Publications by authors named "Werner F Blum"

81 Publications

Childhood trauma and insulin-like growth factors in amniotic fluid: An exploratory analysis of 79 women.

Psychoneuroendocrinology 2021 Feb 27;127:105180. Epub 2021 Feb 27.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Background: Perinatal stress has adverse effects on fetal outcome, yet the effect of early maternal trauma on fetal outcome has scarcely been studied. We investigated effects of maternal childhood trauma and current environment on important regulators of prenatal growth, fetal insulin-like growth factor (IGF)-1 and IGF-2 in amniotic fluid and assessed the impact of IGFs on newborn anthropometrics.

Methods: 79 pregnant women in their second trimester who underwent amniocentesis (15.9 ± 0.9 weeks of gestational age) and their newborns at birth were analyzed. Maternal childhood trauma was assessed using the childhood trauma questionnaire (CTQ) and current environment was operationalized by assessing maternal psychosocial, physical health and endocrine measurements in amniotic fluid.

Results: In this exploratory analysis of 79 pregnant women, maternal childhood trauma, defined as reporting at least low scores on any of the CTQ subscales, negatively correlated with fetal IGF-1 (M = 3.48 vs. 2.98; p = 0.012) and IGF-2 (Mdn = 4.99 vs. 4.70; p = 0.002). Trauma severity, defined as the overall trauma score, negatively correlated with fetal IGF-2 (r = -0.24; p = 0.037). From trauma subscales, maternal sexual abuse correlated with fetal IGF-1 (r = -0.32; p = 0.006) and IGF-2 (r = -0.39; p = 0.001). Maternal BMI negatively correlated with fetal IGF-1 (r = -0.26; p = 0.023) and IGF-2 (r = -0.29; p = 0.011). Newborn anthropometrics were operationalized by length, weight, sex, gestational age, length/gestational age and weight/gestational age at birth. Fetal weight at birth associated with a trend with fetal IGF-1 when controlling for BMI. Maternal hypothalamus-pituitary-adrenal axis activity and maternal exercise did not contribute significantly to predicting fetal IGFs. Maternal childhood trauma (β = -0.27; p = 0.011) and BMI (β = -0.24; p = 0.026) remained significantly associated with fetal IGF-1. Maternal childhood trauma (β = -0.32; p = 0.003), maternal BMI (β = -0.30; p = 0.005) and maternal sexual abuse (β = -0.22; p = 0.049) remained significantly associated with fetal IGF-2 and with a trend with fetal IGF-1 (β = -0.21; p = 0.076) when excluding women with gestational diabetes.

Conclusion: Maternal childhood trauma and BMI associate negatively with fetal IGF-1 and IGF-2 in amniotic fluid. Controlling for maternal BMI, fetal weight at birth remains associated with a trend with fetal IGF-1. The presented data suggests that childhood trauma can affect endocrine measurements of the developing next generation, providing a mechanism by which adverse maternal life events are transmitted to the next generation.
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February 2021

Height Gain and Safety Outcomes in Growth Hormone-Treated Children with Idiopathic Short Stature: Experience from a Prospective Observational Study.

Horm Res Paediatr 2019 11;91(4):241-251. Epub 2019 Jun 11.

University Children's Hospital, Giessen, Germany.

Background/objectives: Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice.

Methods: Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data.

Results: Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and -1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD - most were common childhood conditions or previously reported in GH-treated patients.

Conclusions: GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD.
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January 2020

Genetic Polymorphisms Associated with Idiopathic Short Stature and First-Year Response to Growth Hormone Treatment.

Horm Res Paediatr 2019 10;91(3):164-174. Epub 2019 Apr 10.

Pediatric Endocrinology, Emory University, Atlanta, Georgia, USA.

Background/aims: The term idiopathic short stature (ISS) describes short stature of unknown, but likely polygenic, etiology. This study aimed to identify genetic polymorphisms associated with the ISS phenotype, and with growth response to supplemental GH.

Methods: Using a case-control analysis we compared the prevalence of "tall" versus "short" alleles at 52 polymorphic loci (17 in growth-related candidate genes, 35 identified in prior genome-wide association studies of adult height) in 94 children with ISS followed in the Genetics and Neuroendocrinology of Short Stature International Study, versus 143 controls from the Fels Longitudinal Study.

Results: Four variants were nominally associated with ISS using a genotypic model, confirmed by a simultaneous confident inference approach: compared with controls children with ISS had lower odds of "tall" alleles (odds ratio, 95% CI) for GHR (0.52, 0.29-0.96); rs2234693/ESR1 (0.50, 0.25-0.98); rs967417/BMP2 (0.39, 0.17-0.93), and rs4743034/ZNF462 (0.40, 0.18-0.89). Children with ISS also had lower odds of the "tall" allele (A) at the IGFBP3 -202 promoter polymorphism (rs2855744; 0.40, 0.20-0.80) in the simultaneous confident inference analysis. A significant association with 1st-year height SD score increase during GH treatment was observed with rs11205277, located near 4 known genes: MTMR11, SV2A, HIST2H2AA3, and SF3B4; the latter, in which heterozygous mutations occur in Nager acrofacial dysostosis, appears the most relevant gene.

Conclusions: In children with ISS we identified associations with "short" alleles at a number of height-related loci. In addition, a polymorphic variant located near SF3B4 was associated with the GH treatment response in our cohort. The findings in our small study warrant further investigation.
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December 2019

Safety Outcomes During Pediatric GH Therapy: Final Results From the Prospective GeNeSIS Observational Program.

J Clin Endocrinol Metab 2019 02;104(2):379-389

University of Giessen, Giessen, Germany.

Context: Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy.

Objective: To assess incidence of key safety outcomes.

Design: Prospective, multinational, observational study (1999 to 2015).

Setting: A total of 22,311 GH-treated children from 827 investigative sites in 30 countries.

Patients: Children with growth disorders.

Interventions: GH treatment.

Main Outcome Measures: Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries.

Results: Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors.

Conclusions: GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.
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February 2019

Growth Hormone Treatment for Short Stature in the USA, Germany and France: 15 Years of Surveillance in the Genetics and Neuroendocrinology of Short-Stature International Study (GeNeSIS).

Horm Res Paediatr 2018 10;90(3):169-180. Epub 2018 Sep 10.

Children's Hospital, University of Giessen, Giessen, Germany.

Background/aims: To describe characteristics, auxological outcomes and safety in paediatric patients with growth disorders treated with growth hormone (GH), for cohorts from the USA, Germany and France enrolled in GeNeSIS, a post-authorisation surveillance programme.

Methods: Diagnosis and biochemical measurement data were based on reporting from, and GH treatment was initiated at the discretion of, treating physicians. Auxological outcomes during the first 4 years of GH treatment and at near-adult height (NAH) were analysed. Serious and treatment-emergent adverse events were described.

Results: Children in the USA (n = 9,810), Germany (n = 2,682) and France (n = 1,667) received GH (dose varied between countries), most commonly for GH deficiency. Across diagnostic groups and countries, mean height velocity standard deviation score (SDS) was > 0 and height SDS increased from baseline during the first 4 years of treatment, with greatest improvements during year 1. Most children achieved NAH within the normal range (height SDS >-2). No new or unexpected safety concerns were noted.

Conclusion: GH treatment improved growth indices to a similar extent for patients in all three countries despite variations in GH doses. Data from these three countries, which together contributed > 60% of patients to GeNeSIS, indicated no new safety signals and the benefit-risk profile of GH remains unchanged.
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February 2019

The growth hormone-insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders.

Endocr Connect 2018 Jun 3;7(6):R212-R222. Epub 2018 May 3.

William Harvey Research InstituteBarts and the London School of Medicine & Dentistry, London, UK

The growth hormone (GH)-insulin-like growth factor (IGF)-I axis is a key endocrine mechanism regulating linear growth in children. While paediatricians have a good knowledge of GH secretion and assessment, understanding and use of measurements of the components of the IGF system are less current in clinical practice. The physiological function of this axis is to increase the anabolic cellular processes of protein synthesis and mitosis, and reduction of apoptosis, with each being regulated in the appropriate target tissue. Measurement of serum IGF-I and IGF-binding protein (IGFBP)-3 concentrations can complement assessment of GH status in the investigation of short stature and contribute to prediction of growth response during GH therapy. IGF-I monitoring during GH therapy also informs the clinician about adherence and provides a safety reference to avoid over-dosing during long-term management.
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June 2018

Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver.

Mol Metab 2018 05 15;11:113-128. Epub 2018 Mar 15.

Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Feodor-Lynen-Str. 25, 81377 Munich, Germany; Center for Innovative Medical Models (CiMM), Department of Veterinary Sciences, LMU Munich, Hackerstr. 27, 85764 Oberschleißheim, Germany; Meiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama, Kawasaki, 214-8571, Japan; German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377 Munich, Germany. Electronic address:

Objective: Laron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a large animal model for LS, pigs with GHR knockout (KO) mutations were generated and characterized.

Methods: CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue.

Results: GHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1) levels and reduced IGF-binding protein 3 (IGFBP3) activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was significantly reduced. In contrast, phosphorylation of JAK2 was significantly increased, possibly due to the increased serum leptin levels and increased hepatic leptin receptor expression and activation in GHR-KO pigs. In addition, increased mTOR phosphorylation was observed in GHR-KO liver samples, and phosphorylation studies of downstream substrates suggested the activation of mainly mTOR complex 2.

Conclusion: GHR-KO pigs resemble the pathophysiology of LS and are an interesting model for mechanistic studies and treatment trials.
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May 2018

Growth response to growth hormone treatment in patients with SHOX deficiency can be predicted by the Cologne prediction model.

J Pediatr Endocrinol Metab 2018 Jan;31(1):25-31

Children's Hospital, University of Cologne, Cologne, Germany.

Background Growth hormone (GH) treatment in children with short stature homeobox-containing gene (SHOX) deficiency is recognized to increase height velocity (HV) and adult height. Prediction of growth response continues to be a challenge. A comparatively accurate method is the Cologne prediction model developed in children with GH deficiency. The aim was to investigate whether this model also applies to patients with SHOX deficiency. Methods Included were 48 patients with SHOX deficiency confirmed by DNA analysis and treated with 0.05 mg/kg/day of somatropin. Prediction by the Cologne model uses the following variables: relative bone age (BA) retardation, baseline insulin-like growth factor-I (IGF-I), urinary deoxypyridinoline (DPD) cross-links at 4 weeks and HV at 3 months. Results HV and height standard deviation scores (SDS) increased significantly during the first year of treatment. Predicted and observed HV (cm/year) showed a Pearson correlation coefficient of 0.50 (p<0.001; root-mean-square error=1.63) and for first-year change in height SDS a Pearson correlation coefficient of 0.751 (p<0.001; root-mean-square error=0.32). Poor response could be adequately predicted using SDS change, with sensitivity and specificity both above 70% for certain thresholds.

Conclusions: The results demonstrate that the Cologne model can be used to predict growth response in patients with SHOX deficiency with reasonable precision in the first treatment year, comparable to prediction in patients with GH deficiency.
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January 2018

Mortality in Children Receiving Growth Hormone Treatment of Growth Disorders: Data From the Genetics and Neuroendocrinology of Short Stature International Study.

J Clin Endocrinol Metab 2017 09;102(9):3195-3205

Endocrinology, University Children's Hospital, 35392 Giessen, Germany.

Context: Although pediatric growth hormone (GH) treatment is generally considered safe for approved indications, concerns have been raised regarding potential for increased risk of mortality in adults treated with GH during childhood.

Objective: To assess mortality in children receiving GH.

Design: Prospective, multinational, observational study.

Setting: Eight hundred twenty-seven study sites in 30 countries.

Patients: Children with growth disorders.

Interventions: GH treatment during childhood.

Main Outcome Measure: Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using age- and sex-specific rates from the general population.

Results: Among 9504 GH-treated patients followed for ≥4 years (67,163 person-years of follow-up), 42 deaths were reported (SMR, 0.77; 95% CI, 0.56 to 1.05). SMR was significantly elevated in patients with history of malignant neoplasia (6.97; 95% CI, 3.81 to 11.69) and borderline elevated for those with other serious non-GH-deficient conditions (2.47; 95% CI, 0.99-5.09). SMRs were not elevated for children with history of benign neoplasia (1.44; 95% CI, 0.17 to 5.20), idiopathic GHD (0.11; 95% CI, 0.02 to 0.33), idiopathic short stature (0.20; 95% CI, 0.01 to 1.10), short stature associated with small for gestational age (SGA) birth (0.66; 95% CI, 0.08 to 2.37), Turner syndrome (0.51; 95% CI, 0.06 to 1.83), or short stature homeobox-containing (SHOX) gene deficiency (0.83; 95% CI, 0.02 to 4.65).

Conclusions: No significant increases in mortality were observed for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency, or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non-GH-deficient medical conditions.
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September 2017

Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial.

Horm Res Paediatr 2017 22;87(1):42-50. Epub 2016 Dec 22.

Endocrinology and Diabetes Unit, Eli Lilly, Neuilly-sur-Seine, France.

Background/aims: To assess auxological and safety data for growth hormone (GH)-treated children with SHOX deficiency.

Methods: Data were examined for GH-treated SHOX-deficient children (n = 521) from the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). For patients with near-adult height information, GeNeSIS results (n = 90) were compared with a clinical trial (n = 28) of SHOX-deficient patients. Near-adult height was expressed as standard deviation score (SDS) for chronological age, potentially increasing the observed effect of treatment.

Results: Most SHOX-deficient patients in GeNeSIS had diagnoses of Leri-Weill syndrome (n = 292) or non-syndromic short stature (n = 228). For GeNeSIS patients with near-adult height data, mean age at GH treatment start was 11.0 years, treatment duration 4.4 years, and height SDS gain 0.83 (95% confidence interval 0.49-1.17). Respective ages, GH treatment durations and height SDS gains for GeNeSIS patients prepubertal at baseline (n = 42) were 9.2 years, 6.0 years and 1.19 (0.76-1.62), and for the clinical trial cohort they were 9.2 years, 6.0 years and 1.25 (0.92-1.58). No new GH-related safety concerns were identified.

Conclusion: Patients with SHOX deficiency who had started GH treatment before puberty in routine clinical practice had a similar height gain to that of patients in the clinical trial on which approval for the indication was based, with no new safety concerns.
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April 2017

Sex Differences in Age-Related Decline of Urinary Insulin-Like Growth Factor-Binding Protein-3 Levels in Adult Bonobos and Chimpanzees.

Front Endocrinol (Lausanne) 2016 23;7:118. Epub 2016 Aug 23.

Department of Primatology, Max Planck Institute for Evolutionary Anthropology , Leipzig , Germany.

There is increasing interest in the characterization of normative senescence in humans. To assess to what extent aging patterns in humans are unique, comparative data from closely related species, such as non-human primates, can be very useful. Here, we use data from bonobos and chimpanzees, two closely related species that share a common ancestor with humans, to explore physiological markers that are indicative of aging processes. Many studies on aging in humans focus on the somatotropic axis, consisting of growth hormone (GH), insulin-like growth factors (IGFs), and IGF binding proteins (IGFBPs). In humans, IGFBP-3 levels decline steadily with increasing age. We used urinary IGFBP-3 levels as an alternative endocrine marker for IGF-I to identify the temporal pattern known to be related with age-related changes in cell proliferation, growth, and apoptosis. We measured urinary IGFBP-3 levels in samples from 71 bonobos and 102 chimpanzees. Focusing on samples from individuals aged 10 years or older, we found that urinary IGFBP-3 levels decline in both ape species with increasing age. However, in both species, females start with higher urinary IGFBP-3 levels than males, experience a steeper decline with increasing age, and converge with male levels around the age of 30-35 years. Our measurements of urinary IGFBP-3 levels indicate that bonobos and chimpanzees mirror human patterns of age-related decline in IGFBP-3 in older individuals (<10 years) of both sexes. Moreover, such as humans, both ape species show sex-specific differences in IGFBP-3 levels with females having higher levels than males, a result that correlates with sex differences in life expectancy. Using changes in urinary IGFBP-3 levels as a proxy for changes in GH and IGF-I levels that mark age-related changes in cell proliferation, this approach provides an opportunity to investigate trade-offs in life-history strategies in cross-sectional and in longitudinal studies, both in captivity and in the wild.
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September 2016

Assessment of Primary Cancer Incidence in Growth Hormone-Treated Children: Comparison of a Multinational Prospective Observational Study with Population Databases.

Horm Res Paediatr 2016 26;85(3):198-206. Epub 2016 Feb 26.

Background/aims: Although results of the majority of clinical studies have shown no association between growth hormone (GH) treatment in childhood and risk of primary cancer, concerns remain regarding the potential influence of GH therapy on neoplastic cell growth. This study evaluated the incidence of primary malignancies in a large observational study of paediatric GH treatment.

Methods: Primary cancer incidence was assessed in a cohort of 19,054 GH-treated children without a reported prestudy history of malignancy in the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). The standardised incidence ratio (SIR) for primary cancer in GH-treated children was determined by comparing cancer incidence in the GeNeSIS study population with incidence rates for country-, age-, and sex-matched cohorts of the general population.

Results: During a mean follow-up of 3.4 years in GeNeSIS (64,705 person-years), 13 incident potential primary cancers were identified in GH-treated patients. The SIR (95% confidence interval) for all observed cancers was 1.02 (0.54-1.75), and the crude incidence was 20.1 (10.7-34.4) cases per 100,000 person-years.

Conclusion: Acknowledging the relatively short follow-up in our study, GH-treated children without a history of previous malignancy did not have a higher risk of all-site primary cancer during the study when compared to general-population cancer registries.
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December 2016

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with isolated growth hormone deficiency due to organic causes.

Eur J Endocrinol 2016 May 17;174(5):669-79. Epub 2016 Feb 17.

Department of PediatricsOregon Health and Science University, Portland, Oregon, USA.

Objective: To determine characteristics of children initially diagnosed with isolated growth hormone deficiency (IGHD) of organic aetiology, who later developed multiple pituitary hormone deficiencies (MPHD).

Design: Data were analysed for 716 growth hormone-treated children with organic IGHD, who were growth hormone-naïve at baseline in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study.

Methods: Development of MPHD was ascertained from investigator-provided diagnoses, adverse events and concomitant medications. Analyses were performed for all patients and separately for those who developed MPHD within 4.5 years or had >3.5 years follow-up and continued to have IGHD (4-year cohort).

Results: MPHD developed in 71/716 (9.9%) children overall, and in 60/290 (20.7%) in the 4-year cohort. The most frequent additional deficiencies were thyroid-stimulating hormone (47 patients) and gonadotropins (23 patients). Compared with those who remained with IGHD, children who developed MPHD had more severe GHD at study entry, significantly lower baseline insulin-like growth factor1, peak stimulated growth hormone, and more frequent diagnosis of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Multivariate logistic regression analyses identified female gender, longer follow-up, higher baseline age and lower peak stimulated growth hormone as predictors of MPHD development.

Conclusions: MPHD is more likely to develop in patients with severe organic IGHD, especially those with history of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Older baseline age, female gender and longer follow-up duration were also associated with higher incidence of MPHD. Long-term monitoring of pituitary function is recommended, irrespective of the aetiology of GHD.
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May 2016

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations.

Eur J Hum Genet 2016 Mar 10;24(3):415-20. Epub 2015 Jun 10.

Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.
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March 2016

Radiological Features in Patients with Short Stature Homeobox-Containing (SHOX) Gene Deficiency and Turner Syndrome before and after 2 Years of GH Treatment.

Horm Res Paediatr 2015 6;84(1):14-25. Epub 2015 May 6.

Lilly Research Laboratories, Eli Lilly and Company, Windlesham, UK.

Background/aims: The short stature homeobox-containing (SHOX) gene is one of many genes that regulate longitudinal growth. The SHOX deficiency (SHOX-D) phenotype, caused by intragenic or regulatory region defects, ranges from normal stature to mesomelic skeletal dysplasia. We investigated differences in radiological anomalies between patients with SHOX-D and Turner syndrome (TS) and the effect of 2 years of growth hormone (GH) treatment on these anomalies.

Methods: Left hand/wrist, forearm and lower leg radiographs were assessed at baseline and after 2 years in children with genetically confirmed SHOX-D (GH-treated and untreated groups) and TS (GH-treated) in a randomised, controlled, multinational study.

Results: Radiological anomalies of hand, wrist and forearm were common in SHOX-D and TS. Radial bowing appeared more prevalent in SHOX-D, while lower leg anomalies were more common in TS. There were no significant differences in radiological findings between GH-treated and untreated patients with SHOX-D after 2 years.

Conclusion: GH treatment had no systematic effect on skeletal findings in SHOX-D, based on limited radiological differences between the GH-treated and untreated groups at 2 years. Bone age radiographs allow assessment of radiological signs indicating a potential diagnosis of SHOX-D and may lead to earlier genetic confirmation and initiation of GH therapy.
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May 2016

Sex, Sport, IGF-1 and the Community Effect in Height Hypothesis.

Int J Environ Res Public Health 2015 May 4;12(5):4816-32. Epub 2015 May 4.

Department of Statistics and Econometrics, Otto-Friedrich-Universität Bamberg, Bamberg 96045, Germany.

We test the hypothesis that differences in social status between groups of people within a population may induce variation in insulin-like growth factor-1(IGF-1) levels and, by extension, growth in height. This is called the community effect in height hypothesis. The relationship between IGF-1, assessed via finger-prick dried blood spot, and elite level sport competition outcomes were analysed for a sample of 116 undergraduate men and women. There was a statistically significant difference between winners and losers of a competition. Winners, as a group, had higher average pre-game and post-game IGF-1 levels than losers. We proposed this type of difference as a proxy for social dominance. We found no evidence that winners increased in IGF-1 levels over losers or that members of the same team were more similar in IGF-1 levels than they were to players from other teams. These findings provide limited support toward the community effect in height hypothesis. The findings are discussed in relation to the action of the growth hormone/IGF-1 axis as a transducer of multiple bio-social influences into a coherent signal which allows the growing human to adjust and adapt to local ecological conditions.
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May 2015

Ten-year change in quality of life in adults on growth hormone replacement for growth hormone deficiency: an analysis of the hypopituitary control and complications study.

J Clin Endocrinol Metab 2014 Dec;99(12):4581-8

Lilly Diabetes (D.M., R.Q.), Eli Lilly and Company, Indianapolis, Indiana 46285; Lilly Diabetes (W.F.B.), Eli Lilly and Company, Bad Homburg 61352, Germany; Lilly France (M.R.), 92521 Neuilly sur Seine, France; Department of Endocrinology/Medicine and CIBERER 747 (S.M.W.), Hospital S Pau, Universitat Autonoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain; Department of Endocrinology (C.J.S.), and Diabetes and Nutritional Medicine, Charité-Universitätsmedizin, Campus Mitte, 13353 Berlin, Germany.

Context: Previous studies showed improvement in impaired quality of life (QoL) in adult patients with growth hormone (GH) deficiency (GHD) who were treated with GH; improvement was sustained over a few years after GH therapy.

Objective: To evaluate the QoL over 10 years.

Design: This was a prospective observational study.

Setting: The study was conducted in clinical practice.

Patients: 1436 adult patients with adult-onset (AO) GHD (mean age [standard deviation (SD)]: 49.0 [12.2] years; 49% female) and 96 with childhood-onset (CO) GHD (31.3 [10.0] years; 60% female) (total N = 1532).

Intervention: GH therapy.

Main Outcome Measures: QoL was measured by Questions on Life Satisfaction-Hypopituitarism (QLS-H) in countries where validated questionnaires and normative data for calculation of Z-scores were available. Change in QoL was tested by Student's t test and predicted by mixed-model repeated measures (MMRM) analysis.

Results: At study entry, patients had diminished QoL Z-scores (mean [SD] AO, -1.55 [1.69]; CO -0.98 [1.32]). The largest QoL improvements were in the first year: mean (SD) increase 0.77 (1.37) for AO (P < .001) and 0.50 (1.37) for CO (P < .001). The initial improvement from study entry remained statistically significant throughout 10 years for AO and in years 1 to 4, 6, and 7 for CO (P < .05). MMRM analysis predicted a greater QoL improvement in those who were not depressed, lived in Europe, had poorer Z-scores at entry, had lower body mass index at entry, and had no impaired vision.

Conclusion: These data suggest that GH replacement provides sustained improvement in QLS-H scores toward normality for up to 10 years.
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December 2014

High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency.

J Clin Endocrinol Metab 2014 Jan 20;99(1):299-306. Epub 2013 Dec 20.

Institute of Endocrinology (R.N., N.S., R.V.), Medical Academy (D.A.), Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; Department of Pediatrics (P.D., B.O., O.C., J.L.), Second Faculty of Medicine, Charles University in Prague and University Hospital Prague-Motol, 150 06 Prague, Czech Republic; and University Hospital for Children and Adolescents (R.W.F., W.F.B.), University of Leipzig, 04317 Leipzig, Germany.

Context: PROP1 gene mutations cause multiple pituitary hormone deficiency (MPHD).

Objective: We sought to expand experience with PROP1 mutation carriers by studying a large cohort of Lithuanian patients.

Patients And Methods: Sixty-seven MPHD patients were tested for PROP1 defects. Perinatal and postnatal data were obtained from medical records. Hormonal investigations, pituitary imaging, and GH therapy were provided in a single center in Kaunas, Lithuania.

Results: A biallelic PROP1 gene mutation was found in 47 subjects (70.1%), of which 46 were homozygous for 296delGA. Positive finding rate among MPHD and population prevalence of PROP1 defects in Lithuania (15.8 per million) were the highest reported to date. Patients' birth lengths/weights were normal. Testicular retention was noted in 31% of boys. Median height SD scores declined over years 1-5: -1.56, -2.34, -3.43, -3.52, and -3.70. Mid-parental height predicted severity of growth retardation at diagnosis (r2=0.30; P=.0001). Deficiencies of GH, TSH, ACTH, and FSH/LH were diagnosed in 44/44, 44/44, 19/44, and 22/44 subjects at median age of 5.5, 5.6, 13.1, and 15.0 years, respectively. Pituitary height ranged from 16.6 mm (+20.2 SD) to 1.4 mm (-15.5 SD) and declined with age (r2=0.27, P=.001). GH replacement (dose 0.027 mg/kg/d) led to height velocities 12.2; 9.1; 6.9; 6.8; 6.7; 5.6; and 5.7 cm/y (medians) at years 1-7 and final height SD scores (17 patients) -0.98±1.77 (-1.04±1.41 below target height; P=.008 vs 0).

Conclusions: High prevalence of PROP1 defects in Lithuania is due to 296delGA mutation, suggesting a founder effect.
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January 2014

Early differentiation between good and poor response to growth hormone therapy in short children born small for gestational age (SGA) to improve the outcome of poor responders.

J Pediatr Endocrinol Metab 2014 Mar;27(3-4):229-35

Objective: The aim of this study was to examine height-gain response in relation to predicted good or poor response during first-year low or high growth hormone (GH) dose in short prepubertal children born small for gestational age.

Patients And Methods: The OPTIMA (Optimization of GH Treatment in Short Children Born Small for Gestational Age Based on a Growth Prediction Model) randomised study evaluated 12-month height standard deviation score (SDS) changes in patients receiving GH dose: fixed high (FH; 0.067 mg/kg/day) or 0.035 mg/kg/day individually adjusted (IA) after 3 months according to the Cologne early growth prediction.

Results: Predicted 12-month height SDS gain was <0.75 for 21/89 FH-dose patients, considered poor responders; 11/21 reached a 12-month height SDS gain of ≥0.75. In IA-dose poor responders, increasing GH dose at 3 months maintained mean height velocity (HV), with 73.7% reaching a 12-month height SDS gain of ≥0.75 vs. 73.8% in IA-dose good responders who continued on low GH dose, where mean HV decreased after the initial 3-month period.

Conclusion: GH dose increase at 3 months in patients with predicted poor response maintained catch-up growth. Even when on FH dose, some patients did not achieve a good response.
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March 2014

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency.

Eur J Endocrinol 2014 Jan 22;170(1):13-21. Epub 2013 Nov 22.

Lilly Deutschland GmbH, Werner-Reimers-Strasse 2-4, 61352 Bad Homburg, Germany.

Objective: We assessed the characteristics of children initially diagnosed with idiopathic isolated GH deficiency (IGHD) who later developed additional (multiple) pituitary hormone deficiencies (MPHD).

Design: Data were analyzed for 5805 pediatric patients with idiopathic IGHD, who were GH-naïve at baseline and GH-treated in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study.

Methods: Development of MPHD was assessed from investigator diagnoses, adverse events, and concomitant medications. Analyses were performed for all patients and for those who developed MPHD within 4.5 years or had ≥3.5 years, follow-up and continued to have IGHD (4-year cohort).

Results: MPHD developed in 118/5805 (2.0%) children overall, and in 96/1757 (5.5%) in the 4-year cohort. Patients who developed MPHD had more profound GHD, with decreased height SDS, IGF1 SDS and peak stimulated GH, and greater height decrement vs target, compared with children who continued to have IGHD (P<0.001 for each variable). Delivery complications, congenital anomalies, and perinatal/neonatal adverse events occurred more frequently in patients who developed MPHD. The most frequent additional deficiency was TSH (82 patients overall); four patients developed two pituitary hormone deficiencies and one developed three deficiencies. Multivariable logistic regression indicated that years of follow-up (odds ratio 1.55), baseline age (1.17), baseline height SDS (0.69), and peak stimulated GH (0.64) were associated with the development of MPHD.

Conclusions: MPHD is more likely to develop in patients with more severe idiopathic IGHD. Older baseline age, lower baseline height SDS, and longer follow-up duration are associated with increased risk of development of MPHD.
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January 2014

GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results of a multicenter trial.

J Clin Endocrinol Metab 2013 Aug 29;98(8):E1383-92. Epub 2013 May 29.

Eli Lilly and Company, Werner-Reimers-Strasse 2-4, D-61352 Bad Homburg, Germany.

Context: Growth impairment in short stature homeobox-containing gene (SHOX) deficiency and Turner syndrome share a similar etiology. Because of the established effect of GH treatment on height in patients with Turner syndrome, we hypothesized that GH therapy would also stimulate growth in patients with SHOX deficiency.

Objective: Our objectives were to evaluate long-term efficacy of GH treatment in short patients with SHOX deficiency and to compare the effect on final (adult) height (FH) in patients with SHOX deficiency and Turner syndrome.

Design And Setting: A prospective, multinational, open-label, randomized 3-arm study consisting of a 2-year control period and a subsequent extension period to FH. The treatment groups were 1) SHOX-D-C/GH (untreated during the control period, GH-treated during the extension), 2) SHOX-D-GH/GH, and 3) Turner-GH/GH (GH-treated during both study periods).

Patients: Short-statured prepubertal patients with genetically confirmed SHOX deficiency (n = 49) or Turner syndrome (n = 24) who participated in the extension.

Intervention: Depending on the study arm, patients received a daily sc injection of 0.05 mg/kg recombinant human GH from start of the study or start of the extension until attainment of FH or study closure.

Results: Height SD score gain from start of GH treatment to FH was similar between the combined SHOX-deficient groups (n = 28, 1.34 ± 0.18 [least-squares mean ± SE]) and the Turner group (n = 19, 1.32 ± 0.22). In this FH population, 57% of the patients with SHOX deficiency and 32% of the patients with Turner syndrome achieved a FH greater than -2 SD score.

Conclusions: GH treatment in short children with SHOX deficiency showed similar long-term efficacy as seen in girls with Turner syndrome.
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August 2013

Associations between pituitary imaging abnormalities and clinical and biochemical phenotypes in children with congenital growth hormone deficiency: data from an international observational study.

Horm Res Paediatr 2013 16;79(5):283-92. Epub 2013 May 16.

University of Montreal, Hôpital Sainte Justine, Montreal, Que., Canada.

Background/aims: Magnetic resonance imaging (MRI) is used to investigate the etiology of growth hormone deficiency (GHD). This study examined relationships between MRI findings and clinical/hormonal phenotypes in children with GHD in the observational Genetics and Neuroendocrinology of Short Stature International Study, GeNeSIS.

Methods: Clinical presentation, hormonal status and first-year GH response were compared between patients with pituitary imaging abnormalities (n = 1,071), patients with mutations in genes involved in pituitary development/GH secretion (n = 120) and patients with idiopathic GHD (n = 7,039).

Results: Patients with hypothalamic-pituitary abnormalities had more severe phenotypes than patients with idiopathic GHD. Additional hormonal deficiencies were found in 35% of patients with structural abnormalities (thyroid-stimulating hormone > adrenocorticotropic hormone > luteinizing hormone/follicle-stimulating hormone > antidiuretic hormone), most frequently in patients with septo-optic dysplasia (SOD). Patients with the triad [ectopic posterior pituitary (EPP), pituitary aplasia/hypoplasia and stalk defects] had a more severe phenotype and better response to GH treatment than patients with isolated abnormalities. The sex ratio was approximately equal for patients with SOD, but there was a significantly higher proportion of males (approximately 70%) in the EPP, pituitary hypoplasia, stalk defects, and triad categories.

Conclusion: This large, international database demonstrates the value of classification of GH-deficient patients by the presence and type of hypothalamic-pituitary imaging abnormalities. This information may assist family counseling and patient management.
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January 2014

Incidence of second neoplasm in childhood cancer survivors treated with GH: an analysis of GeNeSIS and HypoCCS.

Eur J Endocrinol 2013 Apr 15;168(4):565-73. Epub 2013 Mar 15.

Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

Objective: Childhood cancer survivors are commonly treated with GH for GH deficiency that develops either as a result of primary malignancy or its treatment. One study--the Childhood Cancer Survivor Study (CCSS)--demonstrated increased risk of second neoplasm (SN) in GH-treated childhood cancer survivors compared with non-GH treated, after adjusting for key risk factors. We assessed the incidence of SN in GH-treated childhood cancer survivors in outpatient observational studies of GH replacement.

Design: Retrospective analysis of two prospective cohort studies that collected data on safety of GH replacement as prescribed in clinical practice.

Methods: Childhood cancer survivors enrolled in Eli Lilly and Company's pediatric (Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS)) and adult (Hypopituitary Control and Complications Study (HypoCCS)) observational studies of GH treatment were assessed for incidence of SN.

Results: The percentage of childhood cancer survivors treated with GH who developed a SN was 3.8% in pediatric GeNeSIS participants and 6.0% in adult HypoCCS participants. The estimated cumulative incidence of SN at 5 years of follow-up in these studies was 6.2 and 4.8% respectively.

Conclusions: The incidence of SN in GeNeSIS and HypoCCS GH-treated participants is similar to the published literature and is thus consistent with increased risk of SN in childhood cancer survivors treated with GH. As follow-up times were relatively short (<3 years), longer observation is recommended. Nevertheless, clinicians should be alerted to the possibility of increased risk of SN in childhood cancer survivors treated with GH and continue chronic surveillance.
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April 2013

Leptin plasma concentrations increase during antidepressant treatment with amitriptyline and mirtazapine, but not paroxetine and venlafaxine: leptin resistance mediated by antihistaminergic activity?

J Clin Psychopharmacol 2013 Feb;33(1):99-103

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Treatment with several psychopharmacological agents has been associated with increased leptin plasma concentrations. We measured leptin plasma concentrations in 76 adult depressed patients after a 6-day washout phase and again after 35 days of treatment with amitriptyline or paroxetine, as well as in 73 depressed patients after 28 days of treatment with either mirtazapine or venlafaxine. Leptin plasma concentrations increased during treatment with amitriptyline and mirtazapine, even after controlling for increased body mass index and irrespective of response to treatment [14.5 (13.8) vs 20.3 (18.7) ng/mL, and 12.2 (15.8) vs 14.4 (16.5) ng/mL in the 2 cohorts, respectively]. In contrast, paroxetine and venlafaxine treatment was not associated with changes in leptin plasma concentrations [14.8 (12.0) vs 13.6 (10.6); 15.9 (17.3) vs 13.5 (14.6) ng/mL] nor with weight gain. We conclude that treatment with amitriptyline or mirtazapine is associated with an increase in leptin secretion beyond change in weight. Thus, high leptin levels apparently are ineffective in the control of weight gain, indicating leptin resistance. Leptin resistance may be mediated by an antihistaminergic effect on hypothalamic nuclei integrating signals relevant for energy balance.
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February 2013

High IGFBP2 levels are not only associated with a better metabolic risk profile but also with increased mortality in elderly men.

Eur J Endocrinol 2012 Jul 3;167(1):111-7. Epub 2012 May 3.

Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Objective: Serum IGF-binding protein 2 (IGFBP2) concentrations are reduced in obese humans and increase after a prolonged period of fasting. We investigated the association between IGFBP2 levels and mortality together with other factors that are related to IGFBP2, including the metabolic syndrome and physical function.

Design: A prospective observational study at a clinical research center of 403 independently living elderly men (aged 73-94 years).

Methods: Mortality was registered during 8.6 years of follow-up. Physical performance score (PPS), grip strength (GS), and bone mineral density (BMD) were measured. The measurements taken a baseline were: IGF1; IGFBP1, -2, and -3; IGF1 bioactivity; triiodothyronine (T(3)); and reverse T(3). Further, BMI, insulin sensitivity, cholesterol, inflammatory markers, and albumin levels were also measured.

Results: During the follow-up, 180 men died. Higher PPS, GS, and BMD were independently related to a reduced mortality (hazard ratio (HR)=0.87/point, 95% confidence interval (95% CI)=0.82-0.91, P<0.001; HR=0.96/kp, 95% CI 0.94-0.98, P<0.001; and HR=0.21/(g/cm(2)), 95% CI 0.07-0.61, P<0.01). Higher serum IGFBP2 levels were strongly related to mortality (HR=2.26/(mg/l), 95% CI 1.57-3.27, P<0.001). This was independent of comorbidity, physical function, IGF1 bioactivity, and other somatotropic parameters, including BMI and the metabolic syndrome. In addition, IGFBP2 levels were higher in subjects with nonthyroidal illness, and higher IGFBP2 levels were significantly associated with lower albumin concentrations.

Conclusion: Despite the strong relationship between high IGFBP2 and low physical function, both were strongly and independently related to increased 8-year mortality in elderly men. IGFBP2 may be a useful biomarker integrating the nutritional status, as well as the biological effects of GH, IGF1, and insulin.
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July 2012

Genotypes and phenotypes of children with SHOX deficiency in France.

J Clin Endocrinol Metab 2012 Jul 19;97(7):E1257-65. Epub 2012 Apr 19.

Medical Department, Lilly France, 13 Rue Pagès, 92158 Suresnes Cedex, France.

Context: The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified.

Objectives: The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France.

Design, Setting, And Patients: Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS).

Intervention And Main Outcome Measure: SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D).

Results: Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies.

Conclusions: SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency.
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July 2012

Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects.

Horm Res Paediatr 2011 18;76(5):348-54. Epub 2011 Oct 18.

Department of Pediatrics, Second Faculty of Medicine, Charles University, Prague, Czech Republic.

Background/aims: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan.

Methods: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5-72.7 (median 16.6) years from 60 kindreds.

Results: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0-20.7) and median volume was 127.6 mm(3) (range 7.5-3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood.

Conclusion: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement.
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March 2012

Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program.

J Clin Endocrinol Metab 2011 Jun 13;96(6):E1025-34. Epub 2011 Apr 13.

Lilly Research Laboratories, Erl Wood Manor, Windlesham GU20 6PH, United Kingdom.

Background: GH has an insulin antagonist effect, and GH treatment has therefore been suggested to impair glucose metabolism and increase risk of diabetes mellitus.

Setting: Data from 11,686 GH-treated patients in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS), a multinational observational study of children with growth disorders, were analyzed for diabetes incidence. Baseline diabetes prevalence was determined from a GH-naive subgroup.

Methods: Prevalence and incidence (by standardized incidence ratio) were compared with results from patients aged less than 20 yr in the U.S. SEARCH for Diabetes in Youth study.

Results: Baseline type 1 diabetes prevalence per 1000 persons was 4.92 (95% confidence interval = 1.91-12.58) in GeNeSIS and 1.03 (0.97-1.10) in SEARCH for 0- to 9-yr-olds, and 7.33 (4.20-12.77) and 2.99 (2.78-2.98), respectively, for 10- to 19-yr-olds; there were no GeNeSIS cases of type 2 diabetes before GH initiation. During a median 1.8 yr of GH treatment, diabetes standardized incidence ratios for U.S. patients were 1.4 (0.5-3.1) for type 1 and 8.5 (2.8-19.5) for type 2, and for all patients was 1.4 (0.7-2.4) for type 1 and 6.5 (3.3-11.7) for type 2. Among the 11 patients with incident type 2 diabetes, risk factors for diabetes were identified in 10 patients. Glucose concentrations normalized for seven of nine patients for whom glycemic status could be determined (three of whom continued GH therapy and four who discontinued).

Conclusion: The incidence of type 2 diabetes was higher in GH-treated children than the general population. Monitoring of glucose, before and periodically during GH treatment, is recommended for those with preexisting type 2 diabetes risk factors.
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June 2011