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Biomedicines Oct 2023Cyclin-dependent kinases (CDKs) play a crucial role in regulation of the mammalian cell cycle. CDK4 and CDK6 control the G1/S restriction checkpoint through their...
Cyclin-dependent kinases (CDKs) play a crucial role in regulation of the mammalian cell cycle. CDK4 and CDK6 control the G1/S restriction checkpoint through their ability to associate with cyclin D proteins in response to growth factor signals. CDK4 deficiency in mice gives rise to a range of endocrine-specific phenotypes including diabetes, infertility, dwarfism, and atrophy of the anterior pituitary. Although CDK6 deficiency can cause thymic atrophy due to a block in the double-negative (DN) to double-positive (DP) stage of T cell development, there are no overt defects in immune cell development reported for CDK4-deficient mice. Here, we examined the impact of a novel -ethyl--nitrosourea-induced point mutation in the gene encoding CDK4 on immune cell development. Mutant mice () showed normal development and differentiation of major immune cell subsets in the thymus and spleen. Moreover, T cells from mice exhibited normal cytokine production in response to in vitro stimulation. However, analysis of the mixed bone marrow chimeras revealed that -derived T cell subsets and NK cells are at a competitive disadvantage compared to -derived cells in the thymus and periphery of recipients. These results suggest a possible role for the CDK4 mutation in the development of some immune cells, which only becomes apparent when the mutant cells are in direct competition with wild-type immune cells in the mixed bone marrow chimera.
PubMed: 37893220
DOI: 10.3390/biomedicines11102847 -
Frontiers in Endocrinology 2023Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth...
OBJECTIVE
Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD.
DESIGN
Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment.
METHODS
Auxological, clinical, laboratory, and MRI data throughout follow-up were collected.
RESULTS
We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, <0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, <0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, <0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, <0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times.
CONCLUSIONS
Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.
Topics: Adult; Child; Humans; Dwarfism, Pituitary; Human Growth Hormone; Hypopituitarism; Retrospective Studies
PubMed: 37881494
DOI: 10.3389/fendo.2023.1270845 -
Children (Basel, Switzerland) Aug 2023Growth hormone (GH) deficiency (GHD) is a rare disorder. The diagnosis of GHD requires a combination of two provocative GH tests. This study aimed to find agreement...
Reliability of Agreement between Insulin, Clonidine, and Glucagon Stimulation Tests for the Diagnosis of Growth Hormone Deficiency in Children: A Retrospective Cohort Study.
Growth hormone (GH) deficiency (GHD) is a rare disorder. The diagnosis of GHD requires a combination of two provocative GH tests. This study aimed to find agreement between commonly used medications to determine which combined tests have high reliability of agreement. This retrospective cohort included 201 children who underwent GH provocation testing from January 2012 to December 2022. The insulin tolerance test (ITT) with the clonidine stimulation test (CST) or glucagon stimulation test (GST) with the CST were performed. We calculated Cohen's kappa to determine the agreement between the test medications by considering the post-stimulation peak GH level with a cut-off value of 10 ng/mL as the primary outcome. A total of 151 patients underwent the two provocative tests and were included in the analysis. Of these patients, 119 underwent the ITT and CST and 54 (45.3%) were diagnosed with GHD. However, 32 patients underwent the GST and CST and 18 (56.2%) were diagnosed with GHD. The kappa value for ITT and CST was 0.258 (25.8%), indicating fair agreement between clonidine and insulin ( = 0.005). However, the kappa value for CST and GST was 0.178 (17.8%), representing slight agreement. The correlation coefficient revealed a very strong relationship between ITT and CST. Clonidine has fair agreement and a very strong correlation coefficient with ITT when used to diagnose GHD in children. Among the commonly used pharmacological tests for GH provocation in our unit, the CST was considered the best pharmacological test in terms of safety and reduced parental anxiety.
PubMed: 37628380
DOI: 10.3390/children10081381 -
Growth Hormone & IGF Research :... Aug 2023Late night spontaneous growth hormone (GH) pulses may influence the pituitary GH response to provocation tests. We evaluated GH response during...
OBJECTIVE
Late night spontaneous growth hormone (GH) pulses may influence the pituitary GH response to provocation tests. We evaluated GH response during arginine-insulin-tolerance test (AITT) after a GH peak during a short spontaneous nocturnal profile (SSNP) in children with short stature or low growth velocity.
DESIGN
Using SSNP and subsequent AITT, we examined 257 children 4-18 years old (138 (53.7%) males) recruited from three hospitals. Medical records were reviewed retrospectively. Refractory children were defined as a GH peak ≥7 μg/L during SSNP but no GH peak ≥7 μg/L during AITT.
RESULTS
In total, 201/257 children had a GH peak ≥7 μg/L at SSNP and/or AITT. Of these, 21.9% were refractory. The proportion of males (p = 0.033) and body mass index (BMI) standard deviation score (SDS) (p = 0.037) were higher in the refractory group than in children with a GH peak ≥7 μg/L during AITT. The median period between last GH peak ≥7 μg/L during SSNP and GH at AITT was 210 (30-390) minutes. The GH at AITT occurred 30 min earlier for children without a peak ≥7 μg/L during the SSNP (p = 0.004). The number of refractoriness differed somewhat between the hospitals (p = 0.025).
CONCLUSIONS
Many children with short stature were refractory at testing; among them we found few clinical characteristics. Refractoriness might be influenced by some differences in procedure, but needs to be considered when evaluating GH response in children.
Topics: Male; Humans; Child; Child, Preschool; Adolescent; Female; Retrospective Studies; Prevalence; Insulin-Like Growth Factor I; Growth Hormone; Human Growth Hormone; Insulin; Dwarfism; Arginine; Growth Disorders
PubMed: 37562165
DOI: 10.1016/j.ghir.2023.101549 -
European Review For Medical and... Jul 2023The aim of this study was to explore the effects of different doses of recombinant human growth hormone (rhGH) treatment on children with growth hormone deficiency (GHD). (Observational Study)
Observational Study
OBJECTIVE
The aim of this study was to explore the effects of different doses of recombinant human growth hormone (rhGH) treatment on children with growth hormone deficiency (GHD).
PATIENTS AND METHODS
Medical records of 174 GHD patients admitted to our hospital from June 2019 to January 2022 were retrospectively evaluated. A total of 136 patients met the inclusion criteria, of which 70 received 0.1 U/ (kg·d) (low-dose group) and 66 received 0.2 U/ (kg·d) dose of rhGH treatment (high-dose group). Growth and development status [height, weight, height standard deviation (HtSDS), growth rate], bone age, bone density, speed of sound (SOS) as distal radius bone mass, biochemical indicators of growth and development [insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3)], growth hormone (GH) levels and incidence of adverse reactions were collected and compared between the two groups before and after one year of the treatment.
RESULTS
After the treatment, height, weight, HtSDS, and growth rate of the two groups increased compared to before the treatment and were significantly higher in the high-dose group than in the low-dose group (p<0.05). After one year of treatment, the following observations were made: the bone age of the two groups increased compared to the baseline values and was higher in the high-dose group compared to the low-dose group (p<0.05). The SOS of the two groups decreased but was significantly higher in the high-dose group compared to the low-dose group (p<0.05). Serum levels of IGF-1, IGFBP-3, and GH in both groups increased compared to the baseline values and were higher in the high-dose group than in the low-dose group (p<0.05). There was no significant difference in the incidence of adverse reactions between the high-dose group (8.6%) and the low-dose group (6.1%) (p>0.05).
CONCLUSIONS
High-dose rhGH treatment for GHD is safe and can more effectively upregulate IGF-1, IGFBP-3, and GH, and promote the growth and development of children.
Topics: Humans; Child; Human Growth Hormone; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Retrospective Studies; Dwarfism, Pituitary; Recombinant Proteins; Growth Hormone
PubMed: 37458672
DOI: 10.26355/eurrev_202307_32972 -
European Journal of Endocrinology Jul 2023Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder... (Observational Study)
Observational Study
BACKGROUND
Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height.
OBJECTIVE
Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls.
METHODS
We included 190 patients, of whom 26 received rhGH. Height, weight, body mass index at various time points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models.
RESULTS
Adult height was available for 11/26 rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 standard deviation scores (SDS) after 1 year (CI +0.5 to +0.8, P < .001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, P < .001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared with untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, P < .001). Body mass index SDS did not vary significantly upon rhGH therapy.
CONCLUSION
Recombinant human growth hormone treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety.
Topics: Humans; Adult; Growth Hormone; Retrospective Studies; Human Growth Hormone; Pseudohypoparathyroidism; Dwarfism, Pituitary; Hypopituitarism; Mutation; Body Height; Recombinant Proteins; Growth Disorders; Chromogranins; GTP-Binding Protein alpha Subunits, Gs
PubMed: 37440712
DOI: 10.1093/ejendo/lvad085 -
The Journal of Clinical Endocrinology... Nov 2023Somapacitan is a long-acting GH derivative for treatment of GH deficiency (GHD). (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Somapacitan is a long-acting GH derivative for treatment of GH deficiency (GHD).
OBJECTIVE
Evaluate the efficacy and tolerability of somapacitan in children with GHD after 2 years of treatment and after the switch from daily GH.
DESIGN
A randomized, multinational, open-labelled, controlled parallel group phase 3 trial, comprising a 52-week main phase and 3-year safety extension (NCT03811535).
SETTING
Eighty-five sites across 20 countries.
PATIENTS
A total of 200 treatment-naïve prepubertal patients were randomized and exposed; 194 completed the 2-year period.
INTERVENTIONS
Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (0.034 mg/kg/d) during the first year, after which all patients received somapacitan 0.16 mg/kg/wk.
MAIN OUTCOME MEASURES
Height velocity (HV; cm/year) at week 104. Additional assessments included HV SD score (SDS), height SDS, IGF-I SDS, and observer-reported outcomes.
RESULTS
HV was sustained in both groups between 52 and 104 weeks. At week 104, mean (SD) for HV between weeks 52 and 104 was 8.4 (1.5) cm/year after continuous somapacitan treatment and 8.7 (1.8) cm/year after 1 year of somapacitan treatment following switch from daily GH. Secondary height-related endpoints also supported sustained growth. Mean IGF-I SDS during year 2 was similar between groups and within normal range (-2 to +2). Somapacitan was well tolerated, with no safety or tolerability issues identified. GH patient preference questionnaire results show that most patients and their caregivers (90%) who switched treatment at year 2 preferred once-weekly somapacitan over daily GH treatment.
CONCLUSIONS
Somapacitan in children with GHD showed sustained efficacy and tolerability for 2 years, and after switching from daily GH. Patients/caregivers switching from daily GH expressed a preference for somapacitan.
CLINICAL TRIAL REGISTRATION
NCT03811535.
Topics: Humans; Child; Insulin-Like Growth Factor I; Human Growth Hormone; Growth Hormone; Growth Disorders; Dwarfism, Pituitary; Body Height
PubMed: 37406251
DOI: 10.1210/clinem/dgad394 -
Journal of Clinical Research in... Nov 2023Recent reports have indicated the role of the prokineticin receptor 2 gene () in the etiology of pituitary hormone deficiencies, suggesting a potential role for the...
OBJECTIVE
Recent reports have indicated the role of the prokineticin receptor 2 gene () in the etiology of pituitary hormone deficiencies, suggesting a potential role for the PROK2 pathway in pituitary development, in addition to its role in gonadotropin releasing hormone-expressing neuron development. Here, we present the clinical and molecular findings of four patients with mutations.
METHODS
Next-generation targeted sequencing was used to screen 25 genes in 59 unrelated patients with multiple pituitary hormone deficiency (MPHD), isolated growth hormone (GH) deficiency, or idiopathic short stature.
RESULTS
Two different, very rare missense alterations classified as pathogenic (NM_144773.4:c.518T>G; NP_658986.1:p. (Leu173Arg)) and likely pathogenic (NM_144773.4:c.254G>A; NP_658986.1:p.(Arg85His)) were identified in four patients in heterozygous form. Patient 1 and Patient 2 presented with short stature and were diagnosed as GH deficiency. Patient 3 and Patient 4 presented with central hypothyroidism and cryptorchidism and were diagnosed as MPHD. No other pathogenic alterations were detected in the remaining 24 genes related to short stature, MPHD, and hypogonadotropic hypogonadism. Segregation analysis revealed asymptomatic or mildly affected carriers in the families.
CONCLUSION
dominance should be kept in mind as a very rare cause of GH deficiency and MPHD. Expressional variation or lack of penetrance may imply oligogenic inheritance or other environmental modifiers in individuals who are heterozygous carriers.
Topics: Growth Hormone; Pituitary Hormones; Dwarfism, Pituitary; Humans; Pedigree; Male; Female; Infant; Child; Receptors, G-Protein-Coupled; Consanguinity
PubMed: 37338295
DOI: 10.4274/jcrpe.galenos.2023.2023-4-4 -
Hormone Research in Paediatrics 2024Genetic forms of growth hormone deficiency (GHD) may occur as isolated GHD (IGHD) or as a component of multiple pituitary hormone deficiency (MPHD). This study aimed to...
INTRODUCTION
Genetic forms of growth hormone deficiency (GHD) may occur as isolated GHD (IGHD) or as a component of multiple pituitary hormone deficiency (MPHD). This study aimed to present the clinical and molecular characteristics of patients with IGHD/MPHD due to the GH1 gene variants.
METHODS
A gene panel accommodating 25 genes associated with MPHD and short stature was used to search for small sequence variants. Multiplex ligation-dependent probe amplification was performed in patients with normal panel results to investigate gross deletion/duplications. Segregation in the family was performed by Sanger sequencing.
RESULTS
The GH1 gene variants were detected in 5 patients from four unrelated families. One patient had IGHD IA due to homozygous whole GH1 gene deletion and one had IGHD IB due to novel homozygous c.162C>G/p.(Tyr54*) variant. Two patients from a family had previously reported heterozygous c.291+1G>A/p.(?) variant in which clinical and genetic characteristics were compatible with IGHD II accompanying MPHD. One patient had clinical and laboratory characteristics of IGHD II with MPHD but the heterozygous c.468 C>T/p.(R160W) variant had conflicting results about the relationship with the phenotype.
CONCLUSION
Expanding our knowledge of the spectrum of GH1 gene variants by apprehending clinical and molecular data of more cases, helps to identify the genotype-phenotype correlation of IGHD/MPHD and the GH1 gene variants. These patients must be regularly followed up for the occurrence of additional pituitary hormone deficiencies.
Topics: Humans; Dwarfism, Pituitary; Human Growth Hormone; Hypopituitarism; Homozygote; Phenotype; Genetic Association Studies; Growth Hormone
PubMed: 37315542
DOI: 10.1159/000531113 -
Best Practice & Research. Clinical... Dec 2023Daily administration of growth hormone (GH) treatment has been in clinical use for treatment for GH deficiency (GHD) in adults for more than 30 years. Numerous studies... (Review)
Review
Daily administration of growth hormone (GH) treatment has been in clinical use for treatment for GH deficiency (GHD) in adults for more than 30 years. Numerous studies have demonstrated evidence that GH treatment improves body composition, cardiovascular risk factors and quality of life with few side effects. Less frequent GH injections are hypothesized to improve adherence and several long-acting GH (LAGH) formulations have been developed and a few have been approved and marketed. Different pharmacological modifications have been applied and the pharmacokinetics and pharmacodynamics of LAGH are different to each other and to those of daily injections and require different dosing and monitoring specific for each LAGH. Studies have shown improved adherence with LAGH, and short-term efficacy and side effects are comparable between daily GH injections and LAGHs. Long-term treatment with daily GH injections is effective and safe, while long-term studies for LAGHs are awaited. In this review challenges, benefits, and risks of treatment with daily and long-acting GH preparations will be compared.
Topics: Adult; Humans; Growth Hormone; Quality of Life; Human Growth Hormone; Hypopituitarism; Dwarfism, Pituitary
PubMed: 37308376
DOI: 10.1016/j.beem.2023.101788