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Height is a heritable and highly heterogeneous trait. Short stature affects 3% of the population and in most cases is genetic in origin. After excluding known causes, 67% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.

Background:Growth prediction models (GPMs) exist to support clinical management of children treated with growth hormone (GH) for growth hormone deficiency (GHD), Turner syndrome (TS) and for short children born small for gestational age (SGA). Currently, no prediction system has been widely adopted.Content:The objective was to develop a stand-alone web-based system to enable the widespread use of an ‘individualised growth response optimisation’ (iGRO) tool across European endocrinology clinics. A modern platform was developed to ensure compatibility with IT systems and web browsers. Seventeen GPMs derived from the KIGS database were included and tested for accuracy.Summary:The iGRO system demonstrated prediction accuracy and IT compatibility. The observed discrepancies between actual and predicted height may support clinicians in investigating the reasons for deviations around the expected growth and optimise treatment.Conclusions:This system has the potential for wide access in endocrinology clinics to support the clinical management of children treated with GH for these three indications.

Objective The adaptor protein p66Shc generates mitochondrial reactive oxygen species and translates oxidative signals into apoptosis. We aimed to analyze potential alterations in total methylation and in p66Shc activation in placental tissues from women delivering intrauterine growth restricted neonates (IUGR) versus appropriate for gestational age (AGA) and small for gestational age (SGA) neonates. Method DNA methylation of the p66Shc promoter and of long interspersed nuclear elements (LINE-1), as a marker for total methylation, was quantified by automatic pyrosequencing in 15 IUGR, 25 AGA and 15 SGA placentas. Placental gene expression of p66Shc was determined by TaqMan real-time polymerase chain reaction. Results No significant difference was found for LINE-1 methylation between IUGR, AGA and SGA newborns. DNA methylation of the p66Shc promoter was significantly decreased in the IUGR compared with the AGA group (p

Background: Ullrich-Turner syndrome (UTS) girls often present with short stature in adolescence to the endocrinologist when the efficacy of growth hormone (GH) to improve growth remains unknown and parameters to estimate individual GH responsiveness have yet to be determined. Objective: Retrospective evaluation of adult height (AH) and predicted adult height at GH start (descriptive model of Ranke, Model PredAH) in early and late GH-treated German UTS patients. Subjects/Methods: 313 patients treated with GH, early [chronological age (CA) at GH start Results: AH (152.5 ± 5.9 vs. 151.1 ± 5.4 cm, p = n.s.) after GH treatment for 7.5 ± 2.12 years (GH start early) and for 5.2 ± 1.2 years (GH start late) were similar (p = n.s.) as Model PredAH (155.7 ± 4.8 vs. 154.7 ± 4.8 cm; p = n.s.) but higher (p < 0.001) than projected adult height (Ranke, ProjAH; 148.2 ± 5.5 vs. 145.2 ± 6.7 cm; p = 0.001). Total height gain over ProjAH was 4.3 ± 4.6 cm (GH start early) and 5.8 ± 4.7 cm (GH start late, p = 0.021), respectively. Conclusions: GH may improve AH in UTS patients even when started late. The individual growth response could be estimated by the descriptive Model PredAH independent of age at treatment start.

We report on monozygotic twins with different clinical phenotypes of X-linked adrenoleukodystrophy. At the age of 10 years both boys were neurologically asymptomatic. The first cranial magnetic resonance examination showed normal findings in the first twin and parietooccipital demyelination in the second. The latter developed behavioral problems 9 months later, followed by visual impairment and gait ataxia. His cranial magnetic resonance image at the age of 11 years showed progressive demyelination. In contrast, neurological status and magnetic resonance images remained normal in the first twin. The same point mutation in exon 8 of the adrenoleukodystrophy gene (C2203T) was detected in both boys. All genotype examinations were consistent with the diagnosis of monozygotic twins, suggesting that some nongenetic factors may be important for different adrenoleukodystrophy phenotypes.

Das Ullrich-Turner-Syndrom (UTS) ist eine genetische Erkrankung, die mit einem kompletten oder partiellen Verlust eines X-Chromosoms einhergeht. Kinder oder erwachsene Patientinnen mit UTS leiden haufig unter metabolischen, kardiovaskularen, renalen und gastrointestinalen Komorbiditaten, unter Ostrogenmangelerscheinungen und psychosozialen Problemen. Wahrend der Kindheit werden die Patientinnen traditionell in spezialisierten Kinderkliniken behandelt, aber es fehlt das Konzept fur die weiterfuhrende Therapie in der Transitionsperiode und danach. Zielsetzung dieses Artikels ist es, die wichtigsten publizierten Empfehlungen zur Behandlung von Madchen und Frauen mit UTS mit dem Fokus auf Transition sowie die Ergebnisse eines interdisziplinaren Expertentreffens fur ein strukturiertes Behandlungskonzept zusammenzustellen. Analysiert man die bisherigen Publikationen, lassen sich die Mangel in der Nachsorge der UTS-Frauen auf folgende Punkte reduzieren: fehlende Gesamtkonzepte in der Weiterbetreuung, Unsicherheiten und Uberforderung bei der Betreuung der Frauen mit UTS durch einige Hausarzte, aber auch fehlendes Krankheitsbewusstsein bei einigen Betroffenen. Komorbiditaten bei erwachsenen Patientinnen mit UTS sind vielfaltig und umfassen metabolische, kardiovaskulare, gastrointestinale und renale Erkrankungen, Hormonmangelerscheinungen, gynakologische Aspekte sowie psychosoziale Probleme. Die notwendige Hormonsubstitutionstherapie u. a. mit Ostrogen/Gestagenen erfordert eine Langzeitbetreuung durch erfahrene Spezialisten. Wir empfehlen eine ausfuhrliche Diagnostik zum Zeitpunkt der Transition sowie konsequente 1- bis 5-jahrliche Untersuchungen nach Klinik und Risikoprofil.

BACKGROUND: Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy agents and clearing reactive oxygen species formed by radiation. In this study, we explored the relationship between the host GSTP1-105 polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1-105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events. METHODS: The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children’s Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and tumor GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and multivariable logistic regression for toxicity comparisons. RESULTS: Patients with a GSTP1-105 AG/GG genotype or who had received a higher dose of craniospinal radiation (median 36 Gy) had a greater risk of requiring hearing aids than their respective counterparts (OR 4.0, 95%CI 1.2 - 13.6, and OR 3.1, 95%CI 1.1 - 8.8, respectively). Additionally, there was a statistically significant interaction between the two variables. Compared with the lowest risk group (GSTP1-105 AA-lower dose radiation) patients with a GSTP1-105 AG/GG genotype who received a higher dose radiation were 8.4 times more likely to require hearing aids (95%CI 1.4 - 49.9, p-trend ¼ 0.005). When adjusted for age, gender, and amifostine use, the association remained. CONCLUSIONS: The GSTP1-105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. A possible mechanism for this finding is that the GSTP1-105 G-allele leads to reduced GSTpi free radical detoxification in the setting of multimodality therapy including cisplatin and radiation. Patients with this allele should be considered for clinical trials employing radiation dose modifications and more targeted cytoprotectant strategies than are currently being used with amifostine.

We hypothesized that overweight children with growth hormone deficiency (GHD) demonstrate a lower response to growth hormone (GH) as a result of a misclassification since obesity is associated with lower GH peaks in stimulation tests.Anthropometric data, response, and responsiveness to GH in the first year of treatment were compared in 1.712 prepubertal children with GHD from the German KIGS database according to BMI (underweight=group A, normal weight=group B, overweight=group C) (median age: group A, B, C: 7.3, 7.28, and 8.4 years).Maximum GH levels to tests (median: group A, B, C: 5.8, 5.8, and 4.0 µg/ml) were significantly lower in group C. IGF-I SDS levels were not different between the groups. Growth velocity in the first year of GH treatment was significantly lower in the underweight cohort (median: group A, B, C: 8.2, 8.8, and 9.0 cm/yr), while the gain in height was not different between groups. The difference between observed and predicted growth velocity expressed as Studentized residuals was not significantly different between groups. Separating the 164 overweight children into obese children (BMI>97th centile; n=71) and moderate overweight children (BMI>90th to 97th centile, n=93) demonstrated no significant difference in any parameter.Overweight prepubertal children with idiopathic GHD demonstrated similar levels of responsiveness to GH treatment compared to normal weight children. Furthermore, the IGF-I levels were low in overweight children. Therefore, a misclassification of GHD in overweight prepubertal children within the KIGS database seems unlikely. The first year growth prediction models can be applied to overweight and obese GHD children.

The efficacy of oral dehydroepiandrosterone (DHEA) in the treatment of atrichia pubis and psychological distress in young females with central adrenal insufficiency is unknown. Our study aimed to evaluate this therapy.A total of 23 young females (mean age 18 yr, range 13-25) was enrolled in a double-blind randomized placebo-controlled trial. Inclusion criteria were ACTH deficiency plus two or more additional pituitary deficiencies, serum DHEA less than 400 ng/ml, and pubertal stage more than B2. Exclusion criteria were cerebral radiation with more than 30 Gy, tumor remission less than 1 yr, amaurosis, hypothalamic obesity, psychiatric disorders, and unstable hormone medication.Patients were randomized to placebo (n = 12) or 25 mg HPLC-purified DHEA/d (n = 11) orally for 12 months after stratification into a nontumor (n = 7) and a tumor group (n = 16).Clinical scoring of pubic hair stage was performed at 0, 6, and 12 months (primary endpoint), and psychometrical evaluation (Symptom Check-List-90-R and the Centre for Epidemiological Studies-Depression Scale) at 0 and 12 months (secondary endpoint). Androgen levels and safety parameters were measured at 0, 6, and 12 months; 24-h androgen urinary excretion rates were calculated at 0 and 12 months.In the placebo group, four patients dropped out because of recurrence of craniopharyngioma, manifestation of type 1 diabetes, and change of residence (n = 2); in the DHEA group, one patient dropped out because of recurrent anxiety attacks. DHEA substitution resulted in normalization of DHEA sulfate and androstanediol glucuronide morning serum levels 2 h after drug intake (P0.006), and of its 24 h urinary metabolite levels (P0.0001), placebo had no effect. Morning serum levels of androstenedione increased in the DHEA group (P0.02) but did not normalize. The DHEA group exhibited significant progress in pubic hair growth from Tanner stage I-III to II-V (mean: +1.5 stages), whereas the placebo group did not (relative risk 0.138; 95% confidence interval 0.021-0.914; P = 0.0046). Importantly, eight of the 10 Symptom Check-List-90-R scores, including those for depression, anxiety, and interpersonal sensitivity, and the global severity index improved in the DHEA group in comparison to the placebo group (P0.048). DHEA was well tolerated.In adolescent girls with central adrenal insufficiency, daily replacement with 25 mg DHEA orally is beneficial: atrichia pubis vanishes, and psychological well-being improves significantly.

Background/Aims: We investigated whether genetic or maternal/environmental risk factors for being born small for gestational age (SGA), e.g. Silver-Russell syndrome, congenital heart defects, infections of mothers or smoking during pregnancy, explain the variation in the first-year growth response to GH therapy. Methods: Secondary analysis was made of growth response in 135 short prepubertal German children (66% males) enrolled in a SGA phase III trial. Initial mean patient age was 6.8 ± 2.6 years; mean patient height SDS –3.8 ± 1.2, and GH treatment dose was 0.066 mg/kg body weight per day. Results: Growth velocity increased by 4.5 ± 2.0 cm/year and height SDS by 1.0 ± 0.5 SDS. Although patient number was limited and variation was high, both growth response (cm/year) and change in height SDS did not appear to differ between subgroups which also did not differ in terms of Studentized residuals set up in the KIGS growth prediction model for SGA. Likewise, in a step-forward multivariate analysis, the variables Silver-Russell syndrome, congenital heart defects, infections of mothers and smoking were not identified as independent factors influencing growth velocity. Conclusion: The retrospectively analyzed genetic and maternal/environmental risk factors for SGA do not appear to explain the observed patient variance in response to GH. Larger prospective studies are needed, however, to substantiate these preliminary findings.

A prospective, multicenter study of patients with Ullrich-Turner syndrome (UTS) was conducted to estimate the prevalence of autoantibodies to tissue transglutaminase (tTg), thyroid stimulating hormone receptor (TSH-R), thyroglobulin (TG) and thyroid peroxidase (TPO) in relation to adult height after long-term growth hormone (GH) treatment. Out of 347 near-adult (> 16 years) patients with UTS from 96 German centers, whose longitudinal growth was documented within the Pharmacia International Growth Study (KIGS), 188 returned for a standardized follow-up visit at a median chronological age of 18.7 (16.0-23.6) years (bone age > 15 years). Serum samples of 120 patients were obtained for central measurements of TSH, thyroxine (T4) and free T4 and autoantibodies by standard immunoassays. Information regarding thyroid disease, karyotype and anthropometric data was extracted from the KIGS database. Thirty-six percent of the patients with UTS had positive TG and/or TPO autoantibodies and 4% had positive tTg autoantibodies, whereas 2% had positive TG and/or TPO autoantibodies as well as positive tTg autoantibodies. TSH-R autoantibodies were undetectable in all patients. The detection of autoantibodies was unrelated to a specific karyotype. Median height standard deviation scores (SDS, UTS) at start of GH treatment (0.43; -1.07, 1.85) and at follow-up (1.36; -0.11, 2.57) were comparable in all patients independent of their antibody status. The total deltaheight SDS, however, was higher in patients with negative autoantibody titers (1.08; -0.03, 2.25) compared to those with positive antibody titers (0.68; -0.44, 1.82; p < 0.01). Our study confirms the high prevalence of autoantibodies in patients with UTS predisposing them to autoimmune thyroid disease and celiac disease, and indicates for the first time that autoimmune pathologies may interfere with GH therapy and thus compromise final height. Therefore, medical care for patients with UTS should routinely include screening for these autoimmune disorders in order to assure early detection and appropriate treatment.

BACKGROUND: To evaluate the factors influencing uterine size in young adult women with Turner syndrome (TS) after long-term growth hormone (GH) treatment. METHODS: Cross-sectional study. Out of 188 women with TS from 96 German centres, whose longitudinal growth was documented within KIGS (Pfizer International Growth Database), data on uterine size were collected voluntarily at a standardized follow-up visit: 75 TS women (ages: 15.8-30.8 years) with complete data were included. Classification according to karyotype: 45,X (78.6%), 45,X/46,XX (5.4%), 45,X/46,iXq (8%), 45,X/46,XY (8%). Puberty was induced with estrogens in all women. At follow-up, 66 were on cyclic estrogens and progestins. RESULTS: 13/66 (19.6%) TS women who received estrogens had a reduced uterine length

A study was performed in which mothers of normal variant short statured children (n=37), were asked to state their own height. Then their body height was measured with a Harpenden Stadiometer. As control group, mothers of normal statured children (n=54) who were presented for various reasons (e.g. obesity, goiter) underwent the same procedure. The results show that the estimations are not reliable in short mothers with short statured children, whereas the control group showed no significant differences between reported and measured heights. There was a direct significant negative correlation (r=0.624; p0.001) between reported and measured heights in women with short children. The smaller the woman, the higher the reported height.

3 alpha-androstanediol glucuronide (3 alpha diolG) is a marker of peripheral tissue androgen metabolism. There are no previous data regarding complete paediatric reference ranges for 3 alpha diolG. In order to obtain reference values for 3 alpha diolG we have measured serum levels of 3 alpha diolG in 283 healthy children and adolescents, 146 boys and 137 girls, age 1 month to 20 years and 28 adults. A non-extraction, solid phase radioimmunoassay employing a polyclonal antiserum that is specific for 3 alpha diolG was used to measure serum 3 alpha diolG levels (intra assay variation 5.1-10.1%, inter assay variation 2.7-9.0%). There was a strong sex and age dependence (r = 0.8; p < 0.0001) of 3 alpha diolG levels throughout childhood and adolescence with males showing significantly higher levels of the androgen than females (p < 0.05). 3 alpha diolG serum levels (nmol/l +/- SD) correlated significantly with pubertal stage (p < 0.01). Interestingly, in 35 children with CAH serum 3 alpha diolG levels correlated well with clinical and metabolic status, i.e. 17OHP serum levels. In summary, we have established percentile curves for 3 alpha diolG levels in healthy children and adolescents. We hypothesize that on the basis of our reference values the single measurement of serum 3 alpha diolG could serve as a means to determine androgen status in children with disorders of puberty and sexual development.

The property of ketoconazole to inhibit adrenal biosynthesis of cortisol was used in a clinical study of 14 patients with Cushing's syndrome (pituitary-dependent Cushing's disease,n=10; adrenocortical adenoma,n=2; adrenocortical carcinoma,n=1; ectopic ACTH syndrome,n=1). Five patients were treated in a short-term manner (1000 mg over 24 h) and nine patients for a longer period (600 mg/die from 1 week up to 12 months). After short-term administration of ketoconazole, serum cortisol levels fell distinctly only in the patient with adrenocortical adenoma, but not at all or only slightly in the other patients, whereas serum levels of progesterone and 11-deoxy-compounds increased markedly in all patients, with the exception of the patient with adrenocortical carcinoma. Plasma ACTH levels increased in the patients with Cushing's disease but not in the patients with tumor. After long-term treatment of three patients with Cushing's disease over 3, 10, and 12 months, the clinical signs of hypercortisolism persisted or were only slightly ameliorated. In these three patients as well as in three other patients with Cushing's disease treated for a shorter period of 1 to 4 weeks, serum and urinary cortisol levels decreased, but were not normalized, whereas plasma ACTH levels increased variably. Only in one patient with Cushing's disease, in the second patient with adrenocortical adenoma, and in the patient with ectopic ACTH syndrome, serum and urinary cortisol levels returned to normal. We concluded from our data, that the antimycotic drug inhibits biosynthesis of cortisol by blocking adrenal 11β- and 17α-hydroxylase activity. This effect was compensated in part by a rebound increase of pituitary ACTH secretion in most patients with Cushing's disease. Therefore, ketoconazole treatment is above all effective in patients with Cushing's syndrome due to an adrenal tumor or in patients with ectopic ACTH syndrome, who cannot respond with an increased pituitary ACTH secretion.

In search for a biochemical marker to differentiate between adrenocortical carcinoma (AC) and adenoma (AA), plasma levels of the following steroids were studied preoperatively and postoperatively: 11-deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S), and cortisol (F). Levels were measured by Sephadex LH-20 chromatography and specific radioimmunoassays. The subjects included eight children ages 2 years, 5 months to 9 years, 10 months. There were three girls and 5 boys with pseudoprecocious puberty due to adrenocortical tumors (histologically, four were AC and four, AA). The preoperative showed that DOC and S levels were elevated in all patients, F levels were elevated in four of eight children when compared with age-matched controls, whereas B was normal. Postoperatively, all levels returned to normal. The ratios of B/DOC and F/S as an index of adrenal 11 beta-hydroxylase activity were calculated. The preoperative ratios of B/DOC were markedly decreased in all patients with AC compared to controls (7.7,4.1,5.9,1.9 versus 23.5, median), but normal in three of four patients with AA (16.2, 29.6, 16.1). The F/S ratios were significantly lower in AC and AA when compared with controls. The data indicate a deficiency in 11 beta-hydroxylation in cases of adrenocortical tumors. Despite a still limited number of patients, the decreased B/DOC ratios may possibly indicate malignancy and could be helpful in distinguishing by biochemical means between benign and malignant adrenocortical tumors.

In order to grade motion sickness objectively, the following 11 adrenal hormones were investigated in subjects with different motion sickness susceptibility: Aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, 17-OH-progesterone, 11-deoxycortisol, cortisol, cortisone, testosterone, androstendione, dehydroepiandrosterone sulfate. Motion sickness was induced by the coriolis effect on a rotary chair. Both severe kinetosis after short rotation time and mild motion sickness after 30 min of rotation occurred together with small hormonal changes. Androstendione and 11-deoxycortisol appear to be sensitive indicators of motion sickness if the rotation time is taken into consideration. A significant increase of all hormones except progesterone, cortisone, testosterone, and dehydroepiandrosterone sulfate was observed when pronounced malaise had come after a long rotation stress (24.6 min). The changes in plasma aldosterone concentration appeared to correlate with time only. The present study demonstrates that hormonal analysis can be helpful in estimating the degree of motion sickness.