result of genetic mutations leading to impaired development and function of osteoclasts. There are several forms of osteopetrosis that differ in the type of inheritance (autosomal recessive, autosomal dominant and intermediate) and the severity of symptoms. The main clinical manifestations of the disease are frequent pathological fractures, anemia, thrombocytopenia, infectious complications, compression of the cranial nerves and impaired function. With timely diagnosis and successful hematopoietic stem cell transplantation (HSCT), the prognosis is favorable. In the vast majority of cases, transplantation is performed in the first 10 months of life. The literature describes only 12 patients with osteopetrosis who underwent HSCT over the age of 5 years. The article presents a clinical case of osteopetrosis due to a mutation in the CA2 gene (Chr8: 86389420C> G, p.Y193X) in a 30-year-old patient who underwent THSC at the age of 27.

Changes in the expression of non-coding ribonucleic acids (ncRNAs) takes part in the formation of various tumors. Multiple endocrine neoplasia syndrome type 1 (MEN1) is a rare autosomal dominant disease caused by mutations of the MEN1 gene encoding the Menin protein. Syndrome is characterized by the occurrence of parathyroid tumors, gastroenteropancreatic neuroendocrine tumors, pituitary adenoma, as well as other endocrine and non-endocrine tumors. The mechanisms for the formation of MEN1-related tumors due to mutations in the MEN1 gene are not . In the absence of mutations of the MEN1 gene in patients with phenotypically similar features, this condition is regarded as a phenocopy of this syndrome. The cause of the combination of several MEN-1-related tumors in these patients remains unknown. The possible cause is that changes in the expression of ncRNAs affect the regulation of signaling pathways in which Menin participates and may contribute to the development of MEN-1-related tumors. The identification of even a small number of agents interacting with Menin makes a significant contribution to the improvement of knowledge about its pathophysiological influence and ways of developing tumors within the MEN-1 syndrome and its phenocopies.

BACKGROUND: The registry is the main source of information about patients with acromegaly for assessing the quality of medical care, effectiveness of treatment, determining the compliance of real clinical practice with existing standards and patient management protocols. AIMS: To evaluate epidemiological, demographic and clinical characteristics of acromegaly in Russian Federation and effectiveness of treatment modalities. MATERIALS AND METHODS: The object of the study was the database of the united Russian registry of patients with pituitary tumors with specific analysis of patients with acromegaly only. We analyzed the data of 4114 patients with acromegaly stored on the online system in February 2019. RESULTS: Based on the data 32% of patients had complete clinical and laboratory remission of acromegaly; the percentage of patients with no remission was 68%, among them 22.5% had significant improvements in clinical symptoms and a decrease in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) without IGF-1 normalization. The average age of patients at the onset of the disease was 42.7 years and at diagnosis 45.8 years. The ratio of men to women was 1:2.6. In patients with acromegaly hypopituitarism was registered in 14.7% of cases and among them hypothyroidism (66%) and hypogonadism (52%) were registered more often. Among other complications the leading were diabetes mellitus (15.7%) and acromegalic arthropathy (15%). The proportion of patients receiving neurosurgical treatment increased from 35.7% to 49.6% in 20122019; the portion of patients undergoing radiation therapy decreased significantly from 17.7% in 2012 to 0.8% in 2019. Remission was achieved in 40.47% after neurosurgery and 28.95% after medical treatment as a first line therapy p0.01. The number of patients receiving medical treatment at the time of the study was 1209. Among them 51% of patients treated with long-acting lanreotide and 24% receiving long-acting octreotide achieved remission (p0.0001) CONCLUSIONS: The remission rate of acromegaly remains suboptimal despite increased surgical activity, which corresponds to global trends. Long-acting lanreotide was significantly superior versus long-acting octreotide in the rate of acromegaly remission, which does not correspond with clinical trials.

Hypoparathyroidism and pseudohypoparathyroidism are rare endocrine disorders, characterized by low serum calcium due to inappropriate parathyroid hormone (PTH) levels or resistance to its action. There is little epidemiological information regarding chronic hypoparathyroidism in Russia. This study aims to build a registry database of Russian patients with chronic hypoparathyroidism who were referred for hospital treatment in order to conduct initial analysis of clinical presentations and hospital management. The Italian registry model was taken to be able to integrate our data in the future. Two hundred patients with hypoparathyroidism (n = 194) and pseudohypoparathyroidism (n = 6) were enrolled over 2 years (2017–2019). The most frequent cause of hypoparathyroidism was neck surgery (82.5%, mostly females), followed by idiopathic hypoparathyroidism (10%), syndromic forms of genetic hypoparathyroidism (4.5%) and forms of defective PTH action (3%). Calcium supplements and alfacalcidol were prescribed in most cases. However, a minority of patients (n = 6) needed to receive teriparatide as the only way to maintain calcium levels and to prevent symptoms of hypocalcemia. Consequently, substitution treatment with parathyroid hormone should be available in certain cases of hypoparathyroidism. This database will be useful to estimate the potential requirement for recombinant PTH in Russia and standards for clinical and therapeutic approaches.

In the era of personalized medicine treatment of acromegaly requires the individual selection of optimal treatment based on the measured parameters. Following the standard algorithm for the management of patients with acromegaly with the choice of neurosurgical treatment as the main and somatostatin analogues as the first line of drug therapy with ineffective surgery prevents the achievement of remission in patients resistant to these types of therapy. The introduction of predictive biomarkers in clinical practice will allow to achieve remission of the disease faster and reduce the financial costs of ineffective treatments. We collected information of possible predictive biomarkers in acromegaly from literature. This review presents data from studies of potential predictive biomarkers in different treatments of acromegaly. According to the analysis of publications, the greatest number of results is devoted to the prediction resistance to somatostatin analogues. Reliable biomarkers predicting the inefficiency of somatostatin analogues include low immunoexpression of somatostatin receptors type 2 and AIP protein, rarely granular type of pituitary adenoma and hyperintensive signal on T2-weighted images in magnetic resonance imaging of the pituitary gland. At the same time, the search for predictors of the effectiveness of pegvisomant is focused on the study of the receptor of growth hormone and opens up new opportunities for pharmacogenomic research. Thus, it is necessary to expand the search of predictive biomarkers for different methods of acromegalys treatment. It is especially important to identify biomarkers that do not require mandatory removal of the tumor. Of great interest is the study of epigenetic biomarkers, in particular miRNAs, which carry out post-transcriptional regulation of gene expression. The study of circulating blood microRNAs in acromegaly opens up prospects for the introduction of a personalized approach in the treatment of this disease.

Introduction: Primary hyperparathyroidism (PHPT) is rare and usually symptomatic in children. There is no approved medication to lower serum calcium levels in this patient group. Denosumab is used in adult patients with osteoporosis and hyperparathyroidism. To our knowledge, only 1 case of denosumab treatment in a child with severe PHPT has been reported to date. Case Presentation: A 16-year-old female was referred to our clinic with symptoms including pathologic fractures, nausea, emesis, and progressive weight loss. At admission, her serum total calcium was 4.17 mmol/L (reference range 2.15–2.55), parathyroid hormone 2,151 pg/mL (15–65), and phosphate 1.07 mmol/L (1.45–1.78). Due to potentially life-threatening hypercalcemia, denosumab 60 mg subcutaneously was administered after obtaining informed consent. Serum calcium levels were reduced within 12 h of injection and the patient’s condition rapidly improved, which allowed genetic testing to be done prior to surgery. A heterozygous mutation in the CDC73 gene was revealed, and a parathyroidectomy was performed on day 22 after denosumab administration. Morphological examination revealed solitary parathyroid adenoma. After surgery, hypocalcemia developed requiring high doses of alfacalcidol and calcium supplements. Conclusion: Our case supports the previous observations in adults that denosumab can be safely and effectively used as a preoperative treatment in patients with PHPT and severe hypercalcemia and shows that it may be used in pediatric patients.

Primary hyperparathyroidism is a socially significant problem due to the fact that the analysis of blood calcium in Russia is not a routine biochemical test, and diagnosis is carried out at the stage of irreversible complications. So, a patient addressed to our clinic which had a clinical picture of hyperparathyroidism complications over time. In the hospital diagnostic studies were carried out, including, first of all, a determination of calcium in blood, followed by more comprehensive survey, on the basis of which hyperparathyroidism has been confirmed. An adenoma of the left lower parathyroid gland was found by the method of topical diagnosis (ultrasound of the parathyroid glands and scintigraphy with Tc-99m-technetril). After the surgical treatment a level of calcium and a level of PTH have declined significantly. The combination of calcium and vitamin D supplementation was prescribed about intensive saturation therapy was needed with intense post-operative hyperparathyroidism. Given the existence of osteo-visceral complications by hyperparathyroidism, at the moment the patient needs a long rehabilitation course. This case shows that in order to avoid late diagnostics, it seems necessary to determine the level of calcium for routine. Therefore, it is possible to prevent the development of complications of the disease and the disability of patients.

Raine syndrome is a rare hereditary disease caused by mutations in the FAM20C gene. Only 18 non-lethal cases have been reported, the majority of them being children and young adults aged up to 30. Due to the rarity of the disease, genotype–phenotype correlations are not available and patient life expectancy is unknown, thus making descriptions of each novel case of particular importance. In this article, we describe a case of an Armenian woman, living in Russia, who was followed-up from age 36 to 39, presenting with pain in the extremities, osteosclerosis with periosteal bone formation, multiple calcifications in solid organs, midface hypoplasia, exophthalmos, amelogenesis imperfecta, shortening of distal phalanges, pectus excavatum, and hypophosphatemia due to renal phosphate wasting. Whole exome sequencing was performed on NextSeq 550 (Illumina, USA) and compound heterozygous variants were identified in the FAM20C gene (reference sequence NM_020223): a frameshift insertion c.1107_1108insTACTG (p.Tyr369fs) and a missense substitution c.1375C > G (p.Arg459Gly). This is the first reported case of a middle-aged patient presenting classical symptoms of Raine syndrome caused by novel compound heterozygous mutations in the conserved C-terminal domain of FAM20C gene.

Osteoporosis medications are divided into two groups: those inhibiting bone resorption and formation (bisphosphonates and denosumab), and those stimulating bone formation i.e. having an anabolic effect. The latter include teriparatide, parathyroid hormone 1-84 and abaloparatide, all of which stimulate bone resorption as well as bone formation, which limits their anabolic effect. The discovery of sclerostin – the key inhibitor of bone formation – has led to development of the concept that inhibition of this protein could stimulate bone formation. Romosozumab is a human monoclonal antibody to sclerostin that binds to sclerostin and enables Wnt-signaling pathway ligands and their co-receptors to interact with each other, which, in turn, leads to increased bone formation and bone mineral density. Unlike classical anabolic drugs in osteoporosis treatment, romosozumab stimulates bone formation and inhibits bone resorption. In clinical trials, romosozumab showed marked increase in lumbar spine and hip bone mineral density. Presented article contains information about pre-clinical and clinical studies of romosozumab.

Primary hyperparathyroidism (PHPT) is sporadic in the majority of cases. Hereditary forms of PHPT are rarer, however, they are of particular interest because they allow a deeper understanding of pathogenesis of parathyroid neoplasia. Hereditary forms of PHPT include multiple endocrine neoplasia type 1 (MEN-1), type 2A (MEN-2A), type 4 (MEN-4), hyperparathyroidism-jaw tumour syndrome (HPT-JT), variants of familial hypocalciuric hypercalcemia (FHH) and familial isolated hyperparathyroidism (FIHP). Mutations in the following genes cause the development of MEN-1, MEN-2A, MEN4, HPT-JT: MEN1, RET, CDKN1B, CDC73, respectively. Variants of FHH are caused by mutations in CASR, AP2S1, GNA11. Gene(s) responsible for the development of the majority of FIHP cases remain unknown. Identification of hereditary forms of PHPT is important for patients and their first-degree relatives, as it allows defining the necessity of screening to reveal other components of the syndrome, in some cases determines the surgical approach to PHPT, and the risk of development of the disease in offsprings. This article provides information on hereditary syndromes associated with PHPT and special features of PHPT in each syndrome.

Cushingrsquo;s syndrome accounts for approximately 20ndash;30% of endogenous hypercortisolism cases, and adrenal involvement can be either unilateral or bilateral. Cushingrsquo;s syndrome due to bilateral adrenal tumors is extremely rare. Adrenal oncocytomas are another rare cause of endogenous hypercortisolism: about 13 cases are described in the literature. Oncocytomas are rare epithelial neoplasms, characterized by abnormally excessive accumulation of defective mitochondria in the cytoplasm of cells, and make up 1.8% of all adrenal neoplasms. We describe a 58-year old patient with Cushingrsquo;s syndrome and bilateral adrenal tumors. Multispiral computed tomography of the adrenals showed signs suspicious of lipid-poor atypical adenomas or malignant tumors. Surgical treatment was the method of choice, and the larger tumor was excised first. Due to the absence of remission of endogenous hypercortisolism the excision of the second tumor was performed. Morphological and immunohistochemical examination confirmed the diagnosis of bilateral oncocytic adrenocortical tumors with uncertain malignant potential. Cases of bilateral hormone-producing adrenal oncocytomas have not been described in the literature.

[English] A summary of the draft federal clinical guidelines on osteoporosis developed by members of the Russian Association of Endocrinologists, the Russian Association for Osteoporosis, the Association of Rheumatologists of Russia, the Association of Traumatologists and Orthopedists of Russia, the Russian Association for Menopause and the Russian Association of Gerontologists and Geriatrics is presented. The recommendations were developed from the perspective of evidence-based medicine, in accordance with the requirements for compiling clinical recommendations of the Ministry of Health of Russia published in 2019. A significant place is given to screening of primary osteoporosis in adults, differential diagnosis with other metabolic diseases of the skeleton, modern methods of diagnosing osteoporosis, principles of prescribing pathogenetic treatment, features of sequential and combination therapy, disease prevention and rehabilitation. Clinical recommendations will be useful both to general practitioners and physicians, as well as to narrow specialists, primarily endocrinologists, rheumatologists, orthopedic traumatologists, nephrologists, obstetrician-gynecologists and neurologists, since osteoporosis is a multifactorial and multidisciplinary disease. [Русский] Представлено краткое изложение проекта федеральных клинических рекомендаций по остеопорозу, разработанных членами Российской ассоциации эндокринологов, Российской ассоциации по остеопорозу, Ассоциации ревматологов России, Ассоциации травматологов-ортопедов России, Российской ассоциации по менопаузе и Российской ассоциации геронтологов и гериатров. Рекомендации разработаны с позиций доказательной медицины, в соответствии с требованиями к составлению клинических рекомендаций Минздрава России, опубликованными в 2019 г. Значительное место в изложении отведено скринингу первичного остеопороза у взрослых, дифференциальной диагностике с другими метаболическими заболеваниями скелета, современным методам диагностики остеопороза, принципам назначения патогенетического лечения, особенности последовательной и комбинированной терапии, профилактики заболевания и реабилитации. Клинические рекомендации полезны будут как врачам общей практики и терапевтам, так и узким специалистам, прежде всего эндокринологам, ревматологам, травматологам-ортопедам, нефрологам, акушерам-гинекологам и неврологам, так как остеопороз является мультифакториальным и мультидисциплинарным заболеванием.

Primary hyperparathyroidism (PHPT) is well studied in elderly patients. Studies of PHPT characteristics in children, adolescents, and young adults are rare. In some of these studies, investigators have compared clinical and laboratory characteristics of PHPT between young and elderly patients and revealed several differences. An early onset of PHPT may indicate familial syndromes associated with PHPT. These include: multiple endocrine neoplasia syndrome type 1, type 2A, and type 4, hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, and familial isolated hyperparathyroidism. However, the need for routine genetic tests to exclude these syndromes in all patients with PHPT manifested at a young age is not obvious. To date, there are a few foreign studies on the need for genetic testing in all young patients with PHPT, but their results are controversial. Our review summarizes the data of foreign and Russian studies on characteristics of PHPT in patients with disease onset at a young age.

We present three clinical cases of successful osteoporosis treatment with denosumab in patients with different courses of osteoporosis: postmenopausal with bisphosphonates ineffectiveness, osteoporosis of mixed etiology in patient on thyroid stimulating hormone suppression and aromatase inhibitor therapy and a case of osteoporosis in a male caused by primary hyperparathyroidism. Mechanism of denosumab action is different from bisphosphonates: denosumab prevents osteoclast differentiation by binding to receptor activator of nuclear factor kappa-B ligand (RANKL) and thus suppressing bone resorption. Clinical trials showed that denosumab promotes further increase of bone mineral density after bisphosphonate treatment. Denosumab has been used in Russian Federation since 2012. Clinical effectiveness and safety profile make denosumab one of the first-line drugs for osteoporosis treatment.

Introduction: Multiple endocrine neoplasia type 1 syndrome (MEN 1) is caused by mutations in MEN1 gene, encoding menin protein. A combination of pituitary adenomas (PA) and primary hyperparathyroidism (PHPT) in patients without MEN1 mutations is defined as MEN 1 phenocopy. The aim of the study is to find if there are any differences in menin expression in PA of patients with genetically confirmed MEN 1, MEN 1 phenocopies and sporadic acromegaly. Materials and Methods: Formalin-fixed paraffin-embedded PA tissues were obtained from 9 genetically confirmed MEN 1 patients (group 1), 12 patients with MEN 1 phenocopies (a combination of PA and PHPT) (group 2) and 14 patients with sporadic acromegaly (group 3). The integrity of the tissues was tested by immunohistochemistry (IHC) using antibodies against the nuclear protein Pit-1. MEN1 mutations were confirmed or excluded by Sanger sequencing or by NGS (NextSeq550, Illumina, USA). Expression of menin was assessed using IHC (Anti-Menin antibody — ChIP Grade, Abcam, UK). Results: The distribution of PA by the type of secretion in group 1 was: 3 — ACTH-secreting, 2 — PRL-secreting, 2 — GH+PRL, 1 — TSH+PRL, 1 — ACTH+PRL, 1 — silent gonadotroph adenoma. All 12 PA from group 2 were GH-secreting. All 14 PA in group 3 were GH-secreting without mixed secretion. The median age at the moment of transsphenoidal surgery in group 1 was 35 years [27; 47], in group 2 — 59 years [56; 65], in group 3 — 56 years [53; 62]. There were 2 men and 7 women in group 1; 2 men and 10 women in group 2; 4 men and 10 women in group 3. In group 1 patients did not receive somatostation analogues (SSA), 7 patients received cabergoline. In group 2 seven patients received SSA, in group 3 — 4 patients received SSA, 2 patients received cabergoline. The results of menin staining were (negative staining/positive cytoplasmic staining/positive nuclear staining): group 1 — 4/4/0; group 2 — 0/11/1; group 3 — 1/7/6. Phenocopy group showed significantly more cytoplasmic expression of menin than in MEN 1 group (p Conclusion: Menin expression is generally preserved in PA in MEN 1 phenocopies and sporadic acromegaly, though with different pattern of nuclear and cytoplasmic expression, while its expression varies in PA in MEN 1. These findings suggest that pathogenesis of PA in MEN 1 phenocopies and sporadic acromegaly may have similarities. The mechanisms of co-occurrence of PA and PHPT in MEN 1 phenocopies are poorly understood and epigenetic modifications downstream menin interacting pathways could play a role.

Background Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial. Objective To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age. Design We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome. Methods The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed. Results NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8. Conclusions Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at CDC73 mutations.

Primary hyperparathyroidism (PHT) is the third most common endocrine disorder in men and women after diabetes mellitus and thyroid disease and one of the most frequent causes of osteoporosis and fractures among the secondary osteopathy. PHT refers to socially significant problems in connection with involvement in the pathological process of the majority of organs and system In recent years, the conception of epidemiology, clinic and tactics of management of patients with PHT has changed due to significant increase of morbidity at the expense of identification of mild forms of disease. The modern management concept tactics depends on clinical manifestations. Bearing in mind the importance of the problem under consideration, the working group was set up for the development of federal recommendations on the treatment of PHT based on the principles of evidence-based medicine. The experience accumulated by the domestic and international experts was summarized in the federal clinical guidelines on PHT.

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 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.

Background. Absence of detectable MEN1 mutations in a patient with multiple endocrine neoplasia type 1 (MEN1) phenotype may disprove the hereditary predisposition and the necessity of a lifelong regular screening for detecting the remaining components of the syndrome, and the examination of the first-degree relatives. Nevertheless, there may be other genes involved in the co-occurrence of several MEN1-associated tumors. Aim — to determine the role of genes, associated with the development of familial pituitary adenomas (PA), and genes, presumably involved in pathogenesis of sporadic PA, in the development of MEN1 phenocopies with PA as one of components.Material and methods. 23 patients with MEN1 phenocopy were included in the study. The patients underwent next-generation sequencing (NGS) (Ion TorrentTM PGMTM, Thermo Fisher Scientific — Life Technologies, USA) using a panel of candidate genes (MEN1, CDKN1B, PRKAR1A, AIP, SDHA, SDHB, SDHC, SDHD, GNAS, PRKCA, CDKN2A, CDKN2C, POU1F1, PTTG2).Results. In 1 (4%) female patient with acromegaly and primary hyperparathyroidism (PHPT) a germline heterozygous change in exon 6 of AIP gene c.911G>A (p.R304Q) was revealed. In four female patients with acromegaly and PHPT we revealed polymorphisms whose pathological significance is not defined: heterozygous change in exon 1 of PTTG2 gene c.134G>A (p.R45H), heterozygous change in intron 1 of PRKAR1A gene (c.–10G>C), heterozygous change in exon 5 of SDHB gene c.487T>C (p.S163P), heterozygous change in 3’-UTR of CDKN1B gene g.3897G>T (c*8G>T).Conclusions. The results of our study show that mutations in the majority of the examined genes associated with the development of hereditary and sporadic PA, do not cause the development of MEN1 phenocopies. The necessity to study AIP gene in all patients with MEN1 phenocopies needs further research. It is recommended to search for new genes, mutations in which could be the cause of the development of MEN1 phenocopies.

When primary hyperparathyroidism (PHPT) is diagnosed in a young patient in the absence of other clinical manifestations differential diagnosis between a sporadic form of PHPT and PHPT as the first manifestation of one of hereditary syndromes may be challenging. Diagnosis of sporadic or hereditary PHPT determines the extent of surgical intervention, a strategy for further observation and treatment, and the need for examination and treatment of first-degree relatives. Aim of the study — to determine genetic characteristics of PHPT with manifestation at a young age (A. In 4 (4/40, 10%) patients we revealed germline heterozygous mutations in CDC73 gene: 3 nonsense mutations in patients with parathyroid carcinoma — in exon 3 p.R91X, exon 6 p.Q166X, exon 7 p.R229X, and 1 missense mutation in a patient with parathyroid hyperplasia in exon 8 p.R263C. Conclusions. In the majority of cases (75%) PHPT in young patients without positive family history is sporadic. Search for germline mutations in the genes, leading to development of hereditary forms of PHPT (first of all in MEN1 and CDC73), is appropriate in young patients with positive family history, or when positive family history may be suspected, and in patients with parathyroid carcinoma. In the majority (75%) of FIHP cases search for other, probably yet unknown, genes is necessary.

Aim. To evaluate the renal concentration capacity in patients with mild and severe primary hyperparathyroidism (pHPT). Materials and methods. The study included 77 patients (median age 57 years [52;61]) with pHPT, first group was comprised of patients with mild form (n=23), second group contained patients with severe pHPT without nephrolithiasis (n=28) and the third group contained patients with pHPT and nephrolithiasis (n=26). Osmolality index was calculated as urine osmolality to blood osmolality ratio. Renal concentration capacity impairment was diagnosed with osmolality index less than 2. Results. Osmolality index in patients with pHPT was low with median 1,66 [1,38;2,1]. We found a high prevalence of renal concentration capacity impairment in patients with pHPT, that was 71,4%. Regardless of presence of nephrolithiasis both patients with mild and severe pHPT had similar prevalence (70%, 75% and 69,2% respectively). Conclusions. Renal concentration impairment is common in mild and severe pHPT. The findings of this study necessitate for measurement of urine osmolality or osmolality index in all patients with pHPT. Комбинированную терапию ожирения ( диета , физические нагрузки + прием орлистата ) в течение 7 ± 1 месяцев получали 15 пациентов первой группы ( СОАС ), 5 – во второй ( инсомния ) и 8 пациентов без нарушений сна . При сравнении групп не выявлено статистически значимых различий по числу пациентов , принимающих медикаментозную терапию ожирения ( р < 0,05). Ч ерез 7 ± 1 месяцев лечения ожирения среднее снижение МТ у больных с синдромом инсомнии составило –2,5 [–4; 0] кг , у больных с СОАС –7 [–18; –2] кг , у пациентов без нарушений сна –6,5 [–12; –2,25] кг .

Summary Parathyroid carcinoma is an extremely rare disorder with little treatment options. It could be misdiagnosed in medical centers with little experience in management of such cases. Our clinical case shows that the initial misdiagnosis of a parathyroid carcinoma in a young woman has led to the development of multiple lung metastases, thus making its treatment hardly possible. Initiation of treatment with sorafenib – a multi-kinase inhibitor approved for treatment of different types of cancer but not parathyroid carcinoma – has led to a significant decrease in the size of lung metastases and has prevented the progression of hyperparathyroidism, which is usually severe in cases of parathyroid carcinoma. The detection of a germline CDC73 mutation in this patient has raised additional concerns about the necessity of periodic screening for early detection of renal, jaw and uterine lesions. Learning points: Diagnosis of parathyroid carcinoma may be challenging due to the absence of reliable diagnostic criteria. Thus, thorough histological examination is needed using immunohistochemical staining of resected tissue in suspicious cases. CDC73 genetic testing should be considered in patients with parathyroid carcinoma. Sorafenib may be a promising treatment of patients with parathyroid carcinoma with distant metastases.

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.