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I read the article of Soylu Üstkoyuncu et al (1) entitled “Novel MTTP Gene Mutation in a Case of Abetalipoproteinemia with Central Hypothyroidism” in Journal of Clinical Research in Pediatric Endocrinology with great interest. The diagnosis of abetalipoproteinemia was suspected in a 9-month-old patient with chronic diarrhea, failure to thrive, decreased subcutaneous adipose tissue, acanthocytosis, elevated liver function test, and decreased triglyceride and total cholesterol levels. Genetic analysis revealed a novel disease-causing variant in MTTP. In addition, because of mild-low free T4, normal free T3 and normal thyroid stimulating hormone (TSH) findings, central hypothyroidism was considered and L-thyroxine (12.5 mcg/day) was started and increased to 37.5 mcg/day at follow-up. Other pituitary hormones and pituitary imaging have been reported to be normal.

ObjectivesCurrent guidelines for genetic testing in childhood-onset diabetes focusses on Maturity Onset Diabetes of the Young (MODY) or rare genetic syndromes and children with diabetes and unclear or isolated additional clinical features are often not tested.1 We aim to determine whether routine genetic testing should be recommended for children with diabetes and additional syndromic features and assess if novel biomarker, type 1 diabetes genetic risk score, can help to select children for genetic testing.MethodsWe conducted a study of 1093 children with diabetes across seven paediatric diabetes clinics. The diabetes related clinical features, islet autoantibody status and additional non-autoimmune extra-pancreatic features were recorded. We generated 30 variants type 1 diabetes genetic risk score (T1D-GRS).2 3 All children with syndromic diabetes had targeted next-generation sequencing to analyse all known dominant and recessive genes causing monogenic diabetes.4 ResultsAmong the 1093 participants, 68 (6.2%) children had diabetes with additional non-autoimmune extra-pancreatic features. In this syndromic cohort, 22% (15/68) found to have monogenic diabetes. The most common causes were WSF (n=3, 20%) and SLC19A2 (n=3, 20%). Of the 30/68 children with high T1D-GRS (>50th centile of T1D population), only 1 (1/30, 3%) was found to have monogenic diabetes compared to 14 (14/38, 37%) of the children with low T1D-GRS (<50th centile) (p=0.0009).Of those with monogenic diabetes, only 2 participants (2/15, 13.3%) would have been tested using current guidance as their clinical features were in keeping with recognised clinical syndromes (https://omim.org).Furthermore, clinician diagnosis of T1D or non-T1D proved to be an ineffective discriminator as 9/46 (19.6%) children with suspected T1D were found to have monogenic diabetes. This was similar in children with clinician suspicion of non-T1D (6/22, 27.3%, p=0.53).ConclusionOne in five children with diabetes and additional non-autoimmune features have monogenic diabetes. Many of these children do not display features in keeping with typical clinical syndromes and clinician predictions often fail to identify these cases. T1D-GRS is a useful, novel biomarker in these children. Our study recommends routine genetic testing for all children presenting diabetes alongside additional syndromic features. This approach can enable personalised and precise management strategies, ultimately leading to improved patient outcomes.ReferencesHattersley et al. ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents 2018.Patel et al. Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes 2016.Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls, The Wellcome Trust Case Control Consortium 2007.Patel et al. Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics 2022.

Background/ObjectivesIn recent years, oxytocin (OXT) and polymorphisms in the oxytocin receptor (OXTR) gene have been reported to play roles in obesity pathogenesis. However, there was no study evaluating OXTR gene variants in childhood obesity. The aim of the study was to investigate the relation of OXTR gene polymorphisms and serum OXT levels with metabolic and anthropometric parameters in obese and healthy adolescents.Subjects/MethodsThe study was a multi-centered case-control study, which was conducted on obese and healthy adolescents aged between 12 and 17 years. Serum OXT and leptin levels were measured, and OXTR gene variants were studied by qPCR (rs53576) and RFLP (rs2254298) methods.ResultsA total of 250 obese and 250 healthy adolescents were included in this study. In the obese group, serum OXT level was lower and leptin level was higher than the control group. In the obese group, frequencies of homozygous mutant (G/G) and heterozygous (A/G) genotypes for rs53576 polymorphism were higher than the control group. Homozygous mutant(G/G) and heterozygous (A/G) genotypes for rs53576 polymorphism were found to increase the risk of obesity compared to the wild type (A/A) genotype [OR = 6.05 and OR = 3.06; p < 0.001, respectively]. In patients with homozygous mutant (G/G) and heterozygous (A/G) genotype for rs53576 polymorphism, serum OXT levels were lower than the wild type (A/A) genotype. In the obese group, hyperphagia score was higher than the control group and correlated negatively with serum OXT level.ConclusionsThis study revealed that low serum OXT level, which is associated with hyperphagia may be an underlying cause for obesity in adolescents. For rs53576 polymorphism of the OXTR gene, obesity risk is higher in patients with homozygous mutant(G/G) and heterozygous(A/G)genotypes.

Aims/hypothesisCurrent 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.MethodsWe 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).ResultsThirty-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/interpretationRecessively 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.

Honey bees need pollen and nectar sources to survive in nature. Particularly, having young bees in colonies is vital before wintering, and proper feeding is necessary to achieve this. In the present study, the effect of feeding with pollen sources of different protein content on colony performance, wintering ability and in-vitro longevity of colonies that weakened after feeding with pine honey in autumn, or that needed to enter the winter period, was investigated. The experiment was carried out in 48 colonies divided into six groups as follows: control, syrup, mixed pollen, Cistus creticus pollen (Pink rock-rose), Papaver somniferum pollen (Opium poppy), and commercial bee cake groups. In particular, the P. somniferum pollen group was different (p < 0.01) from the other experiment groups with the number of bee frames (3.44), the area with brood (1184.14 cm2) and the wintering ability of 92.19%. The effect of nutritional differences on survival was found to be statistically significant in vitro and this supports the colony results in the natural environment (p < 0.001). The P. somniferum group has the longest longevity with 23 days. Pollen preferences of honey bees were P. somniferum, C. creticus, and mixed pollen, respectively.

Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed. Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions. Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families. This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood.

There are limited number of studies evaluating iron overload in childhood leukemia by magnetic resonance imaging (MRI). The aim of this study was to determine the liver iron content (LIC) by MRI in children with acute lymphoblastic leukemia (ALL), who had been completed treatment, and to compare with serum iron parameters. A total of 30 patients between the ages of 7 and 18 who completed ALL treatment were included in the study. Serum iron parameters [serum iron, serum ferritin (SF), and total iron binding capacity], liver function tests were studied. R2 MRI was performed for determining LIC. Normal LIC were detected in 22 (63.4%) of the cases. Seven (23.3%) had mild and 1 (3.3%) had moderate liver iron deposition. In contrast, severe iron overload was not detected in any of the cases. LIC levels were correlated with the numbers of packet red blood cell (pRBC) transfusions (r = 0.637, p <0.001), pRBC transfusion volume (r = 0.449, p <0.013), SF levels (r = 0.561, p = 0.001), transferrin saturation (r=0.353 , p = 0.044). In addition, a positive correlation was found between the number of pRBC transfusions and SF levels (r = 0.595, p <0.001). We showed that the frequency of liver iron deposition was low and clinically less significant after the end of the treatment in childhood ALL patients. LIC was demonstrated to be related with SF and transfusion history. These findings support that SF and transfusion history may be used as a reference for monitoring iron accumulation or identifying cases for further examination such as MRI.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare genetic disease mainly associated with Carney complex (CNC), which is caused by germline mutations of the regulatory subunit type I-alpha of the cAMP-dependent protein kinase ( ) gene. We report three cases suffering from CNC with unique features in diagnosis and follow-up. All cases had obesity and a cushingoid appearance and exhibited laboratory characteristics of hypercortisolism. However biochemical and radiological examinations initially suggested Cushing’s disease in one case. All of the cases were treated surgically; two of them underwent bilateral adrenalectomy at once, one of them had unilateral adrenalectomy at first but required contralateral adrenalectomy after nine months. Contrary to what is usually known regarding PPNAD, the adrenal glands of two cases (Case 2 and 3) had a macronodular morphology. Genetic analyses revealed pathogenic variants in (Case 1: c.440+5 G>A, not reported in the literature; cases 2 and 3: c.349G>T, p.V117F). One case developed Hodgkin lymphoma five year after adrenalectomy, this association was not previously reported with CNC. The findings of these families provides important information for a better understanding of the genetic pathogenesis, diagnosis, and clinical management of CNC. Hodgkin lymphoma may be a component of CNC.

To investigate the relationship between zonulin levels and clinical and laboratory parameters of childhood obesity. The study included obese children with a body mass index (BMI) >95 percentile and healthy children who were of similar age and gender distribution. Clinical (BMI, waist circumferences, mid-arm circumference, triceps skinfold, percentage of body fat, systolic blood pressure, diastolic blood pressure) and biochemical (glucose, insulin, lipid levels, thyroid function tests, cortisol, zonulin and leptin levels) parameters were measured. A total of 43 obese subjects (23 males, mean age: 11.1±3.1 years) and 37 healthy subjects (18 males, mean age: 11.5±3.5 years) were included in this study. Obese children had significantly higher insulin, homeostasis model assessment of insulin resistance, triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), zonulin and leptin levels than healthy children (p<0.05), while glucose levels were not different (p>0.05). Comparison of the obese children with and without insulin resistance showed no statistically significant differences for zonulin levels (p>0.05). Zonulin levels were found to negatively correlate with HDL-C and positively correlate with leptin levels, after adjusting for age and BMI. To the best of our knowledge, this is the first study investigating the relationship between circulating zonulin level (as a marker of intestinal permeability) and insulin resistance and leptin (as markers of metabolic disturbances associated with obesity) in childhood obesity. The results showed that zonulin was significantly higher in obese children when compared to healthy children, a finding indicating a potential role of zonulin in the etiopathogenesis of obesity and related disturbances.

Studies examining changes in thyroid function in the course of chronic liver disease have mostly been conducted in adults. The aim of this study was to investigate thyroid dysfunction in children with chronic liver diseases. Between 2005 and 2018, patients aged up to 18 years of age, diagnosed with chronic liver disease and had thyroid function test results available were included. Anthropometric characteristics, liver and thyroid function results were collected and analyzed. The study included 107 (53 female; 49.5%) patients aged between one month and 18 years-old. Of the 107 patients, 96 (89.7%) had normal thyroid function results, seven (6.5%) had subclinical hypothyroidism (SH) and four (3.7%) had euthyroid sick syndrome. Of the patients with SH, one (14.2%) had glycogen storage diasease, one (14.2%) had biliary atresia, one (14.2%) had undiagnosed cholestatic liver disease, one (14.2%) had Alagille syndrome, one (14.2%) had idiopatic hepatitis, one (14.2%) had progressive familial intra-hepatic cholestasis and one (14.2%) had congenital hepatic fibrosis. Spearman correlation analysis showed a negative correlation between free tri-iodothyronine and direct bilirubin (r=-0.329, p=0.027). In conclusion, euthyroid sick syndrome or SH may affect up to 10% of children with chronic liver diseases. It is suggested that thyroid function should be evaluated in cases of pediatric chronic liver disease at diagnosis and during follow-up. Moreover, this study is the first to show a negative correlation between free T3 levels and direct bilirubin, suggesting a possible association between liver disease severity and thyroid function.