Arginine-stimulated copeptin in children and adolescents.

OBJECTIVE: Copeptin is secreted in isomolar amounts along with arginine vasopressin peptide (AVP) from the neurohypophysis. Its stability makes it a perfect candidate for the endocrine approach in the diagnosis of AVP deficiency (AVPD; cranial diabetes insipidus; CDI). However, pediatric reference values are lacking. DESIGN AND PATIENTS: This is a monocentric retrospective analysis of donated residual serum samples from 72 children and adolescents who underwent arginine or growth hormone-releasing hormone-arginine stimulation to test GH secretory capacity from 2018 to 2022. MEASUREMENTS: Copeptin was measured in baseline, 30-, and 60-min samples by BRAHMS Copeptin proAVP Kryptor immunofluorescence assay. RESULTS: Of the 72 patients, 4 suffered from complete AVPD (CDI). The baseline level of copeptin in the 68 non-AVPD (non-CDI) patients was highly variable (range: 1.3-44.4 pmol/L). The increase after arginine was moderate (30 min range: 1.6-40.4 pmol/L). The median baseline and peak copeptin levels were 5.6 and 8.0 pmol/L, respectively. The 2.5th percentile of the baseline and peak values of copeptin were 2.1 and 3.3 pmol/L, respectively. The increase and peak value of copeptin were inversely related to age (R = -.405; p = .011, and R = -.335; p = .0072, respectively) but not to gender, body mass index (standard deviation score) or GH secretion. In the four patients with AVPD (CDI), baseline or stimulated copeptin was below the 2.5th percentile of non-AVPD (non-CDI) patients. CONCLUSIONS: Stimulated copeptin is a promising parameter for the differential diagnosis of polyuria-polydipsia syndrome. However, the low copeptin increase after arginine and the high limit of quantification of the assay are problematic for use in paediatrics.

Adult height after treatment of neurosecretory dysfunction and comparison to idiopathic GHD.

OBJECTIVE: Neurosecretory dysfunction (NSD) causes growth hormone deficiency (GHD). Data on adult height after recombinant human growth hormone (rhGH) treatment are lacking. DESIGN AND PATIENTS: We collected treatment data of all patients with NSD seen between 1990 and 2017 at our outpatient department (tertiary centre) and measured adult height. For comparison, patients with idiopathic GHD were used. Diagnoses were based on short stature (<-2 standard deviation score [SDS]), continuously low height velocity (<25th percentile), delayed bone age (by >1 SD) and low serum IGF-1 concentration (<-2 SDS). NSD was defined by normal GH challenge results, but subnormal spontaneous GH secretion. Exclusion criteria were no information on adult height, underweight and other short stature disorders. RESULTS: Out of 67 patients diagnosed with NSD, six were still growing, 31 had test results exceeding validated GH cut-offs and three had other disorders causing short stature. Out of the 25 eligible patients with NSD, 21 could be recruited. These patients reached an adult height of -0.85 SDS (mean); 0.34 SDS below midparental height. Height gain during treatment was 2.01 SDS. This outcome was not different to 32 patients with idiopathic GHD. CONCLUSIONS: Long-term results suggest the viability of the diagnosis of NSD and the efficacy of rhGH treatment.

Changes in body composition in male adolescents with childhood-onset GH deficiency during transition.

OBJECTIVE: Restarting rhGH in adolescents with childhood-onset (CO-) GHD is usually based on GH retest, IGF-1, additional pituitary hormone deficiencies, pituitary morphology and history. Short-term changes in body composition in adolescents with CO-GHD when off rhGH may contribute to the identification of those in need of treatment continuation. DESIGN: This is a longitudinal single-centre study. PATIENTS AND MEASUREMENTS: The body composition of 90 male adolescents with low-likelihood severe GHD of adolescence was measured by DXA at the time of rhGH discontinuation and 6 months thereafter. At diagnosis, mean age was 5.4 years, height was -2.68 SDS and stimulated GH peak was 5.1 ng/mL. RhGH treatment was stopped at 16.7 years at near-final height of -0.44 SDS. The adolescents were re-examined after 3 months off rhGH using both IGF-1 and GHRH-arginine tests. Severe GHD of adolescence was defined both by stimulated GH < 16 ng/mL and by IGF-1 < -1.90 SDS. RESULTS: Males with severe GHD of adolescence (n = 8) gained more relative and absolute fat mass and lost significantly more relative lean body mass after 6 months off rhGH than healthy individuals (n = 82; P < 0.001). The sum of absolute fat mass gain and lean body mass loss (=body composition changes score; BCC score) correlated highly with the GH peak (R = 0.17; P < 0.001). A BCC score >7.0 kg was 88% sensitive and 94% specific for detecting severe GHD of adolescence (AUC = 0.975). CONCLUSIONS: Short-term body composition changes when off rhGH are good clinical markers of severe GHD in male adolescents. The novel BBC score is an aggregate of these changes.

Paternally Inherited IGF2 Mutation and Growth Restriction.

In humans, mutations in IGF1 or IGF1R cause intrauterine and postnatal growth restriction; however, data on mutations in IGF2, encoding insulin-like growth factor (IGF) II, are lacking. We report an IGF2 variant (c.191C→A, p.Ser64Ter) with evidence of pathogenicity in a multigenerational family with four members who have growth restriction. The phenotype affects only family members who have inherited the variant through paternal transmission, a finding that is consistent with the maternal imprinting status of IGF2. The severe growth restriction in affected family members suggests that IGF-II affects postnatal growth in addition to prenatal growth. Furthermore, the dysmorphic features of affected family members are consistent with a role of deficient IGF-II levels in the cause of the Silver-Russell syndrome. (Funded by Bundesministerium für Bildung und Forschung and the European Union.).

Surgical treatment of children with total colonic aganglionosis: functional and metabolic long-term outcome.

BACKGROUND: Total colonic aganglionosis (TCA) is a rare variant of Hirschsprung's disease occurring in 3-10% of the cases. Only few studies reported the long-term clinical and metabolic outcomes of patients with TCA. The aim of this study was to evaluate the functional and metabolic long-term outcomes of children undergoing surgical treatment for TCA. METHODS: A 15-year retrospective study was performed. Blood chemistry tests and stool analysis performed at the last follow-up visit were recorded. Height and weight development were assessed using the corresponding percentiles for age. Faecal continence and quality of life were evaluated using a detailed questionnaire. RESULTS: Eleven patients were included in the study. The median age at surgery was 6 months (range: 3-72 months). After histological confirmation, all patients underwent a total colectomy. Ileoanal anastomosis (n = 6), ileorectal anastomosis (n = 1), J-pouch (n = 1) and Duhamel procedure (n = 3) were performed. Temporary ileostomy was closed after a median of 8 weeks in 10/11 patients. After a median follow-up of 78 months (range: 27-199 months), all evaluated patients were continent. Height and weight were appropriate for age in only 5 patients. Vitamin B12 and folic acid serum levels were normal in all examined patients. Ten patients had normal hemoglobin serum levels. Seven patients had low transferrin saturation in serum. Hemoccult tests were negative in all examined patients. Despite complex postoperative courses in some cases, patients and parents showed good overall satisfaction in terms of quality of life. CONCLUSION: The majority of patients reported a good quality of life. This can result from the adaptation of the patients to certain disease states. The failure to thrive seems to be related with the extent of aganglionosis. The inclusion of these patients in interdisciplinary long-term follow-up care, in which pediatric surgeons, gastroenterologists, and dieticians are involved, is essential.

MILK COMPOSITION OF INDIAN RHINOCEROS ( RHINOCEROS UNICORNIS) AND CHANGES OVER LACTATION.

The objective of this study was to determine the major nutrient composition of Indian rhinoceros milk ( Rhinoceros unicornis) over the first 13 mo of an 18-mo lactation period and to compare the results to those of previous studies on rhinoceros, African elephant ( Loxodonta africana), and horse milk ( Equus ferus caballus). The following parameters were measured: dry matter (DM), crude ash (ASH), crude protein (CP), ether extract (EE), nitrogen-free extract (NFE; calculated), lactose, calcium (Ca), phosphorus (P), magnesium (Mg), fatty acids (FAs), and gross energy (GE). DM, ASH, CP, and EE were determined with a proximate analysis, lactose with infrared spectroscopy and an enzymatic method, minerals with an autoanalyzer, FA with gas chromatography, and GE with bomb calorimetry. Milk samples were collected from two Indian rhinoceros cows from Zoo Basel. Rhino A gave birth to her third calf on 10 September 2012; three samples were collected and analyzed (colostrum, milk 1 wk and 2 wk postpartum). Rhino B gave birth to her eighth calf on 05 October 2013; samples were collected and 15 were chosen for the analyses (from colostrum to 13 mo postpartum). The composition of rhino B's colostrum was 13.8% DM (wet-weight basis), 4.8% ASH, 61.8% CP, 0.7% EE, 32.6% NFE, 26.7% lactose, 0.59% Ca, 0.54% P, 0.2% Mg (DM basis), and 20.3 MJ GE/kg DM. Rhino B's sample collected 13 mo postpartum averaged 8.0% DM (wet-weight basis), 3.6% ASH, 16.3% CP, 1.8% EE, 78.3% NFE, 84.7% lactose, 0.54% Ca, 0.48% P, 0.09% Mg (on DM basis), and 17.43 MJ GE/kg DM. The main FAs in rhino B's and rhino A's samples were C10 : 0, C12 : 0, C16 : 0, C18 : 1n9c, and C18 : 2n6c. Milk of the Indian rhinoceros is low in fat and protein but high in lactose, which is comparable to the milk composition of other rhinoceros species and horses, but not African elephants.

Low association between fasting and OGTT stimulated glucose levels with HbA1c in overweight children and adolescents.

BACKGROUND: Diabetes and prediabetes are defined based on different methods such as fasting glucose, glucose at 2-hour in oral glucose tolerance test (OGTT), and glycated hemoglobin A1c (HbA1c). These parameters probably describe different deteriorations in glucose metabolism limiting the exchange between each other in definitions of diabetes. OBJECTIVE: To investigate the relationship between OGTT and HbA1c in overweight and obese children and adolescents living in Germany. METHODS: Study population: Overweight and obese children and adolescents (n = 4848; 2668 female) aged 7 to 17 years without known diabetes. The study population was stratified into the following subgroups: normal glucose tolerance, prediabetes, diabetes according to OGTT and/or HbA1c categories, confirmed diagnosis of diabetes. RESULTS: In the entire study group fasting plasma glucose (FPG) correlated weakly to 2-hour glucose (r = 0.26), FPG correlated weakly to HbA1c (r = 0.18), and 2-hour glucose correlated weakly to HbA1c (r = 0.17, all P < .001). Patients with confirmed diabetes showed a very high correlation between FPG and 2-hour glucose (r = 0.73, n = 50). Moderate correlations could be found for patients with impaired fasting glucose (2-hour glucose vs HbA1c: r = 0.30, n = 436), for patients with diabetes according to OGTT and/or HbA1c (FPG vs 2-hour glucose: r = 0.43; 2-hour glucose vs HbA1c: r = -0.30, n = 115) and for patients with confirmed diabetes (2-hour glucose vs HbA1c: r = -0.47, all P < .001). CONCLUSIONS: Because FPG, 2-hour glucose, and HbA1c correlated only weakly we propose that these parameters, particularly in the normal range, might reflect distinct aspects of carbohydrate metabolism.

Diabetes screening in overweight and obese children and adolescents: choosing the right test.

Type 2 diabetes can occur without any symptoms, and health problems associated with the disease are serious. Screening tests allowing an early diagnosis are desirable. However, optimal screening tests for diabetes in obese youth are discussed controversially. We performed an observational multicenter analysis including 4848 (2668 female) overweight and obese children aged 7 to 17 years without previously known diabetes. Using HbA1c and OGTT as diagnostic criteria, 2.4% (n = 115, 55 female) could be classified as having diabetes. Within this group, 68.7% had HbA1c levels ≥48 mmol/mol (≥6.5%). FPG ≥126 mg/dl (≥7.0 mmol/l) and/or 2-h glucose levels ≥200 mg/dl (≥11.1 mmol/l) were found in 46.1%. Out of the 115 cases fulfilling the OGTT and/or HbA1c criteria for diabetes, diabetes was confirmed in 43.5%. For FPG, the ROC analysis revealed an optimal threshold of 98 mg/dl (5.4 mmol/l) (sensitivity 70%, specificity 88%). For HbA1c, the best cut-off value was 42 mmol/mol (6.0%) (sensitivity 94%, specificity 93%). CONCLUSIONS: HbA1c seems to be more reliable than OGTT for diabetes screening in overweight and obese children and adolescents. The optimal HbA1c threshold for identifying patients with diabetes was found to be 42 mmol/mol (6.0%). What is Known: • The prevalence of obesity is increasing and health problems related to type 2 DM can be serious. However, an optimal screening test for diabetes in obese youth seems to be controversial in the literature. What is New: • In our study, the ROC analysis revealed for FPG an optimal threshold of 98 mg/dl (5.4 mmol/l, sensitivity 70%, specificity 88%) and for HbA1c a best cut-off value of 42 mmol/mol (6.0%, sensitivity 94%, specificity 93%) to detect diabetes. Thus, in overweight and obese children and adolescents, HbA1c seems to be a more reliable screening tool than OGTT.

Accuracy of Endocrine Tests for Detecting Hypogonadotropic Hypogonadism in Girls.

OBJECTIVE: To assess the accuracy of inhibin B and the gonadotropin releasing hormone agonist test for the diagnosis of hypogonadotropic hypogonadism (HH). STUDY DESIGN: We performed a retrospective analysis of data collected 2009-2014 using a strict clinical protocol. All prepubertal nonunderweight girls, aged 13-17.5 years with Tanner breast stage B1/B2 and low estradiol levels, were tested and re-examined at 6-month intervals (n = 21). Constitutional delay of growth and puberty was defined by spontaneous menarche; HH was identified by association with specific causes of HH or no spontaneous progress of puberty during follow-up. Inhibin B was measured using enzyme-linked immunosorbent assay, and follicle-stimulating hormone and luteinizing hormone (basal and stimulated by triptorelin) were measured using a chemiluminescence immunoassay. RESULTS: The cohort comprised 12 girls with constitutional delay of growth and puberty and 9 girls with HH. The causes of HH included hypopituitarism (n = 3), Prader-Willi syndrome, chromosomal aberration, intellectual disability syndrome with ataxia, and idiopathic causes (n = 2). Each measurement, basal inhibin B <20 pg/mL or stimulated follicle-stimulating hormone (4 hours) <11 IU/L, demonstrated a sensitivity and a specificity of 100% for the detection of HH. Stimulated luteinizing hormone (4 hours) <9 IU/L showed 100% sensitivity but only 83% specificity. CONCLUSIONS: Inhibin B seems to be the ideal measurement for detecting HH in girls. The gonadotropin releasing hormone agonist test is an alternative diagnostic modality, although this approach is more invasive and laborious.

Inhibin B plus LH vs GnRH agonist test for distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism in boys.

OBJECTIVE: The distinction between constitutional delay of growth and puberty (CDGP) and isolated hypogonadotropic hypogonadism (IHH) in males with delayed puberty is difficult but important for timely treatment. We assessed the accuracy of the GnRH agonist test (triptorelin 0·1 mg) in comparison with inhibin B alone or in combination with basal LH for the diagnosis of IHH. PATIENTS AND MEASUREMENTS: Ninety-seven prepubertal males aged 13·7-17·5 year, with testicular volumes ≤4 ml, were examined every 6 months. CDGP was defined by a testicular volume ≥8 ml after 18 months, and IHH was defined by a testicular volume <5 ml after 24 months follow-up. Inhibin B concentrations were measured by ELISA, and LH concentrations were measured by CLIA. RESULTS: At follow-up, the cohort comprised 52 boys with CDGP and nine with IHH. The other patients were lost for follow-up (n = 10), had not reached follow-up yet (n = 20) or did not reach a definite testicular volume (n = 6). Basal LH <0·3 IU/l, stimulated LH (4 h) <5·3 IU/l or inhibin B <111 pg/ml had 100% sensitivity for IHH. Only LH (4 h) <5·3 IU/l had a specificity of 100%, and the specificities of basal LH <0·3 IU/l (88%) or inhibin B <110 pg/ml (92%) were lower. The combination of LH <0·3 IU/l with inhibin B <111 pg/ml increased the specificity to 98·1%. CONCLUSIONS: The LH response 4 h after GnRH agonist stimulation has an excellent accuracy for the diagnosis of IHH in prepubertal boys with delayed puberty. However, the measurement of inhibin B and basal LH in combination is a valid, reliable and less-invasive alternative test.

Higher glucose concentrations following protein- and fat-rich meals - the Tuebingen Grill Study: a pilot study in adolescents with type 1 diabetes.

OBJECTIVE: Traditionally insulin dosage is focused on the carbohydrate amount of meals. We investigated the influence of a fat- and protein-rich meal in the evening on glucose concentration over night in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifteen patients, mean age 16.8 [standard deviation (SD) 2.9] yr participated in the study. Mean glycated hemoglobin (HbA1c) was 6.9 (range: 6.0-8.9) %. On two consecutive days the patients received a standard meal (SM) and a fat-protein-rich evening meal (FPRM). The carbohydrate amount remained identical and insulin was adjusted to this carbohydrate amount with the individual carbohydrate bolus. Glucose was measured continuously over night with the Enlite sensor and the Guardian system (Medtronic) during the following 12 h after the meal. RESULTS: Glucose area under the curve (AUC) for SM was 1400 (SD 580) mg/dL/12 h and for FPRM 1968 (SD 394) mg/dL/12 h (p < 0.05). There was a significant difference in the AUC between 4 and 12 h after the meal. Maximal AUC difference was 6 h after the meal. Glucose concentration in the morning (12 h after the meal) differed: 91 (SD 34) mg/dL after SM and 153 (SD 60) mg/dL after FPRM (p < 0.05). For SM 31% of glucose level were <80 mg/dL and 24% >150 mg/dL, for FPRM it was 3 and 48%. CONCLUSIONS: Twelve hours after a FPRM glucose concentration is significantly higher. Dietary counseling should include the effect of protein and fat on glucose levels in adolescents with type 1 diabetes. The data indicate clearly a need for additional insulin for fat-protein-rich meals.

Changes in whole-body fat distribution, intrahepatic lipids, and insulin resistance of obese adolescents during a low-level lifestyle intervention.

The aim of this study was to analyze changes in adipose tissue (AT) distribution, intrahepatic lipids (IHL), and insulin resistance (IR) among a group of obese adolescents undergoing a 7-months low-level lifestyle intervention. Thirty-nine obese Caucasian adolescents (mean age 13.9 years, body mass index standard deviation score (BMI-SDSLMS) 2.14) were included. AT and IHL were determined by T1-weighted magnetic resonance (MR) imaging and single-voxel MR spectroscopy; IR was estimated using the homeostatic model assessment (HOMA-IR). The lifestyle intervention led to a reduction of both BMI-SDSLMS (boys 2.27 to 2.17; girls 2.00 to 1.82) and HOMA-IR (boys 6.1 to 4.4 (p = 0.008); girls 6.2 to 4.7 (p = 0.030)). IHL dropped in both genders (boys 7.5 to 4.3 %; girls 4.6 to 3.4 %) positively correlating with HOMA-IR (boys r = 0.52; girls r = 0.68), while in contrast visceral AT did not change significantly. CONCLUSIONS: Although the lifestyle intervention only slightly reduced BMI-SDSLMS, insulin sensitivity improved in both genders and came along with a marked reduction of IHL. This suggests that IHL might play the dominant role regarding insulin resistance in the youth, especially if compared to other AT compartments such as visceral AT. WHAT IS KNOWN: • MR imaging/spectroscopy can be used to evaluate body fat distribution and intrahepatic lipids in the youth. • The strength of associations between body fat compartments and insulin resistance is under scientific debate. WHAT IS NEW: • The study emphasizes that even a low-level lifestyle intervention has a beneficial effect. • The study suggests that intrahepatic lipids are an important factor in the development of insulin resistance.

Using person reported outcomes: Psychometric properties of the German diabetes treatment satisfaction questionnaire (DTSQ) for teens and parents.

Aims: To examine psychometric properties including the factor structure of the German versions of the Diabetes Treatment Satisfaction Questionnaire for teens and parents (DTSQ-T/-P). Methods: Linguistically validated questionnaires were completed by 363 adolescents with type 1 diabetes and 655 parent-caregivers in a multicenter study. Confirmatory factor analysis (CFA), reliability, and correlations were examined. Results: CFA confirmed the 2-factor model of treatment satisfaction (TS) & perceived diabetes control (PDC) with an adjustment of removing the "medical support" item from the TS and examining it as a single item in this study. Cronbach's α of TS for DTSQ-T/-P was 0.82 & 0.83, respectively, and α of the two-item PDC factor was 0.70 & 0.60, respectively. The DTSQ scale scores positively correlated with time in range and inversely correlated with HbA1c. Scale scores of DTSQ-T/-P showed significantly positive relations to the KIDSCREEN-10 Index and negative associations with the Problem Areas in Diabetes (PAID). The TS of the parents was correlated with depressive symptoms measured in the Patient Health Questionnaire-9. Conclusions: The DTSQ-T/-P produced psychometrically sound scores in measuring diabetes treatment satisfaction in German teens with type 1 diabetes and their parents. German DTSQ versions for teens and parents are recommended in research and clinical practice.

Normal bone density but altered geometry in girls with Turner syndrome.

OBJECTIVES: Data on bone density and stability in Turner syndrome (TS) are contradictory. A confounding factor for interpretation is short stature. The aim was to measure bone density, geometry and stability in girls with TS compared to idiopathic short stature (ISS). METHODS: From 1999 to 2008, 59 girls with TS (35 prepubertal) were evaluated by pQCT. Mean age was 8.9 in prepubertal and 17.3 years in adolescent girls. Mean height was -3.1 and -1.8 SDS in prepubertal treatment-free and in adolescent, formerly rhGH-treated girls. For comparison, 18 prepubertal ISS girls were studied (age 7.7 years; height -3.3 SDS). Examination of radius with pQCT (XCT 2000). Cortical (CD) and trabecular density (TD), total bone area (TBA), cortical area (CA), cortical thickness, muscle area and strength strain index (SSI) were determined and compared with height related references. RESULTS: In prepubertal girls with TS, TD and CD were normal (0.55 and 0.90 SDS) and comparable to ISS (0.95 and 1.53 SDS). TBA was greater in girls with TS than in ISS (0.87 vs. -0.33 SDS) whereas CA was similar (1.48 vs. 1.43 SDS). The SSI was comparable (1.61 vs. 1.56 SDS). Adolescent girls with TS showed similar results with a TD of 0.48 SDS, a CD of -0.32, TBA of 1.99, a CA of -0.05 and an SSI of 0.88 SDS. CONCLUSIONS: The observations are consistent with normal bone density and stability but altered bone geometry in prepubertal and substituted adolescent girls with TS. This peculiarity may reflect SHOX deficiency. We therefore think that timely and adequate estrogen substitution could prevent bone loss in TS.

Increase of jump performance during GH treatment in short children born SGA.

Background: Short children born small for gestational age (SGA) often have low muscle mass. Studies on maximal isometric grip-force (MIGF) observed lower muscle strength in these children. In contrast to MIGF, jumping is an everyday muscle activity for children. Our hypothesis was that GH treatment would cause an increase in jumping strength. So, we aimed to study jumping by mechanography in short SGA children before and during GH treatment. Methods: Monocentric prospective longitudinal study in a tertiary pediatric endocrinology center. We studied 50 prepubertal short children (23 females) born SGA (mean age 7.2 y, height -3.24 SDS) during GH treatment (mean dose 45 µg/kg/d). Main outcome measures were Peak jump force (PJF) and peak jump power (PJP) measured by Leonardo® ground reaction force plate at baseline and after 12 months of GH treatment. Mechanography data were compared to sex, age and height related references (SD-Score). Fitness was estimated as PJP/kg body weight by use of the Esslinger-Fitness-Index (EFI). Results: At start of GH treatment PJP/body weight was low at -1.52 SDS and increased significantly to -0.95 SDS during 12 months of treatment (p<0.001). PJF was low-normal compared to height dependent references and remained unchanged. PJP was normal compared to height dependent references and increased only slightly from -0.34 to -0.19 SDSHT. Conclusions: Jumping performance (EFI) measured by mechanography increased during one year of GH treatment in short children born SGA.

Transition From Childhood to Adult Care in Patients with Type 1 Diabetes: 20 Years of Experience From the Tübinger Transition Study.

AIMS: Transition from pediatric to adult care is difficult for patients with chronic diseases. In this study, factors associated with metabolic control in childhood-onset type 1 diabetes (T1D) after transfer to adult care were analyzed. METHODS: Overall, 224 persons with T1D were contacted yearly from 1998 to 2019. They voluntarily answered a questionnaire about their current hemoglobin A1c (HbA1c) levels, diabetes-associated complications, kind of care, living conditions, and family situation. Then, mixed longitudinal-cross-sectional analyses were carried out. RESULTS: Overall, 190 patients answered at least once (mean age: 26.6 years). Diabetes complications were mentioned by 10 patients (5 microalbuminuria, 5 retinopathy). Most patients (92.6%) were in diabetes-specific care during the first year after transfer, with a trend to leave diabetes-specific care during the observation period. Patients in diabetes-specific care displayed lower HbA1c levels (%/mmol/mol) (7.1/54 vs. 7.5/58). An important predictor for HbA1c after transfer was HbA1c during the year before transfer (r=0.67, p <0.001). Patients living alone showed no difference in HbA1c levels from those living with their parents. Married patients had lower HbA1c levels (7.0/53 vs. 7.3/56, p<0.05) than unmarried ones. Patients with children (15.8%) presented lower HbA1c levels (6.9/52 vs. 7.3/56, p <0.01) than those without. CONCLUSIONS: Good metabolic results are favored in patients followed-up in specialized care, are married, and are parents. We recommend transfer to a diabetologist with experience in T1D at an individual age.

GH Responsiveness Is not Correlated to IGF1 P2 Promoter Methylation in Children With Turner Syndrome, GHD and SGA Short Stature.

Background: The methylation of IGF1 promoter P2 was reported to negatively correlate with serum IGF-1 concentration and rhGH treatment response in children with idiopathic short stature. These findings have not yet been confirmed. Objective: This study aimed to determine IGF1 promoter P2 methylation in short children treated with rhGH and correlate clinical parameters with the methylation status. In addition, long-term stability of methylation during rhGH treatment was studied. Design: This was a single tertiary center study analyzing clinical GH response and IGF-1 serum concentration changes in patients with GHD (n=40), SGA short stature (n=36), and Turner syndrome (n=16) treated with rhGH. Data were correlated to the methylation of two cytosine residues (-137, +97) of the P2 promoter of IGF1 in blood cells measured by pyrosequencing in 443 patient samples. Results: Basal and stimulated IGF-1 concentrations, first year increment in height velocity and studentized residuals of a prediction model did not correlate to the methylation of -137 und +97 in IGF1 P2 promoter. The methylation of these two sites was relatively stable during treatment. Conclusions: This study did not confirm IGF1 P2 promotor being a major epigenetic locus for GH responsiveness in patients treated with a normal dose of rhGH. Additional studies are warranted.

Corrigendum: GH responsiveness is not correlated to IGF1 P2 promoter methylation in children with Turner syndrome, GHD and SGA short stature.

[This corrects the article DOI: 10.3389/fendo.2022.897897.].

Validation of automatic bone age rating in children with precocious and early puberty.

BACKGROUND AND AIMS: Manual bone age (BA) rating in precocious puberty (PP) is associated with considerable rater variability. The aim was to evaluate a new method for automated Greulich and Pyle (GP) BA determination in children with PP. METHODS: Seven hundred forty-one archived X-rays from 13 boys and 103 girls with PP or early puberty of various etiologies (age range at time of X-ray, 0.3-14.8 years; mean BA advancement, 2.3 years) were rated. Automatic rating (BoneXpert BA, or BXBA) was compared with the original manual GP rating (manual BA, or ManBA). X-rays where BXBA deviated from ManBA by more than 1.5 years were rerated by three raters, and the average was formed (ReferenceBA). RESULTS: All 741 X-rays, except nine (three images had poor quality and six were from children with a chronological age younger than 1.5 years), were analyzed automatically. The mean difference of BXBA-ManBA was -0.19 years; the SD of the differences was 0.76 years (95% confidence interval 0.72-0.80). ReferenceBA was determined for 41 images. A discrepancy from ReferenceBA greater 1.5 years was found in four images against BXBA and in 10 images against ManBA. CONCLUSION: Automated BA is efficient and reliable in children with PP.

Long-term Effect of Aromatase Inhibition in Aromatase Excess Syndrome.

CONTEXT: Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens. OBJECTIVE: The objective was to study long-term treatment effects of an aromatase inhibitor. METHODS: Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy. RESULTS: All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30). CONCLUSION: Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS.