Genetic defects causing functional and structural isolated growth hormone deficiency

2011 ◽  
Vol 2 (2) ◽  
Author(s):  
Vibor Petkovic ◽  
Primus Mullis
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Somatic Growth ◽  
Human Growth ◽  
Postnatal Growth ◽  
Metabolic Effects ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Gh Secretion ◽  
Normal Standards

AbstractNormal somatic growth requires the integrated function of many of the hormonal, metabolic, and other growth factors involved in the hypothalamo-pituitary-somatotrope axis. Human growth hormone (hGH) causes a variety of physiological and metabolic effects in humans and its pivotal role in postnatal growth is undisputed. Disturbances that occur during this process often cause subnormal GH secretion and/or subnormal GH sensitivity/responsiveness resulting in short stature. Despite the complexity of this linear growth process, the growth pattern of children, if evaluated in the context of normal standards, is rather predictable. Children presenting with short stature (i.e out of normal standards) are treated with daily injections of recombinant human GH (rhGH), which leads in almost all cases to an increase of height velocity. Although it is becoming more and more evident that many genes are involved in controlling the regulation of growth, the main aim of this review is to focus on the GH-1 gene, the various gene alterations and their important physiological and pathophysiological role in growth.

scholarly journals Comparison of Quality of Life Responses From Caregiver and Children Aged ≥7 Years Using the Quality of Life in Short Stature Youth (QoLISSY) Questionnaire, Following 12 Months of Growth Hormone Treatment With Either a Weekly Somatrogon or a Daily Genotropin Injection Schedule

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A674-A674
Author(s):  
Jane Loftus ◽  
Julia Quitmann ◽  
Srinivas Valluri ◽  
Aleksandra Pastrak ◽  
Lawrence Reiter ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Growth Hormone ◽  
Short Stature ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Hormone Treatment ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Controlled Clinical Trial

Abstract Objective: Paediatric growth hormone deficiency (pGHD) affects 1/4,000 children. Treatment with daily sub-cutaneous injections of recombinant human growth hormone (r-hGH) increase height velocity and quality of life (QoL). A recent randomised controlled clinical trial (NCT02968004) evaluated the efficacy/safety of weekly Somatrogon (hGH-CTP) and daily Genotropin in pGHD. QoL (an exploratory endpoint) was evaluated using the validated Quality of Life in Short Stature Youth (QoLISSY) questionnaire, which includes three subscales (physical, social, emotional) and total score. Methods: The QoLISSY core module was administered to patients (aged 3-11 years [girls], 3-12 years [boys]) and parents in US, UK, Australia, New Zealand, Belarus, Russia, Ukraine and Spain, at Baseline (BL) and 12 months after treatment start. The QoLISSY-CHILD was completed by children aged ≥7 years; QoLISSY-PARENT was completed by the Caregiver for children <7 years, and for some children aged ≥7 years. We report here only the QoLISSY results for children aged ≥7 years (reported from either child or parent). Results: For Total QoLISSY-PARENT, for children aged ≥7 years in the Somatrogon group (N=26), mean scores are 53.65 (BL) and 65.52 (month 12) with mean change of 13.01 (95% Confidence Interval [CI]: 3.99, 22.02). In the Genotropin group (N=28), mean scores are 55.89 (BL) and 63.66 (month 12) with mean change of 6.60 (CI:-0.21, 13.40). For Total QoLISSY-CHILD in the Somatrogon group (N=35), mean scores are 61.48 (BL) and 74.69 (month 12) with mean change of 13.00 (CI: 5.81, 20.19). In the Genotropin group (N=35), these scores are 60.96 (BL) and 69.03 (Month 12) with mean change of 7.84 (CI: 2.71, 12.97). Scores of >70 indicate a good QoL. Conclusions: QoL in children aged ≥7 years improved, following 12 months of either treatment, whether this was reported by caregiver or child. However, these data show that the baseline scores and 12 month scores from the QoLISSY-PARENT in both treatment groups were numerically lower than those reported by the child. This is consistent with the literature¹, in which the caregivers generally report lower QoL scores on behalf of the child. ¹Explaining parent-child (dis)agreement in generic and short stature-specific health-related quality of life reports: do family and social relationships matter? Quitmann et al Health and Quality of Life Outcomes 2016 vol 14, Article 150

Treatment of Short Stature in Aggrecan Deficient Patients with Recombinant Human Growth Hormone: One-Year Response

2021 ◽  
Author(s):  
Gajanthan Muthuvel ◽  
Andrew Dauber ◽  
Eirene Alexandrou ◽  
Leah Tyzinski ◽  
Melissa Andrew ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Human Growth Hormone ◽  
Linear Growth ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Skeletal Maturation ◽  
Height Velocity ◽  
Heterozygous Mutation ◽  
One Year

Abstract Context Patients with aggrecan (ACAN) deficiency present with dominantly inherited short stature, often with advanced skeletal maturation and premature growth cessation. There is a paucity of information on the effects of growth-promoting interventions. Objective The aim of this study was to evaluate the efficacy and safety of recombinant human growth hormone (rhGH) therapy on linear growth in children with ACAN deficiency. Design and Setting Open-label, single-arm, prospective study at Cincinnati Children’s Hospital Medical Center. Patients Ten treatment-naïve patients were recruited. Inclusion criteria were: a confirmed heterozygous mutation in ACAN, age ≥ 2 years, pre-pubertal, bone age (BA) ≥ chronological age (CA), and normal IGF-I concentration. Intervention Treatment with rhGH (50 mcg/kg/day) over one year. Main Outcome Measure(s) Main outcomes measured were height velocity (HV) and change in (Δ) height SD (HtSDS). Results Ten patients (six females) were enrolled with median CA of 5.6 yrs (range 2.4 to 9.7). Baseline median HtSDS was -2.5 (range -4.3 to -1.1). Median baseline BA was 6.9 yrs (range 2.5 to 10.0), with median BA/CA of 1.2 (range 0.9 to 1.5). Median pre-treatment HV was 5.2 cm/y (range 3.8 to 7.1), increased to 8.3 cm/y (range 7.3 to 11.2) after one year of therapy (p=0.004). Median ΔHtSDS after one year was +0.62 (range +0.35 to +1.39) (p=0.002). Skeletal maturation did not advance inappropriately (median Δ BA/CA -0.1, p=0.09). No adverse events related to rhGH were observed. Conclusion Treatment with rhGH improved linear growth in a cohort of patients with short stature due to ACAN deficiency.

Growth hormone-releasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature

1995 ◽  
Vol 133 (4) ◽  
pp. 425-429 ◽  
Author(s):  
J Bellone ◽  
L Ghizzoni ◽  
G Aimaretti ◽  
C Volta ◽  
MF Boghen ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Oral Administration ◽  
Short Stature ◽  
Area Under Curve ◽  
Low Dose ◽  
Height Velocity ◽  
Pubertal Stage ◽  
Gh Secretion ◽  
Short Children ◽  
Releasing Effect

Bellone J, Ghizzoni L, Aimaretti G, Volta C, Boghen MF, Bernasconi S, Ghigo E. Growth hormonereleasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature. Eur J Endocrinol 1995;133:425–9. ISSN 0804–4643 Growth hormone-releasing peptide 6 (GHRP-6) is a synthetic hexapeptide with a potent GH-releasing activity after intravenous, subcutaneous, Intranasal and oral administration in man. Previous data showed its activity also in some patients with GH deficiency. The aim of our study was to verify the GH-releasing activity of oral GHRP-6 administration on GH secretion in children with normal short stature. The effect of oral GHRP-6 (300 μg/kg) was compared with that of the maximally effective dose of intravenous GH-releasing hormone (GHRH-29, 1 μg/kg). As the GHRH-induced GH rise in children is potentiated by arginine (ARG), even when administered by oral route at low dose (4 g), we studied also the interaction of oral GHRP-6 and ARG administration. We studied 13 children (nine boys and four girls aged 6.2–10.5 years, pubertal stage I) with normal short stature (height less than –2 sd score; height velocity more than –2 sd score; normal bone age; insulin-like growth factor I > 70 μg/l), In a first group of children (N = 7), oral GHRP-6 administration induced a GH response (mean ± sem, peak at 60 min vs baseline: 18.8 ±3.0 vs 1.1 ± 0.3 μg/l, p < 0.0006; area under curve: 1527.3 ± 263.9 μgl−1 h) which was similar to that elicited by GHRH (peak at 45 min vs baseline: 20.8 ±4.5 vs 2.2±0.9 μg/l, p <0.007; area under curve: 1429.4 ± 248.2 μgl−1 h−1). In a second group of children (N = 6), the GH response to oral GHRP-6 administration (peak at 75 min vs baseline: 18.5 ±5.1 vs 1.5 ± 0.6 μg/l, p < 0.01; area under curve: 1598.5 ± 289.3 μgl−1 h−1) was not modified by co-administration of oral ARG (peak at 90 min vs baseline: 15.2 ±5.6 vs 0.9±0.3 μg/l, p < 0.002; area under curve: 1327.8 ± 193.2 μgl−1 h−1). The amount of GH released and the timing of the somatotrope response after the oral administration of GHRP-6 were similar in the two groups. In conclusion, the present data show that in normal short children the oral administration of GHRP-6 is able to increase GH secretion to an extent similar to that observed after intravenous administration of the maximally effective GHRH dose. Moreover, in contrast to GHRH, the effect of GHRP-6 is not enhanced by low-dose oral ARG. As this amino acid likely acts via inhibition of hypothalamic somatostatin release, our data suggest that a decrease in the somatostatinergic activity does not improve the GH-releasing effect of GHRP-6 in childhood, at variance with that observed after GHRH. Our results suggest that GHRP-6 could be clinically useful to stimulate GH secretion in short children. E Ghigo, Divisione di Endocrinologia, Ospedale Molinette, C. so. AM Dogliotti 14, 10126 Torino, Italy

scholarly journals Urinary Growth Hormone Excretion as Measured by a Sensitive Immunochemiluminometric Assay

1993 ◽  
Vol 30 (2) ◽  
pp. 180-185 ◽  
Author(s):  
G Turner ◽  
R C Brown ◽  
I Weeks ◽  
G E Butler ◽  
F N Creagh ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Individual Variability ◽  
Height Velocity ◽  
Growth Disorders ◽  
Serum Growth Hormone ◽  
Renal Handling ◽  
Gh Secretion ◽  
Normal Stature ◽  
Optimum Sampling

A sensitive immunochemiluminometric assay with a detection limit of 1 · 1μU/L was developed for the measurement of urinary growth hormone (UGH). The assay was shown to be specific and precise. There was a good correlation between serum growth hormone (GH) and UGH concentrations in 20 patients with acromegaly and six volunteers following an intravenous injection of recombinant GH. We concluded therefore that UGH measurements appear to provide a satisfactory index of GH secretion. The use of the assay in the investigation of growth disorders was assessed. We studied 11 pre-pubertal children, six of normal stature, and five of short stature, over a 6-month period. Sequential fortnightly measurements of UGH were carried out and height velocity was determined. The children of short stature grew at a slower rate and excreted less GH than the children of normal stature. However, we observed considerable within-individual variability in GH excretion in both groups (CV 22–98%). We therefore recommend that sequential UGH analyses should be carried out and the results interpreted in conjunction with growth measurements. However, further investigations into the renal handling of GH are needed to establish optimum sampling regimes.

Isolated Growth Hormone Deficiency in Children and Adolescents

2001 ◽  
Vol 14 (s2) ◽  
Author(s):  
J. Argente ◽  
S.A.S. Abusrewil ◽  
G. Bona ◽  
F. Chiarelli ◽  
C.J.H. Kelnar ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Transcription Factor ◽  
Children And Adolescents ◽  
Growth Hormone Deficiency ◽  
Hormonal Regulation ◽  
Human Growth ◽  
Hormone Deficiency ◽  
Imaging Method ◽  
Gh Secretion ◽  
Definition Of

AbstractAlthough it is difficult to reach international agreement on the definition of growth hormone deficiency (GHD) in children and adolescents, great efforts to do so have been made during the last two decades. A somewhat limited definition of GHD is: a combination of auxological, clinical, biochemical and metabolic abnormalities caused by lack or insufficiency of GH secretion that results in a decrease in the production of GH-dependent hormones and growth factors. Its aetiology is very complex. Therefore, specific studies must be performed during different periods of childhood (neonatal, prepubertal and pubertal periods). Auxological parameters, particularly growth velocity (GV), are still considered the best clinical measures for analysing human growth. The spectacular advances in our understanding of molecular biology during the past twenty years have allowed, and will continue to allow, a more and more precise diagnosis of the molecular anomalies of human growth. This will, in turn, allow changes caused by genetic lesions to be more efficiently distinguished from those due to nutritional, organic, tumoural, psychological or traumatic causes. Our knowledge of the molecular bases of undergrowth due to a deficiency in GH has developed as a result of the localisation and characterisation of human genes which code for proteins implicated in the hormonal regulation of growth. These genes include pituitary GH (GH1), pituitary transcription factor 1 (Pit-1), the prophet of Pit-1 (PROP-1), the pituitary; transcription factor LHX3, the transcription factor HESX1 and the GH-releasing hormone receptor (GHRHr). In addition, magnetic resonance imaging is the best available imaging method for the evaluation of size and structure of the pituitary and the parasellar region.

scholarly journals Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengjun Sun ◽  
Biao Lu ◽  
Yu Liu ◽  
Yaqin Zhang ◽  
Haiyan Wei ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Human Growth Hormone ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Clinical Trial Registration ◽  
Long Acting ◽  
Phase Iv

ContextLong-acting recombinant human growth hormone (rhGH) has transformed growth hormone deficiency (GHD) treatment. However, the possibility and rationality for flexible time regimen are pending.ObjectiveWe studied the efficacy of biweekly versus weekly PEGylated rhGH (PEG-rhGH) therapy in GHD children.Design, Setting, and PatientsThis multicenter, phase IV trial with a non-inferiority threshold ≥20% enrolled 585 Tanner stage I GHD children.InterventionSubjects randomly received 0.20 mg/kg once-weekly or biweekly PEG-rhGH, or 0.25 mg/kg.w rhGH once daily for 26 weeks.Main Outcome MeasureThe primary outcome was height SD scores for chronological age (HtSDSCA) at week 26 and safety measurements including adverse events (AEs), IGF-2, and IGFBP-2 changes.ResultsAt week 26, the median HtSDSCA changed from −2.75, −2.82, and −2.78 to −2.31, −2.43, and −2.28 with weekly and biweekly PEG-rhGH, and daily rhGH, respectively. The difference in HtSDSCA was 0.17 ± 0.28 between weekly and biweekly PEG-rhGH, and 0.17 ± 0.27 between daily rhGH and biweekly PEG-rhGH, failing the non-inferiority threshold. Nevertheless, the height velocity of children receiving biweekly PEG-rhGH reached 76.42%–90.34% and 76.08%–90.60% that of children receiving weekly PEG-rhGH and daily rhGH, respectively. The rate of AEs was comparable among the groups. No statistical difference was observed in IGF-2 and IGFBP-2 levels among the groups. IGFBP-2 levels decreased over time in all groups, with no notable difference in IGF-2 and IGFBP-2 changes among the three treatment groups.ConclusionsAlthough notably promoted height velocity, biweekly PEG-rhGH failed the non-inferiority threshold as compared with either weekly PEG-rhGH or daily rhGH. Compared with short-term rhGH, long-acting PEG-rhGH did not significantly increase tumor-associated IGF-2 and IGFBP-2 expressions.Clinical Trial Registrationclinicaltrials.gov, identifier NCT02976675.

Use of Growth Hormone in the Treatment of Short Stature: Boon or Abuse?

1991 ◽  
Vol 12 (12) ◽  
pp. 355-363
Author(s):  
Paul Saenger
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Recombinant Dna ◽  
Gh Deficiency ◽  
Hormone Deficiency ◽  
Vigorous Exercise ◽  
Gh Secretion ◽  
The Many ◽  
Definition Of ◽  
First Time

Growth hormone (GH) was isolated approximately 30 years ago. Since then, we have witnessed major advances in understanding the regulation and pattern of GH secretion and its many metabolic actions.1 With the advent of recombinant DNA-generated growth hormone (rhGH) in 1985, the opportunities to treat children who have organic or idiopathic GH deficiencies are now, for the first time, unlimited. DEFINITION OF GROWTH HORMONE DEFICIENCY Although a role for GH in the treatment of certain children deficient in GH is established, the definition of GH deficiency remains controversial. The controversy surrounding the diagnosis of GH deficiency was highlighted recently when it was shown that, among the many commercial assay kits available, the same serum sample yielded GH concentrations that differed by as much as 100% for the same sample. Using different GH assay kits, a child who has short stature could be determined to be deficient in GH in the view of one endocrinologist but to have sufficient GH (ie, to be normal) by another endocrinologist.2,3 Despite these obvious limitations, GH testing has an important role in the clinical evaluation of the child who is short. When a child fails a simple screening test (ie, serum GH level of &lt;10 ng/mL following vigorous exercise, such as running for 20 minutes), more definitive GH testing is the next step.

HUMAN GROWTH HORMONE: CURRENT STATUS OF AVAILABILITY AND USEFULNESS

PEDIATRICS ◽  
1969 ◽  
Vol 44 (5) ◽  
pp. 766-767
Author(s):  
Sumner J. Yaffe ◽  
Charles F. Weiss ◽  
Mary Ellen Avery ◽  
Howard M. Cann ◽  
Arnold P. Gold ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Human Growth Hormone ◽  
Extraction Procedure ◽  
Somatic Growth ◽  
Human Growth ◽  
Hormone Deficiency ◽  
Current Status ◽  
Number Of Children ◽  
Increasing Demand

About 10% of short patients referred for endocrine consultation have hypopituitarism. This may be in the form of growth hormone deficiency in association with the loss of other pituitary trophic hormones or isolated growth hormone deficiency. For treatment of these patients, pediatricians inquire whether human growth hormone (HGH) is available and what growth response will result from its administration. Excellent responses in augmenting somatic growth and controlling hypoglycemia in the treatment of growth hormone deficiency have been obtained with intramuscular injections of HGH. Growth rates increase to supranormal levels, permitting "catch up" growth in amounts as much as 15 cm per year during therapy. It is frequently necessary to treat with HGH for several years, since the hypopituitary patient is usually well below the 3rd percentile in height at the time of diagnosis. The minimum amount of HGH required would at present seem to be of the order of 3 units per week. Since most HGH preparations have a potency of the order of 1 unit or less per milligram, and the human pituitaries from which HGH is extracted yield from 3 to 5 mg (depending on the extraction procedure), many pituitaries are required to treat each patient. The increasing availability of growth hormone immunoassay has made it possible to diagnose growth hormone deficiency relatively easily; therefore, the number of children who need therapy has increased considerably. However, the supply of growth hormone is still entirely dependent on the collection and extraction of human pituitaries. This laborious procedure has not been able to keep up with the increasing demand for the hormone.

TRANSITORY GROWTH HORMONE DEFICIENCY SUCCESSFULLY TREATED WITH HUMAN GROWTH HORMONE

1977 ◽  
Vol 84 (1) ◽  
pp. 11-22 ◽  
Author(s):  
Olav Trygstad
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Human Growth ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Growth Spurt ◽  
Isolated Growth Hormone Deficiency ◽  
Short Children

ABSTRACT This study was carried out in order to determine whether children with a transitory type of growth hormone deficiency showed an accelerated growth in height velocity on treatment with human growth hormone (HGH). Following careful diagnostic routine procedures 13 extremely short children were diagnosed as having isolated growth hormone deficiency, and were successfully treated with HGH. A true isolated growth hormone deficiency was present in 5 of the children, whereas 8 showed a normal increase in serum growth hormone on repeated growth hormone stimulation tests after their development of puberty and termination of HGH treatment. Three boys with bone ages of 5.5, 8.0 and 9.5 years showed an undisputable effect following HGH administration. They showed an initial growth at the start of treatment, and a second growth spurt during development of puberty. Two of the boys reached final statures of 14 cm taller than the predicted heights. The other patients, including the children with true isolated growth hormone deficiency showed an initial spurt of growth at the start of the HGH treatment immediately followed by a pubertal growth spurt. The mean acceleration of height velocity for the children with true isolated growth hormone deficiency was from 3.4 cm during the year before treatment to 7.0 cm during the first year on treatment, as compared to 2.8 and 7.4 cm, respectively, for the children with transitory growth hormone deficiency. A girl with severe anorexia nervosa who had a transitory growth hormone deficiency, showed an accelerated high velocity from 1.1 cm to 7.6 cm during the first year following treatment with HGH. The question whether HGH treatment should be made available to all short children with no known syndrome, and presenting a height less than −3.5 sds, a bone age/chronological age ratio of less than ⅔, and a height velocity less than −2 sds is discussed. The only way to know if a child will respond to HGH treatment is to give it for a trial period of at least six months. At least a physiological stimulus to growth hormone secretion should be decisive in the selection of growth retarded children for HGH treatment. Different mechanisms seem to be responsible for physiological growth hormone secretion to sleep or exercise, and the secretion obtained with pharmacological stimuli.

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