[Hyperparathyroidism of different genesis in young patients with Turner syndrome: case series and brief review].

Hyperparathyroidism is a syndrome characterized by an excessive secretion of parathyroid hormone. Etiologically, hyperparathyroidism is subdivided into primary hyperparathyroidism, which develops as a result of parathyroid adenoma, carcinoma or hyperplasia, and secondary hyperparathyroidism, which happens as a compensatory response to a hypocalcemia caused by condition outside the parathyroid glands. Turner syndrome may also be accompanied by mineral metabolism disorders of various etiology. An association of hyperparathyroidism and Turner syndrome is interesting because of multifactorial impact on bone mineral density, but only few cases of such coexistence have been previously described in the literature. This article describes two patients with Turner syndrome and hyperparathyroidism of different etiology. Hyperparathyroidism, normocalcemia, vitamin D deficiency, osteoporosis, parathyroid tumors were found in both cases. In one case a number of assays was performed to confirm the patient's normocalcemic primary hyperparathyroidism, and surgery was performed to achieve remission. In the second case, treatment of vitamin D deficiency resulted in normalization of serum concentration of parathormone, after which the patient was prescribed antiresorptive therapy. The pathogenetic association between Turner syndrome and hyperparathyroidism requires further investigation. Comprehensive approach to the diagnosis and treatment of mineral metabolism disorders are essential for patients with coexistence of these two diseases.

[Predicting the presence of MEN1 gene mutation based on the clinical phenotype of patients with primary hyperparathyroidism].

BACKGROUND: Timely referral of patients for genetic testing to rule out MEN1-associated primary PHPT is important factor in determining treatment strategy and prognosis. In the context of the limited availability of genetic testing, the search for clinical markers indicative of MEN1 gene mutations remains an extremely relevant task. AIM: To determine the diagnostic value of clinical features of primary PHPT in young patients for predicting the presence of MEN1 gene mutations. MATERIALS AND METHODS: A single-center, prospective study was conducted at the Endocrinology Research Centre, involving 273 patients with PHPT in the period 2015-2022. Based on the results of genetic and laboratory tests, patients were divided into three groups: those with MEN1 gene mutations (MEN+ group, n=71), those without MEN1 gene mutations - isolated sporadic PHPT (MEN- group, n=158), and patients with PHPT and associated endocrine gland disorders - MEN-1 syndrome phenocopies (PHEN group, n=32). Subgroups of patients younger than 40 years of age were also identified. Comparative analysis was performed among the independent groups and subgroups, and logistic regression analysis was used to develop a mathematical model for predicting the probability of the presence of MEN1 gene mutation. RESULTS: Patients in the MEN+ and MEN- groups were comparable by gender and age at manifestation, as well as calcium-phosphorus metabolism parameters and PHPT complications. In the PHEN group, PHPT manifested at older age compared to the other groups (p<0.001 for all), with lower total calcium levels and a trend toward lower iPTH concentrations. The MEN+ group had a significantly higher frequency of multiglandular parathyroid (PG) involvement, PHPT recurrence, and positive family history compared to the MEN- and PHEN groups. Histologically, adenomas predominated in the PHEN and MEN- groups (92% and 94%, respectively), whereas hyperplasia of PGs were more common in the MEN+ group (49%). None of the PHEN patients had all three «classic¼ components of the MEN-1 syndrome, and the clinical course of PHPT was similar to that of the MEN- group. These differences were also observed in the subgroups of patients younger than 40 years, which formed the basis for the development of a mathematical model. The logistic regression equation for predicting the probability of the presence of the MEN1 gene mutation included eight predictors, with a diagnostic sensitivity of 96% and specificity of 98%. CONCLUSION: Based on the analysis performed, eight hereditary predictors of PHPT within the MEN-1 syndrome were identified. A mathematical model was developed to predict the presence of the MEN1 gene mutation in patients, which demonstrated high classification performance on the training dataset. Further refinement of the model will help improve the quality of medical care for patients with PHPT.

[Dynamics the parameters of mineral metabolism in hospitalized patients with COVID-19, the impact of etiotropic and pathogenetic therapy].

The high prevalence of COVID-19 requires the research progress on the disease pathogenesis. There is a lot of data confirming the association between mineral metabolism and the severity of COVID-19. AIM: To study the dynamics of mineral metabolism parameters in patients with a confirmed COVID-19 at the time of hospitalization and after discharge, including the impact of etiotropic and pathogenetic therapy on them. MATERIALS AND METHODS: A single-center study of 106 patients (aged ≥18 years) with clinically or laboratory confirmed diagnosis of COVID-19 was carried out at the Endocrinology Research Centre, Moscow. Baseline biochemical parameters, including serum calcium, phosphorus, albumin, 25(OH)D, parathyroid hormone (PTH), inflammatory markers, and instrumental assessment of COVID-19 severity were performed before specific immunotherapy, as well as on 3rd and 7th days of hospitalization and before discharge. Statistical analysis was performed with Statistica 13 software (StatSoft, USA). RESULTS: On the first day, hypocalcemia (low albumin-adjusted calcium level) was detected in 40.6% of cases, the prevalence of vitamin D deficiency/insufficiency amounted to 95.3% of cases. At the same time, secondary hyperparathyroidism was identified only in 14.2% of patients. A comparative analysis of mineral metabolism during hospitalization (between 1, 3, 7 days of hospitalization and before discharge) during baricitinib treatment revealed a statistically significant increase in albumin-adjusted calcium by the end of hospitalization (p<0.001, Friedman criterion, Bonferroni correction p0=0.01). A pairwise comparison of subgroups, depending on the therapy, revealed a statistically significantly lower level of albumin-adjusted calcium on 3rd day among patients on baricitinib monotherapy or combined with tocilizumab compared with a subgroup of patients undergoing etiotropic treatment (2.16 [2.13; 2.18] mmol/l vs 2.23 [2.19; 2.28] mmol/l, p=0.002, U-test, Bonferroni correction p0=0.012). CONCLUSION: Patients with severe coronavirus infection are characterized by a high prevalence of vitamin D deficiency and hypocalcemia. Associations between calcium and saturation as well as the severity of lung lesion characterizes hypocalcemia as an important predictor of severe course and poor outcome in COVID-19. Pathogenetic therapy with baricitinib, including in combination with tocilizumab, contributes to achieve normocalcemia, but further studies are required.

[The short test with hydrochlorothiazide in differential diagnosis between primary normocalcemic and secondary hyperparathyroidism for inpatient treatment].

BACKGROUND: Differential diagnosis between the normocalcemic primary hyperparathyroidism (nPHPT) and secondary hyperparathyroidism (SHPT) due to hypercalciuria remains a challenge. AIM: The aim of this study was to investigate the capability of short test with hydrochlorothiazide for the differential diagnosis of nPHPT and SHPT. MATERIALS AND METHODS: A retrospective study was conducted with the participation of 28 patients who underwent a functional test with thiazide diuretics during hospitalization in the Department of parathyroid glands pathology and mineral disorders of the Endocrinology Research Centre, Russia. Parameters of mineral metabolism were evaluated before and 3-5 days after taking hydrochlorothiazide 50 mg/day. RESULTS: According to baseline and dynamic biochemical evaluation patients were divided into 3 groups. Group 1 (n=21) included patients with confirmed PHPT, who reached hypercalcemia accompanying with an elevated level of iPTH (n=19) or an increased level of iPTH accompanying with normocalcemia (n=2). In group 1, baseline Caadj. was 2.48 mmol/l [2.47; 2.52], iPTH 107.5 pg/ml [86.8; 133.0], after short test - 2.63 mmol/l [2.59; 2.66] and 102.1 pg/ml [95,7; 124,1]. Group 2 included only one who was diagnosed with SHPT, a normal value of iPTH with concomitant normocalcemia was achieved after 4 days of hydrochlorothiazide therapy (baseline Caadj. 2.35 mmol/l, iPTH 74.5 pg/ml vs at 2.27 mmol/l and 50.7 pg/ml respectively). Patients with doubtful results of the test entered in group 3 (n=6), they did not achieve significant changes in the calcium and iPTH levels, so it was recommended to continue the test on an outpatient basis (baseline Caadj. 2.39 mmol/l [2.33;2.45], iPTH 97.0 pg/ml [83.1;117.0]); after short test - 2.47 mmol/l [2.42; 2.48] and 91.3 pg/ml [86.9; 124.0] respectively). Groups with PHPT and SHPT and doubtful results significantly differed from each other in Caadj (р=0.003, U-test, Bonferroni correction Р0=0.006), but not in iPTH, daily calciuria, eGFR, and phosphorus. There were no significant differences in the incidence of classical complications of PHPT. CONCLUSION: The diagnosis of PHPT was confirmed in 21/28 patients 3-5 days after taking hydrochlorothiazide 50 mg/day. The obtained results are significant for the differential diagnosis in hospitalized patients with an unspecified genesis of hyperparathyroidism.

[Severe bone complications of primary hyperparathyroidism in a young patient with the rare verified mutation of MEN1].

Multiple endocrine neoplasia type 1 syndrome (MEN1) is a rare inherited disorder that can include combinations of more than 20 endocrine and non-endocrine tumors. Unfortunately, none of the described MEN1 mutations has been associated with a peculiar clinical phenotype, even within members of the same family, thus a genotype-to-phenotype correlation does not exist. MEN1 syndrome is the most common cause of hereditary primary hyperparathyroidism (PHPT), the disease penetrance of which exceeds 50% by the age of 20 and reaches 95% by the age of 40. At the same time, PHPT with hyperplasia or adenomas of the parathyroid glands (PTG) is the most distinctive manifestation of the MEN1 syndrome. One of the main symptoms of PHPT, both in sporadic and hereditary forms of the disease, is bone damage. At the time of diagnosis in PHPT/MEN1, the bone mineral density is generally lower in comparison with the sporadic form of PHPT. This may be due to excessive secretion of parathyroid hormone during the period of peak bone mass, concomitant components of the syndrome, extended surgical treatment, and the direct effect of a mutation in the menin gene on bone remodeling. This clinical case describes a young patient with severe bone complications of PHPT and uncertain rare MEN1 mutation. PHPT was diagnosed five years later from the first onset of bone complications and repeated orthopedic operations. There was the «hungry bones¼ syndrome after successful surgery of PHPT, which was managed with vitamin D and calcium carbonate supplementation and there is a positive dynamic in increased bone mineral density in the main skeleton after 6 months.

[Sporadic primary hyperparathyroidism with multiple parathyroid adenomas].

Multiple lesions of the parathyroid glands (PTG) in primary hyperparathyroidism (PHPT) can be sporadic or develop as part of hereditary syndromes, manifesting at young age. There the description of a severe sporadic PHPT with big parathyroid neoplasms in the young patient is presented. Clinical data made it possible to suspect MEN-1 syndrome or parathyroid carcinomas; however, mutations CDKN, CDC73, MEN1 were excluded. The patient underwent removal of three identified tumors: benign adenomas of the left PTG and hyperplasia of the right one. Postoperative hypocalcemia and severe hungry bone syndrome required the administration of vitamin D and calcium carbonate preparations. However, a year after the operation, a «mild¼ recurrent disease was confirmed. Taking into account the patient's refusal to reoperation and a significant improvement of the target organs state, active observation was continued. The patient needs further careful dynamic monitoring by specialists in order to timely identify indications for repeated surgical treatment to improve the life quality and span.

[Mineral metabolism and COVID-19: is there a connection?]

Due to global spread of COVID-19, the search for new factors that could influence its clinical course becomes highly important. This review summarize the relevant publications on the association between immune system and the main regulators of mineral homeostasis including. In addition, we have highlighted the various aspects of phosphorus-calcium metabolism related to the acute respiratory diseases and in particular to COVID-19. The data about the calcium-phosphorus metabolism in SARS-CoV-2 infection is required to understand the possible clinical implications and to develop new therapeutic and preventive interventions.

[A series of clinical cases of familial hypocalciuric hypercalcemia syndrome].

Familial hypocalciuric hypercalcemia (FHH) - rare disease with predominantly autosomal dominant inheritance. FHH typically develops due to a heterozygous inactivating mutation in the calcium-sensitive receptor gene (CASR), less commonly due to heterozygous mutations in GNA11 and AP2S1. CASR mutations lead to an increase in the threshold for calcium sensitivity, which requires a higher concentration in serum to reduce the release of PTH. These changes are accompanied by an increase of calcium and magnesium reabsorption in the proximal tubules, which leads to hypercalcemia and hypocalciuria. Basically, FHH may be asymptomatic or accompanied by mild hypercalcemia. FHH doesn't require surgical treatment, unlike primary hyperparathyroidism (PHPT), therefore, differential diagnosis of these two conditions is extremely important. In addition, immediate relatives of a proband with FHH also require the exclusion of disease inheritance. We analyzed a series of clinical cases with a genetically confirmed diagnosis of FHH. Our clinical cases indicate a variety of clinical manifestations and the difficulties of differential diagnosis with PHPT.

[Dynamic changes of renin-angiotensin-aldosterone system parameters after surgery of primary hyperparathyroidism].

AIM: To study an activity of the Renin-Angiotensin-Aldosterone System (RAAS) components in patients with primary hyperparathyroidism (PHPT) before and after parathyroidectomy (PTE). MATERIALS AND METHODS: A comparative study of patients with PHPT and control group. The first stage of the study included 56 patients with PHPT (group 1) before and on the third day after PTE. The second stage was carried out in 27 patients with remission of PHPT (group 2). All patients and healthy volunteers were tested for the main parameters of phosphorus-calcium metabolism and the RAAS parameters (plasma renin activity PRA, serum aldosterone, angiotensin II AT II). RESULTS: Patients with active PHPT demonstrated changes in RAAS activity (lower PRA, higher AT II level) comparing to control group, that have statistical significance in group 1 (p0.001 for both parameters). There were no significant differences in aldosterone levels (p1=0.090;p2=0.140). On the third day after PTE (group 1), a decrease in aldosterone level (p=0.009) and a tendency to decrease in PRA (p=0.030) were detected. However, an increase in PRA (p=0.018), a decrease in AT II concentration (p=0.032) comparing to the initial values and their normalization were observed 12 months after surgery when permanent normal serum calcium and PTH levels had been achieved. There were controversial correlations between the parameters of phosphorus-calcium metabolism and RAAS. The influence of angiotensin-converting-enzyme inhibitors and AT II receptor blockers on phosphorus-calcium metabolism in patients with PHPT was not observed. CONCLUSION: In patients with PHPT, there were no сlear correlations of phosphorus-calcium metabolism parameters with RAAS, however an increase of AT II concentration was noted, that can take part in a development of hypertension for this endocrinopathy. PTE can have a positive effect on AT II level.

[Ectopic ACTH-syndrome caused by neuroendocrine tumor of lung]. / AKTG-éktopicheskii sindrom pri neiroéndokrinnoi opukholi legkogo.

Ectopic ACTH-syndrome is a relatively rare neuroendocrine disease. It is characterized by hypercortisolemia-associated severe complications that justifies need for timely diagnosis and radical therapy. Case report of young patient with ACTH-producing lung tumor is presented. There was 1-year diagnostic search on background of endogenous hypercorticism. Treatment resulted severe postoperative adrenal insufficiency that demonstrates current difficulties in management of these patients.