Idiopathic Growth Hormone Deficiency Patients Research Articles

Prospective Follow-up of Children with Idiopathic Growth Hormone Deficiency After Termination of Growth Hormone Treatment: Is There Really Need for Treatment at Transition to Adulthood?

Objectives:Continuation of growth hormone (GH) treatment in adolescents with severe childhood onset idiopathic GH deficiency (IGHD) during the transition period, irrespective of achievement of final height, is still debatable. We aimed to prospectively investigate the metabolic profile, bone mineral density (BMD) and body composition of patients with IGHD in whom GH treatments were terminated after they had reached their final height, six months after the cessation of therapy.Methods:Twelve patients, six of whom had peak GH levels <5 ng/mL [permanent GH deficiency (GHD), group 1], and six who had peak GH levels >5 ng/mL (transient GHD, group 2) after insulin stimulation test were evaluated for anthropometric and laboratory parameters including fasting blood glucose (FBG), fasting insulin, lipid profile, BMD, body composition measurements and 24-hour ambulatory blood pressure monitoring before (baseline) and at six months after discontinuation of GH.Results:No differences were found in clinical, laboratory, BMD and body composition measures between groups 1 and 2 at baseline. All IGHD patients had significant increments of body weight (BW), body mass index (BMI), BMD, total body fat (TBF), TBF%, truncal fat (TF) and TF% after GH cessation. Six months later BW, BMI, BMD and TF% was increased significantly while FBG and lipids showed no change in group 1. In group 2, TBF% and TF% were increased, FBG, total cholesterol and high-density lipoprotein decreased after six months. Changes in these parameters in group 2 were not statistically different from group1.Conclusion:TF% increase in both groups after cessation of therapy. We did not observe a clinical condition requiring GH treatment in any of the study subjects during the follow-up period.

Near final height in patients with idiopathic growth hormone deficiency: A single‐centre experience

We analysed near final height (NFH) data in children with growth hormone deficiency (GHD) treated with recombinant human GH (rhGH). We divided the idiopathic GHD patients into two groups, isolated GHD (IGHD) and multiple pituitary hormone deficiency, to evaluate NFH. Then, data were grouped according to gender, pre-pubertal/pubertal status and spontaneous or induced puberty. The trial was performed as a retrospective study. Median values are given, and measurements are expressed as standard deviation scores (SDSs). rhGH therapy was started at a median age of 12.1 (range 9.1-14.9) years in the IGHD group (n = 162, 83 males) and 9.1 (range 4.9-13.4) years in the multiple pituitary hormone deficiency group (n = 33, 22 males) at a median dose of 0.20 mg/kg/week. Height SDSs at the onset of therapy were -3.2 (range -4.4 to -2.6) and -3.9 (-6.8 to -2.8) in the two groups, respectively (P < 0.001). NFH SDSs were -1.8 (-2.9 to -1) and -1.6 (-3.1 to -0.4) (P = 0.139), and delta height SDSs (finish - start) were 1.4 (0.3-2.5) and 2.6 (1.5-4.6) (P < 0.001), respectively. Total delta height was 1.4 SDS (0.4-3.1) in patients who started rhGH treatment in the pre-pubertal period and 1.3 SDS (0.3-2.4) (P = 0.106) in those who started rhGH in the pubertal period. About 85% of the cases reached their genetic height potential. Delta height SDSs were higher than expected in cases that started treatment during the pubertal period. Therefore, it is possible to achieve NFH within the mid-parental height range in patients who start therapy during puberty.

Genetic analysis of IRF6, a gene involved in craniofacial midline formation, in relation to pituitary and facial morphology of patients with idiopathic growth hormone deficiency

IntroductionGrowth hormone is secreted by the pituitary gland, which forms part of the craniofacial midline. IRF6 encodes a transcription factor involved in the development of the craniofacial midline and mutations in IRF6 are known to disturb craniofacial development. Craniofacial and pituitary development are closely related. After whole exome sequencing revealed a new mutation in IRF6 in a family with Idiopathic Growth Hormone Deficiency (IGHD), we screened the remainder of our IGHD cohort for mutations in this gene and related their genotypes to pituitary and craniofacial morphology.Materials and methodsWe sequenced all coding exons and exon–intron boundaries of IRF6 in 81 patients with IGHD. We performed a multiplex ligation-dependent probe amplification (MLPA) in order to exclude copy number variations in IRF6. We analyzed facial measurements taken from standardized digital pictures of 48 patients.ResultsWe found two new variants and eleven polymorphisms. Apart from the new mutation found in the index family (p.Arg233Cys), we found one other new heterozygous missense mutation in IRF6 (Pro456Ser). p.Arg233Cys was reported as extremely rare in exome databases (1 allele out of 120.852 alleles sequenced), strictly conserved among species and was predicted deleterious by all variant predictor programs. Pro456Ser was predicted to be benign. MLPA did not reveal any exon deletions or duplications in any of the patients.ConclusionThis is the first report of IRF6 analysis in an IGHD cohort. We found one new mutation which, based on in silico analysis, could be of functional relevance. However, we did not find any mutations in the other patients. Therefore, we conclude that IRF6 defects are rare in IGHD patients and further research should focus on new candidate genes.

Utility of prediction models in growth hormone therapy in children with idiopathic growth hormone deficiency

<h3>Aims</h3> Growth prediction models are thought to be helpful in detecting children with Idiopathic Growth Hormone Deficiency (IGHD) with poor response to recombinant human growth hormone (rhGH) therapy. This study aims to determine adequacy of rhGH therapy responses in the first two years of treatment in children with IGHD by comparing with a validated prediction model. <h3>Methods</h3> Growth records of IGHD patients started on rhGH therapy between 1999 and 2009 at single tertiary endocrinology centre were analysed in order to calculate pre-treatment, year one and year two height velocities (HVs). HVs were expressed as standard deviation score (SDS). Growth prediction formula determinants (age at onset, birth weight SDS, height SDS, weight SDS, mid-parental height SDS, maximum GH on stimulation test and rhGH dose) were obtained. Observed and predicted HVs were compared using an unpaired t-test. <h3>Results</h3> Of 54 patients identified, 18 pre-pubertal children (median (range) age 10 (4-16) years; 13 male) had sufficient data for HV analysis (figure 1). In year one, 3 of the 18 patients received an rhGH dose below recommended national prescribing guidelines (0.7–1.0 mg/m²/day), increasing to 5 patients in year two. Significant differences between observed and predicted HVs were observed in year one of rhGH therapy (p=&lt;0.01), but not in year two (p=0.19) (n=11). 55% achieved HVs below the predicted range. There was no relationship between the observed and predicted HV discrepancy and the rhGH dose, suggesting that patient compliance may be a factor in the failure to attain predicted HVs. In year one, baseline pre-treatment insulin-like growth factor-1 (IGF-1) levels were negatively correlated to the difference between observed and predicted HV (figure 2). <h3>Conclusion</h3> In children with IGHD receiving rhGH therapy: –Improvements in HV were observed, although considerable variability is seen particularly in year two. –Prediction models do not appear to give an accurate year one growth prediction. –Baseline IGF-1 level may be a valuable parameter for future growth prediction formulae. –Close attention to rhGH dose is needed in order to optimise growth responses.

The Potential of Prediction Models Based on Data from KIGS as Tools to Measure Responsiveness to Growth Hormone

Various prediction models have been developed, based on data documented within KIGS (Pharmacia International Growth Database), for use in the growth hormone (GH) treatment of children with short stature resulting from GH deficiency (GHD) or other causes. In addition to the practical value of such models as part of a ‘forward strategy’ guiding GH treatment, we now propose that prediction models may also be useful for the identification of individual variance in responsiveness. In a comparison involving 1,800 children with idiopathic GHD (IGHD), 151 children who acquired GHD after treatment for medulloblastoma and 192 children with GHD accompanying craniopharyngioma, it was shown that the responsiveness to GH of patients with craniopharyngioma equalled that of IGHD patients, whereas patients with medulloblastoma were less responsive. These observations and the identification of ‘good’ and ‘poor’ responders to GH have practical clinical consequences (e.g. modification of treatment), and will, in the future, lead to the identification of those factors which determine the variability of sensitivity to GH. This will improve the efficacy and safety of GH treatment as well as reducing the costs involved.

Arm span as measurement of response to growth hormone (GH) treatment in a group of children with meningomyelocele and GH deficiency.

Children with meningomyelocele (MMC) frequently have impaired linear growth. A number have associated structural brain defects with resultant GH deficiency (GHD). Reproducible measurements of height or length in MMC patients are often hampered by lower limb contractures, spasticity, and scoliosis. Arm span has been proposed as a more reproducible measure of linear growth. Five MMC children documented to have GHD were treated with recombinant human GH (hGH) for 1-3 yr. Their height, arm span, and growth velocity were compared with 32 children with idiopathic GHD treated similarly with hGH. These measures are compared with normal children by being expressed as standard deviation scores. The results of this study indicate that arm span measurements in GHD MMC patients are almost identical to height measurements in idiopathic GHD patients both before and during hGH therapy. The physical condition of children with MMC makes reproducible longitudinal height measurements difficult. Routine determinations of arm span measurements for children with MMC will assist in recognizing growth failure as well as monitoring treatment results.

Response to Growth Hormone Treatment and Final Height after Cranial or Craniospinal Irradiation

Growth hormone (GH) deficiency (GHD) induced by cranial irradiation has become a frequent indication of hGH substitutive therapy. This study analyses the growth response to hGH therapy and the factors involved in the decrease in growth velocity observed after cranial irradiation. One hundred children (61 boys and 39 girls) given cranial radiation for pathology distant from the hypothalamo-pituitary area were studied. Fifty-six of them received hGH therapy for GHD resulting in decreased growth velocity. The initial annual height gain in the cranial-irradiated group was comparable to that of patients treated for idiopathic GHD; additional spinal irradiation significantly reduced the growth response. Twenty-eight hGH-treated patients reached final heights which were compared to those of 2 untreated irradiated groups, one with GHD (n = 27) and the other with normal GH secretion (n = 17). The height SD score changes observed in hGH therapy were +0.3 in the cranial (n = 10) and -1.2 SD in the craniospinal (n = 18) groups. GH deficiency had contributed to a mean height loss of 1 SD and spinal irradiation to a loss of 1.4 SD. The small effect of hGH therapy on final height is probably linked to the small bone age retardation at onset of hGH therapy and to the fact that irradiated children entered puberty at a younger age in terms of chronological age (10.6 +/- 0.3 yr in girls and 11.0 +/- 0.3 yr in boys) and bone age (9.6 +/- 0.4 yr in girls and 12.6 +/- 0.3 in boys) than the idiopathic GHD patients. These data suggest that the results of hGH therapy in irradiated children might be improved with higher and more fractionated hGH doses and, in some patients, by delaying puberty using luteinizing hormone releasing hormone analogs.

GROWTH HORMONE SECRETION ON COMPLETION OF TREATMENT IN ISOLATED "IDIOPATHIC" AND POST-IRRADIATION GROWTH HORMONE DEFICIENCY

After completion of growth hormone (GH) treatment, 19 patients with isolated “idiopathic” growth hormone deficiency (IGHD) and 15 with post-irradiation growth hormone deficiency (PRGHD) were asked to undergo retesting of GH secretion with an insulin tolerance test and/or an arginine stimulation test. PRGHD patients are those with CNS tumours distant from the hypothalamic-pituitary axis (n=13) or acute lymphatic leukaemia (n=2), who had received cranial or cranospinal irradiation.All 15 patients with PRGHD remained GH deficient [peak GH level <7mU/l (n=10) and 7-15mU/l (n=5)]. However of the 19 retested IGHD patients, 5 (26%) had peak GH responses >15mU/l (regarded now as transient or false F-IGD) and were indistinguishable from the remainder [permanent or true T-IGHD, peak GH levels <7mU/l (n=12) and 7-15 mU/1 (n=2)] by pre-treatment anthropometry and post-treatment height SDS, but had a lower first year height velocity (Mean Velocity 5.4cm/yr ±0.9 for F-IGHD v 8.7cm/year ±1.75 for T-IGHD p<0.01) and height acceleration on treatment (Mean acceleration 2.1cm/yr ±1.7 for F-IGHD v 5.2cm/yr ±2.3 for T-IGHD p<0.05). By current practices 2 F-IGHD patients may have been distinguished by sex-steroid priming.Thus post-irradiation GH deficiency appears to be permanent but errors of diagnosis in IGHD are common.

Idiopathic growth hormone (GH) deficiency, and GH deficiency secondary to hypothalamic germinoma: effect of single and repeated administration of human GH-releasing factor (hGRF) on plasma GH level and endogenous hGRF-like immunoreactivity level in cerebrospinal fluid.

Plasma GH responses to iv administered synthetic human GH-releasing factor-(1-44)-NH2 (hGRF) and the concentration of endogenous hGRF-like immunoreactivity (hGRF-LI) in the cerebrospinal fluid (CSF) were examined in 16 children with GH deficiency (GHD). Ten patients had idiopathic GHD, and six had GHD secondary to germinoma. An iv bolus hGRF (1 microgram/kg BW) injection test was performed the day before and the day after treatment, with a daily 1-h iv infusion of hGRF (2 micrograms/kg BW) for 3 days. Plasma GH increases (greater than 5 ng/ml) after the first iv bolus injection of hGRF occurred in 2 of the 10 idiopathic GHD children and in 4 of the 6 GHD patients with germinoma whereas the first bolus hGRF injection failed to elicit GH release in the remaining 10 patients. The mean +/- SEM peak plasma GH level after the first bolus hGRF dose in the patients with germinoma (8.2 +/- 2.2 ng/ml) was significantly higher than that in the idiopathic GHD patients (2.9 +/- 0.9 ng/ml; P less than 0.05), but significantly lower than that in normal children with short stature (18.5 +/- 2.5 ng/ml; P less than 0.05). In the 2 patients with germinoma and in 5 of the 8 idiopathic GHD children who did not respond to the first hGRF bolus dose, a significant plasma GH response to hGRF occurred during a daily iv infusion of hGRF for 3 consecutive days, whereas the remaining 3 idiopathic GHD children failed to respond to the daily hGRF infusions. The plasma GH response after the second hGRF bolus dose given after treatment with daily hGRF infusions for 3 days was not different from that after the first hGRF bolus in patients with germinoma or that in the idiopathic GHD children. hGRF-LI was not detected (less than 5.8 pg/ml) in the CSF in any of 5 patients with germinoma, whereas it was present in 5 idiopathic GHD patients (mean, 17.5 +/- 0.9 pg/ml), 3 of whom were nonresponders to daily hGRF infusions. From these results, GHD secondary to destruction of hypothalamic GRF neurons might be defined by the following findings: 1) lack of a GH response to the standard provocative tests acting through the hypothalamus; 2) significant increase in plasma GH after a single bolus and/or repetitive iv administration of hGRF; and 3) undetectable or extremely low levels of endogenous hGRF-LI in the CSF. Most of the idiopathic GHD patients responded to the repetitive hGRF infusion, suggesting insufficient secretion of hypothalamic hGRF as the primary defect. However, since hGRF-LI was detectable in the CSF in some of the idiopathic GHD patients, its pathogenesis must be multifactorial.