Lawrence A. Silverman

Update of guidelines for the use of growth hormone in children: the Lawson Wilkins pediatric endocrinology society drug and therapeutics committee

The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee guidelines for the use of growth hormone were first published in 1983, near the end of the era of human pituitary-derived growth hormone (GH), and again in 1995, a decade after the introduction of recombinant human (rh)GH. The LawsonWilkins Pediatric Endocrine Society also endorsed an international consensus document led by the Growth Hormone Research Society published in 2000. This report serves to update those guidelines with an emphasis on new recommendations. The recommendations included here are limited primarily to the use of GH in infants, children and adolescents.

Immunoreactive inhibin, müllerian inhibitory substance, and activin as biochemical markers for juvenile granulosa cell tumors

Ovarian juvenile granulosa cell tumors are a rare cause of sexual precocity. Clinical examination, serum estradiol levels, and pelvic imaging studies have been used traditionally to detect such tumors. Immunoassays for müllerian inhibitory substance and inhibin have recently been noted to provide a more sensitive means of tumor detection in adults. We now describe two girls with this type of tumor in whom serum concentrations of inhibin and müllerian inhibitory substance were used as tumor markers.

Results of a Second Year of Therapy with the 12-Month Histrelin Implant for the Treatment of Central Precocious Puberty

Background. Gonadotropin releasing hormone analogs (GnRHas) are standard of care for central precocious puberty (CPP). The histrelin subcutaneous implant is safe and effective in the treatment of CPP for one year. Objective. The study evaluates a second year of therapy in children with CPP who received a new implant after one year of treatment. Methods. A prospective one-year study following an initial 12-month treatment period was conducted. Results. Thirty-one patients (29 girls) aged years received a second implant. Eighteen were naïve to GnRHa therapy at first implantation. Peak LH declined from  mIU/mL at 12 months to  mIU/mL at 24 months (< .0001) in naïve subjects, and from  mIU/mL at 12 months to  mIU/mL at 24 months () in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months (). Minor implant site reactions occurred in 61%, while minor difficulties with explantation occurred in 32.2% of subjects. Conclusion. The histrelin implant demonstrates profound hypothalamic-pituitary-gonadal axis suppression when a new implant is placed for a second year of treatment. Prospective follow-up of this therapeutic modality for the treatment of CPP is needed.

Evaluation of the American-English Quality of Life in Short Stature Youth (QoLISSY) questionnaire in the United States

BackgroundThe European Quality of Life in Short Stature Youth (QoLISSY) is a novel condition-specific instrument developed to assess health related quality of life (HrQoL) in children/adolescents with short stature from patient and parent perspectives. Study objective was to linguistically validate and psychometrically test the American-English version of the QoLISSY instrument.MethodsUpon conversion of the British-English version to American-English, content validity and acceptance of the questionnaire were examined through focus group discussions with cognitive debriefing in 28 children/adolescents with growth hormone deficiency (GHD) or idiopathic short stature (ISS) and their parents. In the subsequent field test with 51 families and a re-test with 25 families the psychometric performance of the American-English version was examined and compared with the original European dataset.ResultsPilot test results supported the suitability of the American-English version. Good internal consistency with Cronbach’s Alpha ranging from 0.84 to 0.97 and high test-re-test reliabilities were observed in the field test. The QoLISSY was able to detect significant differences according to the degree of short stature with higher HrQoL for taller children. Correlations with a generic HrQoL tool support the QoLISSY’s concurrent validity. The scale’s operating characteristics were comparable to the original European data.ConclusionResults support that the QoLISSY American-English version is a psychometrically sound short stature-specific instrument to assess the patient- and parent- perceived impact of short stature. The QoLISSY instrument is fit for use in clinical studies and health services research in the American-English speaking population.

Predictors of First-Year Growth Response to a Fixed-dose Growth Hormone Treatment in Children Born Small for Gestational Age: Results of an Open-Label, Multicenter Trial in the United States

BACKGROUND Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.

A four-year, open-label, multi-center, randomized, two-arm study of Genotropin® in patients with idiopathic short stature: comparison of an individualized, target-driven treatment regimen to standard dosing of Genotropin® - analysis of two-year data.

Background: Several models have been developed to predict growth response to growth hormone (GH) based on auxological and biochemical parameters for children with non-GH-deficient, idiopathic short stature (ISS). Objective: To demonstrate if an individualized, formula-based, target-driven GH regimen for children with ISS would lead to a height (Ht) gain to -1.3 SDS during the first 24 months of treatment of this 4-year study, with less variability than with standard weight-based dosing. Methods: A 4-year, open-label, multi-center, randomized, two-arm study comparing formula-based dosing of Genotropin® GH from 0.18 to 0.7 mg/kg/week versus standard FDA-approved ISS dosing of Genotropin® (0.37 mg/kg/week). Subjects (n = 316, 89 females) were prepubertal, 3-14 years of age, bone age 3-10 years (m) and 3-9 years (f), naive to GH treatment, Ht SDS -3 to -2.25, Ht velocity <25th percentile for bone age, and peak GH >10 ng/ml. Results: The majority (83%) of subjects had Ht SDS within the normal range by 2 years. All subjects displayed catch-up growth consistent with other studies of GH treatment of ISS. Conclusion: The formula-based therapy did not meet the primary endpoint achieving targeted gain with lower variability. No new safety concerns were found.

A 4-Year, Open-Label, Multicenter, Randomized Trial of Genotropin® Growth Hormone in Patients with Idiopathic Short Stature: Analysis of 4-Year Data Comparing Efficacy, Efficiency, and Safety between an Individualized, Target-Driven Regimen and Standard Dosing.

Background/Aims: Growth hormone (GH) treatment regimens for children with non-GH-deficient, idiopathic short stature (ISS) have not been optimized. To compare the efficacy, efficiency, and safety of an individualized, target-driven GH regimen with standard weight-based dosing after 4 years of treatment. Methods: This is a 4-year, open-label, multicenter, randomized trial comparing individualized, formula-based dosing of Genotropin® versus a widely used ISS dose of Genotropin®. Subjects were prepubertal, had a bone age of 3-10 years for males and 3-9 years for females, were naive to GH treatment, and had a height standard deviation score (Ht SDS) of -3 to -2.25, a height velocity <25th percentile for their bone age, and peak stimulated GH >10 ng/ml. After the first 2 years, the individualized-dosing group was further randomized to either 0.18 or 0.24 mg/kg/week. Results: At 4 years, subjects in all treatment regimens achieved similar average height gains of +1.3 SDS; however, the individualized dosing regimen utilized less GH to achieve an equivalent height gain. Conclusion: Individualized, formula-based GH dosing, followed by a dose reduction after 2 years, provides a more cost-effective growth improvement in patients with ISS than currently employed weight-based regimens.

Veganism as a cause of iodine deficient hypothyroidism.

Abstract Background: Iodine deficiency is the most common cause of acquired hypothyroidism worldwide. Although uncommon in the Western world, the incidence of iodine deficiency may be rising due to the increased use of restrictive diets. Case presentation: We present a 23-month-old boy diagnosed with iodine deficiency hypothyroidism, induced by a vegan diet. Conclusions: This case highlights the risk for iodine deficiency in children on a vegan diet after discontinuation of breast/formula feeding that could lead to acquired hypothyroidism.

Adrenal Causes of Electrolyte Abnormalities: Hyponatremia/Hyperkalemia

1. Sodium and potassium homeostasis is tightly controlled by adrenal mineralocorticoid production.