Telemedicine maintains good glucose control in children with type 1 diabetes but is not time saving for healthcare professionals: KITES randomized study.

AIMS: To evaluate glucose control non-inferiority and time benefits of telemedicine follow-up in children with type 1 diabetes (CwD). METHODS: In a single-center 9-month-long randomized controlled study (clinicaltrials.gov NCT05484427), 50 children were randomized to either telemedicine group (TG) followed-up distantly by e-mail, or to face-to-face group (FFG) attending standard personal visits. The primary endpoint was non-inferiority of HbA1c at final visit (level of non-inferiority was set at 5 mmol/mol). The secondary endpoints were subcutaneous glucose monitoring parameters and time consumption from both study subjects' and the physicians' point of view. RESULTS: Non-inferiority of HbA1c in the TG was proven (mean HbA1C 45.8 ± 7.3 [TG] vs. 50.0 ± 12.6 [FFG] mmol/mol, 6.3 vs. 6.7 % DCCT, p = 0.17; between groups HbA1C difference 95 % CI -10.2 to 1.9 mmol/mol). Telemedicine saved time for participants (mean visit duration [MVD] 50 [TG] vs. 247 min [FFG], p < 0.001). There were no other differences between groups neither in CGM parameters nor physician's time consumption (MVD 19 [TG] vs. 20 min [FFG], p = 0.58). CONCLUSIONS: Nine-month telemedicine follow-up of the children with well-controlled T1D is not inferior to standard face-to-face visits. Telemedicine visits saved time for the participants but not for their diabetologists.

Genetic testing of children with familial tall stature: is it worth doing?

CONTEXT: Familial tall stature (FTS) is considered to be a benign variant of growth with a presumed polygenic etiology. However, monogenic disorders with possible associated pathological features could also be hidden under the FTS phenotype. OBJECTIVES: To elucidate the genetic etiology in families with FTS and to describe their phenotype in detail. DESIGN, SETTINGS AND PATIENTS: Children with FTS (height in both the child and his/her taller parent >2 SD) referred to the Endocrinology center of Motol University Hospital were enrolled to the study. Their DNA was examined cytogenetically and via next-generation sequencing panel of 786 genes associated with growth. The genetic results were evaluated by the American College of Molecular Genetics and Genomics guidelines. All of the participants underwent standard endocrinological examination followed by specialized anthropometric evaluation. RESULTS: In total, 34 children (19 girls) with FTS were enrolled in the study. Their median height and their taller parent's height were 3.1 SD and 2.5 SD, respectively. The genetic cause of FTS was elucidated in 11/34 (32.4%) children (47, XXX and 47, XYY karyotypes, SHOX duplication, and causative variants in NSD1 [in 2], SUZ12 [in 2], FGFR3, CHD8, GPC3, and PPP2R5D genes). Ten children had absent syndromic sings and 24 had dysmorphic features. CONCLUSION: Monogenic (and cytogenetic) etiology of FTS can be found among children with FTS. Genetic examination should be considered in all children with FTS regardless of the presence of dysmorphic features.

SALL4 Phenotype in Four Generations of One Family: An Interplay of the Upper Limb, Kidneys, and the Pituitary.

INTRODUCTION: The SALL4 gene encodes a transcription factor that is essential for early embryonic cellular differentiation of the epiblast and primitive endoderm. It is required for the development of neural tissue, kidney, heart, and limbs. Pathogenic SALL4 variants cause Duane-radial ray syndrome (Okihiro syndrome), acro-renal-ocular syndrome, and Holt-Oram syndrome. We report a family with vertical transmission of a SALL4 pathogenic variant leading to radial hypoplasia and kidney dystopia in several generations with additional growth hormone deficiency (GHD) in the proband. CASE PRESENTATION: Our male proband was born at the 39th week of gestation. He was born small for gestational age (SGA; birth weight 2,550 g, -2.2 SDS; length 47 cm, -2.0 SDS). He had bilateral asymmetrical radial ray malformation (consisting of radial hypoplasia, ulnar flexure, and bilateral aplasia of the thumb) and pelvic kidney dystopia, but no cardiac malformations, clubfoot, ocular coloboma, or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 µg/L (-1.0 SD), and growth hormone (GH) after stimulation 6.2 µg/L. Other pituitary hormones were normal. A brain CT revealed normal morphology of the cerebral midline and the pituitary. He had a dental anomaly - a central mandibular ectopic canine. MRI could not be done due to the presence of metal after multiple corrective plastic surgeries of his hands. His mother's and father's heights are 152.3 cm (-2.4 SD) and 177.8 cm (-0.4 SD), respectively. His father has a milder malformation of the forearm. The affected paternal grandfather (height 164 cm; -2.3 SD) has a radial ray defect with missing opposition of the thumb. The family reports a similar phenotype of radial dysplasia in the paternal grandfather's mother. The proband started GH therapy at age 6.5 years when his height was 109 cm (-2.8 SDS) and he experienced catch-up growth as expected in GHD. Puberty started spontaneously at the age of 12.5 years. At age 13, his height was 158.7 cm (-0.2 SDS). Whole-exome sequencing revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. CONCLUSION: This is the first observation of a patient with a congenital upper limb defect due to a pathogenic SALL4 variant who has isolated GHD with no apparent cerebral or facial midline anomaly and has been successfully treated with growth hormone.

The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature.

INTRODUCTION: Among children born small for gestational age, 10-15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. METHODS: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <-2 SD for gestational age and life-minimum height <-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. RESULTS: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. CONCLUSIONS: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.

Analysis of children with familial short stature: who should be indicated for genetic testing?

Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤-2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader-Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, 4 (11%) a variant affecting GH-insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent's height (P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent's heights ≤-2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, and gene variants affecting the growth plate are the most common. Shorter parent's height and BA are clinical predictors of monogenic FSS.

First Use of Open-Source Automated Insulin Delivery AndroidAPS in Full Closed-Loop Scenario: Pancreas4ALL Randomized Pilot Study.

Objective: We evaluated the safety and feasibility of open-source automated insulin delivery AndroidAPS in adolescents and young adults with type 1 diabetes (T1D) and compared its efficacy in three different scenarios: hybrid closed loop (HCL) with meal boluses, meal announcement only (MA), and full closed loop (FCL). Research Design and Methods: In an open-label, prospective, randomized crossover trial (clinicaltrials.gov NCT04835350), 16 adolescents with T1D (10 females) with mean age of 17 years (range 15-20), glycated hemoglobin 56 mmol/mol (range 43-75), and mean duration of diabetes 5.9 years (9-15) underwent three distinct 3-day periods of camp living, comparing the above-mentioned scenarios of AndroidAPS. We used modified and locked version of AndroidAPS 3.1.03, which was called Pancreas4ALL for study purposes. The order of MA and FCL periods was assigned randomly. The primary endpoints were feasibility and safety of the system represented by percentage of time of glucose control by the system and time in hypoglycemia below 3 mmol/L. Results: The glycemia was controlled by the system 95% time of the study and the proportion of time below 3 mmol/L did not exceed 1% over the whole study period (0.72%). The HCL scenario reached significantly higher percentage of time below 3 mmol/L (HCL 1.05% vs. MA 0.0% vs. FCL 0.0%; P = 0.05) compared to other scenarios. No difference was observed among the scenarios in the percentage of time between 3.9 and 10 mmol/L (HCL 83.3% vs. MA 79.85% vs. FCL 81.03%, P = 0.58) corresponding to mean glycemia (HCL 6.65 mmol/L vs. MA 7.34 mmol/L vs. FCL 7.05 mmol/L, P = 0.28). No difference was observed in the mean daily dose of insulin or in the daily carbohydrate intake. No serious adverse event occurred during the study period. Conclusions: Our pilot study showed that FCL might be a realistic mode of treatment for people with T1D.

Changes in the gut bacteriome upon gluten-free diet intervention do not mediate beta cell preservation.

AIMS/HYPOTHESIS: We previously detected indications that beta cell function is protected by gluten-free diet (GFD) introduced shortly after the onset of childhood type 1 diabetes. The present aim was to assess whether GFD was associated with changes in the gut bacteriome composition and in its functional capacity, and whether such changes mediated the observed effects of GFD on beta cell function. METHODS: Forty-five children (aged 10.2 ± 3.3 years) were recruited into a self-selected intervention trial primarily focused on determining the role of GFD on beta cell preservation ( ClinicalTrials.gov NCT02867436). Stool samples were collected prior to the dietary intervention and then at 3-month intervals. A total of 128 samples from the GFD group and 112 from the control group were analysed for bacteriome 16S rDNA community profiles, the bacteriome functional capacity was predicted using PICRUSt2 and actual gut metabolome profiles measured using NMR. Intestinal permeability was assessed using serum zonulin concentrations at 1, 6 and 12 months and lactulose/mannitol tests at the end of intervention. Dietary questionnaires were used to ensure that the dietary intervention did not result in differences in energy or nutrient intake. RESULTS: The bacteriome community composition changed during the intervention with GFD: of abundant genera, a 3.3-fold decrease was noted for Bifidobacterium genus (adjusted p=1.4 × 10-4 in a DESeq2 model, p=0.026 in generalised estimating equations model), whereas a 2.4-fold increase was observed in Roseburia (adjusted p=0.02 in DESeq2 model, p=0.002 in generalised estimating equations model). The within-sample (alpha) diversity did not change, and there was no statistically significant clustering of GFD samples in the ordination graphs of beta diversity. Neither of the genera changes upon GFD intervention showed any association with the pace of beta cell loss (p>0.50), but of the remaining taxa, several genera of Bacteroidaceae family yielded suggestive signals. The faecal metabolome profile ordination correlated with that of bacteriomes but did not associate with GFD or categories of beta cell preservation. There was no indication of changes in gut permeability. CONCLUSIONS/INTERPRETATION: The bacteriome reacted to GFD, but the changes were unrelated to the pace of beta cell capacity loss. The previously observed moderately protective effect of GFD is therefore mediated through other pathways.

Isolated growth hormone deficiency in children with vertically transmitted short stature: What do the genes tell us?

Introduction: The growth hormone deficiency (GHD) diagnosis is controversial especially due to low specificity of growth hormone (GH) stimulation tests. It is therefore believed that children diagnosed with GHD form a heterogeneous group with growth disorder frequently independent on GH function. No study evaluating the complex etiology of growth failure in children with diagnosed GHD has been performed thus far. Aims: To discover genetic etiology of short stature in children with diagnosed GHD from families with short stature. Methods: Fifty-two children diagnosed with primary GHD and vertically transmitted short stature (height SDS in the child and his/her shorter parent <-2 SD) were included to our study. The GHD diagnosis was based on growth data suggestive of GHD, absence of substantial disproportionality (sitting height to total height ratio <-2 SD or >+2 SD), IGF-1 levels <0 for age and sex specific SD and peak GH concentration <10 ug/L in two stimulation tests. All children were examined using next-generation sequencing methods, and the genetic variants were subsequently evaluated by American College of Medical Genetics standards and guidelines. Results: The age of children at enrollment into the study was 11 years (median, IQR 9-14 years), their height prior to GH treatment was -3.0 SD (-3.6 to -2.8 SD), IGF-1 concentration -1.4 SD (-2.0 to -1.1 SD), and maximal stimulated GH 6.3 ug/L (4.8-7.6 ug/L). No child had multiple pituitary hormone deficiency or a midbrain region pathology. Causative variant in a gene that affects growth was discovered in 15/52 (29%) children. Of them, only 2 (13%) had a genetic variant affecting GH secretion or function (GHSR and OTX2). Interestingly, in 10 (67%) children we discovered a primary growth plate disorder (ACAN, COL1A2, COL11A1, COL2A1, EXT2, FGFR3, NF1, NPR2, PTPN11 [2x]), in one (7%) a genetic variant impairing IGF-1 action (IGFALS) and in two (12%) a variant in miscellaneous genes (SALL4, MBTPS2). Conclusions: In children with vertically transmitted short stature, genetic results frequently did not correspond with the clinical diagnosis of GH deficiency. These results underline the doubtful reliability of methods standardly used to diagnose GH deficiency.

Low-Carbohydrate Diet among Children with Type 1 Diabetes: A Multi-Center Study.

AIMS/HYPOTHESIS: The proportion of children with type 1 diabetes (T1D) who have experience with low-carbohydrate diet (LCD) is unknown. Our goal was to map the frequency of LCD among children with T1D and to describe their clinical and laboratory data. METHODS: Caregivers of 1040 children with T1D from three centers were addressed with a structured questionnaire regarding the children's carbohydrate intake and experience with LCD (daily energy intake from carbohydrates below 26% of age-recommended values). The subjects currently on LCD were compared to a group of non-LCD respondents matched to age, T1D duration, sex, type and center of treatment. RESULTS: A total of 624/1040 (60%) of the subjects completed the survey. A total of 242/624 (39%) subjects reported experience with voluntary carbohydrate restriction with 36/624 (5.8%) subjects currently following the LCD. The LCD group had similar HbA1c (45 vs. 49.5, p = 0.11), lower average glycemia (7.0 vs. 7.9, p = 0.02), higher time in range (74 vs. 67%, p = 0.02), lower time in hyperglycemia >10 mmol/L (17 vs. 20%, p = 0.04), tendency to more time in hypoglycemia <3.9 mmol/L(8 vs. 5%, p = 0.05) and lower systolic blood pressure percentile (43 vs. 74, p = 0.03). The groups did not differ in their lipid profile nor in current body height, weight or BMI. The LCD was mostly initiated by the parents or the subjects themselves and only 39% of the families consulted their decision with the diabetologist. CONCLUSIONS/INTERPRETATION: Low carbohydrate diet is not scarce in children with T1D and is associated with modestly better disease control. At the same time, caution should be applied as it showed a tendency toward more frequent hypoglycemia.

Pre-school and school-aged children benefit from the switch from a sensor-augmented pump to an AndroidAPS hybrid closed loop: A retrospective analysis.

OBJECTIVE: Data on closed loop systems in young children with type 1 diabetes (T1D) are limited. We tested the efficacy and safety of an open-source, do-it-yourself automated insulin delivery system AndroidAPS in preschool and school-aged children. RESEARCH DESIGN AND METHODS: This retrospective study analyzed diabetes control in 18 preschool (3-7 years) and 18 school-aged children (8-14 years) with T1D who switched from a sensor-augmented pump (SAP) to AndroidAPS. We compared the CGM parameters and HbA1c levels 3 months before and 6 months after the initiation of AndroidAPS therapy and evaluated frequency of severe adverse events during AndroidAPS use, the most frequent reasons for its interruption, and the experience and psychosocial benefits of AndroidAPS use. RESULTS: General glycemic control was significantly improved after the switch from SAP to AndroidAPS. Time in range (TIR) increased in both preschool (70.8%-78.6%, p = 0.004) and school-aged children (77.2%-82.9%, p < 0.001), whereas HbA1c levels decreased (preschool children 53.8-48.5 mmol/mol, p < 0.001; school-aged children 52.6-45.1 mmol/mol, p = 0.001). Time spent in range of 3.0-3.8 mmol/L increased slightly in school children (2.6%-3.8%, p = 0.040), but not in preschool children (3.0%-3.0%, p = 0.913). Time spent at <3 mmol/L remained unchanged in both preschool (0.95%-0.67%, p = 0.432) and school-aged children (0.8%-0.8%, p = 1.000). No episodes of severe hypoglycemia or DKA and significant improvement of quality of life were reported by AndroidAPS users. CONCLUSIONS: AndroidAPS seems effective for T1D control both in preschool and school-age children but further validation by prospective studies is necessary.

Familial Short Stature-A Novel Phenotype of Growth Plate Collagenopathies.

CONTEXT: Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X, and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with short stature. Less is known about oligosymptomatic collagenopathies. OBJECTIVE: This work aims to evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. METHODS: Eighty-seven FSS children (pretreatment height ≤ -2 SD both in the patient and his or her shorter parent) treated with GH were included in the study. Next-generation sequencing was performed to search for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes. The results were evaluated using American College of Medical Genetics and Genomics guidelines. The GH treatment response of affected children was retrospectively evaluated. RESULTS: A likely pathogenic variant in the collagen gene was found in 10 of 87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2 of 10 and 4 of 10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after 1 year of treatment. Their height improved from a median of -3.1 SD to -2.6 SD and to -2.2 SD after 1 and 3 years of therapy, respectively. The final height reached by 4 of 10 children differed by -0.67 to +1.0 SD and -0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent's height, respectively. CONCLUSION: Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.

Semen analysis and treatment risk factors in long-term survivors of childhood cancer.

The objective of this study was to compare semen quality (sperm density, progressive motility and spermia) between long-term childhood cancer survivors and a control group of males. The second objective was to correlate the semen analysis of the survivors with cancer treatment and endocrine status. The semen quality of 143 survivors (median age, 23.6 years) was compared to 200 men (median age, 27.9 years) who had not been diagnosed with cancer. The cancer-related risk factors and gonadotrophin levels were compared. Overall, 65% of the survivors had abnormal semen analysis compared to 26.5% of the controls (p < 0.0001). Survivors with nonaspermia had lower sperm density than the controls (p < 0.001). Other observed correlations were not significant. Survivors who were treated with alkylating agents were more likely to have abnormal semen analysis (p < 0.008). Follicle-stimulating hormone and luteinising hormone levels were significantly elevated (p < 0.0001) in survivors with abnormal semen analysis. The semen quality parameters, except for low sperm density, did not differ in survivors with nonaspermia compared to the controls. The risk factors included treatment with alkylating agents. Elevated gonadotrophin levels correlated with abnormal semen analysis. All cancer survivors should be made aware of the possibility of suffering from cancer treatment-related infertility.

Myeloid - derived suppressor cells in Type 1 diabetes are an expanded population exhibiting diverse T-cell suppressor mechanisms.

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-ß production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.

Newborn screening-detected 21-hydroxylase deficiency: growth pattern is not associated with the genotype.

BACKGROUND: Normalising growth in children with congenital adrenal hyperplasia due to 21- hydroxylase deficiency (21OHD-CAH) requires a long-term maintenance of a fragile balance between hydrocortisone (HC) replacement and androgen suppression. The growth pattern inchildren with 21OHD-CAH diagnosed by clinical symptoms has been evaluated in numerous retrospective studies. The aim of this study was to evaluate growth of patients with 21OHD-CAH detected by newborn screening (NBS), prior to clinical symptoms. METHODS: Nation-wide NBS for 21OHD-CAH was implemented in the Czech Republic in 2006. Since then, 1,317,987 neonates were screened (2006-2017) and 21OHD-CAH was confirmed in 108 patients. Growth was evaluated as height-standard deviation score (SDS) at regular time-points, related to bone age and compared to recent population standards. In 88 patients, available data allowed long-term evaluation of growth, HC and fludrocortisone doses (in half-year intervals), with a median observation period of ten years. RESULTS: Body height in affected children was shorter between years 1-9 of life with a nadir at age 1-3 years. Their height did not differ from general population at the age 10-12 years. There were not found differencies according to 21OHD-CAH severity. CONCLUSIONS: NBS is an effective secondary prevention tool for the early detection of 21OHD-CAH which improves growth patterns. A significant growth deceleration was observed during infancy and early childhood periods but with following height normalization. Growth pattern was not associated with the genotype of 21OHD, if patients have been detected by NBS.

Gluten-free diet in children with recent-onset type 1 diabetes: A 12-month intervention trial.

AIM: To test whether a gluten-free diet (GFD) is associated with the deceleration of the decline in beta-cell capacity in non-coeliac children with recently diagnosed type 1 diabetes. METHODS: Forty-five children (aged 10.2 ± 3.3 years) were recruited into a self-selected intervention trial: 26 started with a GFD within a median of 38 days postonset, whereas 19 remained on a standard diet. The main outcomes were the decline in C-peptide area under the curve (AUC) in mixed-meal tolerance tests (MMTTs) at 6 and 12 months relative to 1 month after diabetes onset and the difference in insulin dose, insulin dose-adjusted A1c (IDAA1c) and HbA1c assessed every 3 months. The adherence to the GFD was verified by immunoreactive gluten in the stool and by food questionnaires at every visit. Quality of life (QoL) questionnaires were administered to the participants at the end of the intervention at 12 months. The data were analysed as per protocol (in 39 subjects who duly completed the whole follow-up: 20 in the GFD group, 19 in the control group) by linear and longitudinal regression models adjusted for sex, age and baseline variables. RESULTS: At 12 months, the difference in C-peptide AUC between subjects in the GFD group and controls was 205 pmol/L (95% CI -223 to 633; P = 0.34) in a model adjusted for age, sex and body weight, and for baseline insulin dose, MMTT C-peptide AUC and HbA1c assessed at 1 month after diagnosis. In a longitudinal analysis of all three time points adjusted for age, sex and body weight, C-peptide declined more slowly in the GFD group than in controls, with the difference in trends being 409 pmol/L/year (P = 0.04). The GFD group had a marginally lower insulin dose (by 0.15 U/kg/day; P = 0.07), a lower IDAA1c (by 1.37; P = 0.01) and a lower mean HbA1c (by 0.7% [7.8 mmol/mol]; P = 0.02) than those of the controls at 12 months. There was no appreciable difference between the groups in daily carbohydrate intake (P = 0.49) or in the QoL reported by the patients (P = 0.70) and their parents/caregivers (P = 0.59). CONCLUSIONS: A GFD maintained over the first year after type 1 diabetes diagnosis was associated with better HbA1c and a prolonged partial remission period. There was a hint of slower C-peptide decline but the association was not strong enough to make definite conclusions.

NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy.

CONTEXT: The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results. OBJECTIVES: To identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response. DESIGN, SETTINGS AND PATIENTS: Out of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height ≤ -2 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated. RESULTS: In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment. CONCLUSIONS: NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.

Changes in innate and adaptive immunity over the first year after the onset of type 1 diabetes.

AIMS: The development of the immune phenotype in patients with type 1 diabetes (T1D) during the first year following disease onset remains poorly described, and studies analysing the longitudinal development of a complex set of immunological and metabolic parameters are missing. Thus, we aim to provide such complex view in a cohort of 38 children with new onset T1D who were prospectively followed for 1 year. METHODS: All subjects were tested for a set of immunological parameters (complete blood count; serum immunoglobulins; and T, B and dendritic cells), HbA1c and daily insulin dose at baseline and at 6 and 12 months after T1D diagnosis. A mixed meal tolerance test was administered to each of the subjects 12 months after diagnosis, and the C-peptide area under the curve (AUC) was noted and was then tested for association with all immunological parameters. RESULTS: A gradual decrease in leukocytes (adjusted p = 0.0012) was reflected in a significant decrease in neutrophils (adjusted p = 0.0061) over the post-onset period, whereas Tregs (adjusted p = 0.0205) and originally low pDCs (adjusted p < 0.0001) increased. The expression of the receptor for BAFF (BAFFR) on B lymphocytes (adjusted p = 0.0127) markedly increased after onset. No immunological parameters were associated with C-peptide AUC; however, we observed a linear increase in C-peptide AUC with the age of the patients (p < 0.0001). CONCLUSIONS: Our study documents substantial changes in the innate and adaptive immune system over the first year after disease diagnosis but shows no association between immunological parameters and residual beta-cell activity. The age of patients remains the best predictor of C-peptide AUC, whereas the role of the immune system remains unresolved.

Primary School Performance of Girls with Turner Syndrome: A Transcultural Assessment.

OBJECTIVES: We analyzed primary school performance of girls with Turner syndrome (TS) in two distinct countries to ascertain if the cognitive phenotype of TS causes selective learning difficulties. METHODS: The cohort comprised of 44 Czech and 50 Egyptian girls with TS who attended public schools. School reports from grades 1 to 9 were obtained retrospectively from Czech participants with TS. Only recent school reports were obtained from Egyptian participants. Two controls per participant were requested - biological sisters and/or female classmates. The results were converted into a 5-point scale (1-excellent; 5-unsatisfactory). RESULTS: Analysis of longitudinal Czech data displayed a strong time component in both subjects and controls. Showing better points in lower grades with its gradual worsening as the education complexity increased. In contrast, there was a strong statistically significant difference between groups in Mathematics (p=0.0041, p=0.0205 after Bonferroni correction) and this difference increased over time. The points for Mathematics did not differ in grades 1+2 (0.05 difference in mean grade between the two groups), however, they differed by 0.28 in grades 6+7 and by 0.32 in grades 8+9. While slightly different in character (cross-sectional vs. longitudinal), the Egyptian cohort data confirmed our findings, showing no difference in general school performance but having similar trends in Mathematics (grades 1+2: 0.11, grades 6+7: 0.54, grades 8+9: 0.68; p=0.0058, p=0.029 after Bonferroni correction). CONCLUSION: Excluding results in Mathematics, which showed pronounced worsening in relation to age in comparison with unaffected controls, girls with TS performed similarly to their controls.

Screening of monogenic autoimmune diabetes among children with type 1 diabetes and multiple autoimmune diseases: is it worth doing?

Background Paediatric type 1 diabetes (T1D) and rare syndromes of monogenic multi-organ autoimmunity share basic features such as full insulin dependency and the presence of circulating beta-cell autoantibodies. However, the aetiopathogenesis, natural course and treatment of these conditions differ; therefore, monogenic multi-organ autoimmunity requires early recognition. We aimed to search for these monogenic conditions among a large cohort of children with T1D. Methods Of 519 children with T1D followed-up in a single centre, 18 had multiple additional autoimmune conditions - either autoimmune thyroid disease (AITD) and coeliac disease (CD) or at least one additional organ-specific autoimmune condition in addition to AITD or CD. These 18 children were tested by direct Sanger sequencing (four patients with a suggestive phenotype of immune dysregulation, polyendocrinopathy, enteropathy, X-linked [IPEX] or signal transducer and activator of transcription 3 [STAT3]- and cytotoxic T-lymphocyte protein 4 [CTLA4]-associated syndromes) or by whole-exome sequencing (WES) focused on autoimmune regulator (AIRE), forkhead box protein 3 (FOXP3), CTLA4, STAT3, signal transducer and activator of transcription 1 (STAT1), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) and interleukin-2 receptor subunit α (IL2RA) genes. In addition, we assessed their T1D genetic risk score (T1D-GRS). Results We identified novel variants in FOXP3, STAT3 and CTLA4 in four cases. All patients had a severe phenotype suggestive of a single gene defect. No variants were identified in the remaining 14 patients. T1D-GRS varied among the entire cohort; four patients had scores below the 25th centile including two genetically confirmed cases. Conclusions A monogenic cause of autoimmune diabetes was confirmed only in four patients. Genetic screening for monogenic autoimmunity in children with a milder phenotype and a combination of AITD and CD is unlikely to identify a monogenic cause. In addition, the T1D-GRS varied among individual T1D patients.

High Prevalence of Growth Plate Gene Variants in Children With Familial Short Stature Treated With GH.

CONTEXT: Familial short stature (FSS) is a term describing a growth disorder that is vertically transmitted. Milder forms may result from the combined effect of multiple genes; more severe short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not been thoroughly elucidated to date. OBJECTIVES: To identify the genetic etiology of severe FSS in children treated with GH because of the diagnosis of small for gestational age or GH deficiency (SGA/GHD). DESIGN, SETTINGS, AND PATIENTS: Of 736 children treated with GH because of GHD/SGA, 33 with severe FSS (life-minimum height -2.5 SD or less in both the patient and shorter parent) were included in the study. The genetic etiology was known in 5 of 33 children prior to the study [ACAN (in 2], NF1, PTPN11, and SOS1). In the remaining 28 of 33, whole-exome sequencing was performed. The results were evaluated using American College of Medical Genetics and Genomics standards and guidelines. RESULTS: In 30 of 33 children (90%), we found at least one variant with potential clinical significance in genes known to affect growth. A genetic cause was elucidated in 17 of 33 (52%). Of these children, variants in growth plate-related genes were found in 9 of 17 [COL2A1, COL11A1, and ACAN (all in 2), FLNB, FGFR3, and IGF1R], and IGF-associated proteins were affected in 2 of 17 (IGFALS and HMGA2). In the remaining 6 of 17, the discovered genetic mechanisms were miscellaneous (TRHR, MBTPS2, GHSR, NF1, PTPN11, and SOS1). CONCLUSIONS: Single-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.