Growth Hormone Stimulation Tests Research Articles

Growth Hormone Therapy in a Child with Fetal Alcohol Syndrome: Personal Experience with Literature Review

Introduction: Fetal alcohol syndrome (FAS) is associated with a positive maternal history of drinking during pregnancy and the presence of characteristic dysmorphic features due to alcohol teratogenic effect. No evidence is yet available regarding the use of growth hormone (GH) for children with FAS for whom GH deficiency has not been confirmed. Case Presentation: We have highlighted an improvement in auxological parameters of a child with FAS and normal GH stimulation tests, using a GH dosage similar to that used in idiopathic GH deficit, without side effects. Conclusion: GH therapy in children with FAS may lead to an improvement in growth rate and an increase in final height, although, this condition is not included in the specific recommendations for use of GH. Prolonged follow-up and prospective studies are needed to evaluate long-term efficacy and monitor any possible onset of side effects.

Contribution of GH stimulation tests in the exploration of growth hormone deficiency in children

Contribution of GH stimulation tests in the exploration of growth hormone deficiency in children

Once upon a time: the glucagon stimulation test in diagnosing adult GH deficiency.

The clinical features of adult GH deficiency (GHD) are nonspecific, and its diagnosis is established through GH stimulation testing, which is often complex, expensive, time-consuming and may be associated with adverse side effects. Moreover, diagnosing adult GHD can be challenging due to the influence of age, gender, and body mass index on GH peak at each test. The insulin tolerance test (ITT), GHRH + arginine test, glucagon stimulation test (GST), and, more recently, testing with macimorelin are all recognized as useful in diagnosing adult GHD. To date GST is still little used, but due to the unavailability of the GHRH all over the world and the high cost of macimorelin, in the next future it will probably become the most widely used test when ITT is contraindicated. The aim of the present review is to describe the current knowledge on GST. Narrative review. In the last years several studies have suggested some changes in the original GST protocol and have questioned its diagnostic accuracy when the classic GH cut-point of 3 μg/L is used, suggesting to use a lower GH cut-point to improve its sensitivity and specificity in overweight/obese patients and in those with lower pretest GHD probability. This document provides an update on the utility of GST, summarizes how to perform the test, shows which cut-points should be used in interpreting the results, and discusses its drawbacks and caveats referring to the most recent studies.

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

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. 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%). 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%). 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.

Pragmatic Evaluation of Growth Hormone Stimulation Tests in Short Stature

Abstract Introduction: To assess the performance of growth hormone stimulation tests (GHSTs) in the evaluation of short stature. Methods: It was a single-centre retrospective study carried out in children evaluated for short stature between January 2005 to March 2020. The clonidine stimulation test (CST) and glucagon stimulation test (GST) were used to assess growth hormone (GH) reserve (GST was performed only when peak GH levels were between 5 to ≤10 ng/mL on CST). A GH level of &lt;5 ng/mL on CST or ≤10 ng/ml on both was used to corroborate GH deficiency. Results: A total of 556 children were eligible for this study. The mean (SD) age was 12.9 (3.5) years, and 66.3% were male. The peak GH level [median (IQR)] was 5.50 ng/ml (1.90 – 7.50) on CST (at 60 minutes) and 7.45 ng/ml (2.15 – 10.77) on GST (at 120 minutes). On restricting sampling to two time points, the false positive rate was 13.6% on CST (60, 90 minutes) and 11.5% on GST (120, 150 minutes). Similarly, restricting to three time points was associated with a false positive rate of 8.5% on CST (60, 90, 120 minutes) and 3.8% on GST (90, 120, 150 minutes). Using the treating clinician-determined diagnosis of GHD as a reference standard, the optimal cut-off of peak GH on CST was 7.79 ng/ml (sensitivity: 83.8%; specificity: 89.4%). Conclusion: Restricting the GH sampling to fewer time points is associated with an increase in the false positivity rate (FPR).

Changes in FeNO, d-ROMs, and BH4 by Intravenous L-Arginine in Children and Its Putative Role in Asthma Treatment.

Pteridines are metabolites of tetrahydrobiopterin (BH4), being coenzymes for nitric oxide synthase (NOS). No study has clarified the relationship among pteridines and NOS, fractional exhaled nitric oxide (FeNO) generated by pteridines, and reactive oxygen species. In this study, we administered arginine, a precursor of NO, and confirmed changes in the levels of pteridines, FeNO, and reactive oxygen species and their relationship to clarify the pathogenesis of airway inflammation in which oxidative stress is involved, such as bronchial asthma. This is a prospective, randomized open-label study. Children, aged 2 to 15 years, who were scheduled for growth hormone stimulation tests and were able to undergo a respiratory function test were recruited. They were randomly divided into two groups: arginine-administered and control groups. In the former, L-arginine hydrochloride was intravenously administered. After administration, the levels of diacron-reactive oxygen metabolites (d-ROMs), serum pteridines, serum amino acids, and fractional exhaled NO (FeNO) were measured. We analyzed 15 children aged 4 to 14 years. In the arginine-administered group, there was an increase in the FeNO level and a decrease in the d-ROMs level, reaching a peak 30 min after administration, compared with the control group. In addition, there was a decrease in the serum biopterin level and an increase in the d-ROMs level, reaching peak 60 min after administration. The administration of L-arginine increased the NO level and decreased the d-ROMs level. Due to this, biopterin may be consumed and decreased, leading to an increase in the d-ROMs level. As a reduction in reactive oxygen species leads to the relief of inflammation, arginine and biopterin may be useful for inhibiting inflammation.

Auxological, Clinical, and MRI Abnormalities in Pediatric Patients With Isolated Growth Hormone Deficiency.

This study aimed to assess the auxological, clinical, and MRI features of pediatric patients with isolated growth hormone deficiency (GHD) by analyzing the demographic and clinical characteristics of the study cohort. A cohort of 115 pediatric patients diagnosed with isolatedGHD was included. The patients were evaluated at a tertiary center in Jeddah, Saudi Arabia. Collected data included demographic information and auxological evaluations, such as height standard deviation (SD), height centile, weight SD, weight centile, and bone age SD. Neuroradiological assessments, particularly magnetic resonance imaging (MRI) of the hypothalamic-pituitary region, were collectedto identify any structural abnormalities contributing to GHD. A total of 67 (SD 58.3) were males. The mean age was 9.55 years (SD 3.45). The mean bone age was 7.37 years (SD 3.24), indicating delayed bone development. Height measurements reflected a significant growth impairment, with a mean height SD of -2.45 (SD 1.12). Out of the 115 pediatric patients in the study cohort, 84 (73%) underwent neuroradiological assessments using brain MRI. Among these, 12% were found to have MRI abnormalities. The prevalence of MRI abnormality in the subgroup with severe growth hormone deficiency was higher, reaching 21%. The peak growth hormone (GH) in the growth hormone stimulation test was 6.38 ng/mL (SD 3.24). There was a significant difference in the peak GH levels between the subgroup of patients with normal MRI findings (mean 6.02 ng/mL, SD 2.47) and those with abnormal MRI findings (mean 3.2 ng/mL, SD 2.8) (p=0.01). Children with isolated GHD exhibited significant growth impairment and clinical characteristics consistent with thedisorder. Neuroradiological abnormalities are common among patients with severe growth hormone deficiency; therefore, radiological assessment including MRI of the pituitary gland is recommended in patients with severe isolated growth hormone deficiency.

Clinical, genetic profile and therapy evaluation of 11 Chinese pediatric patients with Fanconi-Bickel syndrome

BackgroundFanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction.MethodsClinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed.ResultsHepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3−) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3− and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from − 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient.ConclusionsEarly diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.

Evolving growth hormone deficiency: proof of concept.

We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST). We performed a retrospective chart review of children who presented for short stature (height less < 2SD for mean/mid-parental height) and/or growth failure (sustained growth velocity < 0 SD) to pediatric endocrinology at Mount Sinai Kravis Children's Hospital, New York and who had 2 GSTs. Data collected from electronic medical records were analyzed using SPSS v28.0. Of 53 patients included, 42 were males. Average GH peak on initial GST was 15.48 ± 4.92 ng/ml, at 10.07 ± 2.65 years, mean height -1.68 ± 0.56SD(28% had <2SD), IGF-1 -1.00 ± 0.88SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height SDs decreased to -1.82 ± 0.63SD and IGF-1 was -1.08 ± 0.84SD. At repeat GST, average GH peak was 7.59 ± 2.12 ng/dL, with 36% ≤7 ng/dl and 32% in puberty. 12 males reached adult height of 0.08 ± 0.69 SD with a mean height gain of 1.83 ± 0.56SD(p<0.005), IGF-1 of -1.15 ± 0.81SD after 4.64 ± 1.4 years of GH. We offer evidence for Evolving Growth Hormone Deficiency (EGHD) through repeat GST in children with persistent growth slowdown, even with pubertal progression; emphasizing the need for careful longitudinal follow-up to make accurate diagnosis.

Diagnostic significance and considerations of growth hormone stimulation testing and insulin-like growth factor 1 in growth hormone deficiency

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.

Very elevated serum copeptin concentrations occur in a subset of healthy children in the minutes after phlebotomy.

Although AVP and its surrogate, copeptin, are mainly regulated by osmotic and volume stimuli, their secretion is also elicited by stress and growth hormone (GH) stimulating agents. The aim of this report is to describe unusual patterns of copeptin response in a subset of children undergoing GH stimulation tests (GH-ST). We conducted a secondary analysis of a cohort of 93 healthy short children with no polydipsia, polyuria or fluid/electrolyte abnormalities, undergoing GH-ST with intravenous arginine, insulin, oral clonidine, or L-Dopa/carbidopa in various combinations. Serum copeptin concentrations were measured 1-3 min after phlebotomy (0 min) and at 60, 90, 120 min during GH-ST. In 85 subjects (normal response group, NRG) serum copeptin concentrations increased from a 0 min median of 9 pmol/L (IQR 6, 11.5) (all values≤21) to a median peak between 60 and 120 min of 22 (IQR15, 38) pmol/L, which varied depending on the stimulating agent. Conversely, in the eight outliers, copeptin concentrations decreased gradually from a median of 154 (IQR 61, 439) pmol/L (all≥40 pmol/L) to values as low as 14 % of the basal value, by 120 min. Test-associated anxiety was described in 17 subjects in the NRG (20 %) and five of the outliers (63 %). A distinctive pattern of very elevated serum copeptin concentrations occurred in 9 % of children undergoing GH-ST, similar to reports in previous pediatric studies. Etiology may include pain or stress of phlebotomy. This phenomenon should be recognized for proper interpretation of copeptin values in children.

The influence of pituitary volume on the growth response in growth hormone-treated children with growth hormone deficiency or idiopathic short stature.

Magnetic resonance imaging (MRI) can be used for assessing the morphology of the pituitary gland in children with short stature. The purposes of this study were: (1) to determine if pituitary volume (PV) can distinguish patients with growth hormone (GH) deficiency from those with idiopathic short stature (ISS), (2) to validate an association between PV and severity of GH deficiency, and (3) to compare PV between good and poor response groups in children with GH deficiency or ISS after 1 year of treatment. Data were collected from the medical records of 152 children with GH deficiency or ISS who underwent GH stimulation test, sella MRI, and GH treatment for at least 1 year. Estimated PVs were calculated using the formula of an ellipsoid. We compared the PVs in patients with GH deficiency with those of patients with ISS. In addition, we assessed the association between PV and severity of GH deficiency, and we assessed growth response after treatment. No difference was observed in PV between patients with GH deficiency and those with ISS. The severity of the GH deficiency seemed to be associated with PV (P=0.082), and the height of the pituitary gland was associated with severity of GH deficiency (P<0.005). The PV in the good response group was less than that of the poor response group in patients with GH deficiency (P<0.005), and PV showed no association with responsiveness to GH treatment in patients with ISS (P=0.073). The measurement of PV cannot be used for differential diagnosis between GH deficiency and ISS. In patients with GH deficiency, PV tended to be smaller as the severity of GH deficiency increased, but the difference was not significant. PV may be a good response predictor for GH treatment. Further studies, including a radiomics-based approach, will be helpful in elucidating the clinical implications of pituitary morphology in patients with short stature.

Evaluation of the Relationship Between Peak Growth Hormone Response to Growth Hormone Stimulation Tests and Body Mass Index

Objective: A contrary relationship between body mass index (BMI) and growth hormone (GH) secretion has been demonstrated in adults. BMI-specific cutoff levels are suggested for identifying growth hormone deficiency (GHD) in adulthood. However, specific values for BMI and growth hormone stimulation test responses in the childhood age group are not certain. In this research, our purpose was to investigate the relationship between GH peak response and BMI in children who underwent GHST with a pre-diagnosis of GHD. Material and Methods: This was a retrospective study of stimulative GH testing with clonidine and L-dopa performed in 150 children 2–18 year-old with short stature (&lt; -2 SDS) in the Pediatric Endocrinology Unit at Bakırçay University Çiğli Training and Research Hospital from the years of 2018 to 2023. Anthropometric measurements, insulin-like growth factor-1 (IGF-I) and IGFBP- 3 levels, especially peak-stimulated GH, were evaluated. Results: A total of 150 patients [98 boys (65.3%) and 52 girls (34.7%)] were included in the study. The mean age of the individuals during testing was 10.26 ± 3.37 years, mean height standard deviation score (SDS) was -2.64 ± 0.89, mean weight SDS was -1.85 ± 1.01 and mean body mass index (BMI) SDS was -0.47 ± 1.07. Ninety-two of the patients (63%) were prepubertal. The mean value for maximum growth hormone serum level (GHmax) clonidine collected during the growth hormone stimulation test was 4.46 ± 2.83 ng/mL, while the mean value in L-dopa test was 3.29 ± 2.57 ng/mL. There was no statistical distinction in terms of both test responses. The correlation between peak GH and BMI-SDS, in terms of clonidine and L-dopa tests, was significantly negative [β = -0.257 (p = 0.010), β = -0.283 (p = 0.004), respectively]. Age, gender and puberty were not significantly associated with peak GH value. In terms of L-dopa peak GH level, the GH level in group 4 (&gt;1 SDS) was revealed to be statistically lower than that in group 1 (&lt; -1 SDS), nevertheless, similar relationship was not detected for clonidine. Conclusion: In our study, a negative correlation was found between GHmax and BMI-SDS in terms of clonidine and L-dopa tests. Therefore, keeping BMI-SDS in mind when evaluating growth hormone stimulation tests performed in short children may be guiding. Still, future studies are needed to make it a determining factor when deciding on treatment.

FRI598 Evolving Growth Hormone Deficiency: A Proof Of Concept

Abstract Disclosure: S. Chimatapu: None. S. Sethuram: None. J. Samuels: None. M. Savage: None. R. Rapaport: None. Introduction: Most cases of growth hormone deficiency (GHD) in pediatric patients are idiopathic, isolated and acquired. All acquired conditions commence with a period during which the diagnosis maybe unapparent. We document here evidence for evolution of GHD in a group of adolescent males who tested sufficient on initial GH stimulation test (GST) but tested deficient upon reevaluation. The rationale for repeat GST was ongoing growth failure. Hypothesis: We hypothesize that GHD in some individuals evolves with time and can be diagnosed by repeat testing (EGHD). We also postulate that their response to GH therapy is similar to other patients with GHD. Methods: We performed an IRB-approved retrospective chart review of children who presented for short stature (height less &amp;lt; 2SD for mean or &amp;lt; 2SD for mid-parental height) to pediatric endocrinology at Kravis Children’s Hospital at Mount Sinai, New York and who had 2 GST. GST were performed using two different stimuli (arginine and glucagon) and highly sensitive assay serum GH measurements were processed by the same laboratory, Esoterix. No patient had obesity, chronic illnesses, or any genetic conditions affecting growth. Data were collected from electronic medical records and analyzed using SPSS v28.0 once at least half the population studied reached adult height. We defined adult height as bone age ≥ 16 years and growth velocity ≤ 2 cm/year. Results: Of 42 charts analyzed, all male, 25 had EGHD. Their average GH peak on initial GST was 15.48 ± 4.92 ng/ml, mean age 10.07 ± 2.65 years, mean height -1.68 ± 0.56 SD , IGF-1 -1.00 ± 0.88 SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height decreased to -1.82 ± 0.63 SD and IGF-1 was -1.08 ± 0.84 SD. At repeat GST, GH peak was 7.59 ± 2.12 ng/mL and 28% were in puberty. All patients had MRI before starting GH therapy; 40% had small anterior pituitary glands. 12 males who reached adult height had a height of -1.88 ± 0.64 SD, IGF-1 of -1.15 ± 0.81 SD, with 42% pubertal and peak GH of 7.33 ± 2.47 ng/mL at repeat GST. They had a mean height gain of 1.83 ± 0.56 SD(p&amp;lt;0.005), with an adult height of 0.09 ± 0.70 SD after 4.64 ± 1.4years of treatment. They were 2.10 ± 4.20 cm taller than their mid-parental target heights. Discussion/Conclusions: We provide proof of concept for the diagnosis of EGHD. The diagnosis could be established by repeat GST in children with ongoing growth deceleration despite pubertal progression and a non-diagnostic initial GST. Our patients who reached adult height had a height gain consistent with that reported by KIGS for patients with growth hormone deficiency (1.7SD; Cutfield,1999) and indeed better than patients with ISS (0.7SD; Maghnie,2022). Presentation: Friday, June 16, 2023

THU176 Identification Of IGF1R Gene Variants In Short Children Born Small For Gestational Age

Abstract Disclosure: E. Kwon: None. M. Kang: None. I. Hwang: None. Introduction: In short stature children born small for gestational age (SGA-SS), IGF1R gene is one of important candidate genes in catch-up failure. Various deletions and single nucleotide variants of IGF1R have been reported. In this study, we aimed to find the prevalence of IGF1R gene mutation and to analyze their clinical characteristics. Method: Short stature children who met the following criteria were included: 1) Birth weight ≤ 10 percentile, and 2) Height at initial visit ≤ 3 percentile, and 3) IGF-1 SDS &amp;gt; 0 or Height z-score &amp;lt; -2.5. Calculations of IGF-1 SDS and birth weight SDS were based on previous reports (Clin chem 2012;45:16-21 and Ann Pediatr Endocrinol Metab 2014;19:146-153, respectively). Deletions were detected using SALSA MLPA probemix kit P217-B2 IGF1R (MRC Holland, Amsterdam, the Netherlands) and single nucleotide variants were analyzed by sanger sequencing of whole exon (#21) and exon-intron boundaries. Results: Mean age, birth weight SDS, height z-score, and BMI z-score of total 65 subjects were 8.0 years, -1.88, -2.83, and -0.52, respectively. Number of subjects whose birth weight ≤ 3 percentile was 25. Maximal value of IGF-1 SDS was 1.45. Family history of parental short stature (≤ 3 percentile) was found in 18 subjects. Growth hormone stimulation test was undergone in 64 subjects. Peak GH level was 1.35-41.74 ng/mL and 25 subjects had peak GH level &amp;lt; 10 ng/mL. A heterozygous deletion in 15q26.2q26.3 was found in one subject. She was 6.6 years old and her height z-score, BMI z-score, and birth weight SDS were -4.22, 2.36, and -3.23, respectively. She had no family history of parental short stature and her serum levels of peak GH was 3.72 ng/mL and IGF-1 SDS was -0.66. Conclusion: In this study, the prevalence of IGF1R mutation was 1.5% (1/65 subjects). Although clinical characteristics of SGA-SS subjects are various and heterogenous, IGF1-IGF1R axis is an important mechanism in SGA-SS, therefore, further investigation is needed. Presentation: Thursday, June 15, 2023

THU131 Functional Hypogonadotropic Hypogonadism And Failure To Thrive In A Poorly Controlled Type 1 Diabetes Patient

Abstract Disclosure: P. Rakhra: None. V. Wright: None. I. Athanassaki: None. Background: Multiple reports exist of obese males with type 2 diabetes linked to hypogonadotropic hypogonadism. We report a rare case of poorly controlled type 1 diabetes leading to functional hypogonadotropic hypogonadism as well as failure to thrive. Clinical Case: A 16-year-old Caucasian male with type 1 diabetes, antibody positive, diagnosed at 3 years of age presented in severe diabetic ketoacidosis. Patient had been lost to follow-up and had not had a clinic visit in over three years. He had reportedly been using a family member’s Tresiba and over the counter Humulin in the interim. Upon presentation, his hemoglobin A1c was found to be 11.8%. It was last documented at greater than 14%. He was also at less than the first percentile for height and weight, with a BMI of 16 kg/m2. His mid-parental height was 68.5 inches (25 – 50th percentile). His physical exam was remarkable for Tanner III pubic hair with 12 cc testicular volume bilaterally. Biochemical analysis revealed LH was in pubertal range of 0.5 mIU/mL (0.2 – 2.3 mIU/mL), low FSH &amp;lt;0.7 mIU/mL (0.7 – 6.2 mIU/mL), and low testosterone 7.7 ng/dL (200 – 1036 ng/dL). IGF-1 was low at 49 ng/mL (230 – 769 ng/mL) and low IGF-BP3 at 2.6 mg/L (3.1 – 8.9 mg/L). Bone age per the standards of Greulich and Pyle was delayed at 14 years with a predicted adult height of 68 inches. Associated conditions known to cause failure to thrive in patients with diabetes, such as adrenal insufficiency, hyperthyroidism, and celiac disease were ruled out. ACTH stimulation test revealed cortisol peak of 24.6 ug/dL (&amp;gt;18.0 ug/dL). TSH was normal 2.474 mIU/mL (0.5 – 3.4 mIU/mL) and normal Free T4 0.8 ng/dL (0.8 – 2 ng/dL). Mauriac syndrome was considered however, patient lacked any Cushingoid features, did not have hepatomegaly on exam, and had normal liver function tests. A brain/pituitary MRI was performed prior to discharge and was found to be normal, ruling out concerns for a central lesion causing delayed puberty. Patient was able to gain weight during the admission with intensive insulin management. However, he remains less than the first percentile for height and weight. A growth hormone stimulation test (with clonidine and arginine) was performed outpatient. Patient was primed with estrace prior to the test and results revealed a peak of 15.0 ng/mL (&amp;gt;10 ng/mL) ruling out concerns for growth hormone deficiency. Conclusion: We report this case to highlight that although uncommon in the developed world, delayed puberty and growth failure are known but rare complications of poorly controlled type 1 diabetes. Presentation: Thursday, June 15, 2023

THU243 Fitting Together The Pieces Of The Puzzle Between Isolated ACTH Deficiency And Immunodeficiency: DAVID Syndrome

Abstract Disclosure: K.V. Buchanan: None. A.C. Hurst: None. A.P. Ashraf: None. Objectives: DAVID syndrome is a rare genetic disorder with common variable immunodeficiency (CVID) and anterior pituitary hormonal deficiencies due to a pathogenic variant in NFKB2. We aim to describe asymptomatic ACTH deficiency identified after the diagnosis of CVID in a patient with DAVID syndrome. Methods: A retrospective chart review of a patient with DAVID syndrome was performed. Results: The patient is a 15 year and 9-month-old female with weight in the 71st percentile and height in the 64th percentile, who was diagnosed with DAVID syndrome at 10 years through a Primary Immunodeficiency panel which identified a pathogenic variant in NFKB2 c.2557C&amp;gt;T,p.Arg853* and a variant of unknown significance in STAT2 c.1301C&amp;gt;T (p.Thr434Met). The panel was performed due to the patient’s history of recurrent sinus infections, hypogammaglobulinemia, and alopecia totalis. The patient did not have symptoms of ACTH deficiency including hypoglycemia and hypotension. After the genetic diagnosis was made, an anterior pituitary hormone evaluation was performed which showed an ACTH &amp;lt;5 pg/ml, AM cortisol &amp;lt;0.2 mcg/dL, TSH 3.48 uIU/ml, FT4 0.82 ng/dL, thyroid peroxidase antibody 29 IU/mL (normal &amp;lt;9), somatomedin-c 44 ng/mL (reference range 152-593), LH 5.36 mIU/mL, and FSH 14.25 mIU/mL. Adrenal insufficiency was diagnosed since the patient did not show incremental cortisol response (serum cortisol &amp;lt;0.2 mcg/dL at 30 and 60 minutes) post Cosyntropin stimulation test. The patient had normal electrolytes. Hydrocortisone replacement therapy was initiated. A growth hormone stimulation test was not performed since the patient had normal height and interval height velocity. The thyroid function remained stable, and the patient attained menarche at age 14. Conclusions: This patient is unique in having asymptomatic, acquired, isolated ACTH deficiency diagnosed in later childhood, despite having frequent sinopulmonary infections since infancy as part of DAVID syndrome. Further research needs to be done to elucidate how NFKB2 variants contribute to acquired, isolated, central ACTH deficiency or autoimmune pituitary disease. Presentation: Thursday, June 15, 2023

THU170 Clinical And Immunological Response To Somatrogon In Two Siblings With A Homozygous Whole Gene Deletion Of The Growth Hormone 1 Gene

Abstract Disclosure: R. Gupta: None. R. Khadgawat: None. R.G. Rosenfeld: Advisory Board Member; Self; Lumos, DNARx, BioMarin. Consulting Fee; Self; OPKO Health. M.T. Dattani: Advisory Board Member; Self; Ferring Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sandoz. Consulting Fee; Self; Ipsen, Novo Nordisk, Pfizer, Inc. Speaker; Self; Pfizer, Inc., Novo Nordisk, Sandoz, Ipsen. L. Dyer: Employee; Self; GeneDx. B. Friedman: Employee; Self; GeneDx. J. Korth-Bradley: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M. Nijher: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.L. Roland: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.T. Taylor: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J.F. Cara: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J. Hsiao: Employee; Self; OPKO Health. Stock Owner; Self; OPKO Health. M.P. Wajnrajch: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. Introduction: Somatrogon, a long-acting recombinant human growth hormone (LAGH), is approved in multiple countries as a once-weekly treatment for pediatric growth hormone deficiency (GHD). A global Phase 3 study in pediatric subjects with GHD compared the efficacy and safety of once-weekly somatrogon (0.66 mg/kg/wk) vs once-daily Genotropin® (0.24 mg/kg/wk) in a 12-mo main study, followed by an open-label extension (OLE) where all subjects received somatrogon (0.66 mg/kg/wk). Results: Subjects #1 (male; 6 y) and #2 (female; 9 y) are siblings from India randomized in the main study to somatrogon and Genotropin, respectively. Both had severe growth and weight attenuation at baseline, with peak GH levels (GH stimulation test) of 0.1 ng/ml; their IGF-1 standard deviation scores (SDS) were -3.96 and -3.94, respectively. At main study Mo 12, subject #1 had an annual height velocity (HV) of 11.77 cm/year (height SDS improved from -7.48 to -6.4) and IGF-I SDS increased to -1.84. After a 116-day drug holiday (started at the end of main study Mo 12), he continued into the OLE; at OLE Mo 9, his HV decreased to 3.08 cm/y, there was no additional improvement in height SDS (-6.76) and his IGF-1 SDS was -2.31. A test for anti-drug antibodies (ADAs) to somatrogon was positive at main study Mo 6; tests for ADAs, and neutralizing antibodies (NAbs) were positive at Mo 12. At OLE ∼Mo 1 and 3, tests were ADA+ and NAb-; at OLE Mo 6 and 9, tests were ADA-. At main study Mo 12, subject #2 had an annual HV of 11.87 cm/year (height SDS improved from -9.93 to -7.36); IGF-I SDS increased to -2.97. After a 123-day drug holiday, she switched to somatrogon during the OLE (per protocol) and had an HV of 10.01 cm/y and IGF-1 SDS of -1.83 at OLE Mo 9. Low titer ADAs to human GH were detected during the drug holidays. In the OLE, anti-GH ADAs were still detected, but at very low titers and tests were NAb−. Whole exome sequencing revealed a homozygous whole gene deletion of the GH1 gene in both siblings. Both completed the main study and OLE without any serious adverse events or dose reductions. Conclusions: Both siblings have classic congenital isolated GHD due to a homozygous GH1 deletion. Development of anti-GH ADAs and growth attenuation during GH therapy are likely due to lack of exposure to GH during fetal life followed by exposure to exogenous GH. The variability in antibody production and heterogeneity in clinical responsiveness to GH replacement has been well described, even in siblings,1 and if encountered in clinical practice, should prompt clinicians to consider the possibility of a GH1 deletion. To our knowledge, this is the first description of GH1 deletions in LAGH-treated subjects and the study findings are wholly consistent with those for daily GH products. Clinicaltrials.gov: NCT02968004 Reference: Ghosh et al. J Clin Res Pediatr Endocrinol 2021;13:456-60. Acknowledgements: The authors wish to thank all the investigators involved in this study. Presentation: Thursday, June 15, 2023

THU154 The Effects Of Combined Arginine And Sinemet Stimulation On Copeptin Levels In The Pediatric Population

Abstract Disclosure: S. Sastry: None. C. March: None. L. Garibaldi: None. M.J. McPhaul: None. S. Wheeler: None. Introduction: Most agents that stimulate the secretion of growth hormone (GH) also induce secretion of copeptin (COP), a stable surrogate of AVP. For the evaluation of the polyuria-polydipsia syndrome (PPS), COP stimulation by intravenous (IV) arginine (ARG) has been proposed as a less invasive test than those based on osmotic stimulation of the posterior pituitary, though it provides a weaker stimulus in children than in adults (∼30% vs. 50% increase). After having observed a robust COP response to combined ARG and insulin stimulation (March C, Horm Res Pediatr 2023, PMID: 36513057), we explored the effect of combined IV ARG and oral L-Dopa/carbidopa (LDc, 10:1 ratio), another known stimulus for GH secretion, on COP secretion in non-AVP deficient children. Subjects and Methods: We enrolled 30 healthy subjects with short stature (73% male, mean age ± SD 10.5±3.0 years) undergoing fasting GH stimulation testing in a prospective, single-arm study to assess their COP response. At 0 minutes (min), ARG (500 mg/kg) was infused over 30 min IV and LDc (200 mg/m2 BSA of L-Dopa) was given orally. Serum COP (B.R.A.H.M.S Kryptor assay, Quest Diagnostics) was measured at 0, 60, 90 and 120 min. Results: Median (interquartile range (IQR)) COP values (pmol/L) were 8 (5-10) at 0 min, 17 (13-44) at 60 min, 24 (13-41) at 90 min, and 30 (16-56) at 120 min. Peak COP concentrations at 60, 90, and 120 min all increased significantly from baseline (p&amp;lt;0.001, Wilcoxon sign rank test), but were highly variable in both value (range 10-449) and the timing of the peak (60 min in 33%, 90 min in 17%, 120 min in 50%). Except for 1 subject whose COP values did not change, all subjects had a robust COP peak, ranging from 1.6 to ∼90x the baseline value. The median (IQR) copeptin peak value [50 (41-129) pmol/L] was higher in subjects experiencing nausea/vomiting than in those who did not show this known side effect of LDc [25 (16-44), p=0.03 by Wilcoxon test]. Conclusions: Combined ARG and LDc appear to induce intense stimulation of COP secretion, with widely variable stimulated COP responses. The lowest COP peak value and the median response in this series were much greater than those previously reported to ARG alone in our previous study and the literature. Side effects were well tolerated. The data suggest that this test should be piloted for the differential diagnosis PPS as an alternative to ARG stimulation alone and/or the water deprivation test. Presentation: Thursday, June 15, 2023

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.