John Germak

Variable Degree of Growth Hormone (GH) and Insulin-Like Growth Factor (IGF) Sensitivity in Children with Idiopathic Short Stature Compared with GH-Deficient Patients: Evidence from an IGF-Based Dosing Study of Short Children

CONTEXT We recently showed that, in IGF-based GH therapy, the IGF-I target chosen affects GH dose requirements, and higher IGF-I targets are associated with more robust growth parameters. OBJECTIVE The objective of the study was to compare the response of GH-deficient (GHD) vs. idiopathic short-stature (ISS) children to IGF-based GH therapy. DESIGN This was a 2-yr, open-label, randomized trial. SETTING The setting was multicenter and outpatient. PATIENTS Prepubertal short children [height sd score (SDS) < -2] with low IGF-I levels (<or=-1 SDS), subclassified based on the peak stimulated serum GH concentration at baseline, into two subgroups: GHD (n = 63, GH < 7 ng/ml) and ISS (n = 102, GH >or= 7 ng/ml). INTERVENTIONS Patients were randomized 2:2:1 to three treatment groups: IGF-I target of 0 SDS (IGF0T), 2 SDS (IGF2T), or a conventional weight-based GH dosing of 40 microg/kg x d (Conv). MAIN OUTCOME MEASURES Change in (Delta) height SDS, IGF-I SDS, and GH dose was measured. RESULTS ISS subjects required higher GH doses than GHD patients in the IGF2T (but not IGF0T) arm (medians 119 and 65 microg/kg x d, respectively), indicating that ISS represents a partial GH-insensitive state that manifests during treatment with higher doses of GH. GHD children grew more than those with ISS in both IGF-targeted dosage groups despite similar IGF-I levels (suggesting a degree of IGF insensitivity in ISS subjects): Delta height SDS of 2.04 +/- 0.17 for GHD and 1.33 +/- 0.09 for ISS groups in IGF2T, 1.41 +/- 0.13 for children with GHD, and 0.84 +/- 0.07 for those with ISS in IGF0T. CONCLUSION IGF-based GH dosing is clinically feasible in both GHD and ISS patients, although GH dose requirements and auxological outcomes are distinct between these groups. This suggests a degree of both GH and IGF insensitivity in subjects with ISS that requires specific management strategies to optimize growth during GH therapy.

Thyroid abnormalities in infantile hepatic hemangioendothelioma

We report an infant with hepatic hemangioendothelioma (HAE) associated with compensated hypothyroidism. The hepatic lesions regressed with steroid therapy and his thyroid function normalized with high doses of thyroxine supplement. Pediatr Blood Cancer 2007;49:1021–1024.

Identification of factors associated with good response to growth hormone therapy in children with short stature: results from the ANSWER Program®.

ObjectiveTo identify factors associated with growth in children on growth hormone (GH) therapy using data from the American Norditropin Studies: Web-enabled Research (ANSWER) Program® registry.MethodsGH-naïve children with GH deficiency, multiple pituitary hormone deficiency, idiopathic short stature, Turner syndrome, or a history of small for gestational age were eligible (N = 1,002). Using a longitudinal statistical approach, predictive factors were identified in patients with GHD for change from baseline in height standard deviation score (ΔHSDS) following 2 years of treatment.ResultsGradual increases in ΔHSDS over time were observed for all diagnostic categories. Significant predictive factors of ΔHSDS, ranked by significance were: height velocity (HV) at 4 months > baseline age > baseline HSDS > baseline body mass index (BMI) SDS > baseline insulin-like growth factor I (IGF-I) SDS; gender was not significant. HV at 4 months and baseline BMI SDS were positively correlated, whereas baseline age, HSDS, and IGF-I SDS were negatively correlated with ΔHSDS.ConclusionsThese results may help guide GH therapy based on pretreatment characteristics and early growth response.

Impact of Age and Duration of Growth Hormone Therapy in Children with Turner Syndrome

Background/Aims: To assess height standard deviation scores (HSDS) in patients with Turner syndrome (TS) by age at treatment initiation and varying durations of treatment with growth hormone (GH). Methods: GH treatment-naïve patients with TS from the American Norditropin Studies: Web-enabled Research (ANSWER) Program® Registry were analyzed at baseline, 4 months, and annually. Results: Three hundred and eighty-two patients with TS had a baseline mean (±SD) HSDS of –2.6 ± 0.9. Patients received short-term (1 year), long-term (<3 years), and extended GH treatment (≧3 years, mean = 4.54 years), resulting in 40.2% (n = 99/246), 60.5% (n = 69/114), and 62.3% (n = 86/138) of the patients achieving HSDS >–2. Patients starting GH at a younger age experienced better growth response, regardless of treatment duration. Change in HSDS from baseline (ΔHSDS) at 4 months correlated positively with ΔHSDS at 1 and 3 years, and ΔHSDS at 1 year with ΔHSDS at 3 years (p values from 0.0017 to<0.0001). Conclusions: Height gains in patients with TS during short-term treatment were found to be highly predictive of longer-term results. Continuation of GH treatment (≧3 years) resulted in 62.3% of the patients achieving an HSDS within the normal population range, indicating the clinical importance of early initiation and continuation of GH treatment in patients with TS.

The NordiNet® International Outcome Study and NovoNet® ANSWER Program®: rationale, design, and methodology of two international pharmacoepidemiological registry-based studies monitoring long-term clinical and safety outcomes of growth hormone therapy (Norditropin®)

Objective Randomized controlled trials have shown that growth hormone (GH) therapy has effects on growth, metabolism, and body composition. GH therapy is prescribed for children with growth failure and adults with GH deficiency. Carefully conducted observational study of GH treatment affords the opportunity to assess long-term treatment outcomes and the clinical factors and variables affecting those outcomes, in patients receiving GH therapy in routine clinical practice. Design The NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web Enabled Research (ANSWER Program®) are two complementary, non-interventional, observational studies that adhere to current guidelines for pharmacoepidemiological data. Patients The studies include pediatric and adult patients receiving Norditropin®, as prescribed by their physicians. Measurements The studies gather long-term data on the safety and effectiveness of reallife treatment with the recombinant human GH, Norditropin®. We describe the origins, aims, objectives, and design methodology of the studies, as well as their governance and validity, strengths, and limitations. Conclusion The NordiNet® IOS and ANSWER Program® studies will provide valid insights into the effectiveness and safety of GH treatment across a diverse and large patient population treated in accordance with real-world clinical practice and following the Good Pharmacoepidemiological Practice and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.

Factors Influencing the One- and Two-Year Growth Response in Children Treated with Growth Hormone: Analysis from an Observational Study

To assess gender-, pubertal-, age-related differences in change from baseline height standard deviation score (), data from 5,797 growth hormone (GH) naïve pediatric patients (<18 years) with growth hormone deficiency (GHD), multiple pituitary hormone deficiency (MPHD), Turner syndrome (TS), small for gestational age (SGA), Noonan syndrome (NS), and idiopathic short stature (ISS) were obtained from the ANSWER (American Norditropin Studies: Web-enabled Research) Program registry. For patients with SGA, at year 1 was significantly greater for males versus females (), but no other gender differences were observed. For patients with GHD, was greater in prepubertal than in pubertal patients. Younger patients for both genders (<11 years for boys; <10 years for girls) showed a greater ( for GHD, MPHD, and ISS). Overall, positive were observed in all patients, with greater growth responses in younger prepubertal children, emphasizing the importance of starting GH treatment early.

Maternal 21-hydroxylase deficiency and uniparental isodisomy of chromosome 6 and X results in a child with 21-hydroxylase deficiency and klinefelter syndrome

Elizabeth A. Parker, Karine Hovanes, John Germak, Forbes Porter, and Deborah P. Merke* National Institutes of Health, Developmental Endocrinology Branch, NICHD, Bethesda, Maryland Esoterix, Inc., Molecular Genetics Department, Calabasas Hills, California Novo Nordisk, Inc., Princeton, New Jersey NIH—Heritable Disorders Branch, NICHD, Bethesda, Maryland NIH—Reproductive Biology & Medicine Branch, NICHD and NIH Clinical Center, Bethesda, Maryland

Dose-sparing and safety-enhancing effects of an IGF-I-based dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations.

Titrating the dosage of growth hormone (GH) to serum levels of insulin‐like growth factor‐I (IGF‐I) is a feasible treatment strategy in children with GH deficiency (GHD) and idiopathic short stature (ISS). The objective was to assess the dose‐sparing effect and theoretical safety of IGF‐I‐based GH therapy.

Effect of 4 years of growth hormone therapy in children with Noonan syndrome in the American Norditropin Studies: Web-Enabled Research (ANSWER) Program® registry

BackgroundNoonan syndrome (NS) is a genetic disorder characterized by phenotypic features, including facial dysmorphology, cardiovascular anomalies, and short stature. Growth hormone (GH) has been approved by the United States Food and Drug Administration for short stature in children with NS. The objective of this analysis was to assess the height standard deviation score (HSDS) and change in HSDS (ΔHSDS) for up to 4 years (Y4) of GH therapy in children with NS.MethodsThe American Norditropin Studies: Web-Enabled Research (ANSWER) Program®, a US-based registry, collects long-term efficacy and safety information on patients treated with Norditropin® (somatropin rDNA origin, Novo Nordisk A/S) at the discretion of participating physicians. A total of 120 children (90 boys, 30 girls) with NS, naïve to previous GH treatment, were included in this analysis.ResultsThe mean (SD) baseline age of subjects (n = 120) was 9.2 (3.8) years. Mean (SD) HSDS increased from –2.65 (0.73) at baseline to –1.32 (1.11) at Y4 (n = 17). Subjects showed continued increase in HSDS from baseline to Y4 without significant differences between genders at Y1 or Y2. The mean (SD) GH dose was 47 (11) mcg/kg/day at baseline and 59 (16) mcg/kg/day at Y4. There was a negative correlation between baseline age and ΔHSDS at Y1 (R = –0.3156; P = 0.0055) and Y2 (R = –0.3394; P = 0.017). ΔHSDS at Y1 was significantly correlated with ΔHSDS at Y2 (n = 37; R = 0.8527, P < 0.0001) and Y3 (n = 20; R = 0.5145; P = 0.0203), but not Y4 (n = 12; R = 0.4066, P = 0.1896).ConclusionsGH treatment-naïve patients with NS showed continued increases in HSDS during 4 years of treatment with GH with no significant differences between genders up to 2 years. Baseline age was negatively correlated with ΔHSDS at Y1 and Y2. Whether long-term therapy in NS results in continued increase in HSDS to adult height remains to be investigated.Trial registrationClinicalTrials.gov NCT01009905

Efficacy of IGF-based growth hormone (GH) dosing in nonGH-deficient (nonGHD) short stature children with low IGF-I is not related to basal IGF-I levels.

Weight‐based GH dosing is the standard for treating children with short stature. The current study validates the usefulness of IGF‐based GH dosing for GH therapy in nonGH‐deficient (nonGHD) children and its relationship with pretreatment serum IGF‐I concentration.