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Context Treatment of children with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is challenging. Linear growth and adult height are compromised according to recent publications. However, most of these data were obtained in the era before CAH newborn screening. Design Body height of patients with classical CAH diagnosed before and after the establishment of newborn screening were analyzed retrospectively. Patients and Methods We identified 600 patients with classical CAH (227 male) with data on near-adult height (NAH), target height (TH), and information on newborn screening from the electronic German CAH registry (DGPAED society). Newborn screening was performed in 101 (16.8%) patients. All patients received hydrocortisone with or without fludrocortisone. To assess the effects of newborn screening, a linear regression model adjusted/stratified for sex and phenotype was used (SAS 9.4). Results TH corrected NAH (mean; 95% confidence interval) was closer to zero in patients with CAH and newborn screening (-0.25 SDS; -0.44 - -0.06) than in patients without newborn screening (-0.44 SDS; -0.52 - -0.36) (p=0.069). Screening had no effect on NAH in female patients. In male patients, NAH was significantly better (p=0.033) with screening than without screening. After stratifying for CAH phenotype, screening did not affect the NAH of patients with Salt-wasting-CAH. Patients with Simple-virilizing-CAH had a significantly better cNAH (p=0.034) with screening (0.15 SDS; -0.28 - 0.59) than without screening (-0.35 SDS; -0.52 - -0.18). Conclusions Our data suggest that newborn screening might be associated with improved near-adult height in male CAH patients and in patients with SV-CAH. more...

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. more...

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. more...

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. more...

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 more...

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. more...

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. more...

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. more...

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 more...

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. more...

Short stature is a common pediatric disorder affecting 3% of the population. However, the clinical variability and genetic heterogeneity prevents the identification of the underlying cause in about 80% of the patients. Recently, heterozygous mutations in the ACAN gene coding for the proteoglycan aggrecan, a main component of the cartilage matrix, were associated with idiopathic short stature. To ascertain the prevalence of ACAN mutations and broaden the phenotypic spectrum in patients with idiopathic short stature we performed sequence analyses in 428 families. We identified heterozygous nonsense mutations in four and potentially disease-causing missense variants in two families (1.4%). These patients presented with a mean of −3.2 SDS and some suggestive clinical characteristics. The results suggest heterozygous mutations in ACAN as a common cause of isolated as well as inherited idiopathic short stature. more...

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. more...

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. more...

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 more...

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. more...

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. more...

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. more...

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. more...

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin ( PCNT ) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly ( MCPH1, CDK5RAP2, ASPM , and CENPJ ). more...

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. more...

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 more...

Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified. In a patient with a Jeune-like phenotype we performed exome sequencing and identified compound heterozygous missense and nonsense mutations in DYNC2LI1 segregating with the phenotype. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein-2 complex important for retrograde IFT. Using DYNC2LI1 siRNA knockdown in fibroblasts we identified a significantly reduced cilia length proposed to affect cilia function. In addition, depletion of DYNC2LI1 induced altered cilia morphology with broadened ciliary tips and accumulation of IFT-B complex proteins in accordance with retrograde IFT defects. Our results expand the clinical spectrum of ciliopathies caused by defects of the dynein-2 complex. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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) more...

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. more...

Deletions within HSA band 4p16.3 cause Wolf-Hirschhorn syndrome (WHS), which comprises mental retardation and developmental defects. A WHS critical region (WHSCR) of approximately 165 kb has been defined on the basis of 2 atypical interstitial deletions; however, genotype–phenotype correlation remains controversial, due to the large size of deletion usually involving several megabases. We report on the first known patient with a small de novo interstitial deletion restricted to the WHSCR who presented with a partial WHS phenotype consisting only of low body weight for height, speech delay, and minor facial anomalies; shortness of stature, microcephaly, seizures and mental retardation were absent. The deletion was initially demonstrated by FISH analysis, and breakpoints were narrowed with a “mini-FISH” technique using 3–5 kb amplicons. A breakpoint-spanning PCR assay defined the distal breakpoint as disrupting the WHSC1 gene within intron 5, exactly after an AluJb repeat. The proximal breakpoint was not found to be associated with a repeated sequence or a known gene. The deletion encompasses 191.5 kb and includes WHSC2, but not LETM1. Thus, manifestations attributable to this deletion are reduced weight for height, minor facial anomalies, ADHD and some learning and fine motor deficiencies, while seizures may be associated with deletions of LETM1. © 2001 Wiley-Liss, Inc. more...

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 more...

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. more...

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... more...

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. more...

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. more...

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. more...