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With an increasing understanding of growth hormone deficiency, there has been a growing emphasis on the management of transition growth hormone deficiency (TGHD) in clinical practice. The inadequate diagnosis and treatment of TGHD have been a major clinical concern, leading to the development of relevant guidelines and consensus internationally. This article summarizes the evaluation, diagnosis, treatment, and clinical challenges of TGHD based on these guidelines, consensus, and existing clinical studies, aiming to optimize and further improve the clinical diagnosis, treatment, and management of TGHD.

Clinical and laboratory characteristics but not response to treatment can distinguish children with definite growth hormone deficiency from short stature unresponsive to stimulation tests.

Introduction: It has been proposed that not all children with short stature displaying an inadequate response to tests for growth hormone (GH) secretion truly suffer from GH deficiency (GHD). Only children with a monogenic cause of GHD or an identifiable combined hormonal deficiency or anatomical anomaly in the hypothalamic-pituitary axis should be considered definite GHD (dGHD). The remaining patients can be defined as a separate group of patients, "short stature unresponsive to stimulation tests" (SUS). The aim of this proof-of-concept study, was to assess whether SUS patients treated with rhGH exhibit any differences compared to GHD patients undergoing the same treatment. Methods: Retrospective analysis on 153 consecutive patients with short stature and pathological response to two GH stimulation tests. Patients with dGHD were defined as those with a clear genetic or anatomical hypothalamic-pituitary anomaly, as well as those with combined pituitary hormone deficiencies and those with a known insult to the hypothalamic-pituitary axis (i.e. total brain irradiation) (n=38, 25%); those without any of the previous anomalies were defined as SUS (n=115, 75%). Results: At diagnosis, dGHD and SUS populations did not differ significantly in sex (F 32% vs 28%, p=0.68), age (11.9 vs 12.1, p=0.45), height SDS at diagnosis (-2.2 vs. -2.0, p=0.35) and prevalence of short stature (height <-2 SDS) (56% vs 51%, p=0.45). IGF-1 SDS were significantly lower in dGHD (-2.0 vs -1.3, p<0.01). After 1 year of treatment, the prevalence of short stature was significantly reduced in both groups (31% in dGHD vs. 21% in SUS, p<0.01) without any significant differences between groups (p=0.19), while the increase in IGF-1 SDS for bone age was greater in the dGHD category (+1.9 vs. +1.5, p<0.01), with no further difference in IGF-1 SDS between groups. At the last available follow-up, 59 patients had reached the near adult height (NAH) and underwent retesting for GHD. No differences in NAH were found (-0.3 vs. -0.4 SDS, 0% vs. 4% of short stature). The prevalence of pathological retesting was higher in dGHD (60% vs. 10%, p<0.01) as well as of overweight and obesity (67% vs. 26%). Conclusion: Stimulation tests and the equivalent benefit from rhGH therapy, cannot distinguish between dGHD and SUS populations. In addition, lower IGF-1 concentrations at baseline and their higher increase during treatment in dGHD patients, and the lack of pathological retesting upon reaching NAH in SUS patients, are facts that suggest that deficient GH secretion may not be the cause of short stature in the SUS studied population.

Growth hormone treatment in children with short stature: impact of the diagnosis on parents.

OBJECTIVES: This prospective multicenter study aimed (1) to examine changes in parent-reported health-related quality of life (HRQOL) of children with short stature and the effects of the children's condition on parents themselves within the first year of human growth hormone (hGH) treatment and (2) to predict effects on parents based on main and interaction effects of children's HRQOL and increase in height. METHODS: A total of 110 parents of children aged 4-18 years, diagnosed with idiopathic growth hormone deficiency, small for gestational age, or idiopathic short stature, were recruited from 11 participating German pediatric endocrinologists and asked to fill out the short stature-specific Quality of Life in Short Stature Youth (QoLISSY) Questionnaire before hGH treatment was initiated and one year later. RESULTS: Negative effects of the children's short stature on the parents decrease over time, independent of diagnosis and treatment status. Furthermore, treatment status and height increase moderated the links between children's improved HRQOL as perceived by their parents and decreased caregiving burden. CONCLUSIONS: Based on the children's improved HRQOL and the parent's decrease in caregiving burden, patient-reported outcomes that consider parental and child's perspectives should be considered when deciding on hGH treatment for children.

[Diagnostic significance and considerations of growth hormone stimulation testing and insulin-like growth factor 1 in growth hormone deficiency]. / ç”Ÿé•¿æ¿€ç´ æ¿€å‘è¯•éªŒå’Œèƒ°å²›ç´ æ ·ç”Ÿé•¿å› å­1æ°´å¹³æ£€æµ‹å¯¹ç”Ÿé•¿æ¿€ç´ ç¼ºä¹ç—‡çš„è¯Šæ–­æ„ä¹‰å’Œæ€è€ƒ.

The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis is an essential component of the hypothalamic-pituitary growth hormone axis and plays a crucial role in childhood growth and development. Disruptions and abnormalities in the GH/IGF-1 signaling pathway and its pathways typically manifest as short stature in children. Children with short stature often undergo GH stimulation testing and IGF-1 level measurements to differentiate growth hormone deficiency (GHD) from other causes of growth delay. This article aims to analyze and elucidate the values of GH stimulation testing and IGF-1 measurement, providing reference for the diagnosis of GHD in children.

Evaluation of the growth response of children with growth hormone deficiency according to the peak growth hormone levels in provocation tests.

BACKGROUND: We aimed to evaluate the relation between the peak growth hormone (GH) levels in provocation tests and response to recombinant human GH (rhGH) therapy in patients with GH deficiency (GHD). METHODS: This was a cross-sectional, single-center, and retrospective study. A total of 135 patients under the age of 16 years who were diagnosed with GHD through insulin tolerance tests and L-DOPA stimulation tests and who received rhGH therapy for at least 2 years in the Pediatric Endocrinology Clinic of Akdeniz University Hospital between 1997 and 2021 were included in the study. RESULTS: The patients were divided into two groups: idiopathic GHD (group I, n = 119) and multiple pituitary hormone deficiencies or organic pathology on magnetic resonance imaging (group II, n = 16). The patients in group I were classified into three subgroups according to the peak GH values in the provocation tests (group Ia: peak GH <3 µg/L, n = 34; group Ib: peak GH between 3 and 7 µg/L, n = 71; group Ic: peak GH between 7 and 10 µg/L, n = 34). The median age was 11.5 years in group I (8.8 in group Ia, 12.1 in group Ib, 12.3 in group Ib) and 8.8 years in group II. The height standard deviation score (SDS) was -2.93 in group I (-2.85 in group Ia, -2.99 in group Ib, -2.94 in group Ic) and -3.79 in group II. The median Δheight SDS was 0.61 in group I and 1.05 in group II at the end of the first year of treatment and 0.31 in group I and 0.45 in group II at the end of the second year (p = 0.005 and p = 0.074, respectively). When the subgroups of group I were compared, height SDS, Δheight SDS, and height velocity (HV) SDS were all higher in group Ia at the end of the first year of rhGH therapy (p = 0.040, p = 0.029, and p = 0.005, respectively). The height SDS was still significantly higher in group Ia (p = 0.033) while the HV SDS and Δheight SDS were similar between the groups at the end of the second year of therapy (p = 0.164 and p = 0.522, respectively). There was a statistically significant association between the first-year HV SDS and the peak GH value in provocation tests in multiple regression analyses (p<0.001). In addition, the final model revealed that height SDS and weight SDS at the start of the treatment and the first-year HV SDS are the factors with a statistically significant effect on the second-year HV SDS (p = 0.022, p = 0.001, and p<0.001, respectively). CONCLUSION: Our findings show that the lower the GH peak in provocation tests, the better the response to treatment. The best HV was observed in the first year of rhGH therapy, and the diagnosis should be checked in those patients who had a low first-year HV and did not have a severely low GH peak in provocation tests.

Identifying patient-related predictors of permanent growth hormone deficiency.

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, p<0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, p<0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, p<0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, p<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.

Clinical profile of Laron dwarfism - experience from a tertiary care institute in Chennai.

OBJECTIVES: Laron dwarfism is a rare genetic disorder first reported among Israeli jewish children, subsequently about 350 cases cases have been reported worldwide. We aim to describe the clinical profile of nine children with Laron dwarfism from Institute of Child Health, Chennai. METHODS: Analysis of case records from 2010 to 2018. RESULTS: Male:female ratio is 6:3. Mean age of the children at the time of diagnosis was 3 years. All children were extremely short, and mean height Z score (SD) was -7.7(0.8). All children had characteristic facies with no hypoglycaemic episodes. Microcephaly was present in four children out of which two had developmental delay. Three out of six boys had micropenis. All children had low insulin like growth factor-1 (IGF-1) and high basal growth hormone (GH) with a mean (SD) of 39.6 (11.2) ng/mL. CONCLUSIONS: Suspicion of Laron syndrome should be high when child presents with features of Growth Hormone Deficiency (GHD) with extreme stunting.

Growth hormone responses during arginine and clonidine stimulation test: Correlations with patients' auxological and metabolic parameters in a single centre study.

BACKGROUND: Children with auxological parameters defining a 'short stature' is routinely subjected to various blood tests and, if necessary, to growth hormone stimulation test (GHST) for differentiating GH deficiency (GHD) and other causes of stunted growth. AIM: This retrospective monocentric study aimed to evaluate any correlations between GH peaks during GHST in children assessed for short stature and their auxological/metabolic parameters, highlighting differences between GHD and idiopathic short stature. PATIENTS AND METHODS: We reviewed the medical records of 74 children with short stature (height lower than the third percentile according to standardized growth curves for the Italian population) managed at the Pediatric Day Hospital of our Department of Life Sciences and Public Health in Università Cattolica Sacro Cuore, Rome, who performed at least two GHSTs, using arginine and clonidine as stimulants, for assessment of GH secretion. The results of a total number of 161 GHSTs, performed in 42 children diagnosed with GHD and in 32 children with other causes of short stature, were analyzed. RESULTS: We found significantly lower serum levels of insulin growth factor-1 (IGF-1) and increased levels of thyroid-stimulating hormone (TSH) in children with GHD, without other metabolic differences in comparison to children with other causes of short stature. There was also a correlation between triglycerides and GH peak during arginine test, while fT4 and LDL concentrations correlated with GH peak during the third test, if performed. Pre-test BMI (rho -0.274, p = 0.01) and weight (rho -0.251, p = 0.03) have influenced GH peak during clonidine stimulation test. Metabolic and auxological parameters could influence GH peak during clonidine and arginine stimulation tests and must be taken into account when interpreting GHST results.

Growth hormone deficiency in a case of septo-optic-dysplasia due to SOX2 mutation: should we re-test patients during the transition period?

Gene mutations encoding transcription factors, including SOX2, have been associated with growth hormone deficiency (GHD) and abnormal pituitary development. Guidelines on GHD management in the transition period state that patients with genetic-based childhood-onset GHD can skip retesting due to a high likelihood of permanent GHD. We describe a case of septo-optic-dysplasia due to SOX2 mutation characterised by childhood-onset GHD, which showed a normal somatotropic function at the transition period. This case raises the opportunity to retest for GHD during the transition period, even in patients with a known genetic cause, in order to avoid inappropriate GH treatment.

Sex steroid priming in short stature children unresponsive to GH stimulation tests: Why, who, when and how.

Despite decades of experience, the diagnosis of growth hormone deficiency (GHD) remains challenging, especially in peripubertal children. Failure to respond to GH stimulation tests (GHSTs) is needed to confirm GHD, but long-standing controversies regarding the number of tests needed and the interpretation of GH peaks are still a matter of debate worldwide. Diagnostic workup is even more problematic in short children with slow growth and delayed sexual development: they often exhibit low GH peaks under GHST, which often normalize as puberty progresses. Consequently, this transient suboptimal response to GHST may result in GH overtreatment, carrying both health and economic concerns. Considering the complex and bound link between GH axis and sex steroids, the use of sex steroid priming prior to GHST might be helpful in peripubertal setting. However, its use is still controversial. There is no consensus regarding patient selection, timing, dose, and preparation of sex steroids. In this review, we aim to overview the use of sex steroid priming in clinical practice, highlighting the need to develop appropriate guidelines in order to overcome diagnostic pitfalls in peripubertal age.

Somapacitan: a long-acting growth hormone derivative for treatment of growth hormone deficiency.

Growth hormone deficiency (GHD) is characterized by inadequate HG production from the anterior pituitary gland. Adult patients with GHD have increased fat mass, an abnormal lipid profile, decreased lean body mass and bone mineral density, decreased muscle strength and exercise endurance, and a diminished quality of life. Adult GHD (AGHD) has been treated with GH replacement therapy by daily subcutaneous injections. However, the administration of daily injections can be burdensome for some patients and affect treatment adherence. Somapacitan is a new long-acting human GH (hGH) analogue that is administered once a week by subcutaneous injection. It was first approved by the U.S. Food and Drug Administration (FDA) as GH replacement therapy for adults with GHD, becoming the first hGH therapy for AGHD administered by once-weekly injection, compared with other approved hGH therapies for AGHD administered by daily injection. This article reviews the pharmacokinetic, clinical and safety data that led to the approval of somapacitan as the first long-acting GH therapy for adults with GHD.

Skeletal and dental age discrepancy and occlusal traits in children with growth hormone deficiency and idiopathic short stature.

OBJECTIVES: The aim of the study was to evaluate the dental and bone age delay and occlusal traits of children with growth hormone deficiency (GHD) and idiopathic short stature (ISS). MATERIAL AND METHODS: The study group included 46 patients aged 5 to 14 years: 15 with ISS, 17 with GHD before growth hormone treatment, and 14 with GHD during substitution therapy. The control group consisted of 46 age and sex-matched subjects of normal height. A calibrated dentist assessed all subjects in terms of dental age and occlusal characteristics. Bone age was evaluated only in GHD and ISS children as a part of a hospital's diagnostic protocol. RESULTS: The subgroup of GHD before treatment differed significantly concerning dental age delay from their healthy peers (- 0.34 and 0.83 year, respectively, p = 0.039). Dental age delay in short stature children was less marked than bone age delay (- 0.12 and - 1.76, respectively, p < 0.00001). Dental crowding was recorded in 57% of ISS patients and 53% of GHD children before treatment compared to only 22% of the control subjects (p = 0.027 and p = 0.021, respectively). CONCLUSIONS: Dental age was retarded in GHD children before growth hormone (GH) therapy, but the delay does not seem clinically significant. ISS children and GHD children before therapy showed marked bone age delay and tendency to crowding. CLINICAL RELEVANCE: The different pace of teeth eruption and skeletal growth in short stature children should be considered when planning their dental treatment.

The landscape of retesting in childhood-onset idiopathic growth hormone deficiency and its reversibility: a systematic review and meta-analysis.

Objective: Children diagnosed with idiopathic isolated growth hormone deficiency (IGHD) are frequently observed to no longer be GH-deficient at a later stage of growth as a result of 'GHD reversal'. Reevaluation of GH status by stimulation test is currently incorporated into management guidelines at attainment of final height (FH). Over the past three decades, numerous studies have evaluated reversal rates using different methodologies including crucial parameters like GHD aetiology, GH cut-off and retesting time point, with heterogeneous results. We aimed to systematically analyse the reversibility of childhood-onset IGHD dependent on retesting GH cut-offs and retesting time points. Methods: PubMed, Cochrane Library, TRIP database and NHS Evidence were searched for publications investigating the reversibility of IGHD from database initiation to 30 June 2020 following PRISMA recommendations. Study cohorts were pooled according to retesting GH cut-off and time point. Reversal rates were calculated using random-effects models. Results: Of the 29 studies initially identified, 25 provided sufficient detail for IGHD analysis, resulting in 2030 IGHD patient data. Reversal rates decreased significantly as the retesting GH cut-off increased (P = 0.0013). Pooled (95% CI) reversal rates were 80% (59-92%, n = 227), 73% (62-81%, n = 516) and 55% (41-68%, n = 1287) for cohorts using retesting GH cut-offs of 3-4 ng/mL, 5-6 ng/mL and 7.7-10 ng/mL, respectively. Individuals retested at FH (n = 674) showed a pooled reversal rate of 74% (64-82%) compared to 48% (25-71%) when retested before FH (n = 653). Conclusion: Provided evidence supports reevaluation of current IGHD management guidelines. The high reversal rates should instigate consideration of early retesting.

Growth Hormone Stimulation Testing: To Test or Not to Test? That Is One of the Questions.

The evaluation of children with short stature includes monitoring over a prolonged period to establish a growth pattern as well as the exclusion of chronic medical conditions that affect growth. After a period of monitoring, evaluation, and screening, growth hormone stimulation testing is considered when the diagnosis of growth hormone deficiency (GHD) is entertained. Though flawed, growth hormone stimulation tests remain part of the comprehensive evaluation of growth and are essential for the diagnosis of growth hormone (GH) deficiency. Variables including testing length, growth hormone assay and diagnostic cut off affect results. Beyond the intrinsic issues of testing, results of GH stimulation testing can be influenced by patient characteristics. Various factors including age, gender, puberty, nutritional status and body weight modulate the secretion of GH.

Isolated childhood growth hormone deficiency: a 30-year experience on final height and a new prediction model.

PURPOSE: We aimed to evaluate the near-final height (nFHt) in a large cohort of pediatricpatients with growth hormone deficiency (GHD) and to elaborate a new predictive method of nFHt. METHODS: We recruited GHD patients diagnosed between 1987 and 2014 and followed-up until nFHt. To predict the values of nFHt, each predictor was run in a univariable spline. RESULTS: We enrolled 1051 patients. Pre-treatment height was -2.43 SDS, lower than parental height (THt) (-1.09 SDS, p < 0.001). The dose of recombinant human GH (rhGH) was 0.21mg/kg/week at start of treatment. nFHt was -1.08 SDS (height gain 1.27 SDS), higher than pre-treatment height (p < 0.001) and comparable to THt. 1.6% of the patients were shorter than -2 SDS from THt. The rhGH dose at nFHt was 0.19 mg/kg/week, lower than at the start (p < 0.001). The polynomial regression showed that nFHt was affected by gender, THt, age at puberty, height at puberty, age at the end of treatment (F = 325.37, p < 0.0001, R2 87.2%). CONCLUSION: This large national study shows that GHD children can reach their THt. The rhGH/kg/day dose significantly decreased from the start to the end of the treatment. Our model suggests the importance of a timely diagnosis, possibly before puberty, the beneficial effect of long-term treatment with rhGH, and the key-role of THt. Our prediction model has a very acceptable error compared to the majority of other published studies.

Diagnosis of GH Deficiency Without GH Stimulation Tests.

Growth hormone deficiency (GHD) is the most commonly affected pituitary hormone in childhood with a prevalence of 1 in 4000-10000 live births. GH stimulation testing (GHST) is commonly used in the diagnostic workup of GHD. However, GHD can be diagnosed in some clinical conditions without the need of GHST. The diagnosis of GHD in newborns does not require stimulation testing. Likewise infants/children with delayed growth and/or short stature associated with neuroradiological abnormalities and one or more additional pituitary hormone deficiencies may not need GHST. This review summarizes the current evidence on the diagnosis of GHD without stimulation tests.

Isolated growth hormone deficiency in children with vertically transmitted short stature: What do the genes tell us?

Introduction: The growth hormone deficiency (GHD) diagnosis is controversial especially due to low specificity of growth hormone (GH) stimulation tests. It is therefore believed that children diagnosed with GHD form a heterogeneous group with growth disorder frequently independent on GH function. No study evaluating the complex etiology of growth failure in children with diagnosed GHD has been performed thus far. Aims: To discover genetic etiology of short stature in children with diagnosed GHD from families with short stature. Methods: Fifty-two children diagnosed with primary GHD and vertically transmitted short stature (height SDS in the child and his/her shorter parent <-2 SD) were included to our study. The GHD diagnosis was based on growth data suggestive of GHD, absence of substantial disproportionality (sitting height to total height ratio <-2 SD or >+2 SD), IGF-1 levels <0 for age and sex specific SD and peak GH concentration <10 ug/L in two stimulation tests. All children were examined using next-generation sequencing methods, and the genetic variants were subsequently evaluated by American College of Medical Genetics standards and guidelines. Results: The age of children at enrollment into the study was 11 years (median, IQR 9-14 years), their height prior to GH treatment was -3.0 SD (-3.6 to -2.8 SD), IGF-1 concentration -1.4 SD (-2.0 to -1.1 SD), and maximal stimulated GH 6.3 ug/L (4.8-7.6 ug/L). No child had multiple pituitary hormone deficiency or a midbrain region pathology. Causative variant in a gene that affects growth was discovered in 15/52 (29%) children. Of them, only 2 (13%) had a genetic variant affecting GH secretion or function (GHSR and OTX2). Interestingly, in 10 (67%) children we discovered a primary growth plate disorder (ACAN, COL1A2, COL11A1, COL2A1, EXT2, FGFR3, NF1, NPR2, PTPN11 [2x]), in one (7%) a genetic variant impairing IGF-1 action (IGFALS) and in two (12%) a variant in miscellaneous genes (SALL4, MBTPS2). Conclusions: In children with vertically transmitted short stature, genetic results frequently did not correspond with the clinical diagnosis of GH deficiency. These results underline the doubtful reliability of methods standardly used to diagnose GH deficiency.