First case of Hajdu-Cheney syndrome in Lithuania caused by novel NOTCH2 gene likely pathogenic variant.

Hajdu-Cheney syndrome (HCS) is an extremely rare autosomal dominant skeletal disorder. The prevalence rate of less than 1 case per 1,000,000 newborns and only 50 cases were reported in the medical literature. HCS is characterized by progressive bone resorption in the distal phalanges (acro-osteolysis), progressive osteoporosis, distinct craniofacial changes, dental anomalies, and occasional association with renal abnormalities. HCS is caused by pathogenic variants in the NOTCH2 gene, 34th exon. We report first familial case of HCS caused by likely pathogenic variant of NOTCH2 gene c.6449delC, p.(Pro2150LeufsTer5).

Kinetics of C-peptide during mixed meal test and its value for treatment optimization in monogenic diabetes patients.

AIM: The mixed meal tolerance test (MMTT) is a gold standard for evaluating beta-cell function. There is limited data on MMTT in monogenic diabetes (MD). Therefore, we aimed to analyze plasma C-peptide (CP) kinetics during MMTT in young MODY and neonatal diabetes patients as a biomarker for beta-cell function. METHODS: We included 41 patients with MD diagnosis (22 GCK, 8 HNF1A, 3 HNF4A, 4 KCNJ11, 2 ABCC8, 1 INS, 1 KLF11). Standardized 3-hour MMTT with glycemia and plasma CP measurements were performed for all individuals. Pancreatic beta-cell response was assessed by the area under the curve CP (AUCCP), the baseline CP (CPBase) and the peak CP (CPmax). Threshold points of CPBase, CP90, CPmax and CPAUC were determined from analysis of ROC curves. RESULTS: GCK diabetes patients had significantly higher AUCCP, CPBase and CPmax compared to HNF4A and KCNJ11 patients. In HNF4A, KCNJ11 and ABCC8 patients with all CP levels < 200 pmol/L, the treatment change attempt to sulfonylurea agent was unsuccessful. The ROC analysis showed that CP baseline threshold equal or higher to 133.5 pmol/L could be used to predict successful switch to oral agents. CONCLUSION: A pretreatment challenge with MMTT might be used to guide the optimal treatment after molecular diagnosis of MD.

Systematic Genetic Study of Youth With Diabetes in a Single Country Reveals the Prevalence of Diabetes Subtypes, Novel Candidate Genes, and Response to Precision Therapy.

Identifying gene variants causing monogenic diabetes (MD) increases understanding of disease etiology and allows for implementation of precision therapy to improve metabolic control and quality of life. Here, we aimed to assess the prevalence of MD in youth with diabetes in Lithuania, uncover potential diabetes-related gene variants, and prospectively introduce precision treatment. First, we assessed all pediatric and most young-adult patients with diabetes in Lithuania (n = 1,209) for diabetes-related autoimmune antibodies. We then screened all antibody-negative patients (n = 153) using targeted high-throughput sequencing of >300 potential candidate genes. In this group, 40.7% had MD, with the highest percentage (100%) in infants (diagnosis at ages 0-12 months), followed by those diagnosed at ages >1-18 years (40.3%) and >18-25 years (22.2%). The overall prevalence of MD in youth with diabetes in Lithuania was 3.5% (1.9% for GCK diabetes, 0.7% for HNF1A, 0.2% for HNF4A and ABCC8, 0.3% for KCNJ11, and 0.1% for INS). Furthermore, we identified likely pathogenic variants in 11 additional genes. Microvascular complications were present in 26% of those with MD. Prospective treatment change was successful in >50% of eligible candidates, with C-peptide >252 pmol/L emerging as the best prognostic factor.

Factors Affecting Cardiovascular Risk in Children, Adolescents, and Young Adults with Type 1 Diabetes.

Cardiovascular risk and obesity are becoming major health issues among individuals with type 1 diabetes (T1D). The aim of this study was to evaluate cardiovascular risk factors and obesity in youth with T1D in Lithuania. Methods. 883 patients under 25 years of age with T1D for at least 6 months were investigated. Anthropometric parameters, blood pressure, and microvascular complications were evaluated, and the lipid profile and HbA1c were determined for all patients. Results. Study subjects' mean HbA1c was 8.5 ± 2%; 19.5% were overweight and 3.6% obese. Hypertension and dyslipidemia were diagnosed in 29.8% and 62.6% of participants, respectively. HbA1c concentration was directly related to levels of total cholesterol (r = 0.274, p < 0.001), LDL (r = 0.271, p < 0.001), and triglycerides (r = 0.407, p < 0.001) and inversely associated with levels of HDL (r = 0.117, p = 0.001). Prevalence of dyslipidemia increased with duration of diabetes (p < 0.05). Hypertension was more prevalent in overweight and obese compared to normal-weight patients (40.6 and 65.6 vs. 25.6%, respectively, p < 0.001). Frequency of microvascular complications was higher among patients with dyslipidemia (27.2 vs. 18.8%, p = 0.005) and among those with hypertension (25.9 vs. 23.2%, p < 0.001). Conclusion. The frequency of cardiovascular risk factors is high in youth with T1D and associated with diabetes duration, obesity, and metabolic control.

Unusual case of chronic recurrent multifocal osteomyelitis.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory bone disorder that primarily affects young girls, with a mean age of 10 years at onset. Generally, it is a self-limited disease. However, recent data indicate that more than 50% of patients have a chronic persistent disease and about 20% a recurring course of this condition. Also, there are more cases reported with associated auto-inflammatory and autoimmune diseases. In this case report, we present a rare case of sporadic CRMO in which the patient eventually developed C-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies)-associated renal vasculitis and hyperparathyroidism. CASE PRESENTATION: A 14 year old female patient was brought to the emergency department with a sudden onset of left leg pain and oedema. After physical evaluation and initial investigation, she was diagnosed with femoral and pelvic deep vein thrombosis. While searching for possible thrombosis causes, osteomyelitis of the left leg was identified. Additional CT and MRI scans hinted at the CRMO diagnosis. Due to the multifocal lesions of CRMO, endocrinological evaluation of calcium metabolism was done. The results showed signs of hyperparathyroidism with severe hypocalcaemia. Moreover, when kidney damage occurred and progressed, a kidney biopsy was performed, revealing a C-ANCA associated renal vasculitis. Treatment was started with cyclophosphamide and prednisolone according to the renal vasculitis management protocol. Severe metabolic disturbances and hyperparathyroidism were treated with alfacalcidol, calcium and magnesium supplements. Secondary glomerulonephritis (GN) associated hypertension was treated with ACE (angiotenzine converting enzyme) inhibitors. Anticoagulants were prescribed for deep vein thrombosis. After 1.5 years of treatment, the patient is free of complaints. All microelement and parathormone levels are within normal range. Kidney function is now normal. To date, there are no clinical or diagnostic signs of deep vein thrombosis. CONCLUSIONS: This case report presents a complex immunodysregulatory disorder with both auto-inflammatory and autoimmune processes. We hypothesize that the long lasting active inflammation of CRMO may induce an autoimmune response and result in concomitant diseases like C-ANCA-associated vasculitis in our patient. Any potential specific pathogenic relationships between these two rare pathologies may need to be further studied. Furthermore, there is a lack of specific biomarkers for CRMO and more studies are necessary to identify CRMO's characteristic patterns and how to best monitor disease progression.

Thirty-Five Years of Thyroid Cancer Experience in a Paediatric Population: Incidence Trends in Lithuania between 1980 and 2014.

BACKGROUND: Thyroid cancer (TC) is a rare condition in children. It may be associated with radiation, iodine deficiency or familial inheritance. AIMS: The objectives of this study were to analyse the prevalence and incidence trends over 3 decades and clinical features of TC in the paediatric population in Lithuania. METHODS: We reviewed all TC cases diagnosed in children aged less than 18 years during the period 1980-2014 using medical records from 3 main hospitals in Lithuania where such TC cases are managed. RESULTS: During the 35-year period (1980-2014) there were 57 cases (45 females) of TC in children in Lithuania. The mean age at the time of diagnosis was 14.51 ± 0.52 years. The crude incidence rate of TC ranged from 0 to 0.93 cases per 100,000 children per year and the mean annual increase was 5.26% (p < 0.001). Papillary carcinoma was the most common histological type (73.7%). No association was found between the incidence of TC and the reported areas of radioactive contamination after the Chernobyl accident. In total, 8.8% of patients had secondary TC after initial radiotherapy of a primary oncologic disease. CONCLUSION: The incidence of TC in the Lithuanian paediatric population between 1980 and 2014 ranged from 0 to 0.93 cases per 100,000 children per year and there was a 5.26% annual increase (p < 0.001), most probably related to the increased use of ultrasound testing.

Thiamine responsive megaloblastic anemia syndrome: a novel homozygous SLC19A2 gene mutation identified.

Thiamine responsive megaloblastic anemia syndrome (TRMAS) is a rare autosomal recessive disorder especially in countries where consanguinity is uncommon. Three main features are characteristic of the disease - megaloblastic anemia, early onset deafness, and non-type I diabetes. TRMAS is a Mendelian disorder; a gene SLC19A2 coding high affinity thiamine transporter mediating vitamin B1 uptake through cell membrane has been identified. We present the first patient with TRMAS in Lithuania - a 3-year-old boy born to a non-consanguineous family with a novel homozygous SLC19A2 gene mutation. The patient had insulin dependent diabetes (onset 11 months), respiratory illness (onset 11 months), bilateral profound hearing loss (onset at 7 months, verified at 20 months), refractory anemia (onset 2 years), and decreased vision acuity and photophobia (onset 2.5 years). The psychomotor abilities developed according to age. Phenotypic evaluation did not reveal any dysmorphic features. The clinical diagnosis of TRMAS was suspected and daily supplementation with thiamine 100 mg was started. The condition of the patient markedly improved several days after the initiation of treatment. The results of SLC19A2 gene molecular testing confirmed the clinical diagnosis - novel homozygous c.[205G>T], p.[(Val69Phe)] mutation changing conserved amino acid residue or even interfering the mRNA splicing. Clinical heterogeneity, diverse dynamics, and wide spectrum of symptoms are aggravating factors in the diagnosis. The possibility of treatment demands early recognition of disorder to facilitate the improvement of the patient's condition.

Routine sensor-augmented pump therapy in type 1 diabetes: the INTERPRET study.

BACKGROUND: Sensor-augmented pump (SAP) therapy can improve glycemic control, compared with multiple daily insulin injections or with insulin pump therapy alone, without increasing the risk of hypoglycemia. SUBJECTS AND METHODS: A 12-month observational study in patients with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII), upon the introduction of continuous glucose monitoring (CGM), was conducted in 15 countries (in Europe and in Israel) to document the real-life use of SAP and assess which variables are associated with improvement in type 1 diabetes management. RESULTS: Data from 263 patients (38% male; mean age, 28.0 ± 15.7 years [range, 1-69 years]; body mass index, 23.3 ± 4.9 kg/m(2); diabetes duration, 13.9 ± 10.7 years; CSII duration, 2.6 ± 3 years) were collected. Baseline mean glycated hemoglobin A1c (HbA1c) was 8.1 ± 1.4%; 82% had suboptimal HbA1c (≥ 7%). The average sensor use for 12 months was 30% (range, 0-94%), and sensor use decreased with time (first 3 months, 37%; last 3 months, 27%). Factors associated with improvement in HbA1c after 12 months in patients with baseline HbA1c ≥ 7% were high baseline HbA1c (P<0.001), older age group (P<0.001), and more frequent sensor use (P = 0.047). Significantly less hospitalization, increased treatment satisfaction, and reduced fear of hypoglycemia were reported after 12 months of SAP. CONCLUSIONS: This is the largest and longest multicenter prospective observational study providing real-life data on SAP. These results are consistent with those of controlled trials showing the effectiveness of CGM in pump users.

HLA class II alleles and haplotypes in Lithuanian children with type 1 diabetes and healthy children (HLA and type 1 diabetes).

OBJECTIVE: Type 1 diabetes mellitus is a slowly progressive autoimmune disease. The genetic background of type 1 diabetes mellitus is polygenic with the major disease locus located in the human leukocytes antigen (HLA) region. High risk and protective alleles, haplotypes, and genotypes have been determined in Lithuanian children with type 1 diabetes mellitus and healthy children. MATERIAL AND METHODS: In this case-control study, 124 children with diabetes (55 males and 69 females; mean age, 9.2±3.9 years) were tested for HLA class II and compared with 78 healthy controls (43 males and 35 females; mean age, 10.8±3.4 years; range, 0-15 years). HLA DRB1, DQA1, and DQB1 alleles were genotyped using a polymerase chain reaction. RESULTS: T1D risk-associated haplotypes (DR4)-DQA1*0301-DQB1*0302, (DR3)-DQA1*0501-DQB1*0201, and (DR1)-DQA1*0101-04-DQB1*0501 were more prevalent among children with diabetes than controls (50.0%, 41.1%, and 37.9% vs. 10.3%, 5.1%, and 24.4%, P<0.001). The haplotypes (DR4)-DQA1*0301-DQB1*0302 and (DR3)-DQA1*0501-DQB1*0201 increased T1D risk by 8.75 and 12.93 times, respectively (P<0.001). Protective haplotypes (DR2)-DQA1*0102-B1*0602, (DR11/12/13)-DQA1*05-DQB1*0301, and (DR13)-DQA1*0103-DQB1*0603 were significantly more prevalent among controls than children with diabetes (25.6%, 33.3%, 19.2% vs. 0%, 3.2%, 0%; P<0.001). These frequencies are quite similar to those from neighbor countries with varying incidence of type 1 diabetes mellitus. CONCLUSIONS: HLA class II haplotypes associated with type 1 diabetes mellitus positively or negatively were the same in Lithuanian children as in other European Caucasian populations. Differences in incidence and clinical manifestations of type 1 diabetes might be due to different environmental factors and/or lifestyle.

Environmental risk factors in prediction of childhood prediabetes.

OBJECTIVE: The damage of beta cells occurs during the asymptomatic prodromal period called prediabetes before onset of diabetes mellitus. It is characterized by the presence of islet cell autoantibodies (ICAs). The aim of this study was to find out what environmental factors predict ICA seroconversion in healthy schoolchildren in Lithuania. MATERIAL AND METHODS: Sera from 3053 nondiabetic schoolchildren living in Lithuania were investigated for ICAs. ICAs were measured in undiluted sera by indirect immunofluorescence method. All ICA-positive and randomly selected ICA-negative children were invited to participate in the study. Response rate in the families of ICA-positive children was 100% and in ICA-negative-76.5%. Data from 13 ICA-positive and 199 ICA-negative schoolchildren were included in the analysis. Information on the environmental factors was collected via questionnaires. RESULTS: Proportions of breastfed children were similar in ICA-positive and ICA-negative schoolchildren. Full cow's milk was introduced at one month of age or earlier more often in ICA-positive than ICA-negative schoolchildren (8.3% and 1.1%, respectively; P=0.05). Cereal before 3 months of age was introduced more often in ICA-positive than ICA-negative schoolchildren (7.7% and 0.5%, respectively; P=0.01). The mothers of cases took medicine during pregnancy more often than mothers of controls did (61.5% and 14.1%, respectively; P<0.001). More than half (53.8%) of ICA-positive children lived in homes where family members were smoking indoors, while this was recorded only for 26.6% of controls (P=0.04). CONCLUSIONS: Early introduction of cow's milk and cereal, the intake of medicine during pregnancy, and indoor smoking of family members are risk factors that predict the development of prediabetes among Lithuanian children.

Longer breastfeeding is an independent protective factor against development of type 1 diabetes mellitus in childhood.

BACKGROUND: Early weaning diet, early introduction of breast milk substitution and cow's milk have been shown to increase the risk of type 1 diabetes later in life. It is also shown that older maternal age, maternal education, preeclampsia, prematurity, neonatal illness and neonatal icterus caused by blood group incompatibility, infections and stress might be risk factors for type 1 diabetes. We aimed to determine whether early nutrition is an independent risk factor for diabetes despite other life events. METHODS: Data from 517 children (268 boys and 249 girls) in south-east of Sweden and 286 children (133 boys and 153 girls) in Lithuania in the age group of 0 to 15 years with newly diagnosed type 1 diabetes mellitus were included into analysis. Three age- and sex-matched healthy controls were randomly selected. Response rate in control families in Sweden was 72.9% and in Lithuania 94.8%. Information was collected via questionnaires. RESULTS: Exclusive breastfeeding longer than five months (odds ratio 0.54, 95% confidence interval 0.36-0.81) and total breastfeeding longer than 7 (0.56, 0.38-0.84) or 9 months (0.61, 0.38-0.84), breastfeeding substitution that started later than the third month (0.57, 0.33-0.98) among Swedish children 5 to 9 years old and later than the seventh month (0.24, 0.07-0.84) among all Swedish children is protective against diabetes when adjusted for all other above-listed risk factors. In Lithuania, exclusive breastfeeding longer than two months in the age group of 5 to 9 years is protective (0.58, 0.34-0.99) when adjusted for other factors. CONCLUSIONS: Longer exclusive and total breastfeeding appears as an independent protective factor against type 1 diabetes.