Clinical and nutritional correlates of bacterial diarrhoea aetiology in young children: a secondary cross-sectional analysis of the ABCD trial.

OBJECTIVE: The objective was to assess the association between nutritional and clinical characteristics and quantitative PCR (qPCR)-diagnosis of bacterial diarrhoea in a multicentre cohort of children under 2 years of age with moderate to severe diarrhoea (MSD). DESIGN: A secondary cross-sectional analysis of baseline data collected from the AntiBiotics for Children with Diarrhoea trial (NCT03130114). PATIENTS: Children with MSD (defined as >3 loose stools within 24 hours and presenting with at least one of the following: some/severe dehydration, moderate acute malnutrition (MAM) or severe stunting) enrolled in the ABCD trial and collected stool sample. STUDY PERIOD: June 2017-July 2019. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Likely bacterial aetiology of diarrhoea. Secondary outcomes included specific diarrhoea aetiology. RESULTS: A total of 6692 children with MSD had qPCR results available and 28% had likely bacterial diarrhoea aetiology. Compared with children with severe stunting, children with MAM (adjusted OR (aOR) (95% CI) 1.56 (1.18 to 2.08)), some/severe dehydration (aOR (95% CI) 1.66 (1.25 to 2.22)) or both (aOR (95% CI) 2.21 (1.61 to 3.06)), had higher odds of having likely bacterial diarrhoea aetiology. Similar trends were noted for stable toxin-enterotoxigenic Escherichia coli aetiology. Clinical correlates including fever and prolonged duration of diarrhoea were not associated with likely bacterial aetiology; children with more than six stools in the previous 24 hours had higher odds of likely bacterial diarrhoea (aOR (95% CI) 1.20 (1.05 to 1.36)) compared with those with fewer stools. CONCLUSION: The presence of MAM, dehydration or high stool frequency may be helpful in identifying children with MSD who might benefit from antibiotics.

Long-acting growth hormone in the treatment of growth hormone deficiency in children: a systematic literature review and network meta-analysis.

The purpose of this study is to compare the relative efficacy and safety of long-acting growth hormone (LAGH) as a growth hormone replacement therapy in prepubertal children with growth hormone deficiency (GHD). We searched the PubMed, Embase, CNKI, and Wanfang databases from inception to July 2023 and identified eleven relevant studies. PEG-LAGH showed better effect on height velocity (mean difference [MD]: - 0.031, 95% credibility interval [CrI]: - 0.278, 0.215) than somatrogon (MD: 0.105, 95% CrI: - 0.419, 0.636), somapacitan (MD: 0.802, 95% CrI: - 0.451, 2.068) and lonapegsomatropin (MD: 1.335, 95% CrI: - 0.3, 2.989) when compared with daily growth hormone (DGH). Furthermore, in terms of height standard deviation score, PEG-LAGH demonstrated better improvement (MD: - 0.15, 95% CrI: - 1.1, 0.66) than somatrogon (MD: - 0.055, 95% CrI: - 1.3, 0.51) and somapacitan (MD: 0.22, 95% CrI: - 0.91, 1.3). PEG-LAGH (risk ratio [RR]: 1.00, 95% CrI: 0.82, 1.2) reduced the risk of adverse events compared with other LAGH (somatrogon, RR: 1.1, 95% CrI: 0.98, 1.2; somapacitan, RR: 1.1, 95% CrI: 0.96, 1.4; lonapegsomatropin, RR, 1.1, 95% CrI: 0.91, 1.3) and was comparable with DGH. This is the first study to indirectly compare the LAGH thorough a network meta-analysis and provide evidence of the optimal efficacy of various LAGH specifically PEG-LAGH and acceptable safety profile in prepubertal children with GHD.

[Growth hormone - 30 years of clinical practice: past, present, future].

The recombinant technologies era, which began in the second half of the XX century, made it possible to produce recombinant growth hormone (rGH) necessary for the treatment of stunting of various genesis. The time of practically unlimited possibilities of rGH production has come, which served as a stimulus for studying the efficacy and safety of rGH application, searching for optimal ways of its use and dosing regimes. Many years of experience in the use of somatropin in clinical practice allowed us to obtain data on its effectiveness primarily in somatotropic insufficiency in children, to study its effect on the functional state of various organs and systems, and to expand the indications for the use of RGR.

Molecular diagnosis is an important indicator for response to growth hormone therapy in children with short stature.

BACKGROUND: Significant differences have been observed in the efficacy of recombinant human growth hormone (rhGH) treatment for short children. The present study aimed to identify the genetic etiology of short stature and to assess the role of molecular diagnosis in predicting responses to rhGH treatment. METHODS: A total of 407 short children were included in the present study, 226 of whom received rhGH treatment. Whole-exome sequencing (WES) was conducted on short children to identify the underlying genetic etiology. Correlations between molecular diagnosis and the efficacy of rhGH treatment were examined. RESULTS: Pathogenic or likely pathogenic mutations were identified in 86 of the 407 patients (21.1%), including 36 (41.9%) novel variants. Among the multiple pathways affecting short stature, genes involved in fundamental cellular processes (38.7%) play a larger role, especially the RAS-MAPK pathway. In general, patients without pathogenic mutations responded better to rhGH than those with mutations. Furthermore, patients with hormone signaling pathway mutations had a better response to rhGH, while those with paracrine factor mutations had a worse response to rhGH. CONCLUSIONS: This study highlights the utility of WES in identifying genetic etiology in children with short stature. Identifying likely causal mutations is an important factor in predicting rhGH response.

Effect of Growth Hormone Therapy on Pubertal Timing: Systematic Review and Meta-Analysis.

INTRODUCTION: Recombinant human growth hormone (rhGH) therapy effectively increases height in various disorders of childhood growth. However, whether rhGH affects pubertal timing is unclear. We aimed to review systematically published evidence on the effect of rhGH on pubertal timing. METHODS: Embase, MEDLINE, and Cochrane Library databases were searched until December 2021 on randomized and non-randomized controlled studies of rhGH in children. RESULTS: Twenty-five articles (n = 1,433 children) were identified, describing 12 randomized and 13 non-randomized controlled studies in children with idiopathic short stature (ISS; 15 studies), small for gestational age (n = 6 studies), chronic renal failure (n = 3), Noonan syndrome (n = 1), and growth hormone deficiency (n = 1). Significant differences in the effects of rhGH on pubertal timing were found by clinical indication. Only among children with ISS, rhGH promoted earlier age at pubertal timing (mean difference = -0.46 years; 95% CI, -0.90 to -0.03; 9 studies; n total = 397) or higher relative risk for pubertal onset during study follow-up (1.26; 95% CI, 1.03 to 1.54; 6 studies; n total = 284). CONCLUSIONS: Treatment with rhGH appears to promote earlier pubertal timing among children with ISS. Evidence was lacking in children with growth hormone deficiency due to the absence of studies with untreated controls.

Letrozole combined with rhGH treatment increases the adult height of short pubertal boys.

OBJECTIVES: This study was performed to investigate the effectiveness of the combination of letrozole and recombinant human growth hormone (rhGH) to improve the predicted adult height (PAH) and final adult height (FAH) of Chinese short pubertal boys. METHODS: In total, 171 Chinese short pubertal boys were recruited for this study. 96 of them received letrozole (2.5 mg/d) combined with rhGH (33.3-66.6 µg/kg.d), and the others received rhGH alone. Follow-up visits were conducted at 1, 3, 6, 9, and 12 months or regularly after the first treatment. During each visit, plasma samples were collected for clinical tests and biomedical analyses, all of which were performed according to standard protocols. This study was registered at www.chictr.org.cn under ID number ChiCTR1900026142. RESULTS: After receiving treatment for at least 3 months, 68 boys (91 %) in the rhGH therapy group and 90 (94 %) in the letrozole combined with rhGH (letrozole+rhGH) therapy group achieved an increase in PAH, with the latter treatment leading to a more effective slowing of bone age (BA) advancement. Moreover, the increased PAH showed a significant positive correlation with treatment time in both groups, and letrozole+rhGH increased the PAH to a greater degree than rhGH alone (p=0.0023). And letrozole+rhGH not only slowed the increase in BA more efficiently than rhGH therapy alone (p=0.0025), but also achieved a higher FAH (p=0.0078). CONCLUSIONS: Letrozole combined with rhGH treatment is a promising therapy to increase the PAH and FAH of Chinese short pubertal boys.

Importance of Growth Factors and Bone Maturation Ratio in the Response to Growth Hormone Therapy.

OBJECTIVE: The aim was to identify the influence of insulin-like growth factor I (IGF-1), IGF-binding protein-3 (IGFBP-3), and bone age (BA)/chronological age (CA) ratio on the response to GH therapy after 1 and 2 years of treatment and upon reaching final height. METHODS: Longitudinal, retrospective, observational study of 139 patients treated for idiopathic growth hormone deficiency. Variables examined during follow-up: (1) genetic background; (2) perinatal history; (3) anthropometry; (4) height velocity, BA, BA/CA and height prognosis; (5) analytical results (IGF-1, IGFBP-3). Final response variables: adult height (AH), AH with respect to target height, AH with respect to initial height prognosis, AH with respect to height at the start of treatment, and AH with respect to height at onset of puberty. RESULTS: Lower pretreatment IGF-1 levels and a greater increase in IGF-1 at the end of treatment imply a better response (r = -0.405, P = .007 and r = 0.274, P = .014, respectively), as does a greater increase in IGFBP-3 after 2 years of treatment and at the end of treatment (r = 0.207, P = .035 and r = 0.259, P = .020, respectively). A lower BA/CA ratio pretreatment and at the onset of puberty results in a better response (r = -0.502, P = .000 and r = -0.548, P = .000, respectively), as does a lower increase in BA and BA/CA ratio after the 1 and 2 years of treatment (r = -0.337, P = .000 and r = -0.332, P = .000, respectively). CONCLUSION: Low pretreatment IGF-1, a greater BA delay with respect to CA pretreatment and at the onset of puberty, a greater increase in IGFBP-3 after 2 years of treatment, and a lower increase in BA and BA/CA ratio after 1 and 2 years of treatment imply a better long-term response.

Growth Hormone Treatment for Non-GHD Disorders: Excitement Tempered by Biology.

The success of growth hormone (GH) replacement in children with classical GH deficiency has led to excitement that other causes of short stature may benefit similarly. However, clinical experience has shown less consistent and generally less dramatic effects on adult height, perhaps not surprising in light of increased understanding of GH and growth plate biology. Nonetheless, clinical demand for GH treatment continues to grow. Upon the 20th anniversary of the US Food and Drug Administration's approval of GH treatment for idiopathic short stature, this review will consider the factors underlying the expansion of GH treatment, the biological mechanisms of GH action, the non-GH-deficient uses of GH as a height-promoting agent, biological constraints to GH action, and future directions.

The Treatment of Growth Disorders in Childhood and Adolescence.

BACKGROUND: 3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. METHODS: This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience. RESULTS: Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management. CONCLUSION: There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.

Effects of different therapy regimens to increase final adult height in males at advanced bone age with idiopathic short stature.

BACKGROUND: This retrospective study explored the effect on adult height of a combination of recombinant human growth hormone (rhGH) and aromatase inhibitors (AIs), or rhGH and a gonadotropin-releasing hormone analog (GnRHa), and compared their effects with rhGH alone in males at advanced bone age with idiopathic short stature (ISS). METHODS: In this retrospective study, rhGH or rhGH combined with GnRHa or rhGH combined with AI therapy was given to males with advanced bone age (13-15 years) and diagnosed with ISS. The patients were followed to assess their adult height. RESULTS: (1) A total of 68 patients were reviewed; 22 males were treated with rhGH for 24.9 ± 4.47 months, 22 males were treated with GnRHa + rhGH for 34.1 ± 3.36 months, and 24 males were treated with AI + RHGH for 22.7 ± 2.49 months. (2) Before treatment, the HtSDS-CA for the three groups were -1.04 ± 0.95, -1.23 ± 1.06, and -0.85 ± 0.98, respectively, and the HtSDS-BA were -2.14 ± 0.29, -2.14 ± 0.21, and-2.26 ± 0.31, respectively. The target heights for each group were 169.7 ± 4.0 cm, 169.7 ± 3.9 cm, and 169.1 ± 3.9 cm, respectively. The predicted adult heights were 161.7 ± 3.35 cm, 162.3 ± 1.75 cm, and 161.6 ± 2.89 cm, respectively. (3) After treatment, the HtSDS-CA for the rhGH group increased by 1.30 ± 0.58, and the HtSDS-BA increased by 2.00 ± 0.27. For the GnRHa + rhGH group, the HtSDS-CA and HtSDS-BA increased by1.42 ± 0.73and 2.74 ± 0.28, respectively. The AI + RHGH group increased by1.39 ± 0.64 and 2.76 ± 0.31, respectively. (4) There was no significant difference between the adult height (170.9 ± 0.7 cm) and target height for the rhGH group (P > 0.05), but the adult heights for the GnRHa + rhGH and AI + RHGH groups (173.2 ± 1.5 cm and 173.5 ± 1.0 cm, respectively, P > 0.05) were higher than the target height (P < 0.05). (5) Compared with the predicted adult height, the adult heights for the three groups improved significantly (P < 0.05). (6) No severe adverse reactions during the treatment occurred in any of the children. However, the total incidence of side effects in the three groups was significant (χ2 = 20.433, P = 0.00). CONCLUSION: Different therapeutic approaches have been investigated to improve the final adult height of males at advanced bone ages with ISS, and the optimal strategy remains controversial. In children at advanced bone ages with ISS, clinicians should carefully consider the advantages and disadvantages prior to treatment.

The Effects of Natural Product-Derived Extracts for Longitudinal Bone Growth: An Overview of In Vivo Experiments.

Approximately 80% of children with short stature are classified as having Idiopathic Short Stature (ISS). While growth hormone (GH) treatment received FDA approval in the United States in 2003, its long-term impact on final height remains debated. Other treatments, like aromatase inhibitors, metformin, and insulin-like growth factor-1 (IGF-1), have been explored, but there is no established standard treatment for ISS. In South Korea and other Asian countries, East Asian Traditional Medicine (EATM) is sometimes employed by parents to potentially enhance their children's height growth, often involving herbal medicines. One such product, Astragalus membranaceus extract mixture HT042, claims to promote height growth in children and has gained approval from the Korean Food and Drug Administration (KFDA). Research suggests that HT042 supplementation can increase height growth in children without skeletal maturation, possibly by elevating serum IGF-1 and IGF-binding protein-3 levels. Preclinical studies also indicate the potential benefits of natural products, including of EATM therapies for ISS. The purpose of this review is to offer an overview of bone growth factors related to ISS and to investigate the potential of natural products, including herbal preparations, as alternative treatments for managing ISS symptoms, based on their known efficacy in in vivo studies.

The effect of anastrozole therapy on final height and sex hormone levels in pubertal boys receiving growth hormone therapy.

Objective: This research aimed to evaluate retrospectively the effect of anastrozole on height gain and sex hormone levels in pubertal boys receiving growth hormone (GH). Materials and methods: Pubertal boys who received both GH and anastrozole (GH+A) were one-to-one matched with boys who received only GH (GH-Only) for chronological and bone age, pubertal stage and height before the GH initiation, treatment duration and midparental height. Anthropometric measurements throughout treatment and adult heights were compared between the groups. Sex hormone levels were evaluated longitudinally in the GH+A group. Results: Forty-eight cases (24 in each group) were included. There was no statistical difference in adult height between the GH+A and GH-Only (p = 0.071). However, when the analysis was limited to those receiving anastrozole for at least 2 years, mean adult height was higher in the GH+A than in the GH-Only group (173.1 ± 6.2/169.8 ± 5.6 cm, p = 0.044). Despite similar growth rates between the two groups, bone age advancement was slower in the GH+A than in the GH-Only in a mean anastrozole treatment period of 1.59 years (1.37 ± 0.80/1.81 ± 0.98 years, p = 0.001). The greatest increase for FSH, LH, total and free testosterone and decrease for estradiol levels were observed in the third month after anastrozole was started, albeit remaining within the normal ranges according to the actual pubertal stages. Conclusion: Using anastrozole with GH for at least 2 years decelerates the bone age advancement resulting in adult height gain with no abnormality in sex hormone levels. These results suggest anastrozole can be used as an additional treatment to GH for further height gain in pubertal boys.

Tandem Isotope Therapy with 225Ac- and 177Lu-PSMA-617 in a Murine Model of Prostate Cancer.

Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising option for metastatic castration-resistant prostate cancer. Clinical experience using 177Lu or 225Ac has demonstrated encouraging treatment responses; however, responses are not durable. Dual-isotope combinations, or "tandem" approaches, may improve tolerability while retaining a high tumor dose. In this study, we directly compared α- versus ß-particle treatment, as well as a combination thereof, at different stages of disease in a murine model of disseminated prostate cancer. Methods: First, to determine comparable injected activities from 177Lu- and 225Ac-PSMA-617, ex vivo biodistribution studies were performed at 5 time points after treatment of C4-2 subcutaneous tumor-bearing NSG mice. To establish a more representative model of metastatic prostate cancer, NSG mice were inoculated with luciferase-expressing C4-2 cells in the left ventricle, leading to disseminated visceral and bone lesions. At either 3 or 5 wk after inoculation, the mice were treated with equivalent tumor dose-depositing activities of 177Lu- or 225Ac-PSMA-617 alone or in combination (35 MBq of 177Lu, 40 kBq of 225Ac, or 17 MBq of 177Lu + 20 kBq 225Ac; 10/group). Disease burden was assessed by weekly bioluminescence imaging. Treatment efficacy was evaluated using whole-body tumor burden and overall survival. Results: The ex vivo biodistribution studies revealed that 35 MBq of 177Lu and 40 kBq of 225Ac yield equivalent absorbed tumor doses in a subcutaneous C4-2 model. The disease burden of mice treated at 3 wk after inoculation (microscopic disease) with 177Lu was not significantly different from that of untreated mice. However, 225Ac-PSMA-617 both as a single agent and in combination with 177Lu (17 MBq of 177Lu + 20 kBq of 225Ac) were associated with significant whole-body tumor growth retardation and survival benefit (overall survival, 8.3 wk for nontreatment, 9.4 wk for 177Lu, 15.3 wk for 225Ac alone, and 14.1 wk for tandem therapy). When treated at 5 wk after inoculation (macroscopic disease), all treatment groups showed retarded tumor growth and improved survival, with no significant differences between 225Ac alone and administration of half the 225Ac activity in tandem with 177Lu (overall survival, 7.9 wk for nontreatment, 10.3 wk for 177Lu, 14.6 wk for 225Ac alone, and 13.2 wk for tandem therapy). Conclusion: Treatment of a disseminated model of prostate cancer with simultaneous 225Ac- and 177Lu-PSMA-617 results in significantly decreased tumor growth compared with 177Lu, which was ineffective as a single agent against microscopic lesions. Mice treated later in the disease progression and bearing macroscopic, millimeter-sized lesions experienced significant tumor growth retardation and survival benefit in both monoisotopic and tandem regimens of 177Lu and 225Ac. Although the greatest benefits were observed with the single agent 225Ac, the tandem arm experienced no significant difference in disease burden or survival benefit, suggesting that the reduced activity of 225Ac was adequately compensated in the tandem arm. The superior therapeutic efficacy of 225Ac in this model suggests a preference for α-emitters alone, or possibly in combination, in the microscopic disease setting.

Novel heterozygous mutation in the SHOX gene leading to familial idiopathic short stature: A case report and literature review.

BACKGROUND: The pathogenic mutation of short stature homeobox (SHOX) gene is one of the main genetic causes of short stature in children, with an incidence rate of 1/1000~1/2000 and the main clinical manifestations are short stature and (or) limb skeletal abnormalities. SHOX gene mutations are mostly large deletions of regulatory sequence genes, while exon mutations are relatively rare. The pathogenic rate of mutations occurring in exon 5 is only 1/50 000~1/100 000. This study reviewed the clinical data of a child with SHOX gene mutation in exon 5, and analyzed the clinical phenotype, pathogenesis, diagnosis, treatment and prognosis of SHOX gene mutation in combination with relevant literature at home and abroad. CASE PRESENTATION: The patient was an 8-year-old girl with a height of 105.2 cm (-4.31 standard deviations). Her sitting height/height ratio was 56.8% (>55.5%), and she exhibited high-arched palate, irregular dentition, micrognathia, short fingers, and a normal growth hormone stimulation test. Whole-exome sequencing was performed, and Sanger sequencing was used for site validation. The sequencing results revealed a heterozygous mutation of c.577G > A in exon 5 of the SHOX gene, inherited from the father. The clinical symptoms of the proband were consistent with the phenotype of short stature idiopathic familial associated with SHOX gene mutations. The father, grandfather, uncle, and sister of the proband all had the c.577G > A heterozygous mutation. Therefore, the clinical diagnosis was childhood short stature caused by SHOX gene defects. The SHOX: c.577G > A mutation is likely to be the genetic etiology of familial idiopathic short stature in this family, and this novel mutation enriches the mutation spectrum of the SHOX gene. CONCLUSION: This is the first case report of familial idiopathic dwarfism caused by mutation at the c.577G > A locus of exon 5 of SHOX gene in the world. This novel mutation enriches the mutation spectrum of the SHOX gene. It is important to emphasize genetic testing, including the SHOX gene, in patients with familial idiopathic short stature and to provide timely growth hormone therapy to individuals with short stature caused by SHOX gene mutations in order to improve their adult height.

Correspondence on "Sex steroid priming for growth hormone stimulation testing in children and adolescents with short stature: A systematic review".

Duncan et al. reviewed the response to growth hormone stimulation testing after priming in peripubertal children. The concern is that there is little research documenting the response to growth hormone treatment in patients with sex hormone primed growth hormone stimulation testing and those unprimed. The controversy about priming or not can be summarized as follows: if one wants to know if the production of growth hormone during puberty will be adequate in terms of peak growth hormone responses then stimulation with priming should be done.

Longitudinal assessment of bone health index as a measure of bone health in short-statured children before and during treatment with recombinant growth hormone.

OBJECTIVES: The aim of our study was the longitudinal assessment of bone health index (BHI) in short-statured children during growth hormone (GH) treatment to estimate changes in their bone health. METHODS: 256 short-statured children (isolated GH deficiency (IGHD) n=121, multiple pituitary hormone deficiency (MPHD) n=49, intrauterine growth retardation (small for gestational age (SGA)) n=52, SHOX (short stature homeobox gene) deficiency n=9, Ullrich Turner syndrome (UTS) n=25) who started with GH between 2010 and 2018 were included. Annual bone ages (Greulich and Pyle, GP) and BHI were, retrospectively, analysed in consecutive radiographs of the left hand (BoneXpert software) from GH therapy start (T0) up to 10 years (T10) thereafter, with T max indicating the individual time point of the last available radiograph. The results are presented as the median (25 %/75 % interquartile ranges, IQR) and statistical analyses were performed using non-parametric tests as appropriate. RESULTS: The BHI standard deviation scores (SDS) were reduced (-0.97, -1.8/-0.3) as bone ages were retarded (-1.6 years, -2.31/-0.97) in all patients before start of GH and were significantly lower in patients with growth hormone deficiency (GHD) (-1.04, -1.85/-0.56; n=170) compared to non-GHD patients (-0.79, -1.56/-0.01; n=86; p=0.022). BHI SDS increased to -0.17 (-1/0.58) after 1 year of GH (T1, 0.5-1.49, p<0.001) and to -0.20 (-1/-0.50, p<0.001) after 5.3 years (T max, 3.45/7.25). CONCLUSIONS: BHI SDS are reduced in treatment-naive short-statured children regardless of their GH status, increase initially with GH treatment while plateauing thereafter, suggesting sustained improved bone health.

Response to growth hormone therapy in ring chromosome 15: Review and evidence from a new case on possible beneficial effect in neurodevelopment.

Type 1 Insulin-like Growth Factor Receptor(IGF1R) plays a fundamental role in normal growth and development. Its disruption is usually characterized by severe intrauterine and postnatal growth retardation, microcephaly and neurodevelopmental delay.The efficacy of recombinant human growth hormone treatment remains a challenge for children with IGF1 resistance and pathogenic mutations of IGF1R, with limited data in patients carrying the most severe form of IGF1R defect, the ring chromosome 15. SUBJECT AND METHOD: We tested a high dose of rhGH in a new patient with ring chromosome 15, as confirmed by karyotype and CGH array. We performed a systematic review, and all published r(15) syndrome cases treated by growth hormone(GH) up to April 2023 were searched, and their response to GH therapy was recorded and summarized. RESULTS: Twelve patients with ring chromosome 15 received GH therapy according to a literature review. We expand the spectrum by the 13th case treated by GH, and we report an impressive improvement in intellectual performance and progressive catch-up growth after 5 and 20 months of follow-up. By introducing our new case in the analysis, the sex ratio was 3:10, and GH therapy was started at the age of 5.5 (3/9.4) (years) for an age of diagnosis of 4.75 (1.3/9.5) (years). The height before GH therapy was -5.1(-5.9/-4.1) SDS. The median duration of treatment was 1.7(0.9/2) (years), with a median height gain of 1(0.3/1.8) SDS and an improvement in growth velocity of 4.1(2.8/5.3) (cm/year). CONCLUSION: GH seems to be effective for r(15) syndrome patients with short stature.

Effective GH Replacement With Somapacitan in Children With GHD: REAL4 2-year Results and After Switch From Daily GH.

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.

Growth hormone treatment in pediatrics: What can we improve?

OBJECTIVES: To analyze the age at which treatment with growth hormone (GH) is started in the different indications approved in our country, as well as to assess the response to it and detect points of improvement. MATERIAL AND METHODS: A descriptive, observational and retrospective study of pediatric patients receiving GH treatment in December 2020 and monitored in the pediatric Endocrinology Unit of a tertiary care hospital. RESULTS: A total of 111 patients (52 females) were included in the study. The mean age at the start of treatment was 6.6 years old, being delayed in all diagnostic groups with respect to what is approved for each indication. The indication for which they most frequently received treatment was GH deficiency (n = 60, 54%). In this diagnostic group, there is a predominance of males (39 boys vs 21 girls, and a significantly greater increase in height z score (greater height SDS) is observed in those with early start of treatment compared to those who start late (greaterheight SDS 0.93 vs 0.6; P < .05). All diagnostic groups presented a greater height SDS and height velocity. No adverse effects were observed in any patient. CONCLUSION: GH treatment is effective and safe for the approved indications. The age of initiation of treatment is a point to improve in all indications, especially in SGA patients. For this, good coordination between primary care pediatricians and pediatric endocrinologists is essential, as well as specific training to identify early signs of different pathologies.

Exercise combined with lysine-inositol vitamin B12 promotes height growth in children with idiopathic short stature.

OBJECTIVE: This study was aimed to systematically determine the effect of exercise combined with lysine-inositol vitamin B12 (VB12) therapy on the height of children with idiopathic short stature (ISS). METHODS: Sixty children with ISS were randomly divided into observation and control groups (N = 30). Each group was given lysine-inositol VB12 oral solution (10 mL bid). Simultaneously, the observation group exercised following the "ISS exercise instruction sheet". The height (H), growth velocity (GV), height standard deviation score (HtSDS) and other indicators were compared after 6 and 12 months of intervention, respectively. After 12 months of intervention, the biochemical indicators of the two groups, together with the correlation between the average days of exercise per week and average minutes of exercise per day, GV and serum growth hormone were analyzed. RESULTS: After 6 and 12 months of treatment, the GV, serum GHRH, GHBP, GH, IGF-1, and IGFBP-3 levels in the observation group were significantly higher than those in the control group, and HtSDS was significantly lower than that in the control group (P<0.01). After 12 months of treatment, the height of the observation group was significantly higher than that of the control group (P<0.05). There was no significant difference in the biochemical indicators between two groups (P>0.05). Average days of exercise per week and average minutes of exercise per day were positively correlated with GV and GHBP levels. Serum GHRH, GH, IGF-1, and IGFBP-3 levels were negatively correlated. Average minutes of exercise per day were negatively correlated with GV and GHBP levels. Serum GHRH, GH, IGF-1, and IGFBP-3 levels were positively correlated. CONCLUSION: Regular and moderate stretching exercises combined with lysine-inositol VB12 can effectively promote height growth of children with ISS, which is clinically safe. The mechanism promotes serum GHRH, GHBP, GH, IGF-1, and IGFBP-3 levels.