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Objective: To investigate rates and risk factors of hospital admission for diabetic ketoacidosis (DKA) or severe hypoglycemia in young patients with established type 1 diabetes. Design: In total, 31 330 patients with type 1 diabetes (median age 12.7 years) from the Diabetes Patienten Verlaufsdokumentation (DPV) Prospective Diabetes Registry treated between 2011 and 2013 in Germany were included. Methods: Admission rates for DKA(pH <7.3 or bicarbonate <15 mmol/l) and severe hypoglycemia (requiring assistance from another person) were calculated by negative binomial regression analysis. Associations of DKA or hypoglycemia with patient and treatment characteristics were assessed by multivariable regression analysis. Results: The mean admission rate for DKA was 4.81/100 patient-years (95% CI, 4.51-5.14). The highest DKA rates were observed in patients with HbA1c ≥9.0% (15.83 (14.44-17.36)), age 15-20 years (6.21 (5.61-6.88)) and diabetes duration of 2-4.9 years (5.60 (5.00-6.27)). DKA rate was higher in girls than in boys (5.35 (4.88-5.86) vs 4.34 (3.95-4.77), P=0.002), and more frequent in migrants than in non-migrants (5.65 (4.92-6.49) vs 4.57 (4.23-4.93), P=0.008). The mean admission rate for severe hypoglycemia was 1.45/100 patient-years (1.30-1.61). Rates were higher in migrants compared to non-migrants (2.13(1.72-2.65) vs 1.28(1.12-1.47), P<0.001), and highest in individuals with severe hypoglycemia within the preceding year (17.69 (15.63-20.03) vs patients without preceding hypoglycemia 0.42 (0.35-0.52), P<0.001). Differences remained significant after multivariable adjustment. Conclusions: The identification of at-risk individuals for DKA (patients with high HbA1c, longer diabetes duration, adolescents, girls) and for severe hypoglycemia (patients with preceding severe hypoglycemia, migrants) may facilitate targeted diabetes counselling in order to prevent these complications. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine disease. Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common form of CAH. The aim of the study was to study the functional consequences of three novel and one previously described CYP11B1 gene mutations (p.(Arg143Trp), p.(Ala306Val), p.(Glu310Lys) and p.(Arg332Gln)) detected in patients suffering from classical and non-classical 11β-OHD. Functional analyses were performed by using a HEK293 cell in vitro expression system comparing wild type (WT) with mutant 11β-hydroxylase activity. Mutant proteins were examined in silico to study their effect on the three-dimensional structure of the protein. Two mutations (p.(Ala306Val) and p.(Glu310Lys)) detected in patients with classical 11β-OHD showed a nearly complete loss of 11β-hydroxylase activity. The mutations p.(Arg143Trp) and p.(Arg332Gln) detected in patients with non-classical 11β-OHD showed a partial functional impairment with approximately 8% and 6% of WT activity, respectively. Functional mutation analysis allows the classification of novel CYP11B1 mutations as causes of classical and non-classical 11β-OHD. The detection of patients with non-classical phenotypes underscores the importance to screen patients with a phenotype comparable to non-classical 21-hydroxylase deficiency for mutations in the CYP11B1 gene in case of a negative analysis of the CYP21A2 gene. As CYP11B1 mutations are most often individual for a family, the in vitro analysis of novel mutations is essential for clinical and genetic counselling. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We aimed at developing and cross-validating a mathematical prediction model for an optimal basal insulin infusion pattern for children with type 1 diabetes on continuous subcutaneous insulin infusion therapy (CSII). RESEARCH DESIGN AND METHODS--We used the German/Austrian DPV-Wiss database for quality control and scientific surveys in pediatric diabetology and retrieved all CSII patients <20 years of age (November 2009). A total of 1,248 individuals from our previous study were excluded (dataset 1), resulting in 6,063 CSII patients (dataset 2) (mean age 10.6 ± 4.3 years). Only the most recent basal insulin infusion rates (BRs) were considered. BR patterns were identified and corresponding patients sorted by unsupervised clustering. Logistic regression analysis was applied to calculate the probabilities for each BR pattern. Equations were based on both independent datasets separately, and probabilities for BR patterns were cross-validated using typical test patients. RESULTS--Of the 6,063 children, 5,903 clustered in one of four major circadian BR patterns, confirming our previous study. The oldest age-group (mean age 12.8 years) was represented by 2,490 patients (42.18%) with a biphasic dawn-dusk pattern (BC). A broad single insulin maximum at 9-10 p.m. (F) was unveiled by 853 patients (14.45%) (mean age 6.3 years). Logistic regression analysis revealed that age, to a lesser extent duration of diabetes, and partly sex predicted BR patterns. Cross-validation revealed almost identical probabilities for BR patterns BC and F in the two datasets but some variation in the remaining two BR patterns. CONCLUSIONS--Reconfirmation of four key BR patterns in two very large independent cohorts supports that these patterns are realistic approximations of the circadian distribution of insulin needs in children with type 1 diabetes. Prediction of an optimal pattern a priori can improve initiation and clinical follow-up of CSII in children and adolescents. In addition, these BR patterns represent valuable information for insulin-infusion algorithms in closed-loop CSII. [ABSTRACT FROM AUTHOR]

Introduction. Acute hyperglycemia is considered as a pro-inflammatory state and is related to an adverse outcome in critically ill adults. Neonates are susceptible to infections and systemic inflammatory response syndrome induced by pro-inflammatory cytokines. This study focuses on the interaction between neonatal glucose homeostasis and the pro-inflammatory cytokine production in term and preterm infants in-vitro. Methods. We analyzed the pro-inflammatory cytokine production in whole cord blood of term infants ( n == 10), preterm infants > 32 weeks ( n==16) and preterm infants ≤32 weeks of gestational age ( n == 13) and in adult controls ( n==14) using an in-vitro sepsis-model. Whole blood was pre-incubated with different concentrations of glucose (0-1000 mg/dl) and insulin (0-62.5 IE/l) and stimulated with lipopolysaccharide. The intracytoplasmatic TNF-α, IL-6, and IL-8 response was measured by flow cytometry. Results. In-vitro hyperglycemia induced a dose-dependent increase of IL-8 in all age groups while TNF-α was demonstrated to be stimulated by glucose in cord blood samples of preterm infants ≤32 weeks of gestational age and term infants. In contrast, insulin showed no significant effects on pro-inflammatory cytokine production in-vitro. Conclusion. Acute hyperglycemia may induce pro-inflammatory cytokine responses in neonatal whole blood in-vitro. These data provide a basis for further in-vitro signal transduction studies and in-vivo investigations about the significance of neonatal glucose homeostasis and its impact on long-term outcome of this susceptible patient cohort. [ABSTRACT FROM AUTHOR]

Abstract: Background: There are very few laboratory markers which reflect the biological sensitivity of children to recombinant human growth hormone (rhGH) treatment. Genome-wide transcriptional changes in peripheral blood mononuclear cells (PBMC) have been widely used as functional readout for different pharmacological stimuli. Objective: To characterize transcriptional changes in PBMC induced by rhGH during a routine short-term IGF-I generation test (IGFGT) in children with growth disorders. Materials and methods: Blood was obtained for IGF-I determination and RNA-preparation from PBMC of 12 children before and after 4days treatment with 30μgrhGH/kg body weight/day s.c. Transcriptional changes were assessed by cDNA-microarrays in the first six children. Selected genes were validated in all 12 cases by RT-qPCR. Results: Serum IGF-I rose in all patients except one (p<0.0001), confirming biological response to rhGH. Unsupervised microarray data analysis in the first six children revealed 313 transcripts with abundant transcriptional changes but considerable inter-individual variability of response patterns. Many patients showed a large cluster of up-regulated genes, including EGR1, EGR2, FOS and to a lesser extent STAT2 and 5b. Exemplarily, EGR1, EGR2 and FOS data were independently reproduced by RT-qPCR. Gene ontology analysis revealed that pathways involved in cell proliferation and immune functions were significantly over represented. Conclusion: The IGFGT is a suitable method for measuring reproducible and biologically conclusive transcriptional changes in PBMC. As our unsupervised data analysis strategy exposed a considerable inter-individual variability of response profiles a search for molecules of diagnostic and even prognostic value needs to be based on large long-term studies. [Copyright &y& Elsevier]

17&agr;-hydroxylase/17, 20-lyase deficiency (17OHD) is an autosomal recessive disease causing congenital adrenal hyperplasia and a rare cause of hypertension with hypokalemia. The CYP17A1 gene mutation leads to 17OHD and its clinical features. We described an 18 y/o female with clinical features of 17&agr;-hydroxylase/17, 20-lyase deficiency and characterized the functional consequences of an intronic CYP17A1 mutation. The coding regions and flanking intronic bases of the CYP17A1 gene were amplified by PCR and sequenced. The patient is a compound heterozygote for the previously described p.R358X and IVS1 +2T>C mutations. A first intron splice donor site mutation was re-created in minigene and full-length expression vectors. Pre-mRNA splicing of the variant CYP17A1 intron was studied in transfected cells and in a transformed lymphoblastoid cell line. When the full-length CYP17A1 gene and minigene containing the intronic mutation was expressed in transfected cells, the majority (>90%) of mRNA transcripts were incorrectly spliced. Only the p.R358X transcript was detected in the EBV-transformed lymphoblastoid cell line. The IVS1 +2T>C mutation abolished most 17&agr;-hydroxylase/17, 20-lyase enzyme activity by aberrant mRNA splicing to an intronic pseudo-exon, causing a frame shift and early termination. [ABSTRACT FROM AUTHOR]

Women and girls with complete androgen insensitivity syndrome (CAIS) invariably have a female typical core gender identity. In this case report, we describe the first case of male gender identity in a CAIS individual raised female leading to complete sex reassignment involving both androgen treatment and phalloplasty. CAIS was diagnosed at age 17, based on an unambiguously female phenotype, a 46,XY karyotype, and a 2660delT androgen receptor (AR) gene mutation, leading to a premature stop in codon 807. Bilateral gonadectomy was performed but a short period of estrogen treatment induced a negative emotional reaction and treatment was stopped. Since the age of 3, childhood-onset cross gender behavior had been noticed. After a period of psychotherapy, persisting male gender identity was confirmed. There was no psychiatric co-morbidity and there was an excellent real life experience. Testosterone substitution was started, however without inducing any of the desired secondary male characteristics. A subcutaneous mastectomy was performed and the patient received phalloplasty by left forearm free flap and scrotoplasty. Testosterone treatment was continued, without inducing virilization, and bone density remained normal. The patient qualifies as female-to-male transsexual and was treated according to the Standards of Care by the World Professional Association for Transgender Health with good outcome. However, we do not believe that female sex of rearing as a standard procedure should be questioned in CAIS. Our case challenges the role of a functional AR pathway in the development of male gender identity. [ABSTRACT FROM AUTHOR]

Androgen insensitivity syndrome (AIS) is the most common cause of disorders of sex development usually caused by mutations in the androgen receptor (AR) gene. AIS is characterized by a poor genotype–phenotype correlation, and many patients with clinically presumed AIS do not seem to have mutations in the AR gene. We therefore aimed at identifying a biomarker enabling the assessment of the cellular function of the AR as a transcriptional activator. In the first step, we used complementary DNA (cDNA) microarrays for a genome-wide screen for androgen-regulated genes in two normal male primary scrotal skin fibroblast strains compared to two labia majora fibroblast strains from 46,XY females with complete AIS (CAIS). Apolipoprotein D (APOD) and two further transcripts were significantly upregulated by dihydrotestosterone (DHT) in scrotum fibroblasts, while CAIS labia majora cells were unresponsive. Microarray data were well correlated with quantitative real-time polymerase chain reaction (qRT-PCR; R = 0.93). Subsequently, we used qRT-PCR in independent new cell cultures and confirmed the significant DHT-dependent upregulation of APOD in five normal scrotum strains [13.5 ± 8.2 (SD)-fold] compared with three CAIS strains (1.2 ± 0.7-fold, p = 0.028; t test) and six partial androgen insensitivity syndrome strains (2 ± 1.3-fold, p = 0.034; t test). Moreover, two different 17ß-hydroxysteroid dehydrogenase III deficiency labia majora strains showed APOD induction in the range of normal scrotum (9.96 ± 1.4-fold), supporting AR specificity. Therefore, qRT-PCR of APOD messenger RNA transcription in primary cultures of labioscrotal skin fibroblasts is a promising tool for assessing AR function, potentially allowing a function-based diagnostic evaluation of AIS in the future. [ABSTRACT FROM AUTHOR]

Objective Pseudohypoaldosteronism type I (PHA1) is a rare inborn disease causing severe salt loss. Mutations in the three coding genes of the epithelial sodium channel (ENaC) are responsible for the systemic autosomal recessive form. So far, no phenotype has been reported in heterozygous carriers. Patients A consanguineous family from Somalia giving birth to a neonate suffering from PHA1 was studied including clinical and hormonal characteristics of the family, mutational analysis of the SCNN1A, SCNN1B, SCNN1G and CFTR genes and in vitro analysis of the functional consequences of a mutant ENaC channel. Results CFTR mutations have been excluded. SCNN1A gene analysis revealed a novel homozygous c.1684T > C mutation resulting in a S562P substitution in the αENaC protein of the patient. Functional analysis showed a significantly reduced S562P channel function compared to ENaC wild type. Protein synthesis and channel subunit assembly were not altered by the S562P mutation. Co-expression of mutant and wild-type channels revealed a dominant negative effect. In heterozygote carriers, sweat sodium and chloride concentrations were increased without additional hormonal or clinical phenotypes. Conclusion Hence, the novel mutation S562P is causing systemic PHA1 in the homozygous state. A thorough clinical investigation of the heterozygote SCNN1A mutation carriers revealed increased sweat sodium and chloride levels consistent with a dominant effect of the mutant S562P allele. Whether this subclinical phenotype is of any consequence for the otherwise asymptomatic heterozygous carriers has to be elucidated. [ABSTRACT FROM AUTHOR]

Background: Gender appears to be determined by independent programs controlled by the sex-chromosomes and by androgen-dependent programming during embryonic development. To enable experimental dissection of these components in the human, we performed genome-wide profiling of the transcriptomes of peripheral blood mononuclear cells (PBMC) in patients with rare defined "disorders of sex development" (DSD, e.g., 46, XY-females due to defective androgen biosynthesis) compared to normal 46, XY-males and 46, XX-females. Results: A discrete set of transcripts was directly correlated with XY or XX genotypes in all individuals independent of male or female phenotype of the external genitalia. However, a significantly larger gene set in the PBMC only reflected the degree of external genital masculinization independent of the sex chromosomes and independent of concurrent post-natal sex steroid hormone levels. Consequently, the architecture of the transcriptional PBMC-"sexes" was either male, female or even "intersex" with a discordant alignment of the DSD individuals' genetic and hormonal sex signatures. Conclusion: A significant fraction of gene expression differences between males and females in the human appears to have its roots in early embryogenesis and is not only caused by sex chromosomes but also by long-term sex-specific hormonal programming due to presence or absence of androgen during the time of external genital masculinization. Genetic sex and the androgen milieu during embryonic development might therefore independently modulate functional traits, phenotype and diseases associated with male or female gender as well as with DSD conditions. [ABSTRACT FROM AUTHOR]

Background: Findings have been inconsistent regarding the effect of T1DM (type 1 diabetes) on age at menarche.Objective: The purpose was to investigate in young German women with T1DM menarcheal age and factors potentially affecting menarche, including glycemic control, BMI (body mass index), relative T1DM duration (proportion of life with diabetes), insulin dose, and insulin therapy intensity. Initiated in 1990, the DPV program is an ongoing, prospective long-term longitudinal follow-up study to benchmark the quality of care provided to pediatric and, more recently, adult diabetes patients. Two hundered two German diabetes centers participated in nationwide data collection. Based on ethnicity and the availability of menarche and T1DM onset data as the main inclusion criteria, 643 young German women were selected from 11,629 female T1DM patients aged <20 years, recruited by referral, clinic or hospital ascertainment, or self report. Mean age at menarche (+/-SD) was 13.22 +/- 1.31 years, representing a delay of 0.52 years (p < 0.001) relative to the general population. Significant delay (p < 0.05) was also found for relative T1DM duration, BMI SD score, insulin dose, and HbA1c level, with a 1% increase in HbA1c resulting in a delay in menarche by 0.07 years.Conclusions: Age at menarche is delayed in type 1 diabetes mellitus. The delay increases with relative T1DM duration and poor quality of glycemic control. [ABSTRACT FROM AUTHOR]

\nIntroduction: Dehydroepiandrosterone sulphate is increased in formerly small-for-gestational age singletons and in smaller twins compared to their normal-weight co-twin. Less is known concerning other adrenal hormones. We compared diurnal salivary profiles in monozygotic twins with intra-twin birthweight (bw) differences to analyse the long-term impact of bw and persistent intra-twin auxological differences on various adrenal hormones. Methods: Forty-six monozygotic pre-pubertal twin pairs with bw difference of <1 standard deviation score (SDS) (concordant; n = 29, 13 female) and ≥1 SDS (discordant; n = 17, 6 female) were recruited. At a mean age of 6.9 years, saliva samples were collected (7:00 a.m./waking, 1:00 p.m., 6:00 p.m., and 9:00 p.m.) and analysed with liquid chromatography-tandem mass spectrometry. Results: Diurnal salivary concentrations showed significant intra-twin correlations in all twin pairs for nearly all time points: progesterone and androstenedione (4/4 time points), 17-hydroxyprogesterone (2/4). However, in the discordant group, mean progesterone differed significantly (p = 0.018) between the smaller (3.27 nmol/L, SD 3.87) and the larger twin (0.72 nmol/L, SD 0.42) at 7:00 a.m., and intra-twin differences were observed at 3/4 time points. Regression analyses of intra-twin differences confirmed that actual hormonal parameters were explained mainly by the co-twin parameter. However, at 6:00 p.m., progesterone concentration of the smaller twin was explained by bw (Β −1.102; SE 0.563; p = 0.05) and actual weight (Β 0.799; SE 0.327; p = 0.019). Conclusion: The significant correlations within monozygotic twin pairs in all measured hormones at nearly all time points suggest a strong genetic influence on the adrenal axis. Among the discordant twin pairs, we found significant variations in progesterone, suggesting additional long-lasting influence from intrauterine conditions on adrenal hormones with possible metabolic consequences. Previous research has shown that low birthweight (bw), unfavourable intrauterine conditions, and rapid post-natal catch-up growth can have long-standing negative health impacts, including disruption of the endocrine system. Earlier studies have primarily focused on the impact of low bw on one particular adrenal hormone, dehydroepiandrosterone sulphate, but less is known about the impact on the production of other hormones. In our study, we compared salivary hormone levels and generic health parameters (bw, height, weight, etc.) in identical twin pairs, to investigate the long-standing impact of unfavourable intrauterine conditions. Our cohort consisted of identical twin pairs who suffered from twin-to-twin transfusion syndrome in utero, a condition in which there is unequal blood and nutrient supply among twin pairs. This condition often results in significant bw differences between twins. The twin pairs in this cohort have an identical genetic makeup, very similar post-natal conditions, but contrasting intrauterine conditions, making them an excellent cohort in which to investigate genetic and non-genetic influences on longer term health. [ABSTRACT FROM AUTHOR]

Background: Iatrogenic Cushing's syndrome induced by oral and parenteral glucocorticoid administration is a well-known complication. Immediate withdrawal from exogenous steroids can lead to life-threatening adrenal insufficiency. However, Cushing's syndrome caused by topical treatment with glucocorticoids, such as dexamethasone eye drops or dermal application, is rarely recognized. Young infants in particular are at high risk of suffering from iatrogenic Cushing's syndrome when treated with highly potent topical glucocorticoids. Case presentation: We present a 6-month-old Syrian boy with cushingoid face after dermal clobetasol cream treatment and a 2-year-old Iranian girl with severe growth retardation after application of dexamethasone eye drops. Both families have a migration background and language barriers. In both cases no endogenous cortisol secretion was initially detected in serum and in 24-hour collected urine. After dose reduction of glucocorticoids, severity of symptoms was reversible and serum cortisol was detectable. Discussion and conclusion: Young infants are at high risk of developing Cushing's syndrome from topically applied highly potent glucocorticoids. Precise recommendations of treatment dosage, duration, and frequency must be given to the parents, and if necessary, with the help of an interpreter. Monitoring of height and weight as well as regular pediatric follow-ups should be scheduled. Physicians should be aware of potential adrenal insufficiency following withdrawal from long-term topical glucocorticoid treatment, and hydrocortisone treatment should be considered. [ABSTRACT FROM AUTHOR]

Individuals with complete androgen insensitivity syndrome show a female genital phenotype despite 46, XY gonosomes and the presence of androgen producing testes. This clinical observation indicates the resistance of the body and its cells to androgens like testosterone. At the molecular level, this hormone resistance is caused by hemizygous loss of function mutations in the X-chromosomal androgen receptor (AR) gene. Partial forms of androgen insensitivity syndrome (PAIS) show different degrees of virilisation largely depending on the remaining activity of the AR. Nevertheless, the phenotypic outcome can be variable even in presence of the same mutation and in the same kindred indicating the presence of further influencing factors. Importantly, the majority of clinically diagnosed PAIS individuals do not bear a mutation in their AR gene. A recent assay using the androgen regulated gene apolipoprotein D as biomarker is able to detect androgen insensitivity on the cellular level even in absence of an AR gene mutation. Using this assay a class of AIS without an AR-gene mutation was defined as AIS type II and suggests that unidentified cofactors of the AR are responsible for the PAIS phenotype. Here we outline the scientific progress made from the first clinical definition of AIS over biochemical and molecular characterizations to the concept of AIS type II. This review is based on publications in the PubMed database of the National Institutes of Health using the search terms androgen insensitivity syndrome and androgen receptor mutation. [ABSTRACT FROM AUTHOR]