Search

CHARGE syndrome is a rare autosomal dominant disease caused by CHD7 gene mutations. Individuals with CHARGE display a wide spectrum of clinical features. It might be presented only as a delay puberty, which does not require any hormone replacement therapy to severe CHARGE phenotype, requiring a multidisciplinary therapeutic approach. Wild spectrum of clinical presentation can be seen even among the patients with identical mutation. Diagnosis might be suspected by a combination of major and minor clinical criteria of this disorder, but molecular genetic analysis is mandatory for final verification. Accurate diagnosis is essential to informing patients about all possible clinical features, reproductive status and choosing the correct treatment approach. The most common endocrine abnormality in patients with CHARGE syndrome is the disturbance in gonadotropins function ranged from delay puberty to persistent hypogonadotropic hypogonadism with different olfactory phenotypes, resulted by specific role of CHD7 in GnRH neuronal embryogenesis.We describe a familial case of CHARGE syndrome with significant intrafamilial clinical heterogeneity due to CHD7 gene mutation.

Summary Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS. Learning points Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood. The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation. The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30. The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible. Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.

One of the variants of congenital dysfunction of the adrenal cortex is a deficiency of the enzyme P450scc, which catalyzes the first stage of steroidogenesis. This is a rare autosomal recessive disease, the classic manifestation of which is primary adrenal insufficiency with a deficiency of gluco-and mineralocorticoids and a violation of the synthesis of sex steroids, which usually leads to a complete lack of masculinization in patients with karyotype 46, XY and hypergonadotropic hypogonadism in both sexes. Previously, it was suggested That p450scc deficiency is incompatible with the normal course of pregnancy, since the enzyme is expressed in the placenta, where it is necessary for the synthesis of progesterone, the main pregnancy hormone, and, consequently, the birth of a child with A p450scc deficiency is impossible. However, the literature describes clinical cases of p450scc deficiency with partially preserved enzyme function, which explains the normal course of pregnancy. Whereas cases of confirmed p450scc deficiency with zero enzyme activity are unique, not being explained until now. We present a description of severe p450scc deficiency in a child born from a dizygotic twin pregnancy in which the second Sib was healthy. It is possible that the preserved hormonal function of the second placenta and (or) treatment with progesterone analogs during gestation contributed to gestation in this rare form of steroidogenesis disorder.

Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder. Main clinical manifestations include recurring pathological fractures and progressive skeletal deformation. Five types of OI are distinguished based on clinical symptoms. In most cases, the disease is caused by mutations in the COL1A1 and COL1A2 genes, leading to a defect of type 1 collagen synthesis, which is the main component of the bone matrix. Up to 5% of patients with OI have a mutation in IFITM5 gene, which leads to the development of OI type V. Approximately 150 cases of the OI type V are described in the literature, and mutation c.-14C T in IFITM5 gene is found in most of the cases. Only 5 patients have a c.119C T: p.S40L.mutation. Pathogenesis of OI type V is not fully understood. It is assumed that mutations in the IFITM5 gene cause impaired osteoblastogenesis, decreased bone mineral density and multiple low-traumatic fractures. There is probably a phenotype-genotypic correlation in cases with different mutations of the IFITM5. However, it is currently difficult to assess the relationship in view of the variability of the characters and the low prevalence of the OI type V. We present the first description in Russia of the clinical case of an adult patient with OI type V due to a rare mutation p.119C T: p.S40L in the IFITM5 gene.

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.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of the adrenal cortex characterized by impairment of cortisol biosynthesis (with possible impairment of aldosterone biosynthesis) and excessive pituitary ACTH release, which promotes oversecretion of intact pathways products: 17-hydroxyprogesterone (17OHP), progesterone, and adrenal androgens – androstendione and testosterone. 21-hydroxylase deficiency, being the most common cause of congenital adrenal hyperplasia is a chronic disorder, that requires life-long glucocorticoid treatment, that aims both to replace cortisol and prevent ACTH-driven androgen excess. Nevertheless, reaching the optimal glucocorticoid dose is challenging because currently available glucocorticoid formulations cannot replicate the physiological circadian rhythm of cortisol secretion. The difficulties in striking the balance between uneffective normalizing of ACTH-level and excess glucocorticoid exposure leads to different abnormalities, that starts to develop at first months of life and progress, frequently gaining especial clinical meaning in adult age. In the present clinical case we introduce 35 years old male patient with salt-wasting form of 21-hydroxylase deficiency, which had either complications considered to progress due to insufficient glucocorticoid therapy, and some metabolic abnormalities, associated with supraphysiological doses of glucocorticoids.

Hypophosphatasia (HPP) is a rare hereditary metabolic disease characterized by defective bone and dental mineralization, systemic complications that lead to disability of patients. HPP is classified into six forms according to the age of onset and severity of its clinical picture. The disease is caused by a reduced activity of the tissue nonspecific alkaline phosphatase (TNSALP) and elevated concentrations of pyrophosphates. Asfotase alfa is the only pathogenetic enzyme replacement therapy with recombinant human bone-targeted TNSALP approved for treatment of patients with perinatal, infantile and juvenile‐onset HPP. This treatment is associated with improved skeletal mineralization, respiratory function and overall survival in infants and young children with life-threatening hypophosphatasia. The world experience in application of recombinant alkaline phosphatase in adults is very limited. We present a clinical case that describes the first Russian experience in the use of asfotase alfa in an 18-year-old patient with late diagnosis of childhood-onset HPP.

Objectives Congenital hyperinsulinism (CHI) is a group of rare genetic disorders characterized by insulin overproduction. CHI causes life-threatening hypoglycemia in neonates and infants. Bloom syndrome is a rare autosomal recessive disorder caused by mutations in the BLM gene resulting in genetic instability and an elevated rate of spontaneous sister chromatid exchanges. It leads to insulin resistance, early-onset diabetes, dyslipidemia, growth delay, immune deficiency and cancer predisposition. Recent studies demonstrate that the BLM gene is highly expressed in pancreatic islet cells and its mutations can alter the expression of other genes which are associated with apoptosis control and cell proliferation. Case presentation A 5-month-old female patient from consanguineous parents presented with drug-resistant CHI and dysmorphic features. Genetic testing revealed a homozygous mutation in the KCNJ11 gene and an additional homozygous mutation in the BLM gene. While 18F-DOPA PET scan images were consistent with a focal CHI form and intraoperative frozen‐section histopathology was consistent with diffuse CHI form, postoperative histopathological examination revealed features of an atypical form. Conclusions In our case, the patient carries two distinct diseases with opposite metabolic phenotypes.

Objective To compare the serum miRNA expression profiles between patients with benign and malignant parathyroid tumours. Background Despite recent advances in molecular biology, a histological tissue biopsy is still the method of choice used to diagnose most cancers. The preoperative cytology is not an applicable method for diagnosis of parathyroid cancer (PC); therefore, huge interest exists in terms of finding alternative methodologies to seek specific cancer biomarkers. Design A retrospective cross‐sectional study. Patients and Methods Serum samples of patients with PC (n = 13) and parathyroid adenoma (PA) (n = 11), age (p = .999) and sex (p = .999) were matched and examined via the simultaneous comparative expression analysis of 754 microRNAs (miRNAs). The «TaqMan OpenArray Human MicroRNA Panel» (Applied Biosystems) was used to conduct real‐time PCRs using the «QuantStudio 12К Flex» station (Life Technologies). Results According to the results of a pilot study, significant changes in expression levels between the PC group and the PA group (control) (p, The main objective of this study was to compare the serum miRNA expression profiles between benign and malignant parathyroid tumors. To the best of our knowledge, this study is the first report on serum miRNA profiles derived from PC patients.

BackgroundThere are very few cases of co-occurring pituitary adenoma (PA) and pheochromocytomas (PCC)/paragangliomas caused by MAX mutations. No cases of familial PA in patients with MAX mutations have been described to date.Case PresentationWe describe a 38-year-old female patient, presenting with clinical and biochemical features of acromegaly and PCC of the left adrenal gland. Whole-exome sequencing was performed [NextSeq550 (Illumina, San Diego, CA, USA)] identifying a nonsense mutation in the MAX gene (NM_002382) [c.223C>T (p.R75X)]. The patient had a medical history of PCC of the right adrenal gland diagnosed aged 21 years and prolactinoma diagnosed aged 25 years. Cabergoline treatment was effective in achieving remission of prolactinoma at age 33 years. The patient’s father who died at age 56 years of a heart attack had a medical history of PA and prominent acromegalic features, which supports the familial presentation of the disease.ConclusionThis clinical case gives an insight into the clinical presentation of familial PA and PCC probably associated with a MAX mutation.

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.

The materials of the National Consensus reflect the modern domestic and international experience on this issue. Before conducting a specialized endocrinological examination of a short child, all other causes of short stature should be excluded: severe somatic diseases in a state of decompensation that can affect growth velocity, congenital systemic skeletal diseases, syndromic short stature (all girls with growth retardation require a mandatory study of karyotype, depending on the presence or absence of phenotypic signs of Turner syndrome), endocrine diseases in decompensation. A specialized examination of the state of GH-IGF-I axis is carried out when the proportionally folded child has pronounced short stature: if the child’s height is < –2.0 SDS, if the difference between the child’s height SDS and child’s midparental height SDS exceeds 1.5 SDS and/or a low growth velocity. The consensus reflects clear criteria for the diagnosis of GH-deficiency, central hypothyroidism, central hypocorticosolism, central hypogonadism, diabetes insipidus, hypoprolactinemia, and also the criteria for their compensation. The dose of somatropin with GH-deficiency in children and adolescents is 0.025–0.033 mg/kg/day. With total somatotropic insufficiency, especially in young children, it is advisable to start therapy with somatropin from lower doses: 25–50% of the substitution, gradually increasing it within 3–6 months to optimal. In children with a growth deficit when entering puberty, the dose may be increased to 0.045–0.05 mg/kg/day. With the development of side effects, the dose of somatropin can be reduced (by 30–50%), or temporarily canceled (depending on the severity of the clinical picture) until the complete disappearance of undesirable symptoms. With swelling of the optic nerve, treatment is temporarily stopped until the picture of the fundus of the eye fully normalizes. If therapy has been temporarily discontinued, treatment is resumed in smaller doses (50% of the initial) with a gradual (within 1–3 months) return to the optimum. GH treatment at pediatric doses not continue beyond attainment of a growth velocity below 2–2.5 cm/year, closure of the epiphyseal growth zones, or earlier, when: the achievement of genetically predicted height, but not more than 170 cm in girls, 180 cm in boys, the patient’s desire and his parents / legal representatives satisfied with the achieved result of the final height. Re-evaluation of the somatotropic axis is carried out after reaching the adult height, after 1–3 months GH therapy will be discontinued. Patients with isolated GH-deficiency or patients with 1 (besides GH) pituitary hormone deficiencies in the presence of a normal IGF-1 level (against the background of somatropin withdrawal) and not having molecular genetic confirmation of the diagnosis need re- evaluation. Patients with two or more (besides GH) pituitary hormone deficiencies, acquired hypothalamic-pituitary lesions due to operations on the pituitary and irradiation of the hypothalamic-pituitary area (if the IGF-1 level is low against somatropin withdrawal), specific pituitary/ hypothalamic structural defect on MRI, gene defects of the GH-IGF-I system do not need re- evaluation. If GH deficiency is confirmed, treatment with somatropin is resumed at metabolic doses of 0.01—0.003 mg/kg/day under the control of the IGF-I level in the blood (measurement 1 time in 6 months), the indicator should not exceed the upper limit of the reference value for the corresponding age and floor.

Background: Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by tissue-nonspecific alkaline phosphatase deficiency, characterized by bone mineralization defects and systemic complications. Understanding of the clinical course and burden of HPP is limited by its rarity. This systematic literature review and synthesis of case report data aimed to determine the frequency and timing of clinical HPP manifestations and events. Methods: Case reports and series of patients with HPP who had been followed longitudinally for ≥1 year were identified. Demographics and clinical data of interest, identified through consultation with clinical experts in HPP, were extracted. Occurrences of clinical manifestations/events of interest were categorized, classified by age at first reported occurrence of HPP manifestations and visualized over time. Clinical manifestations/events considered to contribute to the clinical burden of HPP were identified. Kaplan-Meier curves were used to estimate the median (range) age at first occurrence of the most frequently reported manifestations/events. Results: From the 283 studies that met the inclusion criteria, 265 patients with HPP with ≥1 year of longitudinal follow-up were identified (median [interquartile range] age 4 [0-34] years; 45% male). The types of clinical manifestations/events of interest experienced by individuals with ≥1 such manifestation/event (n = 261) often differed between older and younger patients. Most (94%) of the 265 patients experienced ≥1 manifestation/event deemed to contribute to the clinical burden of HPP; premature tooth loss (53.5%), fractures (35.8%), pain (33.6%), and gross motor/ambulation difficulties (30.9%) were most frequently reported. The median (range) age at first reported occurrence of respiratory symptoms, cranial abnormalities, and premature tooth loss ranged from 0.3 to 10 years, whereas the median age at first reported occurrence of fractures, pain, gross motor/ambulation difficulties, and surgery ranged from 33 to 70 years. Conclusions: HPP is associated with a high clinical burden of disease, regardless of age at first reported occurrence of HPP manifestations. Over an individual's lifetime, the types of manifestations/events experienced can change and multiple HPP-related clinical manifestations/events can accumulate. These observations may reflect evolution and progression of the disease., Funding for the conduct of this study and the development of this manuscript was provided by Alexion Pharmaceuticals, Inc.

Diabetes in pregnancy may be associated with monogenic defects of beta-cell function, frequency of which depends on ethnicity, clinical criteria for selection of patients as well as methods used for genetic analysis. The aim was to evaluate the contribution and molecular spectrum of mutations among genes associated with monogenic diabetes in non-obese Russian patients with diabetes in pregnancy using the next-generation sequencing (NGS). 188 non-obese pregnant women with diabetes during pregnancy were included in the study; among them 57 subjects (30.3%) met the American Diabetes Association (ADA) criteria of preexisting pregestational diabetes (pre-GDM), whereas 131 women (69.7%) fulfilled criteria of gestational diabetes mellitus (GDM). A custom NGS panel targeting 28 diabetes causative genes was used for sequencing. The sequence variants were rated according to the American College of Medical Genetics and Genomics (ACMG) guidelines. In total, 23 pathogenic, 18 likely pathogenic and 16 variants of uncertain significance were identified in 59/188 patients (31.4%). The majority of variants (38/59) were found in GCK gene. No significant differences in the number of variants among the two study groups (pre-GDM and GDM) were observed. The study suggests that frequency of monogenic variants of diabetes might be underestimated, which warrants a broader use of genetic testing, especially in pregnancy.

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.

Context Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. Objective This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases. Design and Setting A multi-institutional case series is presented from tertiary pediatric oncology centers. Patients Patients included children with pituitary blastoma. Interventions Genetic testing, surgery, oncologic therapy, endocrine support are reported. Outcome Measures Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes. Results Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. Conclusions Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.

Hypophosphatemic rickets (HR) - a group of diseases characterized by the development of ricketic changes in bone tissue due to increased excretion of phosphorus from the body. This form of rickets is the most common among variants of genetically determined forms of disturbances in mineral metabolism. HR is an actual medical and social problem, requiring constant updating of knowledge of both endocrinologists and doctors of other profile. This is due to the fact that the clinical picture of HR has a significant heterogeneity and can manifest as severe deformations of the skeleton, delay in physical development, severe muscle hypotension, frequent fractures, tooth abscesses, which in some cases leads to disability of the patient and, accordingly, reduces the quality of life. Timely diagnosis and adequate therapy of HR is extremely important for preventing the development of severe complications. Currently, more than 10 candidate genes are known, the defects in which lead to the development of congenital forms of GFR. Genetic diagnostics of the HR is of great importance for determining the form of the HR, and for carrying out genetic counseling of families when planning pregnancy.

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare disorder characterized of renal phosphate wasting and rickets/osteomalacia. ADHR is caused by mutations in a circulating peptide, fibroblast growth factor 23 (FGF23). The clinical manifestations depend on the age of patients and the importance of hypophosphatemia. In childhood, clinical manifestations are rickets with lower extremity deformities. In adult onset, it can cause osteomalacia, osteoporosis, bone pain, tiredness. ADHR displays incomplete penetrance and variability in age of onset of clinical features. Biochemical and hormonal markers of the disease are hypophosphatemia, hyperphosphaturia, increased alkaline phosphatase level and a normal level of 1,25(OH) 2D. We present the first report a baby with ADHR from Russia which one was found heterozygous for the R179Q mutation in FGF23 gene.

Background. Beta-cell antibody tests are used for the differential diagnosis of diabetes mellitus. They permit to discriminate between the type 1 diabetes (T1D) and non-autoimmune diabetes types. To choose an appropriate test for ruling in or ruling out the T1D a physician needs to know how conclusive test results are. The most powerful estimate of test conclusiveness is its likelihood ratio (LHR). The higher LHR of a positive result (LHR+), the more posttest probability of T1D; the lower LHR of a negative result (LHR−), the less posttest probability of T1D. Aims. To compare conclusiveness of single and combined tests for antibodies to islet cells (ICA), glutamate decarboxylase (GADA), and tyrosine phosphatase IA-2 (IA-2A), and to evaluate posttest probabilities of T1D at various pretest probabilities. Methods. All antibodies were tested in parallel in 169 children and adolescents with a new-onset T1D, and in 169 persons without this disease. ICA, GADA, and IA-2A were determined by indirect immunofluorescence, radioimmune assay, and ELISA, respectively. LHR+ and LHR− were calculated with the MedCalc Statistical Software. Posttest T1D probabilities were calculated from Bayes theorem-based equation. Results. Among single tests, an ICA test had the greatest LHR+ and the smallest LHR−, and consequently was the most reliable either for ruling in or ruling out the T1D. Among test combinations, an ICA&GADA combination had the greatest LHR+ and was the most suitable for T1D confirmation. The triple combination ICA&GADA&IA-2A had the smallest LHR− and was the most suitable for T1D exclusion. Conclusions. In the differential diagnosis of diabetes, the most appropriate test for ruling in the T1D is the double combination ICA&GADA. With both antibodies positive, this combination provides the highest posttest T1D probabilities at any pretest probability. The most appropriate test for ruling out the T1D is the triple combination ICA&GADA&IA-2A. With all three antibodies negative, this combination provides the lowest posttest T1D probabilities.

Background. Gestational diabetes (GDM) due to GCK gene mutations is the most frequent form of monogenic diabetes mellitus (DM) presenting during pregnancy. It has been suggested that the use of insulin in pregnancies with fetuses carrying GCK mutations may lead to intrauterine growth retardation. In the present study we evaluated the effect of insulin therapy during pregnancy on birth weight and length in the offsprings of mothers with GDM due to GCK mutations. Aims. The aim was to study birth weight and length in offsprings of mothers with gestational diabetes mellitus due to mutations in GCK, depending on the therapy during pregnancy. Materials and methods. The study included 38 patients with GDM caused by GCK gene mutations (18.7%) and the 45 offsprings. To define molecular basis of GDM in pregnant women we used a targeted NGS. Diabetes panel genes were sequenced using a custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). To found the same mutations in their offsprings was used Sanger sequencing. All children were divided into 3 groups depending of their genotype and therapy received by the mothers during pregnancy. Results. We found statistically significant differences in birth length (p=0.04) and weight (p=0,031) depending on the genotype of the child and therapy in the mother. The risk of macrosomia was shown in non-mutation-carrying offsprings only. The birth weight in children with GCK gene mutations whose mothers received insulin during pregnancy was significantly lower. However, the birth weight remained in the normal range. Conclusions. Since prenatal diagnostics in the mothers with GCK gene mutations is not always justified, we recommend insulin therapy in order to prevent fetal macrosomia, which, however, should be less aggressive than in GDM due to other causes.

Osteogenesis imperfecta (OI) is a rare heterozygous connective tissue disordercaused by mutations in genes that affect collagen components (in most cases mutations in COL1A1 и COL1A2 genes). The current classification system includes 15 types of OI, one of which (type II) is characterized by 100% intrauterine or perinatal mortality. The structure of mortality in other OI types is poorly understood because of the heterogeneity of clinical symptoms and the severity of connective tissue damage. W present a clinical case of type III osteogenesis imperfecta, complicated by generalized osteoporosis with multiple fractures of vertebrae and tubular bones and progressive kyphoscoliosis. Late-initiated treatment led to progression of the disease and led to cardiopulmonary insufficiency and death of the patient. Our clinical case highlights the importance of timely diagnosis, treatment and regular observation in patients with OI.

Lipodystrophy syndromes form a heterogenous group of inherited or acquired rare disorders, characterized by total (generalized lipodystrophy) or partial fat loss (partial lipodystrophy), usually accompanied by different metabolic disorders. Based on etiology lipodystrophies can be inherited or acquired. As a result of a significant progress in molecular genetics 20 new genes, associated with different lipodystrophy syndromes, were discovered during the last 20 years. However according to the majority of researchers data mutations in these causative genes are not found in approximately half of the patients. This might mean the need for both further molecular-genetic studies and the search for autoimmune factors playing a role in lipodystrophy syndromes etiology.

Osteogenesis imperfecta (OI) and X-linked hypophosphataemia (XLH) are rare genetic diseases, which lead to childhood-onset bone fragility, low-trauma fractures and limb deformities. OI occurs as a result of impaired type 1 collagen synthesis at different stages, depending on the type of a genetic mutation, which leads to bone strength impairment. In most cases OI is a disorder with an autosomal dominant inheritance. However, there are also cases of autosomal recessive inheritance. To date, 16 types of OI are distinguished, with type 2 being the most severe due to 100% mortality rate in neonatal and perinatal periods. XLH is characterized by altered bone mineralization due to impaired phosphorus absorption and reabsorption, as a result of mutations in the PHEX gene. The bone tissue «softens», and this process is accompanied by deformities in long tubular bones. In this article we describe the family, in which both diseases are presented, despite their rarity. The case is investigated from points of view: the clinician’s and the patient’s perspective.

Persistent müllerian duct syndrome (PMDS) is a rare variant of the disorder of sex development (DSD) 46,XY characterized by the presence of Müllerian duct derivatives in 46,XY males. Since cryptorchidism is the only external manifestation of PMDS, until recently, PMDS was not diagnosed in patients and detection of Müllerian duct derivatives during the surgical treatment of cryptorchidism in patients with 46,XY karyotype was regarded as a variant of gonadal dysgenesis, leading to an erroneous choice of treatment strategy in these patients. Only the development of the molecular diagnostics methods, in particular, new generation sequencing, which enable simultaneous investigation of several candidate genes, provided accurate differential diagnosis of the PMDS. This article reports a clinical case of late diagnosis of the familial form of PMDS caused by mutation in the AMH gene. Detected persistent Müllerian derivatives in combination with agenesis of the testicle in the proband at an early age led to the diagnosis gonadal dysgenesis. Given the proven high risk of malignization of the gonads located outside the scrotum in patients with gonadal dysgenesis, the patient underwent removal of the only gonad located in the inguinal canal. The correct diagnosis was established after a comprehensive molecular genetic study using a new generation sequencing with the «disorders of sex development» panel. This study detected a homozygous mutation in the AMH gene.

Wolcott-Rallison syndrome is a rare autosomal recessive disease characterized by neonatal diabetes mellitus in combination with osteodysplasia and liver failure. This disease is the most common cause of neonatal diabetes mellitus in consanguineous families. Wolcott-Rallison syndrome is associated with mutations in the EIF2AK3, the gene encoding a transmembrane enzyme PERK (pancreatic endoplasmic reticulum kinase) which inhibits the synthesis of proteins in the event of misfolding in the endoplasmic reticulum. In addition to the core symptoms patients may develop multisystemic clinical manifestation including acute renal and liver failure, short stature, exocrine pancreatic insufficiency, neuro-motor deficit, hypothyroidism, anemia, neutropenia, recurrent hypoglycemia. The disease is characterized by high mortality, more than 50% of patients die from fulminant liver failure. The awareness of Wolcott-Rallison syndrome is extremely low due to the rarity of detection, however in view of the severity of the disease and the unfavorable prognosis patients with this syndrome require timely diagnosis and care of well-organized team of specialists.

McCune-Albright syndrome (MAS) is a rare genetic disorder which is caused by somatic mutations in the GNAS gene. Clinical symptoms of MAS include café-au-lait skin pigmentation, fibrous dysplasia, and autonomous endocrine hyperfunction. Somatic character of the gene defects determines wide variety of syndrome manifestations, from mild forms with minimum presentation to severe conditions with aggressive course. Potential multicomponent form of the MAS syndrome necessitates the dynamic monitoring, including regular screening for possible components of the disease. Therefore, additional methods specifying the diagnosis of MAS syndrome, especially of its suppressed forms, should facilitate selection of patient management strategy and monitoring rate and/or complete exclusion of the diagnosis. Molecular genetic verification of the diagnosis may be one of these methods. Objective — the study was aimed at evaluating massive parallel sequencing (next generation sequencing, NGS) and real-time polymerase chain reaction using the TaqMan technique for detection of somatic mutations (competitive allele-specific TaqMan PCR, CAST-PCR) in the diagnosis of somatic mutations R201C and R201H in the GNAS gene based on DNA obtained from the peripheral blood. Material and methods. The study included patients diagnosed with and suspected for MAS syndrome. Molecular genetic testing of R201C and R201H mutations in the GNAS gene based on DNA extracted from peripheral blood leukocytes was carried out by Next generation sequencing (NGS) and real-time polymerase chain reaction methods using the TaqMan technique for detection of somatic mutations (competitive allele-specific TaqMan PCR, CAST-PCR). Based on clinical data, patients were divided into groups depending on the severity of the disease and the number of MAS manifestations. The results were evaluated by comparing the rate of detected molecular genetic defects in the formed groups of patients. Results. Molecular genetic study included 39 children with MAS syndrome and 6 children with suspected MAS. R201C and R201H mutations in GNAS gene were detected in 16 patients with severe to moderate MAS 16 (41%) 39. No mutations were detected in other MAS patients and patients with suspected MAS. Conclusion. NGS and CAST-PCR methods can detect the presence of mutant alleles R201C and R201H of GNAS gene in DNA samples obtained from the blood in the case of severe to moderate MAS syndrome, but they cannot be recommended for MAS diagnosis based on the peripheral blood samples in children with mild signs of the syndrome or suspected diagnosis.

Given the limited lifespan and with the recent progress in experimental treatments for WS, timely diagnosis and multidisciplinary treatment for DI/DM, hydronephrosis, and visual/psychiatric status—maintaining quality of life—are of crucial importance.

Background. Tissue repair processes are impaired in diabetic foot ulcers (DFUs). Previous research has shown that glycaemic control, cytokines and growth factors play an important role in wound healing. Emerging evidence also suggests that genes play a role via their regulation of cell proliferation, collagen synthesis and granulation tissue formation. Aim. To evaluate collagen genes expression in different stages of wound healing in patients with DFUs. Materials and methods. Prospective study included four patients with neuropathic DFUs after surgical debridement. Tissue samples were taken for morphological and genetic tests on days 0, 10 and 15 of local treatment to evaluate expression of collagen genes (i.e. COL1A1, COL1A2, COL3A1) and to perform morphological tests. Results. The present study confirmed that the size of wounds decreased by 8.8 ± 7% after 10 days of local treatment and by 18.3 ± 8% after 15 days of local treatment. According to histological examination of wound biopsies at day 10, all patients showed a tendency for lower levels of inflammatory infiltrate, increased number of fibroblast-like cells, presence of maturing granulation tissue and emergence of connective tissue fibres. After 15 days, we detected inflammatory infiltration in the wounds, despite the formation of mature granulation tissue. According to results of genetic analysis on day 10 of local wound treatment, we found a tendency for increased expression of collagen genes relative to the baseline: COL1A1 increased by 3.2 ± 1.3 times, COL1A2 by 2.0 ± 1.0 times and COL3A1 by 1.25 ± 1.1 times. On day 15 of local treatment, in contrast, we found a tendency for decreased expression of COL1A1, COL1A2 and COL3A1 relative to the baseline (1.7 ± 0.6, 2.5 ± 2 and 20.0 ± 3 times, respectively). Conclusions. The expression of collagen genes (COL1A1, COL1A2, COL3A1) is more pronounced in proliferation phase and is subsequently reduced towards the end. These data were confirmed by morphological study and clinical pictures.

Here, we report a clinical case of isolated papillary thyroid cancer associated with a germline DICER1 gene mutation in a boy and his father. The father underwent surgery for a euthyroid multinodular goiter at the age of 7 and 9 years. On examination at the age of 27 years, he was diagnosed with papillary thyroid cancer. At the age of 7 years, the boy was suspected of having a multinodular goiter (based on thyroid ultrasonography findings); he underwent total thyroidectomy. A histological examination of the surgical material revealed encapsulated papillary carcinoma. Neither boy nor his father had been exposed to radiation or chemotherapy before the diagnosis of papillary thyroid cancer. To clarify the etiology of disease, a molecular genetic testing was performed using next-generation sequencing (NGS). The proband and his parent had a heterozygous thymine deletion in the exon 4 at position 380, which led to a shift in the reading frame with the formation of a premature stop codon (c.380delT p.L127QfsX3).

Neonatal diabetes mellitus (NDM) is defined as a heterogeneous group of genetic disorders with onset before 6 months of age. Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of NDM. Accurate molecular diagnosis of NDM has significant clinical importance as it may influence diabetes treatment, explain pleiotropic features and define the prognosis in the examined subject as well as in other family members . In this report we present the results of a genetic examination of 70 patients with NDM, generalized the experience of using sulfonylurea in patients with KCNJ11 and ABCC8 genes mutations for the period from 2009 to 2016. A correlation is shown between the type of mutation, the course of the disease, and the sensitivity of patients to glibenclamide.

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.

Familial glucocorticoid deficiency (FGD, MIM*202200) is a rare form of primary chronic adrenal insufficiency characterized by resistance of the adrenal cortex to ACTH, decrease in secretion of glucocorticoids and adrenal androgens, and increase in plasma ACTH level. Currently, at least 7 genes whose mutations lead to the development of FGD have been described. These are MC2R, MRAP, STAR, CYP11A1, NNT, TXNRD2, and AAAS. E. Meimaridou and J. Kowalczyk were the first who described NNT gene mutation in 2012 in one patient who underwent molecular genetic examination and 9 patients with clinical presentation of familial glucocorticoid deficiency. Understanding of the exact cause of primary chronic adrenal insufficiency enables adjusting the treatment, predicting the development of possible complications and related dysfunctions of other organs, as well as the need for medical and genetic counseling of the family.

Congenital hypothyroidism is a genetically heterogeneous group of diseases caused by two mechanisms: gland dysgenesis and dyshormonogenesis. The disease pattern includes a number of syndromic forms, one of which is a combination of congenital hypothyroidism and sensorineural hearing loss (Pendred syndrome) initially associated with SLC26A4 gene defects. The article describes a patient with clinical manifestations of Pendred syndrome who was diagnosed with a TPO gene defect during a molecular genetic analysis using next generation sequencing (NGS). Therefore, a combination of congenital hypothyroidism and sensorineural hearing loss can have a different molecular basis. Our findings illustrate the value of NGS for genetic verification of the diagnosis.

Rationale. One of the most common causes of multiple anterior pituitary hormone deficiency (MPHD) is genetic defects in the PROP1 gene. PROP1 deficiency leads to malfunction of somatotrophs, lactotrophs, thyrotrophs, corticotrophs, and gonadotrophs. Now, there is an opportunity to conduct large-scale population studies of patients with genetic MPHD, describe their clinical and genetic heterogeneity, and evaluate the efficacy of long-term therapy of these patients with a recombinant growth hormone (rGH). Aim. The study aim was to assess the spectrum of PROP1 gene mutations in the Russian population of MPHD patients, rate and expected age of hypopituitarism components, and efficacy of rGH therapy. Material and methods. We analyzed the data of 27 patients diagnosed with MPHD and genetically confirmed mutations in the PROP1 gene who were treated at the Institute of Pediatric Endocrinology of the Endocrinology Research Center (ERC) in 1978―2016. MPHD was diagnosed based on laboratory data and stimulatory tests characterizing the functional activity of the pituitary gland. The molecular genetic study was performed using high-performance parallel sequencing. We used a custom Ampliseq_HP primer panel developed at the Department of Hereditary Endocrinopathies of the ERC, which included coding regions of the following genes: ARNT2 , GH1 , GHRH , GHRHR , GHSR , GLI2 , HESX1 , LHX3 , LHX4 , OTX2 , PAX6 , POU1F1 , PROP1 , SHH , SOX2 , and SOX3 . All patients received rGH therapy at a growth-stimulating dose from the time of GH deficiency diagnosis until final height completion. We evaluated the efficacy of therapy by comparing the achieved final height with the genetically expected one. Results. Non-familial cases prevailed (N=23) in the study cohort of patients with MPHD caused by mutations in the PROP1 gene; only two patients were monochorionic twin sisters; the other two patients were siblings. An analysis of the distribution of PROP1 gene mutations revealed a hot-point mutation c.301_302delAG in 24 patients (89%, 95% CI 71%; 98%). A mutation in the c.150delA locus occurred in 11 patients (41%, 95% CI 22%; 61%). Two patients had other mutations (c.629delC and c.43_49delGGGCGAG). Total GH deficiency was detected in all patients. The rate of secondary hypothyroidism (SHT) in patients of the study sample was 78% (95% CI 58%; 91%) at the time of diagnosis of GH deficiency and 100% (95% CI 81%; 100%) at the time of final height. The rate of secondary hypogonadism (SHG) at the time of final height was 100% (95% CI 81%; 100%), and the rate of secondary hypocorticism (SHC) was 41% (95% CI 22%; 61%). The normal level of prolactin was detected in 83% (95% CI 65%; 94%) of patients. At the time of growth plate closure, patients receiving rGH therapy at the growth-stimulating dose achieved the genetically expected final height. Conclusion. According to our findings, the most common mutation in the PROP1 gene is a deletion of AG nucleotides in the 101 codon (c.301_302 delAG), which is found in 89% (95% CI 71%; 98) patients. Patients with MPHD caused by mutations in the PROP1 gene have total GH deficiency and are diagnosed with secondary hypothyroidism and secondary hypogonadism in 100% of cases. The possibility of delayed manifestation of hypopituitarism components requires regular screening of tropic hormone levels for the timely start of substitution therapy and prevention of life-threatening conditions. rGH therapy is highly effective for GH deficiency caused by PROP1 gene mutations and allows patients to achieve the genetically expected height in the case of early diagnosis of growth hormone deficiency.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare X-linked disorder of water balance, which was first described in two unrelated male infants with severe symptomatic hyponatremia. NSIAD is caused by activating mutations of the arginine vasopressin receptor 2 (AVPR2) gene, resulting in impaired reabsorption of free water, which leads to increased osmolarity of urine, plasma hypo-osmolarity, and persistent hyponatremia. We report, for the first time in the domestic literature, a case of isolated euvolemic hyposmolality hyponatremia in a child with oligodipsia. Because hypocorticism and renal pathology were excluded, and there was no antidiuretic hormone hypersecretion, NSIAD was suggested. A molecular genetic study revealed a new mutation L312S, not described earlier, in the seventh transmembrane domain of the AVPR2 gene. Pathogenicity of the mutation was proved by a functional study. We provide the clinical and laboratory characteristics of SIAD and the main principles of treatment. This disease should be considered in the differential diagnosis of hyponatremia syndrome.

Congenital hyperinsulinism (CHI) is a rare hereditary disease characterized by hypoglycemia in children during the first year of life. Late diagnosis and inadequate therapy may result in severe neurological complications. Mutations in the GLUD1 gene that encodes glutamate dehydrogenase are one of the causes of CHI. This form of CHI is characterized by protein-induced hyperinsulinemic hypoglycemia and hyperammonemia in patients. Diagnosing can be challenging because hyperinsulinemic hypoglycemia cannot be detected using the conventional fasting glucose test. Extensive examination including the protein load test is needed to refine diagnosis. We report a familial case where the mother and two daughters were diagnosed with CHI and had a mutation in the catalytic domain of the GLUD1 gene. The clinical presentation, the laboratory data, the outcome of therapy, and the dynamic follow up data for the patients are presented.

Currently, many AIP mutations responsible for the development of pituitary adenomas have been described. Penetence of pituitary adenomas in AIP-positive FIPA families is incomplete and varies widely. Data on the characteristics of metabolic changes in patients with familial pituitary adenomas associated with mutations in the AIP gene continues to be inadequate. Evaluation of the results of molecular genetic studies, as well as a thorough analysis of metabolic changes in these clinical cases, will help to develop and improve diagnostic and treatment algorithms, identify patient groups that require special attention of endocrinologists, timely screening, aggressive treatment, and careful dynamic observation.

Vitamin D plays a central role in calcium homeostasis. Impaired degradation of 1,25-dihydroxyvitamin D due to loss-of-function mutations in CYP24A1 leads to significant hypercalcemia, hypercalciuria, suppressed level of parathyroid hormone (PTH), nephrocalcinosis and nephrolithiasis. This condition has been called Idiopathic infantile hypercalcemia. Treatment includes low calcium diet, rehydration, furosemid, avoidance of vitamin D supplements and sun protection. In severe cases glucocorticoids, ketoconazole, bisphosphonates and hemodiafiltration may be used. Early diagnosis of the disease allows to develop an individual plan for managing these patients to prevent the formation of kidney disease, to conduct a genetic family counseling. Here, we describe the cohort of patients (3 children, 2 adults) with significant hypercalcemia due to homo- and compound heterozygous mutations in CYP24A1, describe the main clinical and laboratory characteristics, diagnosis, principles and foundations of the management of patients with this pathology.

SertoliLeydig cell tumor is a rather rare type of ovarian neoplasms belonging to the group of sex cordstromal tumors. This malignancy is characterized by androgen overproduction, which results in the so-called virilization and can be accompanied by various metabolic disorders such as abdominal obesity, disturbances of carbohydrate and protein metabolism, and high blood pressure. During differential diagnosis, it is important to identify the source of androgen overproduction. An androgen-secreting ovarian tumor needs to be differentiated from androgen-secreting adrenal tumor, ovarian stromal thecomatosis (hyperthecosis), and endogenous hypercorticism (the Cushings syndrome). In most cases, the SertoliLeydig cell tumor is associated with DICER1 mutation carriership. If a patient is found to carry the DICER1 mutation, patients relatives need to undergo genetic testing as the individuals with mutations in this gene have an elevated risk of developing a broad range of benign and malignant tumors (most of these tumors are relatively rare in the overall population). The awareness of this rare ovarian neoplasm among medical specialists (obstetriciansgynecologists, endocrinologists, and oncologists) is supposed to ensure timely diagnosis and adequate treatment of this disease.Опухоли из клеток СертолиЛейдига представляют собой довольно редкий вид новообразований яичников, относящихся к группе опухолей полового тяжа. Для данного вида новообразований характерны повышенная продукция андрогенов, приводящая к формированию так называемого вирильного синдрома, а также возможное сочетание с различными метаболическими нарушениями, такими как верхний тип ожирения, нарушения углеводного и белкового обмена, артериальная гипертензия. Важным этапом дифференциально-диагностического поиска является установление источника избыточной продукции андрогенов. Андрогенпродуцирующую опухоль яичника следует дифференцировать с андрогенпродуцирующей опухолью надпочечника, стромальным текоматозом (гипертекозом) яичников, эндогенным гиперкортицизмом (синдромом Кушинга). В большинстве случаев опухоль из клеток СертолиЛейдига ассоциирована с носительством мутации гена DICER1, при выявлении которой необходимо проводить генетическое обследование родственников, так как пациенты с мутациями в этом гене имеют повышенный риск развития широкого спектра доброкачественных и злокачественных опухолей, большинство которых относительно редки в общей популяции. Осведомленность специалистов (акушеров-гинекологов, эндокринологов, онкологов) об этом редко встречающемся новообразовании яичника должна обеспечить своевременную диагностику и адекватное лечение заболевания.

Objective . To estimate performance characteristics and diagnostic value of immunofluorescent islet cell antibody (ICA) assay, immunoradiometric glutamic acid decarboxylase antibody (GADA) assay, and ELISA tyrosine phosphatase IA-2 antibody (IA-2A) and insulin antibody (IA) assays. Research Design and Methods . Antibodies were tested in 438 children and adolescents with newly diagnosed diabetes mellitus (DM) type 1, and in 891 subjects without DM type 1. ICA were determined by the classic indirect immunofluorescent method recommended by the Juvenile Diabetes Foundation International, GADA were determined with the Immunotech IRMA Anti-GAD kit, and IA-2A and IA were determined with Medizym Anti-IA2 and Orgentec Anti-Insulin ELISA kits, respectively. Sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of the tests were estimated with contingency tables. Diagnostic accuracy was estimated from areas under receiver operating curves (AUC). Results . ICA test was of the greatest diagnostic value (Se=88%, Sp=96%, PPV=96%, NPV=94%, AUC=0,94), followed by IA-2A (Se=66%, Sp=98%, PPV=98%, NPV=59%, AUC=0,82) and GADA (Se=73%, Sp=84%, PPV=75%, NPV=83%, AUC=0,79). IA test exhibited a very low Se (4,3%) and lacked diagnostic accuracy (AUC=0,5). Conclusions . We recommend to use ICA, IA-2A and GADA tests surveyed in our study for diagnosis of DM type 1 and differential diagnosis of DM. We don’t recommend IA testing with an Orgentec Anti-Insulin ELISA kit for usage in clinical practice.

MODY (Maturity-Onset diabetes of the young) is a heterogeneous group of disorders characterized by autosomal dominant type of inheritance and caused by genetic defects leading to dysfunction of pancreatic b-cells. Currently 13 candidate genes of MODY, and, respectively, 13 MODY subtypes are known. The final diagnosis can be established only on the basis of molecular genetic studies, which is the «gold standard» in the diagnosis of this disease. MODY2 and MODY3 are the most prevalent subtypes and were previously described in our country. Rare MODY subtypes have not been described in Russian literature. In this article we describe the first diagnosed case of MODY6 in Russia (a defect of the NEUROD1 gene, encoding neurogenic differentiation factor 1, which plays an important role in normal differentiation of β-cells of the pancreas and the regulation of transcription of the insulin gene). Molecular genetic study was conducted using the method of next-generation sequencing, has recently been widely used for genetic verification of monogenic diseases and, in particular, MODY. Technology of next-generation sequencing for diagnosing inherited disorders of carbohydrate metabolism in domestic practice used for the first time.

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.

We describe APS1 in a boy with generalized lipodystrophy, oral candidiasis, autoimmune hepatitis and adrenal insufficiency. It is the first time when generalized lipodystrophy is associated with APS1.

Aim — the present research was aimed at identifying the genetic causes for hr in patients, as well as evaluating the clinical, hormonal and biochemical characteristics of the disease in this group of patients. Material and methods . 75 patients (aged, of 3 months to 57 years; females, n=38; males, n=37) with clinical and radiological findings of rickets, low serum phosphate and low tubular reabsorption of phosphate were included. ‘rickets panel’ genes were sequenced using a custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). The panel included primers for multiplex amplification of 22 genes associated with genetic calcium metabolism dysfunctions. Bioinformatic analysis was performed using torrent suite (Ion Torrent) and ANNOVAR software packages. Results . Out of the 75 patients 36 were diagnosed with familial form of hr, and 39 probands had sporadic cases. Out clinical characteristics the most widespread symptoms of the disease included: lower limbs malformations since the patients started to walk (94.5%), hypotonia in the first 12 months of life (70.2%), multiple caries (58%). Mutations were identified in 100% of familial and 88,5% of sporadic cases. In 68 probands (90,5%) mutations were detected in PHEX , 40 of which were novel. For familial forms of the disease mutations were discovered in 100% cases, for sporadic — in 82% cases. One subject had both DMP1 and PHEX mutations. No mutations were detected in FGF23, SLC34A1, SLC34A3, SLC9A3R1, ENPP1, CLClCN5 and SLC2A2 genes. Conclusion . The study confirmed predominance of PHEX mutations among the patients with HR. The identification of causative agent is very important for antenatal diagnostics for familial forms of disease and enables well-timed conservative treatment.