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Aim: To examine the time trends and factors associated with the onset of puberty in children with type 1 diabetes (T1D) using data from the German Diabetes Prospective Follow‐up (Diabetes‐Patienten‐Verlaufsdokumentation [DPV]) registry. Methods: A total of 13 127 children with T1D, aged 6 to 18 years, were included in the analysis. Regression analysis was performed to investigate the relationship between diabetes duration, body mass index (BMI) standard deviation score (SDS), glycated haemoglobin (HbA1c) level, migration background, and the onset of puberty, stratified by sex. Results: Our findings revealed a significant trend towards earlier puberty in both girls and boys with T1D over the observed period (2000 to 2021). Puberty onset in girls (thelarche Tanner stage B2) decreased from 11.48 (11.35‐11.65) years in 2000 to 10.93 (10.79‐11.08) years in 2021 and gonadarche (Tanner stage G2/testicular volume >3 mL) decreased from 12.62 (12.42‐12.82) years in 2000 to 11.98 (11.79‐12.16) years in 2021 in boys (both P < 0.001). Longer diabetes duration, higher BMI SDS, and lower HbA1c level were associated with earlier puberty in both sexes (P < 0.001). Conclusions: Our study highlights earlier puberty in children with T1D, influenced by BMI SDS, HbA1c level, and migration background. This has important implications for diabetes management and supporting healthy development. Further research is needed to understand the underlying mechanisms and develop potential interventions for this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: Events during foetal or early extrauterine life may affect bodily structure and/or functions and even pave the way for adult diseases. Aims: To find whether extremely low birth weight (ELBW) infants differ from healthy controls regarding the excretion of steroid metabolites. Methods: The study compared 17 female and 10 male ELBW infants, all prepubertal, aged 8-11 years, birth weight <1,000 g, with 27 age- and sex-matched controls. All were healthy at the time of the study. Height, weight and BMI did not differ between the groups. Results were adjusted according to body surface area. 36 urinary steroid metabolites were quantified by gas chromatography-mass spectrometry. Results: In the ELBW girls 33/36 steroid metabolites were higher (19 significantly) than in the controls. All 36 steroid metabolites were higher in the ELBW boys (9 significantly) than in the controls. Sums of mineralocorticoid precursors, metabolites descriptive for cortisol and parameters of adrenal androgen production were significantly higher in ELBW infants (both sexes). Only the sum of the metabolites known to be illustrative for adrenal 11β-hydroxysteroid dehydrogenase activity was not different. Conclusion: Prepubertal ELBW children have an augmented urinary excretion of adrenal androgens, cortisol and mineralocorticoid precursors. These findings corroborate and help to explain the link between early-life adversity and subsequent adrenocortical function. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Loss-of-function mutations in the gene encoding the makorin RING finger protein 3 (MKRN3) have recently been reported to underlie familial cases of central precocious puberty (CPP). The imprinted MKRN3 gene is expressed only from the paternal allele, and mutations inherited from the father affect boys and girls equally, which is in contrast to the known female preponderance in idiopathic CPP. By screening a series of 6 families and 1 male patient with idiopathic CPP, we identified 2 further families carrying loss-of-function mutations in MKRN3, the previously reported variant c.475_476insC (p.Ala162Glyfs*14) and a novel one, c.331G>T (p.Glu111*). We conclude that MKRN3 mutations appear to be a frequent cause of familial CPP and, considering the imprinted mode of inheritance, may also account for a certain proportion of isolated CPP cases. Remarkably, four out of six MKRN3 mutations described so far encode either a stop codon or a frameshift followed by a premature stop codon. Consequently, there may be less severe mutations that possibly associate with more subtle phenotypes, which could even explain variation within the physiological range. Mutation screening in larger cohorts is necessary in order to estimate the real prevalence of MKRN3 mutations in idiopathic CPP. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Various studies have demonstrated an increased risk for adult diseases in newborns born small-for-gestational-age (SGA). Adiponectin and resistin can be detected in cord blood and are suggested to affect insulin resistance (IR). This might represent a link between metabolic syndrome and SGA birth. Study Design: We investigated the relationship between the adipocytokines and inter-twin birth weight (BW) difference of 31 monozygotic twins with twin-twin transfusion syndrome; in 14 twin pairs BW difference was >15% (1 SGA twin, 1 appropriate-for-gestational-age, AGA, twin). Results: BW and length of all patients were positively related to adiponectin (r = 0.57; p < 0.0001; r = 0.47; p < 0.0001) and to resistin (r = 0.31; p < 0.01; r = 0.35; p < 0.01). In 71% (10/14), the SGA twins showed lower adiponectin concentrations than their AGA co-twins (only 6/14 for resistin). To correct for gestational age we calculated the relationship between the intrapair differences (Δ) of BW and Δ of the hormones. We found ΔBW positively correlated with adiponectin (r = 0.55; p < 0.001) but not with resistin (r = 0.22; p = 0.2). Δadiponectin was positively correlated with Δresistin (r = 0.45; p < 0.01). Conclusion: These data demonstrate that adiponectin and resistin levels are associated with BW with only adiponectin levels being reduced in SGA children independently of gestational age. Prenatally different metabolic status between the twins might predispose the SGA twin to develop IR later in life. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We describe change in height, segmental proportion and weight in 46 children (19 girls, 27 boys, all but four prepubertal) diagnosed by a multidisciplinary team as having psychosocial short stature (PSS) who had a change in their environment (31 were separated from their family). The classification of PSS has recently been modified to include appetite disturbance at presentation: hyperphagic (IIA), non-hyperphagic (IIB) and anorexic type (III). The 46 patients were subdivided into these three classifications and analysed separately concerning their auxology and change in body mass index before and after intervention. Although in all groups a significant improvement in height velocity SDS was seen after intervention, subtle differences in body proportions could be demonstrated. Proportional short stature was seen in both non-anorexic types of PSS (type IIA and type IIB) and did not change with intervention, whereas a significant change in body proportion was found in the anorexic type (type III). Body mass index at presentation was within normal limits and did not increase significantly in any of the three subgroups after intervention. Conclusion: the main diagnostic feature of psychosocial short stature is catch-up growth after change of environment which occurs in almost all patients. The classification on the basis of appetite disturbance was supported by our auxological data with specific differences in body proportions. [ABSTRACT FROM AUTHOR]

Background: Agranulocytosis is a rare antithyroid drug treatment (ATD) side effect seen in children suffering from Graves' disease (GD). Neutropenia is a recognized adverse event associated with ATD but has also been reported as pre-treatment neutropenia in GD. Methods: We performed a retrospective cohort study to analyze the longitudinal clinical and biochemical data of 161 pediatric patients with GD who received either methimazole (MMI) or carbimazole (CBZ) as ATD. The inclusion criteria were elevated free thyroxine (fT4 >25 pmol/L), suppressed thyrotropin (TSH <0.05 mlU/mL), and elevated thyrotropin receptor antibodies (TSHRAbs >2.5 IU/L). Absolute neutrophil count (ANC) was used to define neutropenia (ANC <1800/µL) and agranulocytosis (ANC <500/µL). Results: Nine of the 161 patients had neutropenia at diagnosis (ANC: 1348/µL ± 250) without further deterioration under ATD. In this subgroup, we found higher levels of free triiodothyronine (fT3: 31.45 pmol/L ± 3.99) at diagnosis in comparison with those who developed neutropenia (26.29 pmol/L ± 12.96; p = 0.07) and those without neutropenia before and during therapy (23.12 pmol/L ± 13.7; p = 0.003). Thirty-eight patients (23.6%) became neutropenic (ANC: 1479/µL ± 262) while receiving ATD. Neutropenia occurred after a mean of 551.8 (range: 10–1376) days, mostly without further deterioration. Two of these 38 patients developed agranulocytosis and underwent emergency thyroidectomy. The patients with neutropenia were significantly younger (p = 0.031). Neutropenia occurred significantly more often in patients receiving CBZ (50%; n = 20/40) than in those receiving MMI (16.5%; n = 18/110; p = 0.001). The minimum ANC was significantly lower in the CBZ (1971/µL ± 1008) than in the MMI group (2546 ± 959); p = 0.004. Conclusions: Neutropenia occurred significantly more often under CBZ than MMI. As this is potentially due to higher immunogenicity, we suggest that children with GD should be treated with MMI. Frequent measurements of ANC may be needed to detect severe agranulocytosis, although low pre-treatment ANC may not necessarily be a contraindication to ATD treatment. Young age may be potentially associated with an increased risk of reduced ANC. Further investigation is necessary to fully understand risk factors for neutropenia in children with GD. [ABSTRACT FROM AUTHOR]

Purpose: To compare the changes in body weight and glycemic control before and during the COVID-19 pandemic in people with type 1 diabetes (T1D). Methods: In 47,065 individuals with T1D from the German Diabetes Prospective Follow-up Registry (DPV), we compared the adjusted mean changes in BMI-Z-scores and HbA1c as well as the distribution of individual changes between four periods from March 2018 to February 2022, by sex and age group (4- < 11, 11- < 16, 16–50 years). Results: At population level, the only significant pandemic effects were a slight increase in BMI Z-score in prepubertal children (girls: + 0.03 in the first COVID year vs. before, P < 0.01; boys: + 0.04, P < 0.01) as well as a stabilization of HbA1c in all subgroups or even improvement in women (− 0.08%, P < 0.01). At individual level, however, heterogeneity increased significantly (p < 0.01), especially in children. More prepubertal children gained weight (girls: 45% vs. 35% before COVID; boys: 39% vs. 33%). More pubertal girls lost weight (30% vs. 21%) and fewer gained weight (43% vs. 54%). More children had a decreasing HbA1c (prepubertal group: 29% vs. 22%; pubertal girls: 33% vs. 28%; pubertal boys: 32% vs. 25%) and fewer had increasing values. More women had stable HbA1c and fewer had increasing values (30% vs. 37%). In men, no significant changes were observed. Conclusion: This real-world analysis shows no detrimental consequences of the two first COVID years on weight and HbA1c in T1D on average, but reveals, beyond the mean trends, a greater variability at the individual level. [ABSTRACT FROM AUTHOR]

PTEN hamartoma tumor syndrome (PHTS) encompasses different syndromic disorders which are associated with autosomal-dominant mutations of the tumor suppressor gene PTEN. Patients are at high risk to develop benign and malignant tumors. Macrocephaly is a diagnostic feature, but there is a paucity of data on auxological development during childhood. Growth charts for height, weight and head circumference for PHTS do not exist yet. In this study, patient data for height, weight and head circumferences (HC) were collected from repeated medical exams or prevention check-up visits starting at birth. Growth charts were generated and compared to German reference data. Standard deviation scores (SDS) of HC, height and body mass index (BMI) were calculated. We included 23 pediatric patients (8 female, 15 male) with molecular proven PTEN gene mutation. Most male patients already demonstrated macrocephaly at birth (73%), whereas only one female patient had documented congenital macrocephaly. By the age of two years all patients exhibited a head circumference above the 97th percentile. Stratified for different age groups the median HC-SDSs were between +3.3 and +5.5 in male patients and between +2.9 and +4.1 in female patients. Height, weight and BMI measurements for both sexes were mostly within the normal range. We conclude that macrocephaly, but not height, weight or BMI, is useful in the identification of PHTS patients. The increased HC in PHTS patients develops early in life and is more pronounced in males than in females, which might explain the finding of a higher percentage of male PHTS patients diagnosed during childhood. [ABSTRACT FROM AUTHOR]

Introduction: BMI or BMI-standardized deviation score (SDS) in children and adolescents is still the standard for weight classification. [BMJ. 2019;366:4293] developed a formula to calculate body fat percentage (%BF) based on age, sex, height, weight, and ethnicity. Using data from the German/Austrian APV registry, we investigated whether the calculated %BF is superior to BMI-SDS in predicting arterial hypertension, dyslipidaemia, and impaired glucose metabolism. Methods: 94,586 children and adolescents were included (12.5 years, 48.3% male). Parental birth country (BC) was used to depict ethnicity (15.8% migration background); 95.67% were assigned to the ethnicity "white." %BF was calculated based on the Hudda formula. The relationship between BMI-SDS or %BF quartiles and outcome variables was investigated by logistic regression models, adjusted for age, sex, and migration background. Vuong test was applied to analyse predictive power. Results: 58.4% had arterial hypertension, 33.5% had dyslipidaemia, and 11.6% had impaired glucose metabolism. Boys were significantly more often affected, although girls had higher calculated %BF (each p < 0.05). After adjustment, both models revealed significant differences between the quartiles (all p < 0.001). The predictive power of BMI-SDS was superior to %BF for all three comorbidities (all p < 0.05). Discussion: The prediction of cardiometabolic comorbidities by calculated %BF was not superior to BMI-SDS. This formula developed in a British population may not be suitable for a central European population, which is applicable to this possibly less heterogeneous collective. Additional parameters, especially puberty status, should be taken into account. However, objective determinations such as bioimpedance analysis may possibly be superior to assess fat mass and cardiometabolic risk than calculated %BF. [ABSTRACT FROM AUTHOR]

Background: The daily demands of type 1 diabetes management may jeopardize adolescents' mental health. We aimed to assess anxiety and depression symptoms by broad-scale, tablet-based outpatient screening in adolescents with type 1 diabetes in Germany. Methods: Adolescent patients with type 1 diabetes mellitus (n = 2,394; mean age 15.4 y [SD 2.0]; 50.7% male) were screened for anxiety (GAD-7) and depression symptoms (PHQ-9) by self-report questionnaires and linked to clinical data from the DPV patient registry. Logistic regression was used to estimate the contribution of clinical parameters to positive screening results. Results: Altogether, 30.2% showed a positive screening (score ≥ 7 in either test), and 11.3% reported suicidal ideations or self-harm. Patients with anxiety and depression symptoms were older (15.7 y [CI 15.5–15.8] vs. 15.3 y [CI 15.2–15.4]; p < 0.0001), had higher HbA1c levels (7.9% [CI 7.8-8.0] (63 mmol/mol) vs. 7.5% [CI 7.4–7.5] (58 mmol/mol); p < 0.0001), and had higher hospitalization rates. Females (adjusted odds ratio (aOR) 2.66 [CI 2.21–3.19]; p < 0.0001), patients > 15 years (aOR 1.40 [1.16–1.68]; p < 0.001), who were overweight (aOR 1.40 [CI 1.14–1.71]; p = 0.001), with HbA1c > 9% (> 75 mmol/mol; aOR 2.58 [1.83–3.64]; each p < 0.0001), with a migration background (aOR 1.46 [CI 1.17–1.81]; p < 0.001), or smoking (aOR 2.72 [CI 1.41–5.23]; p = 0.003) had a higher risk. Regular exercise was a significant protective factor (aOR 0.65 [CI 0.51–0.82]; p < 0.001). Advanced diabetes technologies did not influence screening outcomes. Conclusions: Electronic mental health screening was implemented in 42 centers in parallel, and outcomes showed an association with clinical parameters from sociodemographic, lifestyle, and diabetes-related data. It should be integrated into holistic patient counseling, enabling early recognition of mild mental health symptoms for preventive measures. Females were disproportionally adversely affected. The use of advanced diabetes technologies did not yet reduce the odds of anxiety and depression symptoms in this cross-sectional assessment. [ABSTRACT FROM AUTHOR]

Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson–Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first two years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. We present a case involving a male patient with DS, harbouring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%). However, our patient died at 22 months of age during the course of a respiratory infection in in Libya. Currently available data in the literature comprising more than 30 treated patients worldwide seem to support a trial of rhIGF-I in SIR. rhIGF-I represents a treatment option for challenging SIR cases, but careful consideration of the therapeutic benefits and the burden of the disease is warranted. Continuous application via pump might be advantageous compared to single injections. [ABSTRACT FROM AUTHOR]

Patients with PTEN hamartoma tumor syndrome (PHTS) are at increased risk of developing benign and malignant tumors, including thyroid carcinoma. Benign thyroid lesions and single cases of thyroid carcinoma have been reported in children with PHTS. We conducted a retrospective, single-centered study including children and adolescents with a molecularly proven diagnosis of PTEN. Our cohort consists of 16 patients, with a mean age at diagnosis PHTS of 5.7 years. Twelve of 16 cases exhibited thyroid abnormalities (75%). In seven patients, thyroid abnormalities were already present at first ultrasound screening, in five cases they occurred during follow-up. Eight patients underwent thyroidectomy. Histopathology included nodular goiter, follicular adenoma, papillary microcarcinoma in a boy of six and follicular carcinoma in a girl of 13 years. Two patients had autoimmune thyroid disease.Conclusion: Thyroid disease is common in children with PHTS. Physicians caring for patients with early thyroid abnormalities and additional syndromal features should be aware of PHTS as a potentially underlying disorder. Ultrasound screening should be performed immediately after diagnosis of PHTS and repeated yearly or more frequently. Because of possible early cancer development, we recommend early surgical intervention in the form of total thyroidectomy in cases of suspicious ultrasound findings. What is Known: • PHTS patients are at high risk of developing benign and malignant tumors. • Individual cases of thyroid carcinoma in children have been reported. What is New: • Thyroid disease is even more common in children with PHTS (75%) than previously expected. • Frequently thyroid disease is the first organ pathology requiring diagnostic workup and therefore children with PHTS should be examined for thyroid disease right after diagnosis and receive follow-up on a regular basis throughout life. [ABSTRACT FROM AUTHOR]

Background: Available basal insulin regimes differ in pharmacokinetic profiles, which may be related to subsequent changes in anthropometry in patients with type 1 diabetes. This analysis elucidates the standardized height and body mass index development (height and BMI standard deviation score [height‐SDS and BMI‐SDS]) in pediatric type 1 diabetes patients depending on the choice of basal insulin. Methods: Longitudinal data of 10 338 German/Austrian patients from the Diabetes Prospective Follow‐up (DPV, Diabetes Patienten Verlaufsdokumentation) database were analyzed. Patients aged 5.0 to 16.9 years were treated exclusively with neutral protamine Hagedorn (NPH), insulin detemir (IDet), insulin glargine (IGla), or continuous subcutaneous insulin infusion (CSII) for at least 3 years. Population‐based German reference data were used to calculate height‐SDS and BMI‐SDS. Multiple linear regression was conducted. Results: BMI‐SDS increased significantly in all regimes (NPH P =.0365; IDet P =.0003; IGla P <.0001; and CSII P <.0001). Direct comparison of the therapies revealed a favorable association only for NPH vs IGla. A rise in BMI‐SDS was observed for all insulins in females, but only for IGla in males. BMI‐SDS increment was not observed before 8 years of age. Initially and at the end of the observation period, mean height was above the 50th percentile of the reference population. Across the cohort, height‐SDS declined during the observation period, except for CSII. Apart from the 5.0‐ to 7.9‐year‐old subgroup, long‐acting insulin analogues were associated with a significant loss of height‐SDS. Conclusions: Choice of basal insulin regimen might influence height development. CSII appeared to have a favorable effect on growth trajectories. All therapies were associated with an increase of BMI‐SDS, most evident in females. [ABSTRACT FROM AUTHOR]

Objective: To study the impact of the quality of therapeutic control on f ertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adre nal hyperplasia (CAH). Design: Combined cross-sectional and retrospective clinical study. Methods: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. Results: Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively. Conclusions: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis. [ABSTRACT FROM AUTHOR]

Background: Adverse prenatal conditions can exert a long-lasting impact in later life. Patients and Methods: Thirty-eight post-pubertal monozygotic twin pairs (16 female pairs) with divergent birthweight (bw) due to twin-to-twin transfusion syndrome were examined at a median of 15.1 years. Auxological and endocrine parameters were measured. To evaluate effects of intra-twin bw and hormone differences on mental health, adolescents and their parents completed the Strengths and Difficulties Questionnaire (SDQ), identifying psychological problems. Twins answered the questionnaire on health-related quality of life (HrQoL, KIDSCREEN-52). Results: Parents attributed a higher number of psychological challenges to the formerly smaller twins, for example, total difficulties (8.8 vs. 6.5, p = 0.009). Differences in bw were associated with differences in parental evaluation of problems, for example, peer relationship problems (r = −0.57 and p = 0.0001). In contrast, bw differences did not affect subjects' self-assessment of psychological factors but on physical well-being (r = 0.42, p = 0.017). The formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being (24.9 vs. 26.6, T1,15 = −2.2, and p = 0.043) and moods and emotions (29.8 vs. 32.0, T1,15 = −2.3, p = 0.039). Higher concentrations of androstenedione were linked to greater psychological well-being (r = 0.39 and p = 0.036) in all twin pairs. Conclusion: Our results show that the prenatal environment leading to bw differences exerts a long-lasting impact on diverging parental evaluation of mental health. Formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being and moods and emotions. Higher androstenedione concentrations were linked to greater psychological well-being. [ABSTRACT FROM AUTHOR]

Objective: Adverse prenatal conditions can exert a long‐lasting impact on growth up to final height (FH). Due to different prenatal nutrient availability, monozygotic twin pairs with discordant birth weight (bw) provide an excellent model to examine the impact of genes and environment and to analyse the predictive value of bw, birth length (bl) and cord blood (cb) concentration of IGF‐I on FH. Patients and Methods: Twenty eight monozygotic twin pairs with intra‐twin bw‐/bl‐differences were studied at birth and longitudinally until FH. Intra‐twin bw difference >1 SDS was defined "discordant" (n = 10 pairs). IGF‐I was analysed in cord blood in all twins. Intra‐twin differences (∆) in bw, bl and cord blood IGF‐I were correlated with ∆FH. Results: Throughout growth and up until FH intra‐twin length/height differences remained for all but two (26/28) twins and for all (10/10) discordant twins. In the discordant group, a highly significant intra‐twin difference for FH‐SDS was found with a mean intra‐twin Δheight‐ SDS of 1.23 (range, 0.29‐2.34). This corresponds to a mean Δintra‐twin difference at FH of 7.9 cm (3.1 inch; range, 2‐15 cm [0.79‐5.9 inch]). Correlation coefficients were calculated to identify factors predicting FH: ∆bw (r =.678; P =.0005), ∆bl (r =.333; P =.0002) and ∆IGF‐I in cb (r =.418; P =.0023). Interaction terms showed that IGF‐I is an additional factor to the auxological data, leading to an improvement of the ∆FH modelling. Conclusion: Prenatal environment leading to bw‐/bl‐ and cbIGF‐I differences in monozygotic twins had a long‐lasting impact on growth until FH. Both, anthropometric data at birth and cbIGF‐I are predictive of FH. [ABSTRACT FROM AUTHOR]

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is caused by germline autosomal-dominant mutations of the tumor suppressor gene PTEN. Subjects harbour an increased risk for tumor development, with thyroid carcinoma occurring in young children. Establishing a diagnosis is challenging, since not all children fulfill diagnostic criteria established for adults. Macrocephaly is a common feature in childhood, with cerebral MRI being part of its diagnostic workup. We asked whether distinct cMRI features might facilitate an earlier diagnosis. Methods: We retrospectively studied radiological and clinical data of pediatric patients who were presented in our hospital between 2013 and 2019 in whom PTEN gene mutations were identified. Results: We included 27 pediatric patients (18 male) in the analysis. All patients were macrocephalic. Of these, 19 patients had received at least one cMRI scan. In 18 subjects variations were detected: enlarged perivascular spaces (EPVS; in 18), white matter abnormalities (in seven) and less frequently additional pathologies. Intellectual ability was variable. Most patients exhibited developmental delay in motor skills, but normal intelligence. Conclusion: cMRI elucidates EPVS and white matter abnormalities in a high prevalence in children with PHTS and might therefore aid as a diagnostic feature to establish an earlier diagnosis of PHTS in childhood. [ABSTRACT FROM AUTHOR]

Background: We report a novel mutation within the StAR gene, causing congenital adrenal hyperplasia, with the so far unreported association with heterochromia iridis. Case presentation: In a now 15-year-old girl (born at 41 + 6 weeks of gestation) adrenal failure was diagnosed in the neonatal period based on the clinical picture with spontaneous hypoglycaemia, hyponatremia and an extremely elevated concentration of ACTH (3381 pmol/l; ref. level 1,1–10,1 pmol/l), elevated renin (836 ng/l; ref. level 5–308 ng/l), and a decreased concentration of aldosterone (410 pmol/l; ref. level 886–3540 pmol/l). In addition to hyperpigmented skin the patient exhibited sectorial heterochromia iridis. Sequence analysis of the steroidogenic acute regulatory protein (StAR) gene showed a novel homozygous mutation (c.652G > A (p.Ala218Thr), which was predicted in-silico to be possibly damaging. Under daily steroid substitution her electrolyte levels are balanced while she became obese. Puberty occurred spontaneously. Conclusion: A novel mutation in the StAR gene was identified in a patient with severe adrenal hypoplasia and sectorial heterochromia iridis. We discuss a causal relationship between these two rare phenotypes, i.e. whether very high levels of ACTH and alpha-MSH during early development might have disturbed early differentiation and distribution of uveal melanocytes. If confirmed in additional cases, discolorization of the iris might be considered as an additional phenotypical feature in the differential diagnosis of congenital adrenal insufficiency. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to consider sleep apnea in Prader-Willi syndrome (PWS) children depending on age at growth hormone (GH) therapy onset. Study Design: We analyzed longitudinally cardiorespiratory polygraphy of 62 PWS children (aged 0–2.5 years at baseline). Twenty-one children (Group A) started GH-therapy during and 41 children (Group B) after their first year of life. Data were acquired before, at 3 and 6 months, then 1.2, 2.2, and 3.2 years after GH onset. Outcomes were determined with the obstructive apnea hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), and by measuring obstructive sleep apnea (OSA) and peripheral blood oxygen saturation (SpO2). Results: We observed no significant differences in OAHI, CAI, ODI, and SpO2 depending on treatment onset. At baseline, 5/21 patients (23.8%) in Group A versus 15/41 patients (36.6%) in Group B showed pathological sleep apnea (OAHI ≥1.5). Pathological OSA increased significantly in Group A during the first 3 months of therapy but dropped below baseline after 1 year in both groups. ODI changed during GH therapy in both groups (from 4.0 to 2.6 in Group A, and 3.6 to 1.6 in Group B; baseline to 3.2 years; p < 0.05). Conclusions: OSA in PWS children appears to develop independently of treatment onset. Treatment may therefore safely be initiated early but should be accompanied by regular sleep analysis. [ABSTRACT FROM AUTHOR]

Introduction: Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. Methods: A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. Results: National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. Conclusions: GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence. [ABSTRACT FROM AUTHOR]

Background: Low birth-weight (bw), low birth-length (bl), unfavourable intrauterine conditions and post-natal catch-up growth can have an impact on growth and metabolic health later in life. Objective: We studied genetically identical twins with intra-twin bw-differences due to twin-twin transfusion syndrome from birth to adolescence and analysed the long-term impact of bw and catch-up growth on metabolic parameters. Subjects and Methods: Forty-three postpubertal monozygotic twin-pairs (mean age 17.4 years) were examined. Twenty-two pairs were discordant (intra-twin bw- and/or bl-difference ≥1 SDS) of which 12 (55%) experienced catch-up growth. Auxological parameters and blood pressure were measured, a fasting blood sample was collected and bio-impedance spectroscopy was carried out. Results: Irrespective of differences in birth parameters and postnatal catch-up growth, a significant intra-twin correlation was found for nearly all measured parameters of body composition (skinfold, waist-hip circumference, relative body fat/lean body mass) and metabolic health (total, and low-density lipoprotein-C/high-density lipoprotein-C, Apolipoprotein A and B, C-peptide). As an exception to this, and only for the former smaller twins who showed postnatal catch-up growth, a significantly higher fasting insulin level was found compared to that of the co-twins (mean insulin level: 8.4 vs. 5.7 µIU/mL; p < 0.01). Auxology remained different until adulthood: even in subjects with catch-up growth the former smaller twins were significantly lighter (mean-body mass index-SDS: –0.42 vs. 0.21; p < 0.05) and shorter (mean height-SDS: –0.07 vs. 0.37; p < 0.05) than their co-twins. Conclusion: In this special group of monozygotic twins with intra-twin bw-differences and catch-up growth, we found that the genetic background was a more important factor in determining later metabolic health than bw and/or catch-up growth. [ABSTRACT FROM AUTHOR]

Although thyroid medications are frequently prescribed during pregnancy, paediatricians treating the respective neonates often have no information about the underlying maternal thyroid disease, and inconsistencies in postnatal diagnostics may result. We analysed a cohort of 1819 mothers admitted for delivery in 1 year to one hospital. We analysed the pre- and postpartum diagnostics in the mothers, the postnatal diagnostics in the neonates and their postnatal auxological development. Two hundred thirteen mothers (11.7%) had "thyroid disease"; 37 (2.0%) had Hashimoto thyroiditis, seven (0.4%) Graves' disease and 169 (9.3%) "thyroid disease of other origins". One hundred eighty-eight out of 213 (88%, 10.3% of the entire cohort) took levothyroxine. Pre- and postpartum diagnostics of the mothers and postnatal diagnostics of the neonates revealed striking inconsistencies. For example, 39 % of the gynaecologists routinely determined TSH, while only 59% carried out a dosage adjustment for known hypothyroidism. Second specialists were consulted in 86%. Unnecessary postpartum diagnostics were initiated in 19/213 neonates (9%). TRAb was analysed, however, in only one neonate born from the mothers with Graves' disease-a condition in which further diagnostic efforts are mandatory.Conclusion: Although many pregnant women have thyroid dysfunction, we observed a lack of uniformity in the diagnostic approach of the women and their neonates. What is Known: • Disturbed maternal thyroid function in pregnancy often has an adverse impact on both the mother and the foetus. • Although detailed guidelines for managing impaired maternal thyroid function during pregnancy have been published, their application in clinical practice varies widely. What is New: • Recommendations for managing the newborn of a mother presenting with thyroid disease of unknown entity are remarkably inconsistent. • This leads to a possible over-diagnosis in general and a potentially life-threatening failure to note neonatal hyperthyroidism requiring rapid treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate differences in cardiovascular risk factors and metabolic control in girls with type 1 diabetes with or without use of oral contraceptives (OC) from the multicenter “diabetes prospective follow‐up” (DPV) registry. Methods: Twenty‐four thousand eleven adolescent girls (13 to < 18 years of age) from Germany, Austria or Luxembourg with type 1 diabetes from the DPV registry were included in this cross‐sectional study. Multivariable regression models were applied to compare clinical characteristics (hemoglobin A1c [HbA1C], blood pressure, serum lipids, body mass index) and lifestyle factors (smoking, physical inactivity, alcohol consumption) between girls with or without OC use. Confounders: age, diabetes duration and migration background. Statistical analysis: SAS 9.4. Results: In girls with type 1 diabetes and OC use, clinical characteristics and lifestyle factors were less favorable compared to non‐users. Differences were most pronounced for the prevalence of dyslipidemia (OC‐users: 40.0% vs non‐users: 29.4; P < .0001) and the number of smokers (OC‐users: 25.9% vs non‐users: 12.5%; P < .0001). OC use, sociodemographic characteristics and lifestyle factors explained between 1 and 7% of the population variance in serum lipids and blood pressure. The use of OC explained a small additional proportion in all variables considered (<1%). Conclusions: OC use in adolescent girls with type 1 diabetes was associated with a poorer cardiovascular risk profile. Biological risk factors were partly explained by a clustering of sociodemographic and lifestyle factors with a small additional contribution of OC use. Prescription of OC should therefore be combined with a screening for cardiovascular risk factors and targeted education. [ABSTRACT FROM AUTHOR]

Background In Germany/Austria, data on medical care for cystic fibrosis-related diabetes (CFRD) is limited. Methods Anonymized data from 659 CFRD patients were analyzed and compared to the latest ADA/CFF guidelines. Results Specialized diabetes clinics were attended less frequently than recommended (3.1 vs. 4.0 times yearly). 7.9% of patients had a complete profile of examinations: diabetes education (44.9%), HbA 1c (88.8%), blood pressure (79.5%), BMI (86.5%), lipid status (37.5%), retinopathy (29.9%), microalbuminuria (33.2%), and self-monitoring of blood glucose (71.6%). HbA 1c and blood pressure were measured less frequently than recommended (2.3 and 2.0 vs. 4.0 times yearly). Overall, guidelines were followed more frequently in children than adults. Contrary to recommendations, not all patients were treated with insulin (77.2 vs. 100.0%). Insulin therapy was initiated earlier in children than adults, but there was still a substantial delay (0.9 vs. 2.7 years after diagnosis, p < 0.001). Conclusion In CFRD patients studied, adherence to care guidelines was suboptimal. [ABSTRACT FROM AUTHOR]

Aim To examine the impact of postnatal nutrition on long-term growth in extremely low birth weight infants. Method Retrospective analysis of postnatal nutrition and observational study of growth in 52 ELBW infants until the age of six. Results Changes (Δ) in weight and length standard deviation scores ( SDS) between birth to term correlated with protein intake (rw = 0.36; p = 0.009; rL = 0.35; p = 0.01), whereas Δ HC correlated with lipid intake (rHC = 0.38; p = 0.005). Analysis of various intervals (0-2, 3-5, 6-8 and 9-11 weeks) only showed significant impact on growth for energy (r = 0.3; p < 0.05) and lipids (r = 0.23; p < 0.05) at 6-8 weeks. No significant correlations were found between postnatal nutritional parameters and long-term growth. However, postnatal growth restraint was negatively associated with length SDS (r = −0.34; p = 0.015) and body mass index SDS (r = −0.34; p = 0.018) at the age of six. Infants with postnatal growth restraint (n = 25) caught up more in length (+1.78 SDS) than in weight (+0.43 SDS), whereas small for gestational age infants (n = 8) caught up more in weight (+1.35 SDS) than in length (+1.07 SDS). This difference remained significant at the age of six. Conclusion Although no direct association between postnatal nutrition and long-term growth was found, weight at discharge was a strong predictor for long-term growth. [ABSTRACT FROM AUTHOR]

Modern intensive care techniques have led to higher survival rates of extremely low birth weight infants (ELBW, birth weight <1,000 g). Previous studies have suggested a link between abnormal birth parameters and subsequent endocrine disturbances, but a possible impact on bone maturation during childhood has not been studied. ELBW children were studied (mean chronological age (CA), 6.01 years; range, 4.5-8.2). Skeletal maturation was assessed according to Greulich and Pyle (8). Bone age (BA) was defined as retarded when DeltaBA-CA was < -1 SD and accelerated when DeltaBA-CA was >+1 SD. BA was either retarded or accelerated in 15 patients (24.6%). Twenty-one of 61 radiograms (34.4%) showed a discordant BA with a marked gender difference (14/24 boys; 7/37 girls). DeltaBA-CA correlated significantly with BMI (r = 0.36; p = 0.005) and height SDS (r = 0.35; p = 0.006). We found significant correlations between BA and androgens. Insulin-like growth factor binding protein-1 (IGFBP-1), which decreases in insulin-resistant individuals, correlated negatively with BA. In conclusion, bone maturation in ELBW children is correlative with height and weight. It is modulated by a variety of metabolic factors, including IGFBP-1 and androgens. Bone age, together with height and weight catch-up, can thus possibly serve as early indicators of insulin resistance later in life. [ABSTRACT FROM AUTHOR]

To reduce transmission of the coronavirus disease 2019 (COVID-19), many countries implemented lockdowns, causing the closure of childcare services. This study was designed to evaluate the impact of the COVID-19 lockdown in March–April 2020 on children, adolescents, and young adults with Prader–Willi syndrome (PWS) living in Germany. We recruited 180 participants with a genetically confirmed PWS. All families completed a questionnaire, and participants underwent a post-lockdown assessment; the last examination before the lockdown was determined as the pre-lockdown assessment. We used bivariate analyses to compare pre- and post-lockdown outcomes. Weight standard deviation scores (SDSPWS) and body mass index (BMI)-SDSPWS remained stable or even decreased in some age groups. A statistically significant gain in lean body mass (LBM) was found in all groups <18 years of age. We observed an increase in IGF-I and IGFBP-3 concentrations without a significant change in growth hormone (GH) dosage. Most families (95.4%) reported set mealtimes and implementation of structured activities (72.2%) during the lockdown period. We therefore suggest that the favorable development of weight/BMI and LBM was caused by an interplay of a suspected enhanced GH administration and continuous parental commitment. However, more intense behavioral problems were observed in 45.7%, which persisted post-lockdown in 33.7%. [ABSTRACT FROM AUTHOR]

Background: Prader-Willi-Syndrome (PWS) is characterized by hypothalamic-pituitary dysfunction. Recent research suggests starting growth hormone-treatment (GHT) as soon as possible. The aim of this study is to analyze possible differences in auxological parameters, carbohydrate and lipid metabolism between two groups of children with PWS that started GHT either during or after their first year of life.Study Design: Retrospective longitudinal study of 62 children (31 males) with genetically confirmed PWS. Upon diagnosis all children were offered GHT, some started immediately, others commenced later. Cohort A (n = 21; 11 males) started GHT at 0.3-0.99 yrs. (mean 0.72 yrs) and Cohort B (n = 41; 20 males) commenced GHT at 1.02-2.54 yrs. (mean 1.42 yrs) of age. Fasting morning blood samples and auxological parameters were obtained before the start of therapy and semi-annually thereafter. Differences between the two cohorts were estimated with a linear mixed-effect model.Results: Mean length/height-SDSPWS differed significantly between the groups [1 yr: A: 0.37 (±0.83) vs B: 0.05 (±0.56); 5 yrs.: A: 0.81 (±0.67) vs B: 0.54 (±0.64); p = 0.012]. No significant differences were found in BMI, lean body mass or body fat. Low-density cholesterol was significantly lower in A than in B [LDL: 1 yr: A: 79 (±20) mg/dl vs B: 90 (±19) mg/dl; 5 yrs.: A: 91(±18) mg/dl vs 104 (±26) mg/dl; p = 0.024]. We found significant differences in the glucose homeostasis between the groups [fasting insulin: p = 0.012; HOMA-IR: p = 0.006; HbA1c: p < 0.001; blood glucose: p = 0.022].Conclusions: An early start of GHT during the first year of life seems to have a favorable effect on height-SDS and metabolic parameters. [ABSTRACT FROM AUTHOR]

We report 5 out of 214 children with classical congenital adrenal hyperplasia (CAH) that was not detected by neonatal 17-Hydroxyprogesterone screening. Therefore, diagnosis was only based on a suspect clinical picture and subsequent re-evaluation. In addition to 3 patients suffering from the simple virilizing form of CAH and not reported so far, the remaining 2 children whose CAH was missed by the screening suffered from the severe salt-wasting form. This report underlines the importance of a careful clinical investigation of newborns to detect signs of genital virilization. The differential diagnosis of classical CAH should be kept in mind even if neonatal screening is reported to be normal. [ABSTRACT FROM AUTHOR]