Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics.

AIMS/HYPOTHESIS: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing. METHODS: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity). RESULTS: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases. CONCLUSIONS/INTERPRETATION: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria.

COVID-19-associated multisystem inflammatory syndrome in children: Experiences of three centres in Turkey.

BACKGROUND: The pathogenesis and clinical manifestations of the multisystem inflammatory syndrome in children (MIS-C) has not yet been fully elucidated and there is no clear consensus on its treatment yet. OBJECTIVES: To evaluate our patients diagnosed with MIS-C and present them to the literature in order to contribute to the better understanding of this new disease, which entered paediatric practice with the SARS-CoV-2 peak. METHODS: In this study, 17 MIS-C cases diagnosed according to the Centers for Disease Control and Prevention criteria were included. RESULTS: Of the patients, 7 (41.2%) had a comorbidity. Gastrointestinal system involvement was the most prominent in the patients (70.6%). Laparotomy was performed in 3 patients due to acute abdomen. Two patients had neurological involvement. Of the patients, 15 (88.2%) received intravenous immunoglobulin and 13 (76.5%) received both intravenous immunoglobulin and methylprednisolone. Two patients received invasive mechanical ventilation and 4 patients received high flow rate nasal cannula oxygen therapy. One of our patients who needed invasive mechanical ventilation and high vasoactive-inotrope support died despite all supportive treatments including plasmapheresis and extracorporeal membrane oxygenation. CONCLUSIONS: MIS-C picture can have a fatal course and may present with severe gastrointestinal and neurological signs. Unnecessary laparotomy should be avoided.

Sleep Disorders and Obesity in Childhood: A New Component in Solving Obesity.

Sleep disorders have been widely reported in obese individuals. Previous studies have shown that together with an increase in obesity prevalence, so does sleep duration in children and adolescents decrease. By contributing to energy imbalances, hormonal changes occurring with reduced sleep quality may cause weight gain and obesity. Current evidence shows that short sleep duration has effects on body weight and weight gain. Compared to individuals sleeping for a normal duration, insulin sensitivity is lower in those who sleep less. Lack of sleep increases the desire for food and has a direct effect on physical activity. Further studies are required to determine the contribution of sufficient sleep to obesity treatment.

Long-term follow-up of transient neonatal diabetes mellitus due to a novel homozygous c.7734C>T (p.R228C) mutation in ZFP57 gene: relapse at prepubertal age.

OBJECTIVES: Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes present within the first six months of life. NDM can be transient (TNdM) or permanent (PNDM). About 70% of TNDM cases have abnormalities in the imprinted region of chromosome 6q24. In TNDM, diabetes remits at infancy whilst may relapse later in life. Chromosome 6q24 related TNDM usually relapses at the pubertal period, while in some cases, relapse occurs earlier. It has been reported that these cases can respond to sulfonylurea treatment, while more evidence and experience are needed. CASE PRESENTATION: Herein, we reported relapse of diabetes at prepubertal age and its response to sulphonylurea therapy in a case with TNDM due to a homozygous c.7734C>T (p.R228C) variant in the ZFP57 gene. CONCLUSIONS: A response to the sulphonylurea monotherapy seems not optimal for relapsed TNDM due to chromosome 6q24 abnormalities.

Transient benign hyperphosphatasemia due to COVID-19: the first case report.

OBJECTIVES: Coronavirus disease (COVID-19) rapidly spread worldwide in a few months and was declared as a worldwide pandemic by WHO in March 2020. Transient benign hyperphosphatasemia (THI) is a benign condition associated with marked elevation of alkaline phosphatase (ALP) without any other kidney, bone, and liver pathologies. CASE PRESENTATION: Herein, we report a previously healthy 16-month-old female patient who developed a secondary transient benign hyperphosphatasemia associated with SARS-CoV-2. Patient whole family's SARS-CoV-2 real-time reverse transcription-polymerase chain reaction (RT-PCR) results were positive. Since THI is a diagnosis of exclusion, other reasons that may cause ALP elevation should be ruled out. ALP activity decreased and turned to normal ranges within the following month. THI has been reported to be in association with various conditions. Its relationship with many viruses has been reported previously. CONCLUSIONS: If ALP elevation is detected in patients with COVID 19 due to the increasing number of infections, THI should be considered if there is no other accompanying pathology.

Girls with Premature Thelarche Younger than 3 Years of Age May Have Stimulated Luteinizing Hormone Greater than 10 IU/L

Objective: Premature thelarche (PT) is defined as isolated breast development in girls before eight years of age. Gonadotropin-releasing hormone (GnRH) stimulation test is sometimes used to distinguish between PT and central precocious puberty (CPP), although the interpretation of the test at early ages is challenging. The objective of this study was to determine the follicle stimulating hormone (FSH) and luteinizing hormone (LH) responses to GnRH stimulation in girls with PT below 3 years of age. Methods: A standardized GnRH stimulation test, bone age and pelvic ultrasound were evaluated and those without pubertal progression after a minimum of one-year follow up were included in the study. Results: On GnRH stimulation test, the median (range) baseline LH was 0.29 (0.10-0.74) IU/L, baseline FSH was 4.96 (3.18-7.05) mIU/mL, and the peak median LH was 5.75 (3.31-8.58) IU/L with the peak mean±standard deviation FSH was 40.38±20.37 mIU/mL. Among the patients, 33.3% (n=10) had baseline LH >0.3 IU/L, 67% (n=20) had peak LH >5 IU/l and 16.6% (n=5) >10 IU/L. The mean peak LH/FSH ratio was 0.17±0.09 and was ≤0.43 in all participants. Conclusion: Although consensus statements usually define baseline LH >0.3-0.5 IU/L, peak LH >5 IU/L, and LH/FSH ratios >0.66-1.0 as diagnostic cut-offs for CPP, in children below 3 years of age, the baseline and peak LH values may be similar to pubertal values, possibly due to mini-puberty. A dominant FSH response on GnRH stimulation test is more valuable than the peak LH response in the diagnosis of PT.

Children With Metabolically Healthy Obesity: A Review.

Children with "metabolically healthy obesity" (MHO) are a distinct subgroup of youth with obesity, who are less prone to the clustering of cardiometabolic risk factors. Although this phenotype, frequently defined by the absence of metabolic syndrome components or insulin resistance, was first described during the early 1980s, a consensus-based definition of pediatric MHO was introduced only recently, in 2018. The purpose of this review was to concisely summarize current knowledge regarding the MHO phenomenon in youth. The prevalence of MHO in children varies from 3 to 87%, depending on the definition used and the parameters evaluated, as well as the ethnicity and the pubertal status of the sample. The most consistent predictors of MHO in youth include younger age, lower body mass index, lower waist circumference, and lower body fat measurements. Various hypotheses have been proposed to elucidate the underlying factors maintaining the favorable MHO phenotype. While preserved insulin sensitivity and lack of inflammation were previously considered to be the main etiological factors, the most recent findings have implicated adipokine levels, the number of inflammatory immune cells in the adipose tissue, and the reduction of visceral adiposity due to adipose tissue expandability. Physical activity and genetic factors also contribute to the MHO phenotype. Obesity constitutes a continuum-increased risk for cardiometabolic complications, which is less evident in children with MHO. However, some findings have highlighted the emergence of hepatic steatosis, increased carotid intima-media thickness and inflammatory biomarkers in the MHO group compared to peers without obesity. Screening should be directed at those more likely to develop clustering of cardiometabolic risk factors. Lifestyle modifications should include behavioral changes focusing on sleep duration, screen time, diet, physical activity, and tobacco smoke exposure. Weight loss has also been associated with the improvement of insulin sensitivity and inflammation. Further investigative efforts are needed in order to elucidate the mechanisms which protect against the clustering of cardiometabolic risk factors in pediatric obesity, to provide more efficient, targeted treatment approaches for children with obesity, and to identify the protective factors preserving the MHO profile, avoiding the crossover of MHO to the phenotype with metabolically unhealthy obesity.

Pubertal Status and Gonadal Functions in Obese Boys with Fatty Liver.

BACKGROUND: In adult studies, obese subjects with nonalcoholic fatty liver disease (NAFLD) have been shown to have poor sperm quality, and lower testosterone and luteinizing hormone levels. The aim of this study was to investigate the pubertal status and gonadal functions in obese boys with NAFLD. MATERIALS AND METHODS: The study included 119 obese and 78 nonobese age-matched adolescents. The obese boys were separated into two groups based on the presence (NAFLD group) or absence of liver steatosis with high transaminases (non-NAFLD group). The levels of serum AMH (anti-Mullerian hormone), inhibin B, gonadotropins, total testosterone, lipids, high-sensitivity C-reactive protein, fasting glucose, insulin levels, and aortic intima media thickness were measured in all subjects. RESULTS: Of the total 197 children, 174 had reached puberty. There were no significant differences between the groups in respect of testicular sizes and the prevalence of pubertal status among the groups (84.3% of NAFLD vs. 70.6% of non-NAFLD vs. 98.7% of control subjects). No significant differences were found in respect of gonadotropins and AMH levels. Total testosterone levels in the NAFLD group were significantly lower than those of the non-NAFLD obese group (P < 0.001) and the control group (P < 0.001). Inhibin B levels were also significantly lower in all (NAFLD and non-NAFLD) obese groups compared to the control group (P = 0.008). CONCLUSIONS: The results of the study demonstrated that diminished testosterone and inhibin B levels occur in pubertal obese boys with NAFLD. No significant differences were detected according to pubertal status, AMH levels, and testicular volumes in the age-matched groups.

The Association Between Serum Vaspin and Omentin-1 Levels in Obese Children with Metabolic Syndrome.

BACKGROUND AND AIM: Excess visceral fat accumulation results in altered release of adipokines. The aim of this study was to examine the relationship between new adipokines (omentin-1 and vaspin), insulin resistance, and serum inflammatory markers in obese subjects with metabolic syndrome (MS). PATIENTS AND METHODS: The study included a total of 121 obese children (79 females and 42 males, aged 12-17 years old). The obese subjects were divided into two groups based on the presence or absence of MS criteria (MS group and non-MS group). Serum omentin-1, vaspin, and high-sensitivity C-reactive protein (CRP) were measured in addition to the other glucose metabolism parameters. RESULTS: MS was diagnosed in 45 obese children and 76 children did not meet the MS criteria. Serum omentin-1 (289.5 ± 51.9 ng/mL vs. 268.2 ± 60 ng/mL, P = 0.03) levels were significantly lower in the MS group compared to the non-MS group. Serum vaspin levels (1058.3 ± 118 pg/mL vs. 1178.6 ± 158 pg/mL, P = 0.02) were higher in the MS group than the non-MS group. CRP levels correlated well with both the adipokines (r = -0.236, P = 0.04 for omentin-1 and r = 0.296, P = 0.008 for vaspin), although these adipokines did not show statistically significant correlations with fasting glucose-insulin levels, homeostasis model assessment of insulin resistance, and 2 hr postload glucose level. CONCLUSIONS: Higher vaspin and lower omentin-1 levels were determined in obese MS children compared to non-MS children and these adipokines were significantly correlated with high CRP values. These data support the view that adipokines in MS children contribute to increased inflammation markers before abnormal glucose metabolism.

Anti-Mullerian Hormone and Inhibin B Levels in Obese Boys; Relations with Cardiovascular Risk Factors.

OBJECTIVE: Obesity may reduce sertoli cell functions in men. The aim of the study was to investigate antimullerian hormone (AMH) and inhibin B levels (sertoli cell markers) in obese boys and their relations to cardiovascular risk factors such as insulin sensitivity index, aortic intima media thickness (aIMT) and high sensitive c-reactive protein (hsCRP). PATIENTS, METHODS: 121 obese and 38 healthy lean adolescents were included in the study. Serum AMH, inhibin B, gonadotropins, total testosterone, lipids, hsCRP, glucose and insulin levels were detected and analyzed. Insulin resistance was analyzed using the homeostasis model assessment (HOMA-IR). aIMT was measured by high-resolution B-mode ultrasonography. RESULTS: Serum AMH, inhibin B and total testosterone levels were lower in the obese adolescents (p=0.01, p=0.009 and p=0.002, respectively). aIMT measurements (p<0.001, 0.63±0.09 and 0.47±0.06 mm, respectively) and hsCRP levels (p<0.001, 2.5±0.4 and 0.66±0.69 mg/L, respectively) were significantly increased in the obese group. Obese with IR group had decreased AMH levels (p=0.02, 53.0±20.5 and 66.7±19.5 ng/mL, respectively) and increased triglycerides, HOMA-IR, aIMT measurements than non-IR obese group. AMH levels were correlated negatively with body mass index (r:-0.108, p=0.03), HOMA-IR (r:-0.358, p=0.003) and fasting insulin levels (r:-0.389, p=0.001) in obese group with IR. CONCLUSION: We found that concentrations of both sertoli cell markers (AMH and inhibin B) were significantly lower in obese pubertal boys especially in obese with IR. Obesity and IR might be important factors for the sertoli cell impairment in pubertal boys.

Restless Legs Syndrome and Poor Sleep Quality in Obese Children and Adolescents

OBJECTIVE: Adult epidemiological studies suggest that the rate of Restless Legs syndrome (RLS) in the general population may range from 5% to 15%. The aim of this study was to investigate the frequency of RLS in a community sample of obese adolescents aged 10-16 years and to assess the association with sleep quality and health-related glucose metabolism markers. METHODS: The study group comprised 144 obese and overweight children aged 10-16 yearsand the control group consisted of 66 age-matched healthy children. The RLS Questionnaire devised by the International RLS Study and the Pittsburgh Sleep Quality Index (PSQI), where a score >5 indicates poor sleep quality, was used to assess sleep quality. RESULTS: Mean body mass index (BMI) of the overweight/obese and control groups were 30.5±0.5 and 18.7±0.2, respectively. The frequency of RLS was higher in the obese group (21.7%) than the overweight (3.4%) and control (1.5%) (p<0.001) groups. The frequency of a poor PSQI score was significantly higher (p<0.001) in the obese group (37.3%) than the control group (24.2%). The obese with RLS group also had poorer sleep quality scores than the non-RLS obese group. Many symptoms of sleep disruption were more common in obese patients with RLS and RLS was independently correlated with a high PSQI score [odds ratio (OR): 2.25, confidence interval (Cl): 0.96-5.28, p<0.001)] and an increased BMI z-score (OR: 8.87, Cl: 2.04-38.61, p<0.001). CONCLUSION: RLS is common in obese children and may be associated with altered sleep quality. Obese children with RLS need to be assessed since they may need support to improve their sleep quality.

Microsomal triglyceride transfer protein gene mutations in Turkish children: A novel mutation and clinical follow up.

Abetalipoproteinemia (ABL; OMIM 200100) is a rare autosomal recessive disease that affects the absorption of dietary fats and fat soluble vitamins. Here, we describe the clinical and genetic characteristics of three patients with ABL. Two patients (patients 1 and 2) who were carriers of the c.398-399delAA mutation (previously known mutation) had developmental delay and hepatic steatosis developed at the age of five in patient 1. Patient 3 was the carrier of a novel mutation (g.10886-10902delAAGgtaagtttgtgttg in intron 3 and c.506A>T exon 5) in microsomal triglyceride transfer protein (MTP) gene and had hepatic steatosis.