Proteomics of urinary small extracellular vesicles in early diagnosis of kidney diseases in children-expectations and limitations.

The primary function of the kidneys is to maintain systemic homeostasis (disruption of renal structure and function results in multilevel impairment of body function). Kidney diseases are characterized by a chronic, progressive course and may result in the development of chronic kidney disease (CKD). Evaluation of the composition of the proteome of urinary small extracellular vesicles (sEVs) as a so-called liquid biopsy is a promising new research direction. Knowing the composition of sEV could allow localization of cellular changes in specific sections of the nephron or the interstitial tissue before fixed changes, detectable only at an advanced stage of the disease, occur. Research is currently underway on the role of sEVs in the diagnosis and monitoring of many disease entities. Reports in the literature on the subject include: diabetic nephropathy, focal glomerulosclerosis in the course of glomerulopathies, renal fibrosis of various etiologies. Studies on pediatric patients are still few, involving piloting if small groups of patients without validation studies. Here, we review the literature addressing the use of sEV for diagnosis of the most common urinary disorders in children. We evaluate the clinical utility and define limitations of markers present in sEV as potential liquid biopsy.

Presence of tubuloreticular inclusions in ultrastructural studies of renal biopsies in children with lupus nephropathy - one-center preliminary study.

Introduction: Juvenile systemic lupus erythematosus (jSLE) is an autoimmune disease that develops as a result of multi-level immune dysregulation, including the interferon pathway. Nephropathy develops at an early stage and eventually affects 90% of patients. A renal biopsy allows one to classify lupus nephritis and determine the proper treatment. Biopsy assessment should be done not only in a light microscope but also in a transmission electron microscope (TEM). Its usage may reveal the presence of intracellular tubuloreticular inclusions (TRIs), considered as a morphological marker of interferon hyperactivity. Material and methods: Renal biopsies of 10 children with jSLE and nephropathy were analyzed in TEM. The location, structure, and size of TRIs were assessed. Demographic data, nephropathy manifestation, non-renal symptoms, and serological activity of lupus were analyzed. Results: All the patients were female with an average onset at 12.7 years of age and met SLE criteria. Nephropathy manifested with proteinuria (n = 10) and hematuria (n = 6). Glomerular filtration rate (GFR) was normal in all patients. In three children with early disease onset, it manifested with hematological disorders. TRIs were revealed in 7 biopsies, with the highest expression in the youngest children, with peripheral cytopenia, membranous glomerulonephritis, and lupus nephritis. Conclusions: Demonstration of TRIs in renal biopsies of children with juvenile systemic lupus may confirm the diagnosis of lupus nephritis and is a sign of involvement of the interferon pathway at the early stage of the disease.

The role of assessment of renal biopsy in electron microscopy in making a diagnosis of juvenile-onset systemic lupus erythematosus in a 16-year-old female patient with depression and proteinuria - a case report.

The course of juvenile-onset systemic lupus erythematosus may vary, from rapid multiorgan involvement to insidious development mimicking different medical conditions. Depressive disorder in adolescents poses considerable diagnostic difficulties due to the natural tendency to lowered mood in this age group. However, it may also be the manifestation of a systemic disease. We present a case of a 16-year-old female patient without any somatic symptoms in whom severe depression resistant to treatment was the preceding symptom of juvenile-onset systemic lupus erythematosus (jSLE). Because of isolated proteinuria and presence of antinuclear antibodies, renal biopsy was performed. Light microscopy showed only findings characteristic for membranous nephropathy. Examination on electron microscopy showed characteristic tubuloreticular inclusions (TRIs) which were crucial for making the diagnosis of systemic lupus erythematosus. The evaluation of renal biopsy specimens by electron microscopy could be a useful diagnostic step to confirm the diagnosis, especially in difficult cases where the criteria for SLE are not fully met. The association of mental symptoms with systemic lupus erythematosus and other autoimmune disorders is well documented. However, the increasing prevalence of depression in children and adolescents poses a risk of delaying the diagnosis of a systemic disease.

Multiple variants of obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome - one clinical center case series and the systematic review of 734 cases.

INTRODUCTION: Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome is a rare female urogenital tract malformation. STUDY OBJECTIVE: To present 10 patients with OHVIRA treated at the clinical center. To perform a systematic review of OHVIRA case series related to the prevalence of anatomical variants, surgical interventions and endometriosis, and to compare them with our case series. MATERIALS AND METHODS: Medical records from 10 OHVIRA patients treated between 2016 and 2020 were retrospectively reviewed. For the systematic review, PubMed and Web of Science were used to search for relevant studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were strictly followed. RESULTS: The most common anatomical variant includes left obstructed hemivagina (50.7%) with isolated hematocolpos or hydrocolpos (55.9%), uterus didelphys (82.9%), and ipsilateral renal agenesis (92.2%). Vaginal septectomy was the most common surgical approach (86.5%). Hemivaginectomy (2.2%), hemihysterectomy (4.2%), or total hysterectomy (0.7%) were also performed in several patients. Some subjects required salpingectomy (3.3%) or oophorectomy (1.8%). 7.5% of patients, mainly infants, did not require surgery due to the spontaneous resolution of hydrocolpos. Endometriosis was fortuitously found in 13.6% of the selected cases who underwent laparoscopy or laparotomy. DISCUSSION: The most common variant of OHVIRA includes isolated hematocolpos and a thick vaginal septum between adjacent hemivaginas. Endometriosis was present in approximately 14% of OHVIRA patients, but this number is probably underestimated. Routine laparoscopy is not required. However, all patients need further monitoring due to a higher risk of endometriosis. Based on the analyzed studies and our case series, vaginal septectomy is a sufficient surgical technique to relieve symptoms and prevent possible complications in most OHVIRA patients.

Anorexia nervosa and juvenile lupus erythematosus in a 16-year-old female patient - common disease origin or random coincidence?

Adolescence is a period in which eating disorders and juvenile systemic lupus erythematosus are typically diagnosed. The coexistence of both disorders prompts the search for a common aetiology. In this paper, we present a case of a 16-year-old girl with life-threatening anorexia nervosa followed by clinical and immunological manifestations of systemic lupus erythematosus. The severity of the symptoms of anorexia nervosa resulted in significant delay in proper diagnosis of the concomitant systemic disease which had already been active. The administration of immunosuppressive treatment resulted in decreased lupus activity and resolution of the symptoms of anorexia nervosa.Being affected by one severe and chronic disease does not preclude the coexistence of another disease of different aetiology. However, such coexistence may suggest a common pathophysiology. Many authors have indicated a possible link between anorexia nervosa and many autoimmune disorders. Currently, modern genetic techniques have confirmed a significant correlation between these disorders. This issue needs further investigation and may be helpful in arriving at the final diagnosis in similar cases.

Aggressive Angiomyxoma in an 11-Year-Old Boy - Diagnostic and Therapeutic Dilemmas: An Unusual Case Report and Review of the Literature.

Aggressive angiomyxoma (AAM) is a rare tumor with a high risk of local recurrence. Scrotal AAM mimics common pediatric pathologies including hernia or hydrocele. We present 11-year-old boy who underwent macroscopically radical excision of right scrotal AAM. The patient has been already followed up for 29 months utilizing US every 6 months and MRI every 2 years. Residual scrotal mass has been visualized in MRI 3 months after surgery however no further growth was reported. Long term follow up with reliable local imaging is mandatory.

Contribution of Bone Tissue to Regulation of Calcium and Phosphate Metabolism. Role of FGF23 and Klotho Protein.

Bone tissue actively contributes to the regulation of systemic homoeostasis, and particularly the maintenance of calcium-phosphate balance. The parathyroid hormone-vitamin D feedback axis is balanced by the recently discovered bone-FGF23-kidney hormonal axis. An active complex consisting of FGF23, a receptor and Klotho protein blocks phosphate reabsorption in the proximal tubules, increasing urine phosphate levels and decreasing blood phosphate levels. Mutations of the gene mediating FGF23 transcription lead to a number of diseases, examples including autosomal dominant hypophosphataemic rickets. Klotho protein is a cofactor for FGF23 displaying cardio-, vaso- and nephroprotective activity. It increases calcium reabsorption in the kidneys and inhibits phosphate reabsorption. It also exerts antioxidative and anti-insulin effects and inhibits tissue calcification and apoptosis. As an inhibitor of bone resorption, osteoprotegerin becomes an important contributor to bone remodelling, while RANK/RANKL signalling inhibition is used in the treatment of postmenopausal osteoporosis. Osteocalcin plays an important role in energy metabolism in the human body. Sclerostin exerts a strong catabolic effect on bone tissue. Newly identified contributors to the regulation of calcium and phosphate homoeostasis suggest that bone tissue plays a complex role in the systemic metabolism.

Evaluation of Selected Parameters of Calcium and Phosphate Metabolism in Children with Adolescent Idiopathic Scoliosis.

BACKGROUND: The multifactor aetiology of adolescent idiopathic scoliosis is commonly acknowledged. Both multivariate analyses of large study groups and the search for causes of adolescent idiopathic scoliosis and its progression in individual patients indicate that the aetiopathogenesis of this disorder is remarkably complex. The discovery of novel bone turnover markers, such as Klotho protein and FGF-23, means that their role in this condition also has to be considered. The aim of this paper is to evaluate the FGF-23 and Klotho protein concentration profiles as new contributors to the regulation of calcium and phosphate metabolism in children with adolescent idiopathic scoliosis and compare them with the values seen in healthy children. MATERIAL AND METHODS: The study assessed a total of 70 children, including 35 children treated at the postural defects clinic of the Health Care Facility in Olesno following a diagnosis of adolescent idiopathic scoliosis and 35 healthy children who constituted a control group. The levels of classic bone turnover markers, such as calcium and phosphorus concentration, alkaline phosphatase, 25-OH-D, and parathyroid hormone (PTH) activity, and of newly discovered contributors to calcium and phosphate metabolism regulation, namely Klotho protein and FGF-23, were determined in both groups. RESULTS: There were statistically significant differences in the levels of basic parameters of calcium and phosphate metabolism between children with scoliosis and the control group, with scoliotic patients showing elevated calcium and 25-OH-D levels and reduced parathyroid hormone levels. Klotho protein levels in children with scoliosis were significantly lower than in the control group. Moreover, the scoliotic patients showed a marked trend towards higher FGF-23 levels as compared to the control group. CONCLUSIONS: 1. Adolescent idiopathic scoliosis is characterised by multi-level abnormalities of calcium and phosphate metabolism. 2. The increased FGF-23 levels and reduced Klotho protein concentrations found in serum samples collected from children with ado-lescent idiopathic scoliosis may suggest that these hormones play a role in the aetiopathogenesis of the disorder.

Perinatal hospice care in the opinion of nurses and midwives.

OBJECTIVES: Perinatal medicine is a relatively new, dynamically developing branch of medicine. Its main purpose is taking care of a woman in the pre-conception period, pregnancy and delivery, as well as taking care of a newborn baby. The main aim of the study was to assess the state of knowledge and opinion on hospice perinatal care of professionally active nurses and midwives. MATERIAL AND METHODS: An original and anonymous questionnaire containing 30 questions was used for the study. 572 nurses and midwives from the Silesian Voivodeship took part in the study. The obtained data were analyzed. RESULTS: Only 31.6% of respondents defined the level of their knowledge of pregnancy and neonatal care as high. 12.8% of respondents were able to indicate the definition of perinatal care and accurately determine its goals. The women participating in the study were in favor of enclosing the information about not attempting resuscitation (DNAR) in medical record of children with incurable disease diagnosed in fetal life (99.3%). CONCLUSIONS: The study showed deficits in practical and theoretical knowledge of nurses and midwives in the area of hospice perinatal care. Lack of proper preparation is also one of the most frequently mentioned difficulties in taking care of a child and family with poor prognosis.

Multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab in children with steroid-resistant nephrotic syndrome.

The aim of the study was a multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab (Rtx) in children with steroid-resistant nephrotic syndrome (SRNS) with particular emphasis on the possibility of permanent discontinuation or dose reduction of other immunosuppressive drugs such as glucocorticoids and cyclosporine A after 6 months of observation. The study group consisted of 30 children with idiopathic nephrotic syndrome, who were unresponsive to standard immunosuppressive treatment, and hospitalized in the years 2010-2017 in eight paediatric nephrology centres in Poland. The children were administered a single initial infusion of rituximab at the dose of 375 mg/m2 of the body surface area. Proteinuria, the daily supply of glucocorticoids, and cyclosporine were assessed at the moment of the start of the treatment and after 6 months since its commencement. Before Rtx therapy, complete remission was found in 13 patients (43%) and partial remission was found in 8 patients (26%). These numbers increased to 16 (53%) and 12 (40%), respectively. At the start of the treatment 23 patients (76.6%) were treated with cyclosporine A. After 6 months, this number decreased to 15 patients (35%). At the start of the treatment, 18 patients (60%) were treated with prednisone. After 6 months, this number decreased to 8 patients (44%). Children with SRNS may potentially benefit from Rtx treatment despite relative risk of side effects. The benefits may include reduction of proteinuria or reduction of other immunosuppressants.

Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.

Serum vaspin concentrations in girls with anorexia nervosa.

BACKGROUND: Vaspin (VASP) is a protein detected in pre- and mature adipocytes, the production and secretion of which may be conditioned by nutrition status. VASP may also play a role in the regulation of food intake. Since to date, there are no available studies on serum vaspin concentrations in patients with anorexia nervosa (AN), the aim of our study is to assess serum vaspin concentrations in girls with AN in comparison to healthy subjects and determine its relationship with body weight, body masss index (BMI) and insulin. METHODS: In this cross-sectional study vaspin serum concentrations were evaluated using a commercially available ELISA kit in 47 Polish girls hospitalized due to restrictive AN and 39 healthy controls (H). RESULTS: The mean serum concentration of VASP in girls with AN was significantly higher than in the H group. These differences were also noted after adjustment for body masss index-standard deviation score (BMI-SDS), the homeostatic model assessment-insulin resistance (HOMA-IR) index and insulin levels. There were no statistically significant correlations between the serum concentrations of VASP and body mass, BMI, BMI-SDS, insulin and HOMA-IR in the AN or healthy group. CONCLUSIONS: Serum vaspin levels in lean subjects are regulated in different mechanisms than previously reported in obesity. It should be established if elevated serum vaspin levels in girls with AN may contribute to low food intake in these patients.

The Usefulness of Determining Neutrophil Gelatinase-Associated Lipocalin Concentration Excreted in the Urine in the Evaluation of Cyclosporine A Nephrotoxicity in Children with Nephrotic Syndrome.

Introduction. The use of cyclosporine (CsA) in the treatment of nephrotic syndrome (NS) contributed to a significant reduction in the amount of corticosteroids used in therapy and its cumulative side effects. One of the major drawbacks of CsA therapy is its nephrotoxicity. Prolonged CsA treatment protocols require sensitive, easily available, and simple to measure biomarkers of nephrotoxicity. NGAL is an antibacterial peptide, excreted by cells of renal tubules in response to their toxic or inflammatory damage. Aim of the Study. The aim of this study was to assess the suitability of the NGAL concentration in the urine as a potential biomarker of the CsA nephrotoxicity. Material and Methods. The study was performed on a group of 31 children with NS treated with CsA. The control group consisted of 23 children diagnosed with monosyptomatic enuresis. The relationship between NGAL excreted in urine and the time of CsA treatment, concentration of CsA in blood serum, and other biochemical parameters was assessed. Results. The study showed a statistically significant positive correlation between urine NGAL concentration and serum triglycerides concentration and no correlation between C0 CsA concentration and other observed parameters of NS. The duration of treatment had a statistically significant influence on the NGAL to creatinine ratio. Conclusions. NGAL cannot be used alone as a simple CsA nephrotoxicity marker during NS therapy. Statistically significant correlation between NGAL urine concentration and the time of CsA therapy indicates potential benefits of using this biomarker in the monitoring of nephrotoxicity in case of prolonged CsA therapy.

Influence of Orthodontic Rapid Maxillary Expansion on Nocturnal Enuresis in Children.

BACKGROUND: The etiology of nocturnal enuresis (NE) is multifactorial and has not been fully explained yet. New ways of treatment are constantly being investigated, including the rapid maxillary expansion (RME). METHODS: A total of 41 patients diagnosed with NE were divided into two experimental groups: A and B. Group A included 16 children who have been treated with RME. Group B comprised 25 children who have not undertaken orthodontic treatment. Children from both groups have been monitored in monthly intervals, during a 12-month period, towards the intensification of NE. The comparative analysis of both groups has been conducted after 3 years of observation. RESULTS: Statistical analysis has shown a 4.5 times increase of the probability of reduction of NE in the case of the treated group in comparison with the group of children who have not undergone orthodontic treatment. Unfortunately, the chance of obtaining total dryness diminished proportionally to the higher degree of intensification of enuresis at the beginning of the test. CONCLUSION: RME can constitute an alternative method of NE treatment in children, irrespective of the occurrence of upper jaw narrowing.

Dimethylarginines as risk markers of atherosclerosis and chronic kidney disease in children with nephrotic syndrome.

BACKGROUND: Nephrotic syndrome in children is commonly associated with dyslipidemia, which is considered a risk factor for endothelial dysfunction and atherosclerosis. Recently new markers of endothelial dysfunction, such as asymmetric dimethylarginine (ADMA), have gained importance. Another L-arginine derivative--symmetric dimethylarginine (SDMA)--may reflect the glomerular filtration rate (GFR). OBJECTIVES: The main aim of this study was to assess ADMA as a marker of atherosclerosis. Secondly, SDMA was examined for GFR assessment. MATERIAL AND METHODS: The study involved 32 children with nephrotic syndrome. Several parameters were examined in the remission and relapse phases of nephrotic syndrome, including ADMA, SDMA, cholesterol, triglycerides and GFR. RESULTS: In the relapse phase there was a negative correlation between ADMA and lipids (cholesterol and triglycerides). In both phases SDMA was negatively correlated with GFR. CONCLUSIONS: The role of ADMA as a marker for endothelial dysfunction is not significant. SDMA may be utilized to monitor GFR in children with nephrotic syndrome.

Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.

BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS: Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS: The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

Retrospective cohort study of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis due to CLDN16 mutations.

BACKGROUND: Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder exhibiting a high risk for progressive chronic kidney disease (CKD). METHODS: This is a retrospective multicentre study of 25 paediatric cases with FHHNC in Poland. Median age at diagnosis was 4 years and median follow-up time was 4.8 years. RESULTS: All cases of FHHNC carried recessive mutations in CLDN16. The founder mutation in CLDN16, Leu151Phe, was the most frequent cause of FHHNC in Polish patients, with 13 (52%) cases being homozygous and 5 (20%) carrying Leu151Phe allele in compound heterozygosity. All cases showed nephrocalcinosis, increased urinary fractional excretion of magnesium and hypercalciuria. Other disease features included hypomagnesaemia (76%), hyperparathyroidism (76%), hyperuricaemia (56%) and hypocitraturia (60%). Treatment with thiazides effectively reduced hypercalciuria in most cases. During follow-up, renal function declined in 60% of patients; 12% of patients reached CKD stage 3 or 4 and one patient developed end-stage renal failure. CONCLUSIONS: We report one of the largest cohorts of FHHNC cases caused by CLDN16 mutations. A missense variant of CLDN16, Leu151Phe, is the most common mutation responsible for FHHNC in Poland. Additionally, we found that normomagnesaemia does not exclude FHHNC and the calculation of fractional excretion of Mg can be diagnostic in the setting of normomagnesaemia. We also demonstrate the efficacy of a treatment with thiazides in terms of hypercalciuria in the majority of patients.

Association between polymorphisms in the TSHR gene and Graves' orbitopathy.

BACKGROUND: Graves' orbitopathy (GO) as well as Graves' disease (GD) hyperthyroidism originate from an autoimmune reaction against the common auto-antigen, thyroid-stimulating hormone receptor (TSHR). GO phenotype is associated with environmental risk factors, mainly nicotinism, as well as genetic risk factors which initiate an immunologic reaction. In some patients GO is observed before diagnosis of GD hyperthyroidism, while it can also be observed far after diagnosis. The intensity of GO symptoms varies greatly in these patients. Thus, the pathogenesis of GD and GO may correlate with different genetic backgrounds, which has been confirmed by studies of correlations between GO and polymorphisms in cytokines involved in orbit inflammation. The aim of our analysis was to assess genetic predisposition to GO in young patients (age of diagnosis ≤30 years of age), for whom environmental effects had less time to influence outcomes than in adults. METHODS: 768 GD patients were included in the study. 359 of them had clinically evident orbitopathy (NOSPECS ≥2). Patients were stratified by age at diagnosis. Association analyses were performed for genes with a known influence on development of GD - TSHR, HLA-DRB1, cytotoxic T-lymphocyte antigen 4 (CTLA4) and lymphoid protein tyrosine phosphatase (PTPN22). RESULTS: The rs179247 TSHR polymorphism was associated with GO in young patients only. In young GO-free patients, allele A was statistically more frequent and homozygous carriers had a considerable lower risk of disease incidence than patients with AG or GG genotypes. Those differences were not found in either elderly patients or the group analyzed as a whole. CONCLUSIONS: Allele A of the rs179247 polymorphism in the TSHR gene is associated with lower risk of GO in young GD patients.