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The increased survival rates after pediatric oncological therapy result in an increase in the number of patients showing late effects of tumor therapy. Thyroid function and proliferation disorders in particular are common sequelae of treatment of malignant tumors in childhood and adolescence. They predominantly occur after irradiation of the head and neck and the thyroid glands. The clinical symptoms depend on the thyroid hormone status. The current guidelines on endocrine late effects in these patients are endorsed by the working group of the Scientific Medical Specialist Societies (AWMF). Based on standardized evaluation of currently available literature, this review article summarizes the approaches for late sequelae of tumor therapy on thyroid glands.

Secondary adrenal insufficiency (SAI) is a rare endocrine late effect of childhood cancer treatment and occurs by injury of the hypothalamic-pituitary (HP) axis due to CNS tumors and surgery, and particularly after cranial radiation. SAI can also occur transiently after unilateral adrenalectomy for adrenal hypercortisolism, or after chronic glucocorticoid therapy. Primary adrenal insufficiency plays no role in childhood cancer survivors and occurs as an acute consequence of cancer treatment (e.g., bilateral adrenalectomy or by inhibition of adrenal steroid biosynthesis). There are many different tests assessing the function of the HP-adrenal axis, but the optimal evaluation for ACTH deficiency is still controversial. The clinical diagnosis of SAI can be challenging due to unspecific symptoms which can develop over a long period. Thus, all childhood cancer survivors should have a regular endocrinology examination of the HPA axis. All physicians involved in the long-term follow-up of childhood cancer survivors must be aware of individuals at risk of developing HPA dysfunction. Implementation of an appropriate treatment together with a detailed instruction regarding stress dose and emergency glucocorticoid administration is necessary to prevent life-threatening adrenal crises in SAI patients.

Objective: Classic congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency is characterized by increased prenatal adrenal androgen secretion. There are a small number of reports in the literature showing higher birth weight and length in CAH newborns. Methods: We analyzed birth weight and length data of 116 German newborns (48 boys, 68 girls) with classic CAH who were born during the period from 1990 to 2017. All children have been followed or are currently treated as outpatients in our clinic. All children were born at term. The mothers were healthy and their pregnancies were uneventful. The diagnosis of CAH was confirmed by molecular analyses of the CYP21A2 gene. Birth data were calculated as standard deviation (SD) scores according to German reference values. Results: Weight and length in male CAH newborns (mean ± SD) (3601±576 g; 52.4±2.85 cm) were significantly higher than in female CAH newborns (3347±442 g; 51.2±2.55 cm), but male-female differences in the CAH cohort were lost when the data were converted into SD scores. The birth sizes of the CAH newborns did not differ from the reference group. The birth sizes also did not differ between the different CAH genotypes. Maternal age, mode of delivery and maternal parity had no influence on birth size. Conclusion: Our data show that prenatal hyperandrogenism does not affect fetal growth.

Der M. Basedow ist im Kindes- und Jugendalter selten. Die Diagnosekriterien sind klar definiert; die Therapiemodalitaten werden kontrovers diskutiert. Retrospektive Analyse von Therapie und Langzeitverlauf der Patienten, die in der endokrinologischen Ambulanz der Kinderklinik des Universitatsklinikums Erlangen zwischen 2000 und 2015 betreut wurden. Die Daten von 50 Kindern und Jugendlichen (40 w, 10 m) im Alter von 4,5 bis 17,6 Jahren mit der Diagnose M. Basedow wurden anhand der Krankenakten ausgewertet. Erfasst wurden Anamnese, klinische Symptome, Korpergrose, Gewicht und Laborwerte bei Erstvorstellung sowie bei jeder ambulanten Vorstellung. Ebenso wurden die Dauer bis zum Erreichen der euthyreoten Stoffwechsellage (Remission), der Zeitpunkt des Auslassversuchs, die Dauer der Remission, der Zeitpunkt des Rezidivs und der Zeitpunkt und die Art einer etwaigen endgultigen Therapie erfasst. Korperhohe und BMI wurden in Standard Deviation Score (SDS) anhand der Referenzen von Kromeyer-Hauschild et al. und das sonographische Volumen der Schilddruse (SD) in SDS mit den Daten der KiGGS-Studie berechnet. Die Diagnose wurde 6 Monate nach Symptombeginn im Alter von 12,4 Jahren gestellt. Serum-TSH (thyreoidstimulierendes Hormon) war supprimiert, die freien Hormone fT3 (freies Trijodthyronin) und fT4 (freies Thyroxin) mit 21,6 pmol/l (Norm: 3,5–8,1) bzw. 48,3 pmol/l (Norm: 7,6–17,7) sowie die TRAK (TSH-Rezeptor-Antikorper) mit 9,4 U/l (Norm

Eine Schilddrusenektopie ist extrem selten. Man findet ektopes Schilddrusengewebe als Folge eines gestorten embryonalen Migrationsprozesses gewohnlich im Bereich von der Zunge bis zum Zwerchfell, wobei insbesondere die linguale und sublinguale Lokalisation bevorzugt vorkommen. Bei einem Kind mit angeborener Hypothyreose, die im Neugeborenenscreening entdeckt wurde, kann die Ektopie im Rahmen der weiteren Abklarung diagnostiziert werden. Bei dem Madchen wurde mit 6 3/12 Jahren im Rahmen einer Abklarung von chronischen Bauchschmerzen durch den Kinderarzt als Zufallsbefund eine latente Hypothyreose diagnostiziert (Serum-TSH [Thyreoidea-stimulierendes Hormon] 23,3 mU/l, fT3 [freies Trijodthyronin] und fT4 [freies Thyroxin] normal) und eine Therapie mit L‑Thyroxin (L-T4) eingeleitet. Bis dahin normale psychomotorische Entwicklung, Langenwachstum und Gewichtsentwicklung. Das Madchen war bei Erstvorstellung mit 6 5/12 Jahren in unserer Ambulanz klinisch und laborchemisch euthyreot; die Korpermase waren normal. Die Schilddrusenautoantikorper waren unauffallig. Im Ultraschall der Schilddruse konnte in loco typico kein Schilddrusengewebe nachgewiesen werden, wahrend sich im Bereich des Zungengrundes ein schilddrusenahnliches Gewebe mit einem Volumen von 0,9 ml fand. Eine Schilddrusenszintigraphie bestatigte den Ultraschallbefund. Unter der Therapie mit L‑T4 war die Patientin immer euthyreot und das Schilddrusenvolumen blieb konstant. Das Madchen ist derzeit 11 8/12 Jahre alt (Korperhohe 146,9 cm, Gewicht 33,3 kg, Tanner-Stadium B2) und besucht ein Gymnasium. Eine Zungengrundschilddruse ist eine seltene Ursache einer latenten Hypothyreose und bei fehlenden klinischen Symptomen schwierig zu diagnostizieren. Sie kann als Zufallsbefund in jedem Lebensalter entdeckt werden.

We report on a boy of Albanian descent with the history of juvenile myelomonocytic leukemia (JMML). JMML was diagnosed at the age of 17 months and treated by hematopoietic stem cell transplantation (HSCT). At the age of 14.3 years, about 12 years after HSCT, he was hospitalized with an adrenal crisis. Hormone findings were consistent with primary adrenal insufficiency. Autoimmune adrenalitis was confirmed by positive autoantibodies against 21-hydroxylase and adrenal tissue. Since autoimmune Hashimoto thyroiditis was already known from the age of 9 years, we assume that both diseases are part of the spectrum of autoimmune polyglandular syndrome (APS) type 2. APS type 2 is a rare endocrine disease characterized by Addison’s disease along with autoimmune thyroid disease and/or type 1 diabetes. Learning points: Endocrine sequelae after hematopoietic stem cell transplantation (HSCT) are common and can develop over a long period. Primary adrenal insufficiency after HSCT is absolutely rare. The combination of adrenal autoimmune disease and Hashimoto thyroiditis is consistent with autoimmune polyglandular syndrome type 2. Background Long-term survivors of pediatric hematopoietic stem cell transplantation (HSCT) are at risk for late morbidity and mortality (1, 2, 3). Endocrine late effects including pituitary, adrenal, thyroid and gonadal dysfunctions are common and can develop over a long period (4, 5, 6, 7, 8). These sequelae are influenced by various factors such as the underlying pathological condition, the treatment regimen for the disease and the used therapeutic regimen before HSCT. Secondary adrenal insufficiency (SAI) is the most common form of adrenal insufficiency and mainly related to the duration and cumulative dose of corticosteroid treatment after HSCT (9). For example, SAI was reported in four subjects, who had been treated with corticosteroids for ≥10 months for chronic graft-versus-host disease (GvHD) (10). It was also speculated that the age at HSCT might be an additional risk factor since late effects were more common in young children (2). Reports on primary adrenal insufficiency (PAI) are extremely rare. To the best of our knowledge, we found only three reports on PAI in children after HSCT in the literature (11, 12, 13). In this report, we present the case of a boy with PAI and autoimmune adrenalitis after HSCT.

Background Data on adrenarche and pubarche in girls with Turner syndrome (TS) are inconsistent in the literature. Methods The cohort consisted of 94 girls and young women with TS born between 1971 and 2001 (age range: 3.1–23.2 yrs.), who were treated with human growth hormone and regularly presented at our outpatient clinic every 4 to 6 months.The longitudinal data of all patients were ascertained retrospectively from patient charts. The data collection ended in January 2016. Adrenarche was assessed by serum DHEAS levels and pubertal status by Tanner stages. Pubarche was defined as the appearance of pubic hair (PH2), whereas spontaneous puberty was defined as Tanner stage B2. The patients were retrospectively subdivided in two groups with regard to pubertal development: group 1 (n = 21) with spontaneous puberty and group 2 (n = 70) with induced puberty. Since blood samples were not taken at every visit, we generated seven groups according to the age of the children at which the blood samples were taken: 3–5, 5–7, 7–9, 9–11, 11–13, 13–15, and 15–17 yrs. Serum DHEAS and follicle-stimulating hormone (FSH) levels were measured by chemiluminescence immunoassay and compared with those of a control group of healthy girls. Results Adrenarche started in TS girls between 5 and 7 years. TS girls had higher DHEAS levels than the control group, with statistically significant differences in the age groups 7 to 17 years. No differences were determined between the TS girls with spontaneous puberty and those with POI. TS girls in group 2 reached the Tanner stages PH2 (p

Contains fulltext : 197541.pdf (Publisher’s version ) (Closed access) Context: Inactivating mutations within the AR-gene are present in only around 40% of individuals with clinically and hormonally diagnosed androgen insensitivity syndrome (AIS). Previous studies revealed the existence of an AR-gene mutation negative group of AIS-individuals with compromised AR-function (AIS type II). Objective: To investigate if AIS type II can be due to epigenetic repression of AR-transcription. Design: Quantification of AR-mRNA and AR proximal promoter CpG-methylation levels in genital skin derived fibroblasts (GF) derived from AIS type II individuals and control individuals. Setting: University Hospital endocrine research laboratory. Patients: GF from control individuals (N=11) and AIS type II individuals (N=14). Intervention(s): None. Main Outcome Measure(s): Measurement of AR-mRNA and AR promoter CpG-methylation as well as activity of AR proximal promoter in vitro. Results: 57% of individuals with AIS type II (N=8) show a reduced AR-mRNA expression in their GF. A significant inverse correlation exists between AR-mRNA abundance and methylation at two consecutive CpGs within the proximal AR promoter. Methylation of a 158bp long region containing these CpGs is sufficient to severely reduce reporter gene expression. This region is bound by the Runt Related transcription factor1 (RUNX1). Ectopic expression of RUNX1 in HEK293T cells is able to inhibit reporter gene expression through this region. Conclusions: Aberrant CpGs methylation within the proximal AR promoter plays an important role in the control of AR-gene expression and may result in AIS type II. We suggest that transcriptional modifiers, like RUNX1, could play roles therein offering new perspectives for understanding androgen-mediated endocrine diseases.

Background The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (CAH). Both men and women with classic CAH have lower fertility rates than the general population, and an increased rate of miscarriages has been reported in affected women. There are no data on the incidence rate of miscarriages in families with an offspring that have classic CAH. Methods We studied families with a history of classic CAH. The families came from different parts of Germany and attended the annual meeting of the German CAH support group for parents and patients which was held in Hamburg in September 2014. The data was collected anonymously by a paper-based questionnaire which was completed by the families at home. The families also accepted the responsibility to address this question to their siblings. In all, the data of 50 families with at least one child with classic CAH, and the data of 164 parental siblings were available for evaluation. Miscarriage rates were calculated in relation to the reported pregnancies. Results Twenty-two miscarriages were reported from 19 families. At least one miscarriage occurred in 38% of the families, three families experienced two miscarriages and 16 families had one miscarriage each. The mean miscarriage rate was 15.8%. The heterozygous mothers had a total of 90 siblings (41 m, 49 f), while 74 siblings (33 m, 41 f) were reported from the heterozygous fathers. The miscarriage rate was 10.1% in the families of the mothers` siblings, and 11.4% in the families of the fathers` siblings. The genotype was known in all parents that have an offspring with classic CAH, but not defined in 82% of the maternal siblings, and in 86% of the paternal siblings. No child with classic CAH has been diagnosed in any of the sibling’s families to date. Conclusion Our data show that the miscarriage rate in German families with a child with classic CAH is not elevated. Electronic supplementary material The online version of this article (10.1186/s12884-018-2091-8) contains supplementary material, which is available to authorized users.

Background Adrenal crises in children with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) are life-threatening and have the potential to death. Methods A survey was performed among Paediatric Endocrinologists in Germany to report on deceased children with CAH. Our survey covered the whole of Germany. Results The participating centres reported 14 cases of death (9 female, 5 male) from 1973 until 2004, but no deaths thereafter. 11 children had the SW form and 3 the simple virilizing (SV) form. All patients were on glucocorticoid replacement, and the SW forms additionally on mineralocorticoid replacement. The age at death varied between 6 weeks and 16.5 years. Seven children died before introduction of general neonatal screening, and 7 children thereafter. Before death, the clinical signs of impending crisis were nonspecific. Five patients developed hypoglycaemia and convulsions with cerebral oedema. Half of the deceased patients died at home. The hydrocortisone dosage was only doubled in two of the 14 cases. Conclusions According to the assessments by the attending centres, almost all deaths could be related to an inadequate administration of stress doses of hydrocortisone. Since no deceased CAH children were reported in Germany from 2005 on, we assume the effectiveness of educational programs over the past years. Electronic supplementary material The online version of this article (10.1186/s12902-018-0263-1) contains supplementary material, which is available to authorized users.

Aim There is a scarcity of data on postnatal growth in children with CHARGE syndrome, a genetic disorder. This study analysed spontaneous growth and weight in German children with CHARGE from birth to the age of 6 years. Methods This was a retrospective analysis of 19 children, nine females and 10 males, using data from child health records. Standard deviation scores (SDS) were calculated based on Swiss references. Results The median birthweight was 2950 g (−0.78 SDS), and the birth length was 49 cm (−0.5 SDS). There was a significant loss of median body length, at around 4 weeks of age from −0.5 to −2.3 SDS (p

Aim: The aim of this study was to evaluate the response to recombinant growth hormone (GH) treatment in short children with CHARGE syndrome. Patients: We identified 51 children (28 boys and 23 girls) in KIGS (Pfizer International Growth Database). The median chronological age was 7.6 years at the start of GH therapy and 13.2 years at the latest visit. Evaluation for GH deficiency (n = 33) was based on the following: peak GH level 7.3 μg/l and IGF-I level -2.01 standard deviation score (SDS). Sixteen subjects (9 boys) were followed longitudinally for 2 years. Results: Birth length (median SDS, -0.47) and weight (-0.97) were slightly reduced. At the start of GH therapy, height was -3.6 SDS, BMI -0.7 SDS, and the GH dose was 0.26 mg/kg/week. At the latest visit after 2.7 years of GH therapy, height had increased to -2.2 SDS and BMI to -0.5 SDS. In the longitudinal group, height increased from -3.72 SDS at the start of GH therapy to -2.92 SDS after 1 year to -2.37 SDS after 2 years of therapy (start - 2 years: p < 0.05), height velocity increased from -1.69 to 2.98 to 0.95 SDS, and BMI and GH dose (mg/kg/week) remained almost unchanged. Conclusions: Our data show a positive effect of conventional doses of GH on short-term growth velocity for the longitudinal as well as for the total group, without any safety issues.

Background: Despite the fact that priming with sex steroids in prepubertal children before growth hormone (GH) provocative tests is recommended, there is an ongoing controversial discussion about the appropriate age of the children, the drug used for priming, the dose and the period between priming and the GH test. Interestingly, there is no discussion on the safety of this procedure. To date, only little data have been available on the possible side effects of priming with testosterone. Methods: We analyzed the outcome in 188 short-statured prepubertal boys who had been primed with testosterone enanthate (n=136: 50 mg; n=51: 125 mg, and accidentally one boy with 250 mg) 7 days prior to the GH test. Serum testosterone levels were measured on the day of the GH test in 99 boys. Results: Overall, only five boys developed adverse side effects. Two boys (dose 125 mg) showed severe low-flow priapism and had to undergo decompression of the corpora cavernosa. One boy suffered from self-limiting priapism and testicular pain (dose 50 mg). Two patients reported testicular pain (each dose 50 mg). The single patient with 250 mg testosterone did not show any adverse effects. The total side effect rate was 2.7%. The serum testosterone levels of the boys with side effects were not different from the testosterone levels of the boys without any side effects. Conclusions: Parents and patients should be informed about the possible side effects of priming with testosterone such as priapism and testicular pain. However, the overall side effect rate is low. We found no correlation between the outcome and the testosterone dose used and/or the level of serum testosterone.

Summary Objective Autosomal dominant hypocalcaemia or hypoparathyroidism is caused by activating mutations of the calcium-sensing receptor (CaSR). Treatment with calcium and vitamin D often worsens hypercalciuria and nephrocalcinosis, and renal impairment can result. Our aim was to describe the phenotypic variance of this rare disorder in a large series and to evaluate the outcome after long-term treatment. Design Nationwide retrospective collaborative study. Patients We describe 25 patients (14 men and 11 women), 20 belonging to 11 families and five single cases. Measurements Activating CaSR mutations and clinical and biochemical findings were evaluated. Results Nine different missense mutations of the CaSR, including one novel variant (M734T), were found. Twelve patients (50%) were symptomatic, 9 (36%) had basal ganglia calcifications and 3 (12%) had nephrocalcinosis. Serum calcium was decreased (1·87 ± 0·13 mm), and PTH was decreased (n = 19) or inappropriately low (n = 4). The occurrence of hypocalcaemic symptoms at diagnosis was related to the degree of hypocalcaemia. The occurrence of features like calcification of basal ganglia or kidney calcification did not correlate with the severity of hypocalcaemia or the age at diagnosis. The most common treatment was calcitriol (median dosage 0·6 μg/day), and the mean duration of therapy was 7·1 years (max. 26 years). Hypercalcaemic episodes rarely occurred, and the rate of kidney calcifications was remarkably low (12%). Conclusion This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.

Summary Background There has been controversy in recent years on whether the d3 polymorphism of the GH receptor is associated with a better growth response to GH in idiopathic short children born small for gestational age (SGA). Methods In this prospective study, we evaluated exon 3-GHR polymorphisms in 142 (62 f, 80 m) short prepubertal children born SGA (birth length and/or weight of ≤−2 SD for GA) and treated with rhGH (mean dose of 0·30 mg/kg/week) in 24 centres in Germany. A growth prediction for the first year of therapy was calculated for each child according to Ranke and co-workers. The index of responsiveness (IOR) was calculated by dividing the response (observed growth minus predicted growth) by the standard error of the prediction. All analyses were performed in one centre on samples collected and shipped on filter paper. The DNA fragment containing or missing exon 3 of the GHR was amplified by multiplex PCR. Results The fl-GHR isoform was most common with a frequency of 47·8%, followed by the d3/fl isoform with 38% and the d3-GHR isoform with 14·2%. There were no significant differences regarding gestational age, birth weight and birth length, mid parental height-SDS, chronological age at start of therapy, height-SDS, BMI-SDS, height velocity and GH dose between the different subgroups according to the genotype. After the first treatment year, height (H)-SDS (P

It has been shown that changes in IGF-I and IGFBP levels in children with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) are correlated with different states of metabolic control. Our approach was to analyze the serum levels of IGF-I, IGFBP-3, their molar ratio IGF-I:IGFBP-3 (MR), and ALS in a cohort of CAH children and adolescents, and their associations with different clinical and biochemical parameters.56 patients, aged between 5.6 and 19.0 years were studied cross-sectionally. All patients had genetically proven CAH and received standard steroid substitution therapy. We measured serum levels of IGF-I, IGFBP-3, and ALS by commercial ELISA and calculated MR and assigned population-based SD scores (SDS).(median, quartiles) Overall IGF-I was not significantly altered (0.05 SDS, -1.21, 0.92), whereas IGFBP-3 was significantly elevated (1.50 SDS; 0.58, 1.95, p0.0001) compared to the reference population. Consecutively, MR was decreased (-0.64 SDS; -1.38, 0.32; p=0.0017). ALS was clearly decreased (-1.95 SDS; -3.075, -1.00; p0.0001). ALS, IGF-I, MR, and IGFBP-3 SDS were lower in pubertal than in prepubertal patients (p0.05). ALS SDS were lower in girls (p=0.0038). Correlation analyses (r(s), p) revealed correlations between MR/ALS and chronological age (-0.583,0.0001/-0.428, 0.0010), MR/ALS and Tanner stages (-0.500,0.0001/-0.334, 0.0118), MR/ALS and bone age (0.407, 0.0075/0.426, 0.0049), and between MR and ALS (0.405, 0.0020), respectively. For MR and ALS, we found no significant correlations for BMI, HOMA-IR, hydrocortisone and fludrocortisone dosage, or parameters of metabolic control.Our data provide evidence that the components of the trimeric IGF-I-IGFBP-3-ALS complex are altered in CAH children with possible implications on pubertal growth and final height.

Summary Objective Animal studies suggest pathological foetal programming of hypothalamic circuits regulating food intake in the setting of leptin deficiency and intrauterine growth restriction (IUGR). We aimed to compare placental leptin synthesis and leptin-binding capability in venous cord blood between IUGR newborns and neonates born appropriate for gestational age (AGA). Design Prospective controlled multicentre study. Patients Twenty-one ultrasound-proven IUGR and 33 AGA neonates. Measurements The concentration of leptin and soluble leptin receptor (sOB-R) in venous cord blood at birth was determined. Moreover, placental gene and protein expression of leptin and placental mRNA expression of functional and total leptin receptor isoforms were measured. Results Whereas log-leptin concentration in venous cord blood did not differ between IUGR and AGA newborns, the concentration of log-sOB-R was elevated in IUGR neonates (pconfounder adjusted = 0·009). Placental leptin protein synthesis as well as leptin mRNA was significantly higher in IUGR than in AGA infants (log-transformed, relative gene expression, pconfounder adjusted = 0·004). Analysis of gene expression of functional and total leptin receptor isoforms did not show any difference between both groups. Conclusions Leptin-binding capability in venous cord blood is increased in IUGR newborns. Thus, via foetal programming, reduced biologically active leptin levels might contribute to a perturbed regulation of appetite.

Intrauterine growth restriction (IUGR) is associated with an increased risk for short stature and diseases in adulthood thought to be inflicted by fetal programming. We hypothesized that placental endocrine systems involved in perinatal growth might also play a role in postnatal growth after IUGR. In a prospective controlled multicenter study, placental gene expression of IGF-binding protein-1 (IGFBP-1), leptin and 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) were measured in 14 IUGR infants and 15 children born appropriate for gestational age (AGA) proven by serial ultrasound examinations. Postnatally, IUGR infants experienced a significantly higher growth velocity than AGA neonates (at 1 y: p = 0.001). Gene expression of 11beta-HSD2 at birth correlated positively with birth length (r = 0.55, p = 0.04) and inversely with growth velocity in the first year of life (r = -0.69, p = 0.01) in the IUGR, but not in the AGA group. There was no correlation between gene expression of placental IGFBP-1, leptin and birth weight, length and growth velocity during the first year of life. AGA infants showed significantly higher concentrations of cortisone in venous cord blood after birth (p = 0.02) as a surrogate of a higher 11beta-HSD2 activity in the fetoplacental unit. In conclusion, placental 11beta-HSD2 gene expression might predict postnatal growth in IUGR.

UNLABELLED We report four children originating from two unrelated German families with congenital hypothyroidism (CH) due to mutations in the thyroid peroxidase (TPO) gene. Three female siblings (family 1) were found to be compound heterozygous for two mutations, a known mutation in exon 9 (W527C), and a mutation in exon 8 (Q446H), which has not been described before. In the second family we identified a boy with goitrous CH, who had a novel homozygous mutation in the TPO gene in exon 16 (W873X). All children of family 1 were diagnosed postnatally by newborn screening. The case of the boy of family 2 has already been reported for the in utero treatment of a goiter with hypothyroidism. CONCLUSION Our results confirm existing data on the phenotypic variability of patients with TPO gene mutations.

Background: One important goal in the management of children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is to achieve normal growth. Reviewing available data published over the last few years on growth and height outcomes in CAH patients, it becomes evident that an acceptable height can be achieved by many CAH patients. However, linear growth and final adult height may be stunted in some patients due to factors related to the timing of diagnosis, the age at therapy onset, the start of therapy, the adequacy of metabolic control, the quality of therapy, patient compliance and the experience of the treating physician. In children with CAH who have a poor height prognosis, additional treatment options should be considered. Conclusions: Treatment of children with CAH requires individualized approaches to prevent long-term growth failure.

Background: Levothyroxine (L-T4) treatment of euthyroid children with Hashimoto thyroiditis (HT) is a controversial issue. Patients and Methods: We conducted a prospective, randomized, controlled clinical trial. Out of 79 identified euthyroid patients, 59 started the study; 25 patients (21 female, 4 male; age: 11.8 ± 2.3 years) received L-T4 at a mean dose of 1.6 µg/kg (SD, 0.8) daily, and 34 (27 female, 7 male; age: 12.6 ± 1.2 years) were not treated. Patients developing subclinical hypothyroidism during follow-up (n = 13) were treated with L-T4 and removed from the observation group. As the main outcome measures, thyroid gland volume (determined by ultrasound) as well as serum levels of TSH, free T4, and antibodies against thyroid peroxidase and thyroglobulin were assessed every 6 months for 36 months. Results: At the start, the mean thyroid volume (standard deviation score, SDS) was 2.5 in the treatment group and 1.6 in the observation group. There was a constant decline in mean thyroid volume (SDS) from 2.13 (month 12) to 1.12 (month 30) in the treated group, with a delta thyroid volume of -1.01 SDS. In the observation group, the mean delta thyroid volume increased to +0.27 SDS. The change of the delta thyroid volume was statistically significantly different between both groups during the 12- and 30-month time points (p < 0.05). L-T4 had no effect on thyroid function and serum thyroid antibodies. Conclusions: L-T4 treatment can decrease the thyroid volume in euthyroid children with HT, but the effect is limited to a definite time period. © In Copyright http://rightsstatements.org/vocab/InC/1.0/, publishedVersion

Congenital adrenal hyperplasia (CAH) comprises a group of rare autosomal recessively inherited disorders of cortisol biosynthesis in the adrenal cortex. More than 95% are based on a defect in the CYP21A2 gene causing 21-hydroxylase deficiency. Newborn screening (NBS) for CAH by means of 17-hydroxy-progesterone (17-OHP) determination in dried whole blood on filter paper has been introduced as part of the NBS in many countries worldwide. The goals of CAH screening are early detection of the severe, salt-wasting form, therefore prevention of adrenal crisis or death, early detection of the simple virilizing form, and prevention or shortening of the period of incorrect gender assignment in females. Methodological problems of false-positive samples, especially in pre-term infants, can be corrected by adapting the cut-off values for 17-OHP to birth weight, gestational age and age at the time of collection and by performing a second tier screening. Despite a positive voting for newborn CAH screening by the European Society for Pediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society, it is obvious that the acceptance of CAH screening varies worldwide.

Objective We analyzed postnatal growth in children with familial short stature (FSS) with regard to small (SGA) or appropriate (AGA) for gestational age status at birth. Study design We studied 96 otherwise healthy short-statured children (58 males; SGA: n = 41, AGA: n = 55). At least one of the parents was short-statured. Cross-sectional data for length/height and weight for the first 4 years of age were collected retrospectively. Results AGA children had a mean length of 0.09 ± 1.02 standard deviation score (SDS) at birth, −1.57 ± 1.16 SDS after 1 year of age, and −2.36 ± 0.72 SDS after 4 years. SGA children had a mean length of −2.04 ± 1.06 SDS at birth, −2.70 ± 1.12 SDS at 1 year of age, and −3.05±0.86 SDS at 4 years. The loss of length SDS within the first 2 years of life was greater in AGA than in SGA children. SGA children were significantly shorter than AGA children at all of the study points (p Conclusions Children with an FSS background born AGA show catch-down growth to their lower familial range during the first 2 years of life. SGA children did not catch up to their AGA peers at any time.

Background: Females with Ullrich-Turner syndrome (UTS) have typical clinical features such as short stature, ovarian failure, visible dysmorphic stigmata, and abnormalities in different organs such as kidney or heart. Hypothesis: The aim of the present study was to analyze the distribution, prevalence, and relative risk of cardiovascular anomalies (CVA) in females with Ullrich-Turner syndrome (UTS) seen at one single center compared with that of the regional Bavarian population. Methods: The associations between CVA and karyotype were determined. In all, 117 girls and women with UTS, aged between 3 and 43 years (median 17.4 years) were studied retrospectively. The detailed cardiologic status including echo-cardiography was available in all patients. The prevalences of each cardiovascular anomaly were determined. On the basis of published epidemiologic data of CVA in Bavarian children, we assessed the relative risks of each CVA. Results: Thirty-five (29.9%) girls with UTS had at least one CVA. In all of these CVAs, coarctation of the aorta and bicuspid aortic valve occurred most often (18.5% each). The aortic malformations represented over two-thirds of all CVA (72.8%), whereas anomalies of the septum (8.6%), mitral valve (6.2%), pulmonary veins (4.9%), and other locations together accounted for the otherthird. Bicuspid aortic valve and partial anomalous pulmonary venous drainage were associated with the highest relative risk (RR) (3,603 and 1,293, respectively) compared with the Bavarian population. The overall RR of CVA was 48.7. Of the 117 girls and women examined, 64 (54.7%) had complete monosomy 45 X. Conclusions: Our data demonstrate that about every third female with UTS is affected with at least one CVA, mainly left sided and associated with aortic structures. Our results underline the necessity of thorough cardiologic evaluation.

We report on a newborn with a severe salt-wasting crisis due to congenital adrenal hyperplasia (CAH) with 21-hydroxylase deficiency, in spite of prenatal diagnosis of CAH and awareness of this diagnosis by the parents and the gynecologic and pediatric practitioners. Due to the diagnosis of CAH in the older sister, prenatal treatment with dexamethasone (Dexa) was initiated. Prenatal diagnosis showed an affected male fetus and the prenatal treatment was stopped. The parents and the involved physicians were informed about the diagnosis, treatment, follow-up, and possible complications. Amniotic infection led to preterm delivery in another hospital. Due to perinatal asphyxia, the male newborn received Dexa during mechanical ventilation. Neonatal CAH screening was unsuspicious. An acute salt-wasting crisis with metabolic acidosis at the age of 3 weeks finally led to the correct diagnosis. This experience emphasizes the need to obtain a careful medical history. Furthermore, this case illustrates that neonatal screening for CAH is falsely negative in the event of neonatal Dexa treatment.

OBJECTIVE: Alterations in the growth hormone-insulin-like growth factor (IGF) axis have been considered as a causal factor for intrauterine growth restriction (IUGR) and for the increased risk of metabolic disease in later life. We compared members of the IGF axis in umbilical cord blood between IUGR neonates, small for gestational age without foetal restriction (SGA) and appropriate for gestational age (AGA) neonates.DESIGN: Prospective controlled multicenter study.PATIENTS: Sixteen ultrasound-proven IUGR, 8 SGA and 40 AGA neonates.MEASUREMENTS: Concentrations of total IGF-I and total IGF-II by immunoassays, bioactive IGF by cell-based bioassay and IGFBP-I in mixed venous and arterial umbilical cord blood samples at birth. Auxological parameters at birth.RESULTS: IGF-I concentrations in IUGR [17·7 μg/l (CI 13·8;21·6)] were clearly below those in AGA [48·3 μg/l (CI 43·7;52·9)] and SGA neonates [36·0 μg/l (CI 26·6;45·4)]. IGF-II levels were significantly reduced in IUGR [201·4 μg/l (CI 190·2;212·6)] compared to AGA neonates [231·2 μg/l (CI 220·6;241·9)]. A trend for lower IGF-II concentrations was observed in IUGR when compared to SGA neonates [232·0 μg/l (CI 207·2;256·8)]. These differences could not be explained by confounding. For IGFBP-1, a trend towards higher values in IUGR was observed.CONCLUSIONS: Low IGF-I cord blood concentrations in hypotrophic neonates after IUGR might not only result from low birthweight per se, but also reflect prenatal placental environment. Alterations of the IGF axis could be in the causal pathway of IUGR and thus constitute a potential surrogate marker for IUGR in the assessment of foetal programming.

We have analyzed the kinetics of salivary cortisol (F) and 17-hydoxyprogesterone (17OHP) after a single oral administration of hydrocortisone (HC; 10 mg; 0700 h) in healthy male volunteers (n 10; 18 –29 yr) and in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (males, n 7; females, n 3; 8.5–20.4 yr). The HC doses, related to body surface area, ranged from 6.3–9.2 mg/m 2 in controls and from 4.2–10.7 mg/m 2 in CAH patients. Saliva was collected over 5 h (at intervals of 15–30 min), and the steroids were measured with adapted RIAs. In healthy controls, maximal cortisol values (250.3 35.9 nmol/liter) were reached after 30 min. Values showed a monophasic decrease. A t1/2 of 94.5 min was calculated. The proportion of the HC dose in the total area under the curve was 71.2 3.2%. For 17OHP, a monophasic decrease was found, with a minimum level of 48 27 pmol/liter after 300 min. In CAH patients the salivary steroid profiles showed individual kinetics (maximal cortisol values ranged from 107–726 nmol/liter). Here a monophasic decrease was found with a shorter t1/2 of 56.4 min. The HC dose proportion in the area under the curve was 88.3 6%. 17OHP showed biphasic courses with a decrease to the minimum 17OHP level after 210 min at the latest and a subsequent gradual increase. Our findings of limited normalization of the adrenal cortex by oral HC administration underlines the necessity of optimizing therapy control and indicates the usefulness of kinetic studies for the judgement of therapy in CAH patients. (J Clin Endocrinol Metab 87: 1200 –1204, 2002)

Objective: The conversion of cortisol, which binds avidly to the mineralocorticoid receptor, to cortisone, which no longer has mineralocorticoid function, is predominantly catalyzed by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD 2). It was the objective of the present study to examine the impact of different forms of glucocorticoid excess on the cortisol/cortisone ratio and to differentiate their role in the genesis of hypertension. Design and methods: Plasma cortisol and cortisone levels were determined in 12 adults with Cushing’s disease, 12 adults with hypercortisolism due to an adrenal tumor, and 20 healthy volunteers before and after an intravenous ACTH test, using specific radioimmunoassays after automated Sephadex LH 20 chromatography. Results: The cortisol/cortisone ratios were significantly higher in patients with Cushing’s disease (13.9 ± 1.1), adrenal tumors (11.5 ± 2.3), and in healthy volunteers after ACTH stimulation (14.1 ± 2.0) than in untreated controls (6.0 ± 0.5) (P < 0.001, P < 0.05, and P < 0.001, respectively). Similar differences were seen for cortisol plasma concentrations, whereas cortisone concentrations did not differ among the groups. Conclusions: Our data suggest that the excessive mineralocorticoid effects in patients with hypercortisolism are inflicted by elevated cortisol/cortisone ratios possibly due to an insufficient conversion of cortisol to cortisone by 11β-HSD 2. This may provide a possible explanation for the occurrence of hypertension. This effect seems to be independent of the role of ACTH in the mechanism of hypercortisolism.

OBJECTIVE: The objective of the present study was to examine the impact of major heart surgery with cardiopulmonary bypass (CPB) in childhood on serum leptin concentrations in relation to plasma cortisol, epinephrine, norepinephrine, and insulin. DESIGN: Controlled, prospective study. SETTING: Intensive care unit of a university hospital. Patients and INTERVENTIONS: We enrolled 20 pediatric patients undergoing open heart surgery and 20 children with major surgery not necessitating CPB (surgical control group). Leptin was measured by radioimmunoassay, cortisol and insulin were measured by chemiluminescence, and epinephrine and norepinephrine were measured by high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: In the CPB group, leptin dropped from 0.4 +/- 0.1 preoperatively (mean +/- sem) to 0.2 +/- 0.1 ng/mL intraoperatively (p

Objective: To assess biochemical characteristics of adrenarche in patients with myelomeningocele (MMC), we examined serum levels of dehydroepiandrosterone sulfate (DHEAS) in prepubertal MMC patients. Patients and Methods: The study included a total of 54 prepubertal patients with MMC and shunted hydrocephalus: 13 patients (2 m, 11 f; aged 4.6–10.1 years, mean 8.1 ± 0.4) with isolated pubarche (Tanner stage PH 2–4, B1 or testes volume ≤3 ml) and 41 prepubertal MMC patients without pubarche (17 m, 24 f; aged 2.0–11.9 years; mean 6.8 ± 2.5). DHEAS levels were measured directly by chemiluminescence immunoassay (Nichols, USA). Auxological data (supine length, body mass index (BMI), arm span) and bone age (BA) were recorded. Results(mean ± SD): Basal DHEAS levels correlated with chronological age (CA) (r = 0.32, p < 0.05), BA (r = 0.65, p < 0.01; n = 23), BMI (r = 0.54, p < 0.01) and pubic hair stage (PH1 vs. PH2–4, r = 0.49, p < 0.01). 10/11 patients aged 2–4 years had DHEAS levels in the normal range, whereas 18/40 (45.0%) of the 5- to 9-year-old patients showed elevated levels (>+2 SDS). Ten patients with isolated pubarche (10/13; 2 m, 8 f; CA 8.3 ± 1.5 years) and 9 patients without pubarche (9/41; 6 m, 3 f; CA 6.9 ± 2.1 years) had elevated DHEAS levels (+6.34 and +4.05 SDS, respectively). The values correlated with BA/CA ratio (p < 0.05, n = 23). There was a trend to higher BMI SDS levels in patients with elevated DHEAS levels. Conclusion: Our data show an early and increased activation of adrenal androgen secretion in MMC patients.

Using routine stable isotope dilution/gas chromatography-mass spectrometry, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone, androstanediol, and 5α-dihydrotestosterone have been profiled in amniotic fluid of midgestation in 77 normal fetuses and 38 untreated or dexamethasone-treated fetuses at risk for 21-hydroxylase deficiency. Dexamethasone was suspended 5–7 days before amniocentesis. In normal fetuses, amniotic fluid concentrations (median, range; nanograms per mL) of 17-hydroxyprogesterone did not reveal a sex difference (1.48, 0.21–4.96), whereas those of androstenedione were lower in females (0.53, 0.00–2.71) than in males (0.93, 0.29–1.98). Testosterone levels were higher in males (0.24, 0.00–0.50) than in females (0.00, 0.00–0.27). No sex difference was found for dehydroepiandrosterone (0.47, 0.19–1.77). Levels of androstanediol and 5α-dihydrotestosterone were below the detection limit of our method in most cases. Regarding prenatal diagnosis of 21-hydroxylase deficie...

Fortschritte in der Therapie maligner Hirntumoren im Kindesalter haben in den letzten Jahrzehnten zu einer deutlichen Verbesserung der Uberlebensraten gefuhrt. Daher kommt dem Erkennen therapiebedingter Spatfolgen zunehmend eine Bedeutung zu. Neben Zweittumoren, kognitiven und intellektuellen Einbusen spielen hormonelle Folgestorungen eine bedeutende Rolle. Methode: Eigene Erfahrungen und Literaturrecherche. Ergebnisse: In der Regel kommt es als erstes und am haufigsten zu Storungen der Wachstumshormonsekretion. Storungen der spontanen Wachstumshormonsekretion wurden bereits nach konventionell fraktionierter Schadelbestrahlung mit 18 Gy beobachtet. Mit einiger Latenz konnen auch Storungen der anderen hypothalamo-hypophysaren Achsen bis hin zum Panhypopituitarismus auftreten. Die Pubertat kann verfruht oder verspatet beginnen oder ganz ausbleiben. Insbesondere bei Madchen kommt es nach Hirntumortherapie gehauft zur fruhen und im Ablauf beschleunigten Pubertatsentwicklung, die durch eine akzelerierte Knochenreifung zu einer weiteren Verminderung der Endgrose fuhrt. Hypothalamo-hypophysar bedingte Storungen der Schilddrusenfunktion und der Nebennierenrindenfunktion sind seltener und werden in der Regel erst nach hypothalamo-hypophysaren Strahlendosen von uber 40 Gy beobachtet. Schlusfolgerung:Uberlebende eines Hirntumors im Kindesalter mussen als Langzeituberlebende betrachtet werden, bei denen bereits kurz nach Ende der Tumortherapie die ersten der therapiebedingten Spatfolgen auftreten. Um fur den individuellen Patienten eine maximale Lebensqualitat zu erreichen, ist eine langfristige Betreuung mit enger Kooperation der verschiedenen beteiligten Fachdisziplinen unabdingbar.

Background Chronic hypernatremia is a rare disorder in childhood and normally results from impairment of the water homeostasis. In some cases, chronic hypernatremia is caused by decreased intake of water based on impaired thirst perception. Case report We report a girl with microcephaly, partial agenesis of the corpus callosum, mild midface hypoplasia and absence seizures, who presented with severe hypernatremia (serum sodium concentration 189 mmol/l). Though serum osmolality was increased up to 382 mOsm/kg, the girl showed no signs of thirst. After normalization by intravenous fluid therapy, serum osmolality and serum sodium concentration remained in the normal range with an oral water intake of at least 1500 ml/d. Polyuria was never present, the ability to concentrate urine was preserved. Conclusions In summary, we speculate that the chronic hypernatremia in our patient is caused by a selective hypothalamic osmoreceptor dysfunction associated with mild dysplasia of the midline structures. Only very few similar cases have been documented in the literature.

Puberty is frequently delayed in adolescent patientswith chronic renal failure, due to temporarily insuffi-cient hypothalamo-pituitary stimulation of the gonads.In these patients, basal levels of gonadotropins arenormal or slightly elevated due to increased plasmahalf-life of luteinizing hormone (LH) and folliclestimulating hormone (FSH) [1]. However, the responseto gonadotropin releasing hormone (GnRH), LHand FSH stimulation is inadequate, confirminghypogonadotropic hypogonadism.The exact mechanism of delayed pubertal develop-ment in chronic renal insufficiency is still unknown,but a reduced amplitude of pulsatile gonadotropinsecretion, i.e. LH and FSH, is thought to play animportant role [2]. In patients with chronic renal failuretheonsetofpubertyisdelayedonaverageby2years[2].However, various other reasons may affect pubertaldevelopment in patients with chronic renal insuffi-ciency, including gonadal disorders such as gonadaldysgenesis, Leydig cell hypoplasia, Turner syndromeand Klinefelter syndrome.

Objective Hypothalamic ovarian failure can be considered as a differential diagnosis in women suffering from CAH and amenorrhea. Naltrexone can be used as a tool to exclude hyperandrogenemia as a cause of amenorrhea in that condition. Study design Five women (ages between 16 and 30 years) with congenital adrenal hyperplasia (CAH) due to C21- hydroxylase deficiency and primary or secondary amenorrhoea were treated with the opiate antagonist naltrexone at a dose of 50 mg per day. Result In all patients naltrexone induced normalization of menstrual cycle determined by endocrine parameters and ultrasonography. Conclusion Since naltrexone has been shown to restore normal menstrual cycles in hypothalamic amenorrhea it can be inferred that the cause of amenorrhea in those patients was not of hyperandrogenemic but of hypothalamic origin. Naltrexone may therefore be used to differentiate between hyperandrogenemic and hypothalamic ovarian failure in patients suffering from CAH.

BACKGROUND In 1987, a pilot trial (HIT 88/89) was initiated by GPOH to investigate the effectivity and toxicity of intense preradiation chemotherapy. The aim of this study was to improve the treatment of children with malignant brain tumors, but provided no standardized recording of auxological and/or endocrinological parameters. In 1993 a sub-project, "Endocrinological late effects", was started during the ongoing study to examine the late effects of treatment, and a retrospective evaluation was performed in order to standardize parameters. PATIENTS We considered auxological and hormonal data from those patients (n = 133; 78 m, 55 f) who were alive at the time of the survey, and had completed tumor therapy. RESULTS Analysis of the growth pattern of the children after the end of therapy indicate impaired growth. Group 1 (n = 77, CA 10 yr): Height SDS-CA fell from +0.24 (n = 45) at the time of diagnosis to -0.62 (n = 14) after 3-4.5 yrs. Unfortunately, only body height and weight were recorded regularly, data on sitting height, pubertal stage and bone age were incomplete. Endocrine evaluation after end of therapy was insufficient. CONCLUSIONS A standardization of endocrinological follow up is necessary as soon as possible, for an adequate description of the endocrinological late effects.

Our retrospective analysis of growth and pubertal development includes 109 children and adults with meningomyelocele (MMC) (52 M, 57 F) aged 3.2-21.0 years (median 8.9 years). Anthropometric data, growth-retarding factors and data on pubertal development were analysed in comparison to the normal population using standards from Prader et al. (1). The results (mean +/- SD) were as follows. Fifty patients (46.8%) had short stature (height SDS for chronological age (SDS CA)-2). The supine length was influenced by the level of the lesion (height SDS CA:or = L2 -3.13 +/- 1.62,or = S2 -0.46 +/- 1.27), ambulatory status, skeletal deformities and pubertal stage. The mean adult height (n = 15, age 16.1-21.0 years) measured 141.3 cm for women (height SDS CA -3.83 +/- 1.79) and 159.2 cm for men (height SDS CA -2.27 +/- 1.81). In 82.6% of the subjects (n = 90), arm spans were within the normal range. Reduced arm spans (SDS-2) as found in 19 patients (17.4%) with short stature (mean height SDS CA -3.29 +/- 1.29) may be caused by factors other than neurological lesions and skeletal deformities, and require further endocrinological studies. Out of 27 pubertal patients, central precocious puberty was diagnosed in five girls. The stages of puberty in MMC girls developed earlier than expected for the age-related group.

The F-box protein Fbxw8 is a cofactor of Cullin 7 (Cul7), which regulates protein transfer to the proteasome and cell growth. Cul7 or Fbxw8 deficiency is associated with intrauterine growth restriction (IUGR) due to abnormal placental development leading to poor oxygen supply to the fetus. We studied the role of hypoxia for Fbxw8 and Cul7 expression in trophoblastic cells.Immunomagnetic bead-separated extravillous trophoblast (EVT) and villous trophoblast (VT) and trophoblast cell lines were incubated with 1 or 8% O(2). Fbxw8 and Cul7 expression was determined in IUGR versus matched control placentas.Fbxw8 was expressed uniformly in trophoblasts, whereas Cul7 expression was most prominent in trophoblast cell lines. Hypoxia reduced expression of Cul7 and Fbxw8 in all trophoblastic cells, except for villous trophoblasts. In vivo, Cul7 and Fbxw8 were detected in syncytiotrophoblast cells, VT, and EVT cells. Although no significant changes in expression levels of Fbxw8 or Cul7 were noted in IUGR compared with control placentas, Fbxw8 expression correlated negatively with gestational age in the control, but not in the IUGR group.Fbxw8 and Cul7 expression reveals a complex regulation in trophoblastic cells. Our findings suggest that dysregulation of Cul7 and Fbxw8 expression might affect trophoblast turnover in IUGR.

Summary Manifestations of the metabolic syndrome [obesity, dyslipidaemia, hypertension, blood glucose derangements including prediabetes or type 2 diabetes mellitus (T2DM)] in juvenile populations are becoming increasingly prevalent throughout the world and are at the point of being a global public health concern. Derangements in cortisol regeneration seem to be involved in the pathophysiology. Treatment with selective 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors could be a therapeutic strategy in paediatric patients with manifestations of the metabolic syndrome. Based on preclinical and clinical data regarding development of the 11β-HSD1 enzyme, it appears that maturation occurs within the first year of life. Different changes in biomarkers for assessing the efficacy and safety of 11β-HSD1 inhibitors are to be expected in paediatric patients compared to adults, reflecting differences in metabolism. The effect of 11β-HSD1 treatment in children on bone differentiation and development as well as adrenocorticotropic hormone (ACTH), circulating and local cortisol tissue concentrations, androgens and respective stress response is not yet known. Based on current literature, the concept of inhibition of 11β-HSD1 is considered a potentially effective mean to regulate local cortisol levels in the paediatric population, and 11β-HSD1 inhibitors may provide a valuable target and treatment option for the metabolic syndrome in paediatric patients. However, the uncertainty over effects on the developing skeleton combined with mild increases in adrenal androgen levels raises potential concerns regarding growth as well as onset of puberty as to their future use in children. Future clinical studies are needed to thoroughly assess the risks and benefits of this new class of drugs in the paediatric population.

There have been only a few studies on adrenarche in girls with classic congenital adrenal hyperplasia (CAH) showing that dehydroepiandrosterone sulfate (DHEAS) levels did not rise at the physiological age of adrenarche. Objective: Longitudinal analysis of serum DHEAS levels and Tanner stages in CAH children. Design: We studied 98 CAH patients (52 females), aged between 1 month and 18.0 years. All patients had genetically proven classic CAH and received steroid substitution therapy. Results: Serum DHEAS levels did not differ between CAH children and healthy children from the age of 1 year until 5–6 years. Beginning at the age of 7–8 years, there was a continuous but blunted increase in DHEAS levels in CAH boys and girls compared to healthy children. There was no correlation of DHEAS levels with the genotype, glucocorticoid dosage, auxological data, or quality of metabolic control. Pubarche (PH2) as well as gonadarche (G2) and thelarche (B2) occurred significantly earlier in CAH boys and girls than in the reference group, but timing of menarche was normal. Conclusions: Pubarche and adrenarche are dissociated in classic CAH: earlier pubarche, gonadarche and thelarche, respectively, in both sexes contrast with the absence of typical adrenarche.

Objectives Fetal glucocorticoid excess is thought to play an important role in early-life programming, promoting growth restriction and contributing to adult metabolic, cardiovascular and neuroendocrine disease. We hypothesized that dexamethasone incubation of primary trophoblastic cells from human healthy placentas at term might induce altered gene and protein expression of several endocrine placental regulators. Study design Primary villous trophoblastic cells were incubated with 10 μM dexamethasone for 6, 12, 24, 48 and 72 h. Non-incubated trophoblastic cells served as vehicle control. Gene expression of leptin, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and insulin-like growth factor-binding protein-1 (IGFBP-1) was measured. Moreover, leptin, β-human chorionic gonadotropine (β-hCG) and lactate dehydrogenase (LDH) release into the culture medium was determined. Results Leptin gene expression was significantly increased in dexamethasone-incubated trophoblastic cells after 24, 48 and 72 h. There was a significant increase in leptin concentration in the medium of the cell culture after 48 h. Gene expression of 11β-HSD2 was significantly higher in dexamethasone-stimulated trophoblastic cells compared to vehicle controls after 72 h. The expression rate of IGFBP-1 mRNA was basal throughout the incubation period. The concentration of β-HCG in the supernatant increased significantly after 72 h of dexamethasone incubation, while LDH concentrations remained stable. Conclusion Our findings suggest that dexamethasone incubation stimulates leptin and 11β-HSD2 gene expression in primary villous trophoblastic cells of healthy human placentas, while enhancing cytotrophoblast differentiation.

To assess the effect of human growth hormone (hGH) therapy and other factors on tumor recurrence after treatment of pediatric brain tumors (BTs), we retrospectively analyzed data from 108 craniopharyngioma, medulloblastoma, and ependymoma patients. Risk factors were identified using multifactorial univariate regression analysis. Recurrences occurred in 41 and second malignant neoplasms in 4 patients. There were significant correlations for completeness of tumor removal and recurrence-free survival (RFS). 13/44 hGH-treated and 28/59 non-hGH-treated children relapsed. This difference was found only for medulloblastomas and accounted for by higher rates of incomplete tumor removal in non-hGH patients. Craniopharyngioma recurrence correlated only with RFS. Malignant BT recurrence correlated with completeness of tumor removal, chemotherapy, and RFS. 4 children developed SMNs, 3/4 after hGH therapy. Our regression model yielded accurate within-sample prediction of recurrence for 90% of the study population. We conclude that hGH therapy after treatment of pediatric BTs does not increase tumor recurrence risk.

Objective: It has been shown that adiponectin serves as an insulin-sensitizing adipokine. Serum concentrations of adiponectin are low in children with obesity, and increase with fat mass loss, indicating that adiponectin can serve as a biomarker. Since the prevalence of overweight and obesity is increased in children with congenital adrenal hyperplasia (CAH), our study aimed to evaluate serum levels of adiponectin in a cohort of CAH children and adolescents, and their associations with clinical parameters such as chronological age (CA), body mass index (BMI), Tanner stage (TS), medication and metabolic control. Patients and methods: We studied 51 patients, aged between 5.6 and 19.6 years (median 11.8; 30 females, 21 males), cross-sectionally. All patients had genetically confirmed CAH and received standard steroid substitution therapy. Adiponectin was measured by an enzyme linked immunoassay. Since BMI SDS of the CAH cohort were significantly higher compared to the reference population, we built matched pairs with healthy Caucasian subjects from a normal representative cohort for sex, Tanner stage, chronologic age and BMI. Results: Adiponectin concentrations were significantly higher in CAH patients (median 11 μg/L) compared to the matched controls (6.7 μg/L, p < 0.0001). Correlation analyses in CAH patients revealed a significant inverse relationship between adiponectin and CA, TS, BMI, serum DHEAS and serum testosterone, but no correlation with hydrocortisone and fludrocortisone dosage. Conclusion: Currently, the importance of the elevated adiponectin concentrations in CAH children for risk assessment is not clear. However, our data imply that besides adequate metabolic control of glucocorticoid substitution, a long-term follow-up of other metabolic markers of insulin resistance should be conducted in CAH patients.

ObjectiveCongenital adrenal hyperplasia (CAH) patients are at a higher risk to develop obesity. The role of leptin in CAH is still controversial. Our study aimed to evaluate serum levels of leptin, the soluble leptin receptor (sOB-R), and the sOB-R: leptin molar ratios in a cohort of CAH children and adolescents, and their associations with clinical and metabolic parameters.MethodsWe studied 51 CAH patients, aged 5.6–19.6 years (median 11.8, n=30 females) cross-sectionally. All patients had genetically proven CAH and received standard steroid substitution therapy. Blood specimens were taken after overnight fasting between 0800 and 1000 h. For the analyses of leptin and sOB-R, matched pairs were built with healthy Caucasian patients for sex, Tanner stage (TS), chronologic age (CA), and body mass index (BMI).ResultsBMI and SDS were significantly elevated compared with the reference population. Leptin levels were not different between matched pairs, whereas sOB-R levels were significantly lower in CAH. Consequently, the sOB-R: leptin molar ratios were significantly decreased in CAH. Correlation analyses in CAH patients revealed significant relationship between leptin and CA, TS, BMI, and homeostasis model assessment of insulin resistance. Similar results were obtained for the matched control group. For sOB-R, we found no significant correlation for CA, TS, or BMI in CAH, but we did in the controls. There were significant correlations for androgens within the CAH group. Additional analyses revealed no correlation with steroid medication or metabolic control.ConclusionsOur data show that an altered leptin axis with normal serum leptin concentrations but decreased sOB-R serum levels may contribute to the increased risk of overweight and obesity in CAH.

Introduction 3beta-Hydroxysteroid dehydrogenase (3beta-HSD) deficiency is a rare cause of congenital adrenal hyperplasia caused by inactivating mutations in the HSD3B2 gene. Most mutations are located within domains regarded crucial for enzyme function. The function of the C terminus of the 3beta-HSD protein is not known. Objective We studied the functional consequences of three novel C-terminal mutations in the 3beta-HSD protein (p.P341L, p.R335X and p.W355X), detected in unrelated 46,XY neonates with classical 3beta-HSD type II deficiency showing different degrees of under-virilization. Methods and results In vitro expression of the two truncated mutant proteins yielded absent conversion of pregnenolone and dehydroepiandrosterone (DHEA), whereas the missense mutation p.P341L showed a residual DHEA conversion of 6% of wild-type activity. Additional analysis of p.P341L, including three-dimensional protein modeling, revealed that the mutant's inactivity predominantly originates from a putative structural alteration of the 3beta-HSD protein and is further aggravated by increased protein degradation. The stop mutations cause truncated proteins missing the final G-helix that abolishes enzymatic activity irrespective of an augmented protein degradation. Genital appearance did not correlate with the mutants' residual in vitro activity. Conclusions Three novel C-terminal mutants of the HSD3B2 gene are responsible for classical 3beta-HSD deficiency. The C terminus is essential for the enzymatic activity. However, more studies are needed to clarify the exact function of this part of the protein. Our results indicate that the genital phenotype in 3beta-HSD deficiency cannot be predicted from in vitro 3beta-HSD function alone.

The present review summarizes data on the time course and physiological function of the three major endogenous estrogens estrone (E1), 17β-estradiol (E2), and estriol (E3) during the different phases of life in the human female and male. During fetal life, E3 is the most abundant estrogen produced by the fetoplacental unit. E3 affects cerbral development, leads to breast gland swelling in both girls and boys and promotes uterine growth up to a size that is not reached again until puberty. In infancy and childhood estrogen levels are low before the ovaries are stimulated to increase the production of E2 at puberty. In the complex course of maturation, the onset of puberty is characterized by a gradually increasing pulsatile secretion of hypothalamic gonadotropin-releasing hormone followed by a gradual rise of circulating gonadotropin levels. Increasing E2 concentrations in girls promote development of female sex characteristics, menarche, behavioral changes, pubertal growth spurt and finally the closure of epiphysal growth zones. Throughout fertile life of the human female, ovarian E2 remains the major endogenous estrogen. It is produed by the granulos cells of the growing follicle as well as by the corpus luteum. Among other functions, it is important for endometrial proliferation, as a prerequisite for blastocyst implantaion and pregnancy. E2 induces growth of the uterus and maturation of the breast. E2 production declines gradually during late reproductive life; as a consequence, menstrual bleeding ceases with menopause. During postmenopause, the predominant endogenous estrogen is E1, which is mainly produed by adipose tissue from androgenic precursors secreted by the ovarian stroma and the adrenal gland. Decreased estrogen concentrations lead to atrophy of the inner and outer genitalia, osteoprorosis, an increased risk of cardiovascular disease, hot flashes and emotional instability.

UNLABELLED Precocious puberty is not a typical manifestation of patients with Klinefelter syndrome (KS). However, there is an increased incidence of mediastinal germ cell tumors (M-GCT) in KS, whereas the discussion of a generally higher tumor risk in this condition is still controversial. A rare subgroup of KS patients consists of prepubertal children with precocious puberty due to human chorionic gonadotropin (hCG)-producing M-GCTs. We present clinical data on a boy with KS and sexual precocity, and summarize the published data on 12 boys with KS out of 54 cases of KS and M-GCT. CLINICAL REPORT an 8.5-year-old boy presented with signs of precocious puberty. Laboratory analyses (suppressed gonadotropins, elevated testosterone) and thoracic CT demonstrated a beta-human chorionic gonadotropin (beta-hCG) and alpha(1)-feto protein (alpha-FP) secreting mediastinal tumor. Histological analysis showed a mixed germ cell tumor comprising choriocarcinoma (CH), embryonal carcinoma (EC), mature teratoma (MT), and yolk sac tumor (YS). He was successfully treated by surgery and adjuvant chemotherapy. Epianalysis of published cases: all KS patients (n = 12), age 4-9 years, presented with precocious sexual development (PP), whereas the older ones showed thorax-associated symptoms, mainly chest pain, dyspnea, and cough. The histological distribution was also age-dependent with mixed germ cell tumors predominantly in younger patients. Thus, M-GCTs are strongly associated with precocious puberty in young boys with KS. Therefore, a karyotype analysis should be included in the clinical work-up of boys with precocious puberty and M-GCT. There is still no convincing explanation for the association of M-GCTs and KS.