Growth Hormone Stimulation Tests Research Articles

Abstract 191

Traditionally pharmacological Growth Hormone Stimulation Tests (GHSTs) have been used to distinguish true GHD from ISS and CDGP in pediatric endocrine clinics. However these tests are not physiological and subject the patients to unnecessary stress of multiple samplings and risk of hemodynamic instability. Various clinical and biochemical findings if studied appropriately can predict the need to perform GHSTs in such patients and minimize unnecessary testing. Aim: To study the role of IGF-1 levels as a predictor of and positive GHSTs in children and adolescents presenting with short stature (SS). Materials and Methods: Medical records of children and adolescents presenting with SS were retrieved and their demographic data, IGF-1 centiles and results of GHSTs were studied. A positive GHST was taken as peak GH level (<7 ng/ml). Correlation of IGF-1 centile for chronological age and bone age with GHST results was studied and ROC curves were drawn to study the sensitivity and specificity of IGF-1 centiles in predicting positive GHST. Results: Data of 199 patients presenting with growth failure from 1st January 2010 to 31st March 2021 was collected. 65 females and 134 males were included. Mean age of the cohort was 11 years 4months and mean IGF-1 level was 132.8ng/ml. 166 patients had IGF-1 levels < 30th centile for chronological age. The remainder 33 patients who had IGF-1 centiles > 30th centile for chronological age consistently had negative GHST thus indicating unnecessary pharmacological testing. Conclusion: GHSTs can thus be avoided in children who have IGF-1 centile >30th centile for chronological age and thus avoid unnecessary stress and risk to the patients.

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.

PSAT107 Evaluating Pituitary Volume and the Growth Hormone Stimulation Test in Siblings. Both Together Better Define the Etiology of Short Stature.

Abstract We have shown that short children have significantly reduced pituitary volume (PV)s and have speculated PV as a cause for diminished chronic growth hormone (GH) secretion and poor growth. In this study, we further elucidate the role of PV in the etiology of short stature (SS) in a larger cohort of siblings (SBs).The database of a Peds Endo Center between 2013-21 was queried for siblings with SS who underwent a GH Stimulation test (GHST) and MRI evaluation. Their results were compared with normal controls (NCs) as previously reported. 129 SBs of 60 families were compared to 170 NCs. SBs were divided into 3 groups (GPs). GP1 (n=79) consisted of families with only GHD. GP2 (n=12) contained families with only ISS SBs. GP3 (n=38) comprised families with mixed GHD and ISS. SBs <11 yrs and >11 yrs were considered prepubertal (prePB) and pubertal (PB), RSP. The mean (MN) and median (MD) age for both prePB and PB SBs were significantly different (p 0.05). The 32 PB patients in GP3 had a mean PV of 316.17± 197.53 mm3, which was significantly different from that of the PB NCs of 424.6 ± 138.4 mm3 (p<0.001). Out of 38 children in GP3, 18 passed the GHST and 11 of those children who passed demonstrated a small pituitary gland (61%). 78% of prePB SBs had small PVs, while 88% were GHD. 66% of PB SBs had small PVs, while 70% of PB SBs were GHD. 71% of all SBs had small PVs, while 77% were GHD. When combined, GHST and PV identify the etiology for SS in 92% of subjects. The GHST and PV together identify more patients of SS who should qualify and benefit from GH therapy than the GHST alone. Since ages were significantly different and present as a limitation to this study, future studies should strive for age match control Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT104 Predicting Response to Growth Hormone Therapy with Pituitary Volume and The Growth Hormone Stimulation Test

Abstract Background Patients with diminished growth hormone (GH) secretion are candidates for GH therapy (GHT). The GH stimulation test (GHST) is considered the gold standard for the diagnosis of GH deficiency (GHD), yet its efficacy has been questioned. In this study we explore the GHST and PV's ability to define GHD and determine their individual ability to predict GHT outcomes. Subjects and Methods A database at a Pediatric Endocrinology center was queried for patients aged 6-18 yrs who underwent a GHST, MRI, and GHT between 1/2018 - 1/2021. Patients with a first follow up (FU) between 3 and 9 months were included; of these patients, second FUs were included if they occurred between 9 and 15 months. Patients with relevant comorbidities, those with GHST peak ≥ 10.0 ng/mL, and nonadherent patients were excluded. MRIs were acquired on a Philips 1.5 or 3.0 T scanner (2mm slices) and PV was calculated using the ellipsoid formula (LxWxH/2). PV and height were converted to SDS. Response to treatment was defined as change in height SDS over the assessed time interval. A multiple linear regression was utilized to analyze the response to GHT relative to peak GH and PV, with initial height and age at stimulation included as covariates. The relationship between peak GH and PV SDS was analyzed with a Pearson correlation Results The first FU ranged between 3.1 and 8.9 months, and the second FU ranged between 9.0 and 14.9 months. 145 patients had one FU, and 83 patients had two FUs. Peak GH and PV SDS were not correlated (r=0.03). Patients who were relatively shorter for their age and gender at stimulation had higher growth rates in the first interval, but not in the second interval. Both PV and peak GH provided information about response to GHT. PV SDS negatively predicted the relative growth response to treatment in the first interval (slope=-0.03, p=0.048). However, PV only explained 3.7% of variation in growth. PV SDS was not a useful predictor of response in the second interval (slope=-0.01, p=0.693). Peak GH was a predictor of response to GHT in the first interval only after accounting for age at stimulation and initial height (slope=-0.01, p=0.032; r2=0.01). Peak GH was a predictor of response in the second interval (slope=-0.02, p=0.040), explaining 5.1% of the variation in growth. Conclusion Since peak GH and PV were not correlated, they likely reflect different physiological processes. PV and peak GH both provide information about response to GHT, so they should both be utilized to determine eligibility for GHT. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PMON313 Hyperinsulinemic Hypoglycemia and Growth Hormone Deficiency Secondary to 20p11 Deletion

Abstract Introduction Hyperinsulinism (HI) and growth hormone deficiency (GHD) are known causes of hypoglycemia but not commonly found together. We present a 4-month-old boy with hypoglycemia found to have both HI and GHD with subsequent genetic diagnosis of 20p11 deletion. This deletion has been associated with panhypopituitarism. This case represents a few to report HI as a manifestation of this deletion. Treatment with both recombinant human growth hormone (rhGH) and Diazoxide led to blood glucose (BG) normalization. Clinical Case A 4-month-old, full-term, large for gestational age (96th percentile), born to a nondiabetic mother presented with hypoglycemic seizures. He had transient hypoglycemia at birth, normal newborn screen, and exclusively breastfeeding with normal growth and development. He had a negative 60-hour video EEG. Further work-up was significant for serum glucose of 54 mg/dL despite blood draw being 20 minutes after a breastfeed, prompting endocrinology evaluation. Physical exam showed no dysmorphism and normal genitalia. He had a serum glucose of 39 mg/dL while asymptomatic. Critical sample revealed detectable insulin (3.2 mcIU/mL), low beta hydroxybutyrate (145.6 mcmol/L) and low growth hormone (GH) (4.2 ng/dL). He had normal cortisol, lactic acid and ammonia. A glucagon challenge showed an increase in BG of 26 mg/dL (35-->61 mg/dL). He had a GH stimulation test with arginine (peak GH 3.8 ng/dL) and glucagon (peak GH 6.6 ng/dL). He had mildly elevated liver enzymes that resolved on repeat testing. Plasma amino acid, plasma acylcarnitine profile, urine organic acids, and brain MRI were normal. He was initially started on rhGH with continued hypoglycemia, hence, Diazoxide, and chlorothiazide were added. His BG was monitored until dextrose infusion was successfully weaned, while maintaining normoglycemia. Genetic testing with next-generation sequencing revealed 20p11.22-p11.21 deletion. He was discharged on Diazoxide (12 mg/kg/day), chlorothiazide, and rhGH (0.27 mg/kg/week). Conclusion It is important to determine the cause of hypoglycemia so specific treatment can be provided. HI is a common cause of hypoglycemia in infants due to abnormal insulin secretion in the pancreatic beta cells. GHD can also cause hypoglycemia and be associated with other pituitary hormone deficiencies. Evaluation of our patient's hypoglycemia revealed HI, GHD and 20p11 deletion. This deletion has been associated with hypoglycemia due to GHD and few reports with HI. This patient will need to be regularly screened for other pituitary hormone abnormalities. Other features of 20p11 deletion include cognitive delay, craniofacial dysmorphisms, gastrointestinal and genitourinary anomalies. While hypoglycemia is often the result of a single cause, this case shows that there are pathological conditions that can present with both GHD and HI, so the differential diagnosis for hypoglycemia should remain broad. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP386 Growth Velocity and Growth Hormone Deficiency During Puberty

Abstract Background A subnormal growth velocity (GV) is a characteristic feature of growth hormone deficiency (GHD). During puberty growth hormone (GH) levels increase markedly in response to sex hormone secretion. The normal range for GV declines during childhood, increases during puberty with peak levels at mid-puberty. Hence, pubertal status rather than age alone must be considered in the evaluation of GV in children and adolescents. In most cases, a diagnosis of GHD is established by a subnormal response in GH levels following a stimulation with two pharmacological agents. Objective We determined the reliability of GV as a predictor of GHD during puberty. Methods We conducted a retrospective study of pubertal children and adolescents who underwent a GH stimulation test in our pediatric endocrinology clinic. Seventy-nine subjects (57 boys and 22 girls) were included in this study. Bone age was determined for all patients. Serum levels of insulin like growth factor-1 (IGF-1) were obtained prior to GH stimulation test. Serum IGF-1 levels, expressed as a standard deviation score were compared to the IGF-1 levels expected chronological age (CA), height age (HA), and bone age (BA). Serum GH levels were determined following the administration of arginine and levodopa. GHD was established by a peak GH level <10 ng/mL. IBM SPSS Statistics software version 28. 0. 0. 0 (190) was used for data analysis. Results Subjects ranged in age from 7.3-17.9 years. Thirty-nine patients (49.4%) had GV < 10 th percentile for CA; Forty patients (50.6%) had GV <10 th percentile for BA. Sixty percent of patients with GV <10 th percentile for CA had GHD. A similar number (59%) of patients with normal GV for CA also had GHD. Among patients with GV <10 th percentile for BA, 72.5% of subjects had GHD. By contrast, the percentage of patients who had normal GV for bone age and GHD (46.2%) was significantly less than that of subjects with GV <10 th percentile for BA (p = 0. 015). Positive predictive value, negative predictive value, sensitivity and specificity for GV <10 th percentile for BA in the diagnosis of GHD were 72.5%, 53.8%, 61.7%, and 65.6%, respectively. With respect to the diagnostic value of serum IGF-1, when the area under the ROC curve was used to measure how well the serum IGF-1 standard deviation score distinguished between GHD and normal, serum IGF-1 standard deviation score for CA, HA, and BA were not predictive of GHD (p = 0.1, 0.47, and 0.27, respectively). Conclusions During puberty, slow growth velocity for bone age (but not slow growth velocity for chronological age) was useful to predict a diagnosis of growth hormone deficiency. Presentation: No date and time listed

ODP373 A Tale of Two Syndromes: Coexistence of Russell-Silver and Klinefelter Syndrome

Abstract Background/Aims Klinefelter syndrome is a common condition characterized by an extra X chromosome, tall stature, gynecomastia, and hypogonadism. Russell-Silver syndrome is a rare disorder characterized by intrauterine growth restriction, poor growth after birth, and triangular facies. The coexistence of Russell-Silver and Klinefelter syndrome has so far not been reported in the literature. This study aimed to characterize the phenotype of such an individual. Methods Clinical and endocrinal investigations were performed and followed by pathogenic variant screening of candidate genes. Results An 8-year-old boy was evaluated for short stature. He was a former 27-week preemie who had postnatal growth failure. His mean parental height was5'6" (66 inches). His growth chart showed that he was below the 0. 01% percentile in both height and weight for age. He had behavioral issues. On physical exam, he had high riding prepubertal testes and proportional limbs. He was evaluated by both genetics and endocrine. His bone age was delayed by 4 years. He passed his growth hormone stimulation test. He had a nondiagnostic bone survey. His chromosomal microarray showed an XXY karyotype. Further testing was collected because it did not explain his short stature. He was found to have maternal uniparental disomy of 7q32.2. He was started on growth hormone and his most recent growth velocity was 4 cm a year. He continues to be below the 0. 01% percentile in both height and weight for age Conclusion: This is the first report on a patient with the coexistence of Russell-Silver and Klinefelter syndrome. It shows that the short stature and postnatal growth of Russell-Silver syndrome is the prevailing phenotype in this rare combination. Presentation: No date and time listed

PSUN160 Transfusion Related Endocrinopathies and Thalassemia (TREAT) Study

Abstract Thalassemia (Thal), the most common form of inherited anemia worldwide, may require regular blood transfusions and life-long medical care. The introduction of oral chelators and imaging methods to monitor iron overload transformed Thal from a rapidly fatal disease of childhood to a chronic illness compatible with prolonged life expectancy. Regular blood transfusions resulting in tissue iron overload and oxidative stress may lead to liver disease and polyendocrinopathy. In this observational descriptive study, we described the patient characteristics and prevalence of endocrinopathies (growth failure, hypothyroidism, hypogonadism, low bone mass, and impaired glucose intolerance) in a contemporary group of transfusion dependent Thal patients cared for our tertiary care center since 2000. A total of 253 transfusion dependent Thal patients were identified. Of those patients, 51.8% were female; 22% (n=56) were adopted, mainly from China. The following ethnicities were represented: Chinese 19.9%, Indian 12.6%, Laotian 7.8%, Asian 7.8%, Italian 7.8%, Vietnamese 3.9%, Afgani 3.4%, Pakistani 3.4%, Thai 2.9%, Greek 2.4%, Cambodian 2.4%, Filipino, Caucasian, Iranian 1.9% each. Majority of the diagnoses were Beta Thal Major (69.9%), followed by E Beta 0 Thal (14.6%). The median age at first visit was 10.6 years (IQR1-IQR3: 2.2-25), last visit was 27 years (IQR1-IQR3: 12.1–39.4) with 33.5% of the patients ≤18 years of age. Median follow-up time was 10 years. Median final adult height (height z-score) for females was 159.5 cm (-0.53) (IQR1-IQR3: 152.4,160.3cm; height z-score: -1.68, -0.47) and for males 167.5cm (-1.3) (IQR1-IQR3: 161.5, 171cm; height z-score: -2.13, -0.81). Only, 16.5% (n=14) of children were on growth hormone treatment due to low-normal growth hormone surrogates or peak growth hormone <10ng/ml in growth hormone stimulation test. Hypothyroidism was diagnosed in 9.9% (n=25) of the patients and 5 patients had central hypothyroidism. Hypogonadism was diagnosed in 32.4% of adult female (n=24), and 44.6% of adult male (n=29) patients who were subsequently prescribed sex steroid replacement. Low bone mass in those with z-scores ≤2.0 was noted in 22.9% (n=43) female and 26% (n=49) males. The mean bone mineral density z-score for spine was -2.1±1.1 for females and -2.5±1.3 for males. Either impaired glucose tolerance or insulin-dependent DM was observed in 29% of the patients (n=54). Endocrinopathies are common and continue to be a significant morbidity in transfusion dependent Thal patients despite improved chelation agent availability and tissue iron monitoring. Future long-term longitudinal and intervention studies elucidating and mitigating potential effects of iron overload on developing children's developing endocrine organs are needed. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP380 Case of Skeletal Dysplasia in Post-Menarchal Pediatric Patient due to Novel Mutation of CSGALNACT1

Abstract We report the case of a 14 year old Yemenite female diagnosed with autosomal recessive skeletal dysplasia secondary to a novel mutation of CSGALNACT1. She was initially referred to pediatric endocrine for poor linear growth at the age of 11 year 7 months. At that time, her height was well below the growth curve with z-score of -3.51. She had no reported history of intellectual disability. She had a normal MRI of the brain as well as normal growth factors, growth hormone stimulation test, thyroid function, IgA celiac antibodies, and a normal karyotype (46,XX). SHOX and microarray were negative. Her bone age was slightly delayed at 10-11 years with a chronological age of 11y8m. On initial evaluation by genetics, she was normocephalic with no dysmorphic facial features. She had proportionate limbs but was noted to have mild lumbar lordosis, increased joint laxity, and flattened feet with fifth toe clinodactyly. Notably there was a family history of consanguinity (parents are first cousins once removed). A skeletal dysplasia gene panel was not thought to be indicated, and she was referred back to endocrine. She was lost to follow up with endocrine but returned to clinic after 1 year when she was post-menarchal. She continued to have poor linear growth. Upon reevaluation, she was noted to additionally have a high-arched palate and shortened hallux. A panel for skeletal dysplasia was sent which detected a novel homozygous mutation of CSGALNACT1 with autosomal recessive inheritance. CSGALNACT1 encodes chondroitin sulfate N-acetylgalactosaminyl transferase which is crucial for chondroitin sulfate chain biosynthesis and glycosaminoglycan synthesis. Congenital disorders of glycosylation are genetically inherited conditions due to abnormal glycan biosynthesis. Glycosaminoglycans (GAGs) are vital in normal development of cartilage and the brain. We performed a PubMed search and saw four reported cases of individuals with mutations of CSGALNACT1. Clinically these individuals had relative macrocephaly, rhizomelia, hyperlordosis, joint laxity, and mild neurodevelopmental delay. Reported radiographic findings of affected individuals include advanced bone ages, flattened acetabular roofs, and vertebral anomalies. Our patient in contrast did not have overt dysmorphic features on exam nor reported intellectual disability to prompt a more immediate workup for skeletal dysplasia. There have been only a handful of cases with CSGALNACT1 mutations and skeletal dysplasia. These individuals more typically have findings of dysmorphia on exam including macrocephaly, lordosis, and joint laxity. Our patient lacked these typical features that are more normally associated with skeletal dysplasia yet was revealed to have a novel mutation of CSGALNACT1. Based on her initial genetic evaluation, her clinical findings were subtle and did not indicate a workup for skeletal dysplasia. Her case however shows that even in the absence of dysmorphic features, skeletal dysplasia should be considered in individuals with severe short stature. Presentation: No date and time listed

PMON180 Extremely Elevated Serum Copeptin Concentrations Following Venipuncture Occur in Approximately 5% of Children and May Affect Proper Interpretation of Copeptin Measurement

Abstract Introduction The secretion of copeptin, an easily measurable surrogate of arginine vasopressin (AVP), is mainly regulated by osmotic and volume stimuli, but also increases in situations of physical stress. Venipuncture has been found to be a stressful procedure, due to physical pain and anxiety, particularly in children. Falsely elevated copeptin concentrations can substantially affect establishment of reference intervals and interpretation of results in conditions such as syndrome of inappropriate antidiuresis, sepsis, infections. We thus tested the hypothesis that venipuncture, as a stressful stimulus, could stimulate copeptin secretion in children. Subjects & Methods We evaluated 92 children (75% males, 5-19 years) enrolled in a study assessing fasting and stimulated serum copeptin concentrations in response to arginine-hydrochloride (500 mg/kg IV in 30 minutes, ArgST) or insulin (0.1 U/Kg IV, insulin tolerance test/ITT) during GH stimulation tests in healthy short children. Subjects underwent phlebotomy for placement of an IV cannula (angiocath) by trained nurses, without percutaneous anesthesia. Copeptin was measured at 0 min. and at sampling times of the expected copeptin peak (60 min post arginine; 45, 60 min post-insulin) by the immunometric B.R.A.H.M.S. Kryptor assay (Quest laboratories) Results Two distinct groups of fasting copeptin values were identified. The majority of subjects, 86/92 (93.5%, "controls") had serum copeptin concentrations in the expected range for overnight fasting (median 9, IQR 6-12, range 2-29 pM/L). Six subjects (6.5%) were outliers with very elevated copeptin values (>50 in one, >100 pM/L in five of them). In 50 controls who underwent ArgST, copeptin increased from a median of 9 (IQR 6-13, range 2-25) to 11 (IQR 8-15, range 2-28) pM/L at 60 min; In the 5 outliers who underwent ArgST, it paradoxically decreased, but remained elevated, from 272 (IQR 154-406, range 62-1361) to 95.5 (IQR58-128, range 42-282) pM/L at 60 min. Similarly, in 8 controls who underwent ITT, copeptin increased minimally from a median of 8 (IQR 7-11, range 5-12) to 10 (IQR10-14, range 6-17) at 45 min, and 9(IQR 2-13, range 8-12) pM/L at 60 min. In the outlier who underwent ITT, copeptin decreased from 202 (0 min) to 63 (45 min) and 51(60 min) pM/L. None of these children had abnormalities of fluid regulation (polydipsia, polyuria, abnormal serum Na+ levels). The highest copeptin level (>1000 pM/L) occurred in a subject who had 3 successive attempts at phlebotomy. Conclusions Very elevated serum concentrations of copeptin occur in a minority of pediatric subjects undergoing phlebotomy, suggesting that pain of venipuncture can be a potent stimulus of copeptin secretion. Unexplained high values were observed in another pediatric study (Bonnet, Clin Endocrinol 2022;96: 47-53). This information is relevant to clinicians measuring copeptin for diagnostic or prognostic purposes or to establish reference values. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP399 Growth Hormone Peak did not predict presence of Pituitary Stalk Interruption Syndrome

Abstract Background Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary gland characterized by a triad of the thin or interrupted pituitary stalk, aplasia, or hypoplasia of the anterior pituitary and absent or ectopic posterior pituitary. This can be associated with midline defects and pituitary endocrine deficiencies, ranging from isolated growth hormone deficiency to combined pituitary hormone deficiency. PSIS is a rare entity with an estimated incidence rate of 0.5/1,000,000 births. Clinical case: A 3-year-old neurodevelopmentally appropriate male was initially seen at the PCP office for growth failure. After birth, the patient appeared to have normal growth parameters, as he was in the 61st percentile for length and at the 19th percentile for weight. His growth velocity trended downwards, as he dropped to the 34th percentile at nine weeks old and the 2nd percentile by nine months old. PCP records showed that the patient was at the 10th percentile for height at one year old, but by 18-months, he had fallen below the 1st percentile. His mid-parental height was 175cm, between 25th and 50th percentile. Initial workup showed elevated TSH 9.12 mIU/ml (0.5-4.3 mIU/mL) with negative thyroid antibodies, thus started on 25 mcg of levothyroxine. The screen for systemic disease and inflammatory markers was negative. Insulin-like growth factor 1 (IGF-1) was low at <16 ng/mL (24-148 ng/mL) and insulin-like growth factor binding protein-3 (IGFBP-3) was normal at 1.2mcg/ml (0.7-3.6)A growth hormone (GH) stimulation test was obtained due to suboptimal growth, short stature, and undetectable IGF-1 level. The patient failed his GH stimulation study with a GH peak of 5.1 ng/mL (>10) after clonidine and 2ng/ml (>10) after arginine. A clinical and biochemical diagnosis of GHD was made, an MRI was ordered to evaluate for anatomic cause. Brain MRI showed an ectopic posterior pituitary gland with an absent infundibulum, suggesting PSIS. The patient was started on GH therapy with excellent response. He is currently growing well on a low dose of somatropin, around 0.234mg/kg/week. Conclusion PSIS is a congenital pituitary anatomical defect with a heterogeneous presentation. It is typically encountered in infancy and childhood, possibly progressing to panhypopituitarism by adulthood. Diagnosis can be delayed, as brain MRI imaging is not always obtained based on growth hormone peaks. As seen in our patient, the severity of GHD based on peak levels did not adequately predict the presence of brain anomalies. Historically, severe GHD (<5 ng/mL) is strongly associated with brain MRI abnormalities, but GH levels may not suffice to determine the severity of the disease. Based on our findings, we recommend obtaining brain MRI in all patients diagnosed with GHD to identify critical anatomical abnormalities, like PSIS, that require long-term close monitoring of pituitary function. Presentation: No date and time listed

PMON110 Panhypopituitarism as a Rare Presentation of Erdheim – Chester disease (ECD) in an Adolescent Patient

Abstract Background Erdheim-Chester disease (ECD) is a rare multisystemic histiocytic disorder. Only a dozen pediatric cases are reported. Here, we present a case of ECD in a pediatric patient who presented with short stature and delayed puberty. Clinical Case A 14-year-old male with history of autism and ADHD presented with short stature and pubertal delay. He grew along the 40th percentile until age 7 years when growth velocity declined. On exam, his height was 145.6 cm (0.98%ile, z-score -2.34), weight was 55.6 kg (63.19%ile, z-score 0.34), and testicular size was 5-6 mL. He had increased thirst and episodes of bedwetting since age 7. Bone age was delayed at 11 years 6 months. Further workup was recommended, but family was lost to follow up. At 16, he returned with continued poor growth, polydipsia, and nocturia. Height was 153 cm (0.26%ile, z-score -2.80), weight 61.1 kg (40%ile, z-score -0.25). Labs revealed IGF-BP3 2.8mcg/mL(3.1-8.9), IGF-1 35ng/mL(245-522), LH 1.2mIU/mL(0.29-4.77), and total testosterone <7.0 ng/dL(250-1100). Prolactin, cortisol, thyroid, and karyotype were normal. Growth hormone (GH) stimulation test confirmed GH deficiency. He was referred to oncology clinic when a brain MRI revealed a nodular enhancing suprasellar mass extending from the third ventricular floor to the dorsum sella along the pituitary stalk and rounded sclerotic lesion in the frontal bone. Biopsy of the suprasellar lesion was remarkable for foamy histiocytes positive for CD68, negative for S100 and CD1a, an eosinophilic cell background highlighted by S100 and synaptophysin, SALL4 negative. A diagnosis of xanthomatous hypophysitis was made. Additionally, lab studies confirmed diabetes insipidus (DI), treated with DDAVP. Growth hormone was trialed for 2 weeks, but he developed acute pancreatitis, so it was discontinued. He subsequently developed recurrent pancreatitis of unclear etiology requiring frequent hospitalization with development of insulin-dependent diabetes mellitus due to pancreatic damage. He was lost to follow up for 12 months after leaving home at age 18. He returned to our institution after incidental findings of 7th right rib expansile lytic bony lesions on abdominal CT during a pancreatitis admission. Biopsy of the rib lesion was positive for a BRAF-V600E mutation. Skeletal survey revealed new multiple small lytic skull lesions. Repeat brain MRI demonstrated new calvarial lesions, increased suprasellar mass. Chest CT scan showed a micronodular pattern with mediastinal lymph node enlargement. PET confirmed widespread multifocal FDG hypermetabolic lesions. Final diagnosis of ECD was made; he was started on targeted therapy with Vemurafenib, a BRAF inhibitor. Conclusion Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis, which rarely affects pediatric patients who present with bone pain and DI; however, here we present a case of ECD in an adolescent with short stature and multiple pituitary deficiencies to highlight the varied presentation of the disorder. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Children with Attention Deficit Hyperactivity Disorder Are More Likely to Fail Growth Hormone Stimulation Testing than Children without Attention Deficit Hyperactivity Disorder: A Retrospective Chart Review

Introduction: Children with ADHD often present to pediatric endocrinologists due to growth concerns. Growth hormone stimulation testing (GHST) may be utilized as part of the workup. We evaluate whether children with ADHD and short stature or growth failure are more likely to fail GHST compared to children without ADHD. Methods: We retrospectively studied children who underwent GHST as part of evaluation for short stature and/or growth failure and had an intact pituitary over a 16-year period (2002–2018). We performed univariate and logistic regression analyses with stratification by age. Results: We included 260 children; 78 children had ADHD and were older, mean age (±SD) 12.2 (±2.6) years versus children without ADHD, mean age (±SD) 10.4 (±3.8) years. The population was largely Caucasian, and boys outnumbered the girls. Of the children with ADHD, only 9 were not medically treated. There was no difference in z-scores for height, weight, and BMI, or mid-parental height between the two groups. We found that children with ADHD were more likely to fail GHST than children without ADHD across the peak GH cut-offs of 10, 7, and 5 ng/mL (p = 0.003, p = 0.023, and p = 0.046 accordingly). The same trend persisted after regression analysis with adjustment for sex and stratification by age, and effect was more robust in the older group. Discussion: The result shows higher likelihood of lower GH peaks in response to GHST in children with ADHD and short stature or impaired linear growth. Future work should evaluate possible mechanistic explanation and the role of psycho-stimulant medications.

The Influence of Body Mass Index on the Growth Hormone Peak Response regarding Growth Hormone Stimulation Tests in Children

Introduction: Several studies have analyzed the association between the maximal growth hormone serum level obtained during a growth hormone stimulation test (GH_Max) and the body mass index-standard deviation score (BMI-SDS). However, as sample sizes were quite small, our study aimed to analyze the association between GH_Max and BMI-SDS within a large cohort of 991 children. Further, we investigated other influencing factors, like test type, age, sex, puberty, and preterm birth. Methods: Children with short stature (height <10th percentile) received growth hormone stimulation tests with arginine or glucagon at the Department of Paediatric Endocrinology of the University of Leipzig Medical Center. The study population included a total of 1,438 tests (633 tests on girls, 805 tests on boys), with the majority consisting of prepubertal children (tests = 1,138). The mean age at testing was 7.74 years. Analyses were carried out on the entire cohort as well as stratified by test types. We performed univariate and multivariate analyses using linear mixed-effect models to assess the effects on GH_Max. Results: GH_Max and BMI-SDS were significantly negatively associated with an effect size of β = −1.10 (p < 0.001), independent from the test type. The GH_Max values were significantly (p < 0.001) higher for glucagon (mean value: 9.65 ng/mL) than those for arginine tests (mean value: 8.50 ng/mL). Age, sex, premature birth, and puberty were not significantly related to GH_Max values. Conclusion: We confirmed the negative association between GH_Max and weight status of short children found in previous studies. Therefore, considering BMI-SDS may be helpful in the assessment of growth hormone stimulation tests in short-statured children, but it should not be the determining factor for a treatment decision.

EE413 Budget Impact Analysis of Macimorelin, an Oral Growth Hormone Stimulation Test, As a Diagnostic Test for Adult Growth Hormone Deficiency (AGHD) across 5 European Countries

Macimorelin is a novel, oral growth hormone stimulation test approved by EMA and FDA for the diagnosis of adult growth hormone deficiency (AGHD). The objective of this study is to investigate the budget impact arising from the introduction of macimorelin as a diagnostic test for AGHD across France, Germany, Italy, Spain and the United Kingdom.

Prolactin response to growth hormone stimulation tests

BackgroundDespite many similarities between the structure, receptors, proliferative and growth promoting actions, the relationship between Prolactin (PRL) and Growth Hormone (GH) in clinical conditions has received little attention. ObjectiveTo determine the PRL response to GH stimulation tests. SubjectsPrepubertal and early pubertal boys (n = 581) and girls (n = 502) with idiopathic, non-syndromatic short stature. DesignData was retrieved from the computerized records of the Endocrine Laboratory, Schneider Children's Medical Center. Peak GH and PRL levels during GH stimulation tests with glucagon (Gluc), Clonidine (Clon) and Clonidine with arginine (Clon+Arg), were compared. Both PRL and GH were determined by radioimmunoassay. ResultsWhereas Gluc stimulated both GH and PRL to similar levels, Clon alone or combined with Arg suppressed the PRL secretion (p < 0.0001). It is also evident that in both boys and girls Clon alone and Clon±Arg are superior to Gluc in GH stimulation. The higher GH levels during Clon+Arg than with Clon alone are attributed to the pubertal stage. ConclusionThis study provides further information on the Prolactin-Growth hormone relationship in children.

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.

Is the fear from insulin tolerance test in the evaluation of short stature justified?

A nationwide survey in Israel revealed a high rate of reluctance to perform ITT. The rationale behind this attitude was a sense of fear of performing the test by many endocrinologists. We discuss the preferences for choosing GH stimulation tests and the pros and cons of alternatives to ITT. The fear of not performing ITT was not always justified. • ITT test is considered a gold standard in the evaluation of short stature to diagnose GH deficiency by many endocrinologists. • High reluctance rate found in Israel to perform ITT, prompted us to evaluate the attitudes of pediatric endocrinologists around the world showing conflicting ideas. • The role of a single paper sometimes misquoted also contributed to these conflicting results.

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.

Inclusion and Withdrawal Criteria for Growth Hormone (GH) Therapy in Children with Idiopathic GH Deficiency—Towards Following the Evidence but Still with Unresolved Problems

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most children diagnosed with isolated GHD present with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, and a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature.