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ObjectiveWe assessed the characteristics of children initially diagnosed with idiopathic isolated GH deficiency (IGHD) who later developed additional (multiple) pituitary hormone deficiencies (MPHD).DesignData 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.MethodsDevelopment 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).ResultsMPHD 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 (PConclusionsMPHD 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.

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.

Context: A variant of the human GH receptor (GHR) lacks a 22-amino-acid sequence derived from exon 3 (d3-GHR). It was reported that pediatric patients, born small for gestational age or with idiopathic short stature who were homozygous or heterozygous for this variant responded better to GH treatment than those homozygous for the full-length allele (fl-GHR). Objective: The objective was to study the impact of the GHR genotype on the phenotype and growth response in patients with isolated GH deficiency (IGHD) treated with GH. Design: This was a retrospective, multinational, multicenter observational study. Patients: Patients with IGHD (n = 107) were recruited. Interventions: All patients received GH treatment at replacement doses. The GHR genotype (fl-GHR/fl-GHR, fl-GHR/d3-GHR, or d3-GHR/d3-GHR) was determined by PCR amplification. Main Outcome Measures: Measures included height sd score, height velocity, height velocity sd score at baseline and 1 yr of GH treatment, and their changes. Results: There was no statistically significant difference of the main outcome measures between patients with the d3-GHR allele (n = 48) and patients who were homozygous for the fl-GHR allele (n = 59). Moreover, the genotype group did not contribute significantly to the growth prediction in multiple linear regression models. Conclusions: Our results indicate that the d3-GHR allele does not affect response to GH treatment or contribute to growth predictions in patients with IGHD who received replacement doses of GH aiming to restore a normal GH status. We did not confirm the previously reported data obtained in patients small for gestational age or with idiopathic short stature who received supraphysiological GH doses.

Quality of life (QoL) has not been specifically assessed in GH-deficient (GHD) transition patients.We assessed QoL at baseline and after 1 and 2 yr of GH treatment in severely GHD patients, using an adult GHD-specific questionnaire, QLS(M)-H. Subjects were randomized to GH, 25.0 microg/kg.d (n = 25) or 12.5 microg/kg.d (n = 28), or no treatment (n = 13). sd scores for QLS-H were calculated from normative data, specific to country of origin, gender, and age range of the patients.Baseline QLS-H sd scores were -0.35 +/- 1.17 in females and -0.70 +/- 1.05 in males (P = 0.280). sd scores for individual dimensions of ability to become sexually aroused, ability to tolerate stress, body shape, concentration, initiative/drive, physical stamina, and self-confidence were significantly lower than the normal average. Particularly affected were body shape (sd score, -0.80 +/- 0.99; quartile (Q)1:Q3, -1.52:-0.29) and sexual arousal (sd score, -0.41 +/- 0.88; Q1:Q3, -1.15:-0.13). Total QLS-H sd score increased slightly but not significantly for combined GH treatment groups compared with control at yr 1 (0.047 +/- 1.51 vs. -0.32 +/- 1.66; P = 0.845) but not after yr 2 (-0.00 +/- 0.80 vs. 0.12 +/- 0.89; P = 0.385); no dose effect of GH was observed. GH treatment significantly increased sd score from baseline to yr 2 for sexual arousal and body shape (0.23 +/- 0.78, P = 0.038; and 0.46 +/- 1.26, P = 0.035, respectively).Although overall baseline QoL was not compromised in severely GHD patients during the transition period, dimensions related to age-specific psychological problems were significantly worse than healthy subjects and appeared to positively respond to GH treatment.

To develop reference ranges for the Questions on Life Satisfaction Hypopituitarism Module (QLS-H), a new quality of life questionnaire for patients with hypopituitarism, data from 8177 adults were collected in France, Germany, Italy, The Netherlands, Spain, the United Kingdom, and the United States QLS-H scores declined with age, were lower in females than males, and differed significantly among countries. From these reference ranges we derived equations for z-scores, which adjust for age, gender, and country. QLS-H results from 957 adults with GH deficiency (GHD) participating in clinical trials were analyzed. At baseline, QLS-H scores were lower in females and differed significantly among countries. QLS-H scores significantly increased after GH treatment (6–8 months), but differences by country persisted. Calculating z-scores for patients eliminated all gender and most country differences. Pooled z-scores (mean ± sd) from all patients increased from −0.99 ± 1.39 at baseline to −0.14 ± 1.30 after GH treatment. Quality of life assessment in adults with GHD requires the use of z-scores to correct for age, gender, and country differences. This approach allows pooling of data from different cohorts and comparison with general populations. QLS-H scores in adults with GHD were significantly decreased at baseline and were almost normalized after 6–8 months of GH therapy.

Aim: Validation of a preexisting mathematical model for predicting height velocity in the first year of growth hormone (GH) treatment, using an independent cohort of pediatric patients with confirmed GH deficiency (GHD). Design: 210 prepubertal and pubertal patients with isolated GHD were enrolled within the 'growth prediction module' of a prospective international postmarketing research program (GeNeSIS). Methods: The patients were grouped as 'prepubertal', at 'start of puberty' and 'pubertal', and the performance of the model was validated by comparing predicted and observed height velocity (HV) in the first treatment year for each group. The operational characteristics of the model, when used as a screening method to predict poor and good growth response to GH, were calculated using the first year change in height standard deviation score as a cut-off for treatment response. Results: Depending on pubertal stage, the growth prediction model explained 53-72% of the variability of the first year HV. The model fulfilled the statistical prerequisites to identify patients with poor and good responses to GH with sufficient reliability in individual patients. Conclusions: The growth prediction model was successfully validated in a large cohort of prepubertal and pubertal pediatric patients under field conditions.

Background: Short stature affects approximately 2% of children, representing one of the more frequent disorders for which clinical attention is sought during childhood. Despite assumed genetic heterogeneity, mutations or deletions of the short stature homeobox-containing gene ( SHOX ) are found quite frequently in subjects with short stature. Haploinsufficiency of the SHOX gene causes short stature with highly variable clinical severity, ranging from isolated short stature without dysmorphic features to Leri-Weill syndrome, and with no functional copy of the SHOX gene, Langer syndrome. Methods: To characterise the clinical and molecular spectrum of SHOX deficiency in childhood we assessed the association between genotype and phenotype in a large cohort of children of short stature from 14 countries. Results: Screening of 1608 unrelated individuals with sporadic or familial short stature revealed SHOX mutations or deletions in 68 individuals (4.2%): complete deletions in 48 (70.6%), partial deletions in 4 (5.9%) and point mutations in 16 individuals (23.5%). Although mean height standard deviation score (SDS) was not different between participants of short stature with or without identified SHOX gene defects (–2.6 vs –2.6), detailed examination revealed that certain bone deformities and dysmorphic signs, such as short forearm and lower leg, cubitus valgus, Madelung deformity, high-arched palate and muscular hypertrophy, differed markedly between participants with or without SHOX gene defects (p

Lean body mass (LBM), fat mass (FM), and total bone mineral content are significantly reduced in adult GHD subjects who had received pediatric GH. To test the hypothesis that continued GH therapy after final height is necessary to attain adult body composition, we performed a prospective, multinational, randomized, controlled, 2-yr study in patients who completed pediatric GH treatment at final height. Patients were randomized to GH at 25.0 microg/kg x d (pediatric dose; n = 58) or 12.5 microg/kg x d (adult dose; n = 59) or no GH treatment (control; n = 32). LBM and FM were measured by dual energy x-ray absorptiometry and were centrally evaluated. IGF-I, IGF-binding protein-3, and lipid concentrations were also measured centrally. During the 2 yr, GH-treated patients gained a significant amount of LBM compared with controls (P < 0.001), but the change with the higher pediatric dose (14.2 +/- 11.7%) was not different from that seen with the lower adult dose (12.7 +/- 9.4%; P = 0.970). Similarly, the decrease in FM was significantly (P = 0.029) influenced by treatment, but with no dose effect (adult dose, -7.1 +/- 22.8%; pediatric dose, -6.0 +/- 26.6%; P = 0.950). When the GH treatment effect was analyzed by gender, males gained 15.6 +/- 9.8% and 14.3 +/- 11.7% LBM (P = 0.711) and lost 12.4 +/- 22.2% and 11.0 +/- 27.1% FM (P = 0.921) with the low and high doses, respectively. Females gained 8.3 +/- 7.3% and 12.5 +/- 12.8% LBM with the two doses (P = 0.630), but increased their FM by 3.5 +/- 16.2% with the lower dose and lost only 1.2 +/- 23.2% FM with the higher dose (P = 0.325). A similar pattern was seen in IGF-I sd score; the 2-yr GH dose response was significantly higher with the pediatric than with the adult dose in females (P = 0.008), but not males (P = 0.790). The divergent pattern of change in LBM and FM in males and females is consistent with normal developmental sexual dimorphism and indicates that GH-dependent progress to target body composition continues after the age at which GH treatment is usually terminated. Dose requirements may have to be adjusted by gender, with females requiring a higher dose than males.

Questions on Life Satisfaction-Hypopituitarism (QLS-H) is a new quality-of-life (QoL) questionnaire developed for adults with hypopituitarism. To determine the effects of long-term GH treatment on QoL, we evaluated QLS-H Z-scores in 576 adult patients with GH deficiency (GHD) enrolled in HypoCCS, an international observational study, using data from five countries in which comparative QLS-H data from the general population were available. Baseline QLS-H Z-scores were significantly lower in GH-deficient patients than in the general population of the same age, gender, and nationality. Z-scores were also significantly lower in female patients vs. males (P = 0.006) and in adult-onset vs. childhood-onset GHD (P = 0.002). Multivariate analysis associated female gender, multiple pituitary hormone deficiencies, low serum IGF-I values (75 micro g/liter), and concomitant antidepressant medication with low baseline Z-scores. QLS-H Z-scores increased from -1.02 +/- 1.43 (SD) at baseline to -0.25 +/- 1.34 (SD) after 1 yr of GH treatment (P0.001) and were no longer significantly different from the general population after 4 yr of treatment. There was no correlation between change in Z-score and GH dose or changes in IGF-I and IGF binding protein-3 during treatment. This study demonstrates that 1) improvements in QoL, as measured by the QLS-H, are maintained during long-term GH replacement therapy of adults with GHD, and 2) the QLS-H is a useful tool for evaluating QoL in hypopituitary patients treated in clinical practice. The authors suggest that evaluation of QoL should be a part of the routine clinical management of adult GH-deficient patients, complementing the measurement of surrogate biological markers or other clinical end points.

GH treatment in children with GH deficiency is frequently terminated at final height. However, in healthy individuals bone mass continues to accrue until peak bone mass is achieved. Because no prospective data specifically prove the role of GH in attainment of peak bone mass, we performed a multinational, controlled, 2-yr study in patients who had terminated pediatric GH at final height. Patients were randomized to: GH at 25.0 microg/kg x day (pediatric dose, n = 58) or 12.5 microg/kg x day (adult dose, n = 59), or no GH treatment (control, n = 32). Bone mineral content (BMC) and density were measured by dual-energy x-ray absorptiometry and evaluated centrally. Laboratory measurements were also performed centrally. After 2 yr, significant increases were seen with both GH treatments, compared with control in bone-specific alkaline phosphatase (P = 0.004) and type I collagen C-terminal telopeptide:creatinine ratio (P0.001), but there were no significant dose effects. Total BMC increased by 9.5 +/- 8.4% in the adult dose group, 8.1 +/- 7.6% in the pediatric dose group, and 5.6 +/- 8.4% in controls (analysis of covariance, P = 0.008), with no significant GH dose effect. BMC increased predominantly at the lumbar spine (11.0 +/- 10.6%, P = 0.015) rather than at the femoral neck or hip. In contrast, a significant dose-dependent increase was seen in IGF-I concentrations (adult dose: 114.5 +/- 119.4 microg/liter; pediatric dose: 178.5 +/- 143.7 microg/liter; P = 0.023). There were no gender-related differences in BMC changes with either dose, whereas the IGF-I increase was significantly higher with the pediatric than with the adult dose in females (P0.001) but not males (P = 0.606). In summary, reinstitution of GH replacement after final height in severely GH-deficient patients induced significant progression toward peak bone mass. Although there was a by-gender dose effect on IGF-I concentration, the treatment effect on bone was obtained in both males and females with the adult GH dose regimen.