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Background: Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital hyperinsulinism caused by an activating GLUD1 mutation. Objective: The aim of this study was to determine the clinical profile and long-term neurological outcomes in children with HI/HA syndrome. Method: This study is a retrospective review of patients with GLUD1 mutation, treated at two centers in the UK and Russia, over a 15-year period. Different risk factors for neuro-developmental disorders were analysed by Mann–Whitney U test and Fisher’s exact P test. Results: We identified 25 cases with GLUD1 mutations (12 males). Median age of presentation was 7 months (12 h–18 months). Hypoglycaemic seizures were the presenting feature in 24 (96%) cases. Twenty four cases responded to diazoxide and protein restriction whilst one patient underwent partial pancreatectomy. In total, 13 cases (52%) developed neurodevelopmental manifestations. Epilepsy (n = 9/25, 36%), learning difficulties (n = 8/25, 32%) and speech delay (n = 8/25, 32%) were the most common neurological manifestation. Median age of presentation for epilepsy was 12 months with generalised tonic-clonic seizures being the most common (n = 4/9, 44.4%) followed by absence seizures (n = 3/9, 33.3%). Early age of presentation (P = 0.02), diazoxide dose (P = 0.04) and a mutation in exon 11 or 12 (P = 0.01) were associated with neurological disorder. Conclusion: HI/HA syndrome is associated with wide spectrum of neurological disorders. These neurological manifestations were more frequent in cases with mutations affecting the GTP-binding site of GLUD1 in our cohort.

BackgroundCongenital adrenal hyperplasia (CAH) caused by 3β-HSD deficiency is a rare form of congenital adrenal deficiency with an autosomal recessive type of inheritance. Previously we have demonstrated that a single nucleotide variant (SNV) p.Trp230* in the homozygous state is a frequent cause of CAH among the indigenous population of North Ossetia-Alania represented by Ossetians.MethodsGenotyping of the NM_000198.3:c.690G>A p.Trp230* variant was performed by Real-time PCR. 339 healthy individuals of Ossetian origin were included in the study. Allele frequencies, Fisher’s confidence intervals (CI) were calculated using the WinPepi v. 11.65 software. Comparison of allele frequencies was performed with the z-score test for two proportions.ResultsEight heterozygous carriers of c.690G>A variant in HSD3B2 gene were detected in 339 samples investigated. The total allele frequency of p.Trp230* variant was 0.0118 (n=8/678, 95% CI=0.0051–0.0231). Accordingly, the heterozygous carrier rate was 0.0236 (n=8/339). The frequency of CAH caused by p.Trp230* variant in HSD3B2 in Ossetian population was 1:7183 or 13.9 per 100,000 (95% CI: 1:1874–1:38447 or 3–53 per 100,000).ConclusionThe results demonstrate high frequency of p.Trp230* variant in Ossetians, which is most likely attributed to a founder effect.

BackgroundInsulinomas are very rare in childhood with sparse knowledge on the clinical aspects and the presence of Multiple Endocrine Neoplasia type 1 (MEN1).MethodsWe conducted a retrospective review of patients diagnosed with insulinoma between 1995 and 2021, presenting to one referral centre in Russia. Clinical, biochemical, genetic, imaging and histological data were collected. In addition, follow-up and family data were obtained.ResultsA total of twenty-two children aged 5 to 16 years were identified. The median (range) gap between the first hypoglycaemia symptoms and diagnosis was 10 (1–46) months. Twelve children (55%) were misdiagnosed to have epilepsy and were treated with anticonvulsants before hypoglycemia was revealed. Contrast enhanced MRI and/or CT were accurate to localize the lesion in 82% (n=18). Five patients (23%) had multiple pancreatic lesions. All children underwent surgical treatment. The median (range) diameter of removed tumors was 1.5 (0.3-6) cm. Histopathological studies confirmed the presence of insulinoma in all cases. Immunohistochemical studies revealed G2 differentiation grade in 10 out of 17 cases. Two patients were diagnosed with metastatic insulinoma. One of them had metastases at the time of insulinoma diagnosis, while the other was diagnosed with liver metastases eight years after the surgery. Eight children (36%) were found to carry MEN1 mutations, inherited n=5, de novo n=1, no data, n=2. Children with MEN1 had significantly higher number of pancreatic tumors compared to sporadic cases. All of them developed additional MEN1 symptoms during the following 2-13 years. In the five patients with inherited MEN1, seven family members had hitherto undiscovered MEN1 manifestations.ConclusionsIn this large cohort of children with rare pediatric insulinomas, MEN1 syndrome and G2 tumors were frequent, as well as hitherto undiscovered MEN1 manifestations in family members. Our data emphasize the need of genetic testing in all children with insulinoma and their relatives, even in the absence of any other features, as well as the importance of a prolonged follow-up observation.

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.

Abstract Background Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the lack of adipose tissue and metabolic complications with predominantly autosomal recessive inheritance. There are 6 different genes known to cause CGL with 4 main types recognized to date, which differ by the degree of fat loss, association with mental retardation and metabolic disorders, with CGL type 1 and 2 being the most common. Twenty seven cases of СGL type 4 from Japan, Oman, UK, Turkey, Mexico, Saudi Arabia, USA were reported previously. This report details our clinical experience with the first patient from Russia with CGL type 4. Case presentation A 36-year-old patient, who has been suffering from generalized lipoatrophy since the first months of life and myopathy and gastrointestinal dysmotility since early childhood, developed dysmenorrhea and diabetes mellitus at the age of 19, bilateral cataracts when she was only 22 y.o., osteoporosis with vitamin D deficiency and hypocalcemia at the age of 28, diabetic foot syndrome and hyperuricemia when she was 35 y.o. Sequencing of lipodystrophy candidate genes detected a novel pathogenic homozygous variant p.631G

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.

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.

Abstract 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

One of the causes of diabetes in infants is the defect of the insulin gene (INS). Gene mutations can lead to proinsulin misfolding, an increased endoplasmic reticulum (ER) stress and possible beta-cell apoptosis. In humans, the mechanisms underlying beta-cell failure remain unclear. We generated induced pluripotent stem cells (iPSCs) from a patient diagnosed with neonatal diabetes mellitus carrying the INS mutation in the 2nd intron (c.188-31G>A) and engineered isogenic CRISPR/Cas9 mutation-corrected cell lines. Differentiation into beta-like cells demonstrated that mutation led to the emergence of an ectopic splice site within the INS and appearance of the abnormal RNA transcript. Isogenic iPSC lines differentiated into beta-like cells showed a clear difference in formation of organoids at pancreatic progenitor stage of differentiation. Moreover, MIN6 insulinoma cell line expressing mutated cDNA demonstrated significant decrease in proliferation capacity and activation of ER stress and unfolded protein response (UPR)-associated genes. These findings shed light on the mechanism underlying the pathogenesis of monogenic diabetes.

Neonatal severe primary hyperparathyroidism (NSHPT) is a rare autosomal recessive disorder of calcium homeostasis that manifests shortly after birth with hypercalcemia and bone disease. NSHPT, in most cases, is attributed to mutations in the calcium-sensing receptor (CASR) gene. We reprogrammed dermal fibroblasts derived from a patient with NSHPT carrying a compound heterozygous mutation in the CASR gene into induced pluripotent stem cells (iPSCs). The established iPSCs expressed pluripotency markers, maintained normal karyotype and differentiated into all three germ layers. This line is a valuable resource for modeling of hyperparathyroidism related to CASR mutations.

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.

Abstract 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.

The diagnosis of MODY as a subtype of gestational diabetes mellitus (GDM) is important for an adequate management during pregnancy and the postnatal period. The present report describes a case of GDM caused by a synonymous с.666C>G р.V222V substitution in the GCK gene. The variant, which was initially ranked as ‘likely benign’, was later proven to be pathogenic by in vitro studies. The с.666C>G substitution led to the use of a new donor splice site and synthesis of the aberrant mRNA with deletion of 16 base pairs. The case illustrates that additional clinical and experimental data may be required for the correct interpretation of sequence variants pathogenicity.

Abstract 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.

Insulin gene (INS) mutations prove to be the second most common cause of permanent neonatal diabetes. Here, we report the generation of iPSC line from a patient, heterozygous for the intronic INS mutation that presumably leads to aberrant splicing. Dermal fibroblasts were reprogrammed using non-integrating RNA-based vector. Derivation and expansion of iPSCs were performed under feeder-free culture conditions. The iPSC line expressed pluripotency markers, had normal karyotype, could differentiate into three germ layers in vitro and retained the disease mutation. This line can be a powerful tool for modeling of diabetes and cell replacement therapy as well.

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.

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.

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.

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 clinicians and the patients perspective.

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.

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.

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.

Maturity-onset diabetes of the young (MODY) is a heterogeneous group of disorders characterised by autosomal dominant type of inheritance and caused by genetic defects leading to dysfunction of pancreatic beta-cells. To date, at least 13 subtypes of MODY have been described in the literature, the most frequent of which are MODY types 1–3. MODY2 and MODY3 are the most prevalent subtypes, and were previously described in our country, Russia. Several cases of rare MODY subtypes were subsequently described in the Russian literature. The current report is the first in the Russian literature to present clinical and molecular genetic characteristics of two cases of another rare MODY subtype—MODY9. This type of MODY is associated with mutations in the PAX4 gene, which encodes transcription factor PAX4, one of the factors essential for pancreatic beta-cell differentiation. Molecular genetic analysis was performed using next-generation sequencing, a new method recently applied to verify monogenic diseases and, in particular, MODY. This study reports a novel mutation in the PAX4 gene in MODY patients.

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

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.

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.

Background. Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. Recently, the role of melatonin in the pathogenesis of this syndrome became widely discussed among the scientists, because there is an evidence of its impact on the reproductive function and maturation of oocytes.Aim. To study a informativeness of melatonin determination and its relationship with sleep disorders in PCOS.Materials and methods. The study involved 120 women aged 17–35 years: 60 patients with PCOS and 60 women without this disorder as controls. The level of melatonin in the blood, saliva and its metabolite in urine – 6 sulfatoximelatonin were analyzed. To identify sleep disorders survey was conducted using a questionnaire scoring subjective sleep characteristics.Results. Sleep disorders based on subjective scoring profiles sleep characteristics were identified in PCOS group (up to 70% of patients) regardless of BMI. The level of 6-sulfatoximelatonin in urine, nocturnal melatonin levels in saliva (at 3:00 AM) and melatonin in the blood were significantly higher in patients with PCOS compared with the control group regardless of BMI. The level of melatonin in follicular fluid was lower in patients with PCOS. There was a significant correlation of melatonin levels in the blood and the degree of sleep disorders according to the questionnaire scoring subjective sleep characteristics, the level of melatonin in saliva at 3:00 AM and a 6-sulfatoximelatonin in daily urine (p = 0.046).Conclusions. PCOS is polyetiology disease, and an important role in the formation and progression in which plays melatonin. Correlation of levels of this hormone in different body fluids suggests its systemic action and direct involvement in the regulation of reproductive function.

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.

Two female dizygotic twins with subclinical primary hypothyroidism due to homozygous p.R450H mutation in TSHR gene are presented. A 5-year follow-up in both cases showed no progression of thyroid dysfunction. Indications for levothyroxine replacement in subclinical hypothyroidism are discussed.

OBJECTIVE:Results of the screening of disease causative mutations in congenital hypothyroidism (CH) vary significantly, depending on the sequence strategy, patients' inclusion criteria and bioinformatics. The objective was to study the molecular basis of severe congenital hypothyroidism, using the next generation sequencing (NGS) and the recent guidelines for assessment of sequence variants. DESIGN:243 patients with CH (TSH levels at neonatal screening or retesting greater than 90 mU/l) and 56 control subjects were included in the study. METHODS:A custom NGS panel targeting 12 CH causative genes was used for sequencing. The sequence variants were rated according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS:In total, 48 pathogenic, 7 likely pathogenic and 57 variants of uncertain significance were identified in 92/243 patients (37.9%), while 4 variants of uncertain significance were found in 4/56 control subjects (7.1%). 13.1% (12/92) of the cases showed variants in 'thyroid dysgenesis' (TD) genes: TSHR, n = 6; NKX2-1, n = 2; NKX2-5, n = 1; PAX8, n = 3. The variants in 'dyshormonogenesis' (DH) genes were found in 84.8% (78/92) of cases: TPO, n = 30; DUOX2, n = 24; TG, n = 8; SLC5A5, n = 3; SLC26A4, n = 6; IYD, n = 1. 8 patients showed oligonenic variants. The majority of variants identified in DH genes were monoallelic. CONCLUSIONS:In contrast to earlier studies demonstrating the predominance of TD in severe CH, the majority of variants identified in our study were in DH genes. A large proportion of monoallelic variants detected among DH genes suggests that non-mendelian mechanisms may play a role in the development of CH.