ResearchPad - pediatric-growth-and-adrenal-disorders https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SAT-LB19 Is There a Need to Use Gadolinium Contrast for Pituitary MRI in the Evaluation of Pediatric Short Stature and Growth Hormone Deficiency?]]> https://www.researchpad.co/article/elastic_article_8684 Short stature is a common concern that necessitates pediatric endocrinology evaluation. Growth hormone (GH) deficiency is often included as an etiology. Brain and pituitary Magnetic Resonance Imaging (MRI) with gadolinium-based contrast agents (GBCAs) is the imaging modality of choice in assessing patients with GH deficiency. Given the significant strides made in MRI technology that allow improved spatial and contrast resolution, the necessity of using contrast material when obtaining brain and pituitary MRI in cases of short stature and isolated GH deficiency should be reassessed. We preformed a retrospective review of otherwise healthy patients with short stature and/or GH deficiency who underwent brain and pituitary MRI without and with contrast, to assess the benefit of contrast administration.

Introduction: Short stature is a common concern that necessitates pediatric endocrinology evaluation. The etiologies of short stature are diverse. GH deficiency is often included as an etiology although it accounts for only 1-2% of short stature cases. The prevalence of GH deficiency is reported to be ~ 1:3500. The vast majority of GH deficiency cases are idiopathic in nature with only 20% due to organic causes. The organic causes of GH deficiency include congenital central nervous system (CNS) anomalies, tumors and other pathologic conditions that involve the pituitary-hypothalamic region. As a result, the radiological assessment of the hypothalamic-pituitary region is considered standard of care for evaluating patients with GH deficiency. Although brain and pituitary MRI is the imaging modality of choice in assessing patients with GH deficiency, its yield in cases of isolated GH deficiency is very low. In a study of 40 otherwise normal patients with isolated GH deficiency, 35 (87.5%) had normal brain MRIs. The abnormal findings of brain MRI in the minority of isolated GH deficiency cases included pituitary hypoplasia, pituitary stalk agenesis, lack of the normal T1-weighted pituitary hyperintensity in the posterior part of the sella turcica, and the presence of a high-intensity signal at the infundibular level representing ectopic neurohypophysis. Traditionally, these brain and pituitary MRI images are obtained with the use of contrast material (gadolinium). The main purpose of using contrast material is for the evaluation of pituitary microadenomas. Given the fact that significant strides made in MRI technology and pituitary microadenomas are not appeared to be associated with GH deficiency, the necessity of using contrast material when obtaining brain and pituitary MRI in cases of short stature and isolated GH deficiency should be reassessed. GBCAs have been shown to deposit in different tissues including the kidneys and the brain. The risk increases with repeated doses. The clinical significance of this deposition is unclear at this time but warrants caution especially in pediatric population who have a longer expected lifespan to manifest any delayed effects. Allergic reactions and gastrointestinal symptoms in pediatric patients can occur with GBCA administration, although the incidence is low. Using contrast material also increases the total cost of the MRI study and prolongs the time needed to complete it. Moreover, in order to use contrast material, intravenous venous (IV) access is required which causes discomfort and additional stress to children and their families.

Therefore, we performed a retrospective review of otherwise healthy patients with short stature and/or growth hormone deficiency who underwent brain and pituitary MRI without and with contrast, to assess whether contrast administration led to diagnoses that would have otherwise been missed and/or impacted the patient’s clinical course.Objectives: - To compare the diagnostic yield of non-contrast MRI with pre and post-contrast MRI of the brain and pituitary in evaluation of pediatric patients with short stature and/or growth hormone deficiency.- A secondary objective is to measure the size of the pituitary gland and correlates it with peak growth hormone levels (using insulin/argenine).

Methodology: We included patients who underwent brain/pituitary MRI with/without contrast performed at our institution between Jan 2013-Dec 2018 who have short stature/GH deficiency. We excluded patients with known diagnosis of other pituitary hormone deficiencies prior to obtaining MRI studies, genetic and neurological disorders, known tumors/malignancies of any type, or renal failure. Two pediatric neuroradiologists independently reviewed the brain and pituitary MRI of these patients (each read 50% of the cohort) blinded to the clinical data and diagnoses. Each radiologist initially reviewed only the non-contrast portions of the studies, and subsequently, the same radiologist reviewed the entire study, including pre- and post-contrast portions in a separate session. The two sessions were 6 weeks apart to avoid recall bias. Several imaging findings including size and morphology of pituitary gland, presence of congenital anomalies or focal lesions and any associated intracranial findings systematically recorded, and subsequently analyzed.

Hypotheses: 1.The incidence of finding congenital pituitary cysts is the same when obtaining brain/pituitary MRI imaging using gadolinium contrast versus when not using contrast in patients with short stature and or isolate GH deficiency.

2.The incidence of discovering abnormal infundibulum is the same when obtaining brain/pituitary MRI imaging using gadolinium contrast versus when not using contrast in patients with short stature and or isolate GH deficiency. 3.Small pituitary size correlate with GH deficiency.

Results: -We identified 327 patients with short stature/GH deficiency from Jan 2013-Dec 2018-224 (68.5%) are males and 103 (31.5%) are females. -The mean age at the time of imaging is 10 years and the median is 11 years. -161 (49.24%) have height z-score < -2.25 and 166 (50.76%) have height z-score > -2.25.-82 (25.07%) have IGF1 z-score for age < -2, 102 (31.19%) have z-score ≥-2 to ≤ -1, 141 (43.12%) have z-score > -1 and 2 (0.62%) have no level done.-63 (19.27%) have GH peak <5, 87 (26.61%) have GH peak 5-7.99, 53 (16.21%) have GH peak 8-9.99, 30 (9.17%) have GH peak > 10 and 94 (28.75%) did not undergo GH provocative testing. -The kappa coefficient for pars intermedia cyst on pre vs. post contrast imaging is 0.74 and 0.55 for the infundibulum on pre vs. post contrast imaging. -The mean pituitary height for patients with IGF z-score < -2 is 3.9 mm, 4 mm for z-score ≥- 2 to ≤ -1 and 4.3 mm for z-score > -1-The mean pituitary height for patients with peak GH < 5 is 3.8 mm, 4.2 mm for peak 5-7.99, 4.3 mm for peak 8-9.99 and 4.4 mm for peak > 10.

Conclusion: This question has not been answered or even raised in the literature. Our findings suggest that the there is no added benefit to use gadolinium when obtaining brain/pituitary MRI for the evaluation of GH deficiency/short stature. Furthermore, it seems that there is an association between the pituitary height and the GH status of the cohort which is in line with previous published studies.

]]>
<![CDATA[SAT-108 Growth Hormone Deficiency in a Patient with Ectodermal Dysplasia]]> https://www.researchpad.co/article/elastic_article_8640 Background information:

Ectodermal dysplasia (ED) is a rare heterogeneous group of genetic disorders of ectodermal derived tissues, characterized by abnormalities in skin, teeth, hair and eccrine glands. Growth failure in these children varies depending on the genetic mutation and has not been well characterized. This clinical case report presents a 11-year-old male with a heterozygous mutation in WNT 10 A, a variant of the hypohydrotic ED gene, who was found to have growth hormone (GH) deficiency and treated with GH.

Case report:

He was born at 35 weeks gestation by C-section with a birth weight of 5 lbs. 12 oz. to a mother who had invitro fertilization with donor eggs from the maternal aunt with ocular myasthenia gravis and sperm from the father. Pregnancy was complicated by twin gestation and polyhydraminos. He had transient myasthenia gravis and treated with pyridostigmine for 3 months for feeding problems and swallowing difficulty. He also had arthrogryposis of the distal upper extremities attributed to placental transfer of the maternal aunt’s myasthenia gravis antibodies.

He was referred to the endocrine clinic for evaluation of his growth failure around the age of 8 years. His growth chart indicated that he grew along the 5thpercentile until age 5 year with a gradual decline to the 3rd percentile by age 7 year and close to 2nd percentile by age 8 year. His BMI was at 7th percentile. Mid parental height was 5’9”. There was no history of delayed adolescence in the family. His twin sister had very mild form of arthrogryposis with dental delay but steady linear growth. He also had decreased exercise tolerance. His body tended to become hot during sports activities and had to wrap his face and neck with cold soaked towels. His other problems included delayed dental development with conical incisor, thin nail, missing teeth and hearing defects that raised suspicion for ectodermal dysplasia. Genetic testing at the age of 4 years had demonstrated a heterozygous mutation in the WNT 10A gene, an important gene for tooth development. Physical examination revealed a mild facial dysmorphism with conical incisor, missing teeth and high arched palate. He had contracture of the proximal inter phalangeal joints of the hands. Investigations revealed a normal thyroid function test, IGF-1 and IGFBP-3 level, CBC, sedimentation rate, chemistry panel and celiac titer. The bone age was concordant with his chronological age of 8 years. A GH stimulation study demonstrated a peak GH level of 4.94 ng/ml. An MRI of the brain revealed a normal pituitary gland. He was started on GH therapy with 0.3 mg/kg/week at age 9 year. His height improved from 2nd percentile at age 9 year to 20th percentile by age 11 year on growth hormone therapy. His exercise capacity and stamina also improved.

Conclusion:

Growth failure and GH axis should be evaluated in children with ED. GH therapy improves growth velocity and exercise capacity in patients with ED.

]]>
<![CDATA[SAT-104 Unraveling the Connection Between Cortisol and Pediatric Idiopathic Intracranial Hypertension]]> https://www.researchpad.co/article/elastic_article_8633 Background: Idiopathic intracranial hypertension (IIH) is a condition of elevated intracranial pressure without identifiable secondary causes. The childhood incidence is 0.7 per 100,000 and increases with age, obesity, and female gender. Few case reports in the literature, and our own experience, suggest there may be an association between IIH and adrenal insufficiency (AI) but the real extent is unknown. Aim: To describe the prevalence of AI in children presenting with IIH to a large pediatric referral center. Methods: Retrospective chart review identified all children who presented with IHH and had cortisol measured between January 2010 and September 2019. Based on morning, random or 1 mcg ACTH stimulated cortisol levels, adrenal functioning was classified as: (1) deficient (peak cortisol <16 μg/dl, AM cortisol <5 μg/dl), (2) at risk (peak cortisol 16 - 20 μg/dl, AM cortisol 5 - 13 μg/dl or random < 13 μg/dl), or (3) sufficient (peak cortisol >20 μg/dl, AM or random cortisol >13 μg/dl). Descriptive data present mean (+/- standard deviation), and chi-squared (χ 2) tests of differences are used to examine differences between the adrenal functioning groups. Results: Participants (N=64) were 40.6% male, of mixed ancestry (61% non-Hispanic white; 19% African-American, 16% Hispanic White and 5% Asian), with a mean age of 10.8 (4.8) years. Cortisol levels were obtained at an average of 0.6 (1.9) years after diagnosis of IIH; 23% and 52% of patients had insufficient or at risk cortisol levels. The majority of those in the insufficient (70%) or at risk (80%) groups were exposed to topical, nasal or inhaled corticosteroids, but not systemic. Only 60% and 12 % of those with IIH and insufficient or at risk cortisol testing, respectively, underwent definitive testing with a stimulation test. Adrenal function did not differ by age, race/ethnicity, zBMI, nor prolong exposure to steroids (> 2 weeks), time between IIH diagnosis and cortisol testing (all P>.05). Those in the deficient group were less likely to be female (33%) than those in the at risk (61%; χ 2=3.07, df=1, P=.001) or sufficient (81%; χ 2=7.30, df=1, P<.001) groups. Those with AI were more likely to have history of asthma (53%; vs: 18% at risk and 12% normal; both P>.05) Conclusions: Steroid use and AI are common in IIH and need consideration as a cause of IIH development. Appropriate diagnosis and treatment of AI in children who present with IIH may lead to its resolution, significantly impacting clinical outcomes of these children. In our cohort, the majority had AI or at risk cortisol levels, and many did not undergo further testing. All young children who present with IIH should be evaluated for steroid exposure, including non-systemic steroids, and undergo evaluation for AI. Caution should be utilized in pediatric providers prescribing these medications. More prospective studies are required to evaluate the effects of steroid use in relation to IIH development.

]]>
<![CDATA[SAT-LB13 Clinical Utility of 21-Deoxycortisol in Congenital Adrenal Hyperplasia]]> https://www.researchpad.co/article/elastic_article_8602 Introduction Congenital Adrenal Hyperplasia (CAH) is most often caused by mutation of the 21-hydroxylase gene (CYP21), which results in underproduction of cortisol with overproduction of precursor steroids and their metabolites by the adrenal glands. Historically the most common biomarker used for detecting CAH in pediatric patients is 17-Hydroxyprogesterone (17OHP). Another less commonly used biomarker for 21-Hydroxylase deficiency is 21-deoxycortisol (21DOF), which increases from very low levels in normal patients to high levels in affected patients as 17OHP rises to very high levels. In this study we performed retrospective analysis of serum 21DOF concentration in specimens that had been genotyped for mutations in the CYP21A2 gene, or had been submitted to our laboratory for provocative adrenocorticotropin (ACTH / Cosyntropin) stimulation testing. Methods: Biochemical testing for 21DOF concentration was measured by LC-MS/MS. Briefly, a TX-4 HPLC system (Thermo-Fisher) with Agilent® 1100 pumps (Agilent Technologies, Inc.) and a Sciex® 5000 (Danaher) triple quadrupole mass spectrometer in positive mode atmospheric pressure chemical ionization (APCI) was used for detection in Multiple Reaction Monitoring (MRM) mode. Genetic testing was performed using the CAHDetx test, which detects the 12 most common small mutations and large gene deletions/conversions in CYP21A2. Genetic Correlations: 21DOF was quantifiable (above the LLOQ of the assay) in 4% (n=24/600) of specimens where no mutation was detected. 21-DOF was quantifiable in 42% (122/292) of specimens with 21-hydroxylase enzyme mutations as determined by the CAHDetx test. Those mutations included In2G, I172N, V281L and others. Some mutations such as Q318X did not result in a detectable increase in 21-deoxycortisol. ACTH Stimulation Response: 21-deoxycortisol was below the quantitation limit in both the baseline and stimulated samples in ~35% (52/148) of submitted samples. The 21-deoxycortisol was quantifiable in only the stimulation sample in ~45% (65/148) of ACTH stimulation submitted, and was quantifiable in both baseline and stimulated samples in the remaining ~20% (30/148) of ACTH stimulation pairings. The extent of 21-deoxycortisol increase ranged from 1.2-fold to 116-fold with a median 14-fold increase. Clinical Significance: The use of 21-deoxycortisol may be beneficial in reducing the rate of false positives in CAH diagnosis when used in concert with other steroid hormones, and may eventually reduce the need for provocative testing to confirm CAH diagnosis.

]]>
<![CDATA[SAT-LB17 Triplication of SHOX Downstream Region in Mild Short Stature]]> https://www.researchpad.co/article/elastic_article_8554 Deletions of the downstream flanking regions of the SHOX gene that contain conserved non-coding cis-regulatory DNA elements are a known cause of Leri-Weill dyschondrosteosis or idiopathic short stature (ISS). Functional and comparative genomic studies have demonstrated the existence of four CNE enhancers downstream of SHOX which have transcriptional activity, and a fifth has recently been suggested at approximately X:970,000. Duplications of these downstream regions have also been described in patients with ISS, although with a variable phenotype. We present a family with ISS and the first ever reported SHOX downstream triplication. The index case was a 12-year-old Caucasian female of unrelated parents, born with normal weight and length, and normal hearing/vision and development. At the age of 12, her height was -1.87 SD (-1.35 SD adjusted for parental height). Her growth chart showed a height on the 90th centile at birth, slowly crossing centiles for the first 5 years to the 2nd centile, which she then followed. She had normal proportions and head circumference, and no dysmorphic features apart from inverted nipples. Baseline investigations for short stature were normal, including IGF1, karyotype and celiac screen. Bone age was 1.5 year delayed. Family history: arthritis in the father, early menopause in the mother. Analysis of SHOX and its flanking regions was carried out using Multiplex Ligation-dependent Probe Amplification (MLPA) and direct sequencing of all coding exons. MLPA analysis showed a SHOX downstream triplication with a minimum size of 66kb (X:963670-1029779) and a maximum size of 428kb (X:899389-1327688). The size of the duplication was further defined using array comparative genome hybridization (ACGH) analysis which showed the minimum size to be ~325kb (X:907457-1232802). This triplication includes the proposed regulatory element at ~ X:970,000. The triplication was subsequently shown to be present in the proband’s mother and brother who also have mild ISS. Further analysis of these and other family members is ongoing. The triplication is of a single-sized fragment, and the fragment size is identical to one that has been seen in duplicated form in several other patients, increasing the likelihood that the triplicated fragments are in tandem. The precise mechanism of the pathogenic effect of the triplication is unknown, but it likely exerts a negative effect on SHOXtranscription, reducing its expression and ultimately resulting in SHOX haploinsufficiency. In conclusion, we describe a family with mild ISS and a downstream triplication of the proposed X:970,000 SHOX downstream regulatory element. This provides further evidence for this previously proposed regulatory element downstream of SHOX and adds additional proof that increased dosage of this regulatory element region is a cause of short stature.

]]>
<![CDATA[SAT-094 Evaluation of IGF-1 as a Biomarker to Inform Phase 3 Clinical Trial Design and Dose Selection in Patients Born Small for Gestational Age Who Fail to Demonstrate Catch-Up Growth by Age 2–4 Years]]> https://www.researchpad.co/article/elastic_article_7173 Insulin-like growth factor-1 (IGF-1) is a key hormone in mediating the physiological response to endogenous and exogenous growth hormone (GH). Current clinical guidelines suggest use of IGF-1 for dose titration in adults with GH deficiency and for safety monitoring in adults and pediatric patients. Several GH drug development programs for pediatric indications have collected IGF-1, height standard deviation score (HSDS), and height velocity (HV), to support dose selection in Phase 3 clinical trials. In this analysis, patients born small for gestational age (SGA) who fail to demonstrate catch-up growth by age 2–4 years from different growth hormone product development programs were included. A total of 663 patients from 8 clinical trials were included in this analysis, with 7 placebo arms and 15 growth hormone treated arms. The growth hormone dosing regimen ranged from 33 ug/kg/day to 100 ug/kg/day. Both boys and girls throughout a wide range of ages (3 to 7 years old on average) were represented in this analysis. The average patient was 3 to 4 standard deviations below the age- and sex- adjusted mean height at baseline. IGF-1 was collected and standardized according to age and sex, so called the IGF-1 standard deviation score (IGF-1 SDS). At baseline, the average patient had normal IGF-1 (-1 to 0 on average). Based on preliminary findings, IGF-1 SDS change from baseline (CFB) at 6 months was correlated with HSDS CFB at 12 months. HSDS CFB at 3 months and 6 months were also correlated with HSDS CFB at 12 months, respectively. These findings were consistent across the three GH products included in the analysis, as well as age and gender. However, IGF-1 SDS CFB had much larger variability than HSDS CFB. Both HSDS CFB at 3 months and 6 months precisely and accurately predicted HSDS CFB at 12 months. IGF-1 SDS was more variable and did not add any further contribution in the prediction of HSDS at 12 months and therefore IGF-1 may not be sufficient in informing Phase 3 dose selection in such trials.

Reference: 1. Shoshana Yakar, Clifford J. Rosen, Wesley G. Beamer, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest. 2002 Sep 15; 110(6): 771–781. 2. Locatelli V, Bianchi VE. Effect of GH/IGF-1 on Bone Metabolism and Osteoporosis. Int J Endocrinol. 2014;2014:235060 Nothing to Disclose: TL, JP, BC, MZ, JV, CS

]]>
<![CDATA[SAT-090 Factors Affecting IGF-1 Level and Correlation with Growth Response During Growth Hormone Treatment in LGS Patients]]> https://www.researchpad.co/article/elastic_article_7125 Background: Primary goal of growth hormone (GH) treatment for short children is to achieve an adult height in the normal range. Different GH treatment strategies to achieve this goal include titration of GH dose according to serum insulin-like growth factor I (IGF-I) concentrations. However, IGF-I levels do not always correlate well with the growth response. The purpose of this study is to identify the factors affecting IGF-I concentration in each disease and to correct the related factors and then to identify the relationship between IGF-1 and treatment response. Methods: In this study, data of pre-pubertal children with idiopathic growth hormone deficiency (IGHD), organic GHD (OGHD), Turner syndrome (TS), small for gestational age (SGA) who were treated with recombinant human GH more than one year were obtained from the LGS Database. The LGS has been progressing since 2012 and is an open-label, multicenter, prospective, and retrospective observational study. Results: Among 2,021 registered in LGS, the subjects were 366 except for the violation of selection criteria. Among them, IGHD was 252, 16 OGHD, 31 TS, and 67 SGA. The mean age of IGHD was 6.02, and the mean bone age was 4.49 years. OGHD was 7.38, 5.74, TS was 7.13, 6.52, and SGA was 5.61, 4.96 years. The height SDS according to chronologic age was -2.76 in IGHD group, OGHD -2.33, TS -2.9, SGA -2.57. In the IGHD and SGA group, IGF-I level has a positive correlation with weight and BMI (weight; r=0.0071 in IGHD, r=0.0009 in SGA, BMI; r=0.0411 in IGHD, r=0.003 in SGA). IGF-I showed a negative correlation with chronological age in the IGHD group (r=0.0411) and mid-parental height in the SGA group (r=0.0069). There was no significant relationship between pretreatment IGF-I level and growth response. However, in the IGHD group, the growth response was significantly higher when the change in IGF-I SDS value was 1 or more (P=0.0013). Conclusion: This study is the first study using LGS data to identify factors affecting IGF-I levels in Korean children with short stature and the relationship with treatment response. IGF-I levels were positively correlated with body weight in IGHD and SGA groups. There was no significant relationship between pre-treatment IGF-I levels and post-treatment growth response. In conclusion, IGF-I concentrations should be used as a tool for treatment compliance rather than for efficacy determination.

]]>
<![CDATA[SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene]]> https://www.researchpad.co/article/elastic_article_6952 Central diabetes insipidus (CDI) is a disorder of water balance characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although non-hereditary causes are the most frequent, Familial CDI forms, due to heterozygous mutations in the AVP gene, have also long been recognized. Inheritance occurs mostly in an autosomal dominant manner with almost complete penetrance. The AVP gene encodes for a 164 aminoacids preprotein: the AVP preprohormone which consists of a signal peptide, AVP hormone (9 amino acidpeptide), Neurophysin II (AVP carrier), and a glycoprotein, Copeptin. The AVP preprohormone, is produced in the hypothalamus sand is targeted to the endoplasmic reticulum (ER) by the signal peptide. After cleavage and processing, the AVP hormone is packaged within protein carrier NPII and are transported by axonal trafficking to the neurohypophysis where they can be stored and secreted.

Structural changes in NPII have been associated with intracellular accumulation of mutant AVP precursors that have been postulated to be cytotoxic and decreased cell viability of vasopressin-producing neuronsin the neurohypophysis.

In this study we describe two index cases from two families of four-generation kindred suspected to have Familial neurohypophyseal diabetes insipidus (FNDI), with absent or barely visibleposterior pituitary by MRI. A water deprivation test was performed in both cases, resulting confirmatory for DI in case 1 while it was inconclusive in case 2.

In both cases, molecular studies revealed a pathogenic variant in heterozygous state in the NPII region of the AVP gene, in case 1 we found a previously reported and well characterized variant p.Cys116Gly, cysteine at codon 116 is involved in disulfide bridge important for the secondary structure of NPII. While in case 2 we found a novel variant, p.Gly45Val, in which all in silico tools predict deletereous, whereas there are a previously reported patogenic variant at the same amino acid residueand in 3D modeling it can be observed that structural and conformational changes occur in binding bridge of NPII.

We are reporting two novel non related familial CDI cases, even though lack of functional studies, the clinical phenotype in each pedigree suggest this diagnosis, and support the genetic counseling.

]]>
<![CDATA[SAT-088 The Incidence of Neurological Symptoms During Growth Hormone Therapy in Patients with Chiari Malformation]]> https://www.researchpad.co/article/elastic_article_6868 Background: Patients (PTs) with Chiari malformation (CM) are prone to a wide variety of neurologic symptoms (SX), including headaches (HA), vision abnormalities, and nausea. These SX are attributed to impaired flow of CSF leading to benign intracranial hypertension (BIH). Occasionally, PTs with CM may require growth hormone therapy (GHT). This can potentially increase CSF accumulation and risk of BIH. The literature is limited to a small number of case reports on GHT in PTs with CM. Here, we describe the incidence of neurologic SX in 15 PTs.

Methods: Our database was queried for PTs with CM who were treated with GHT from 2010–18 and records were reviewed for adverse events. PTs with neoplastic disease, active inflammation, or acute trauma were excluded. CM was defined as cerebellar tonsils located below the foramen magnum on MRI.

Results: Mean and median ages of the 15 PTs (10 male, 5 female) who met inclusion criteria were 15.3 and 11.7 years, respectively. 14 were diagnosed as Type 1 and 1 was diagnosed as Type 2 CM. Tonsillar displacement ranged from 2-21mm, but was not specified in 5 PTs. Indications for GHT included isolated GH deficiency, panhypopituitarism, and chronic renal disease. Duration of GHT ranged from 0.2 to 12.25 years with a mean and median of 3.7 and 1.75 years, respectively. 7% (1 of 15) PTs experienced new-onset SX of BIH that could be attributed to GHT.

8 PTs (53.3%) did not experience any SX consistent with CM before, during, or after GHT. 3 PTs (20%) experienced neurologic SX prior to GHT. 1 PT reported diplopia and abnormal sleep patterns prior to GHT that resolved and did not recur during GHT. 1 PT prior to GHT manifested papilledema, 1 seizure, central sleep apnea, and occipital HA that resolved after posterior fossa decompression. Post-operatively and during GHT, this PT developed and continued to manifest nonpathologic pseudopapilledema. 1 PT continued to have pre-existing seizures and insomnia that did not worsen with GHT. 1 PT (7%) had congenital neurologic abnormalities in addition to CM. This PT had surgery to alleviate BIH caused by congenital hydrocephalus and SX permanently resolved. GHT has been continuous since birth with no new manifestations of CM reported post-operatively. 2 PTs (13%) developed new-onset neurologic SX while on GHT. 1 PT with diabetes experienced HA, 1 report of loss of consciousness, and 1 instance of apnea during periods of hyperglycemia. It was determined that these SX were unrelated to BIH and GHT was not interrupted. 1 PT experienced mild HA and 1 episode of occipital pounding with emesis during GHT. These SX resolved without intervention and GHT was continued without interruption. Despite the complexity of these cases, 0 PTs discontinued GHT.

Conclusion: Our study demonstrates that in a majority (93%) of cases, GHT does not cause onset or worsening of SX of BIH in PTs with complicated and uncomplicated CM. GHT should be regarded as a safe treatment in these PTs.

]]>
<![CDATA[SAT-096 Response to RHGH Therapy in Children with Isolated Short Stature with or Without an Identified Genetic Cause]]> https://www.researchpad.co/article/elastic_article_6863 Introduction: Children with isolated (former known as idiopathic) short stature (ISS) have been treated with rhGH with a variable response. Objectives: To evaluate the short-term response to rhGH therapy in children with ISS with or without a genetic diagnosis. Methods: We analyzed retrospectively the growth rate and height SDS change in the first year of rhGH treatment according to the presence or absence of defects in genes that regulate growth plate. The decision to start rhGH treatment was based on clinical features and the genetic results were obtained during the follow-up. Patients were enrolled in several previous genetic studies using gene candidate approach or multigene sequencing analysis. Results: A total of 51 prepubertal children (36 boys) with ISS were treated with rhGH. Thirteen of these children start puberty during the treatment and three of them were concomitant treated with GnRH analog. Basal characteristics of these children were 7.7 ± 3.2 years of age, height SDS -2.5 ± 0.8; sitting height/height (SH/H) SDS 1.2 ± 1.4; BMI SDS 0 ± 1.0 and mild delay of bone age (-1.6 ± 1.3 y). The mean target height SDS was -1.2 ± 0.9y, 18 (35%) of these children have at least one parent with height SDS < -2 and 3 (6%) both parents are short. Consanguinity was present in 3 (6%) cases. Among this cohort, fifteen children had pathogenic or likely pathogenic allele variants in genes that regulate growth plate: IHH (n = 4), SHOX (n = 9) and NPR2 (n = 2). Seven (47%) of these variants were inherited from a short stature parent. Children with or without an identified genetic cause have similar age and height SDS at the start of the treatment. A higher BMI and SH/H SDS were observed in children with genetic defects than in those without (BMI SDS 0.5 ± 1.1 vs. -0.15 ± 0.9, p = 0.02; SH/H SDS 2.0 ± 1.4 vs. 0.9 ± 1.3, p = 0.006). Additionally, children with genetic defects had a less marked bone age delay (-1.0 ± 1.3 vs. -1.9 ± 1.2; p = 0.02). Both groups were treated with similar rhGH dose (50 μg/kg/day). Patients with and without an identified genetic cause had similar improvement in growth velocity during the first year of therapy: 4.8 ± 1.6 to 8.9 ± 1.7 cm/y for patients with molecular diagnosis vs. 4.6 ± 1.2 to 8.5 ± 2.3 cm/y for those without. This resulted in similar height SDS change during this period for both groups (0.6 ± 0.3 vs. 0.6 ± 0.5 SDS for children with or without a genetic cause, respectively). Age at the start of treatment was the main variable that explains growth response variability during this first year (r2 = 0.17, p = 0.009). Conclusion: The presence or absence of an identified genetic cause, involving genes that regulate growth plate, did not significantly influence the short-term growth response to rhGH therapy of children with ISS. Long-term follow-up is still needed to assess the final height of these children and possibly to assess whether there is a different growth rate related to each known affected gene.

]]>
<![CDATA[SAT-106 Growth Hormone Treatment Response in Children]]> https://www.researchpad.co/article/elastic_article_6833 OBJECTIVES: Growth hormone (GH) therapy is an effective treatment in addressing growth failure in children with GH deficiency (GHD). It has also been increasingly used in non-GH deficient (nGHD) conditions. We sought to report the growth response of GHD and nGHD patients who received GH therapy at a tertiary care center. METHODS: Data was collected from health records of patients followed in the endocrinology clinic at Alberta Children’s Hospital, Calgary, Canada, from 2005 to 2019, and used to analyze clinical responses based on indication for GH treatment. RESULTS: A total of 167 patient records (87 males and 80 females) were used for analysis. The average age at the start of GH therapy was 7.3 years (range 0.25 to 16.98 yrs). 74 patients were in the GHD group while 93 were nGHD. Of the patients in the nGHD group, the most common diagnosis were: idiopathic short stature (ISS)(n=45), Turner syndrome (TS)(n=26), and Prader Willi Syndrome (PWS)(n=8). The mean height velocity (HV) in year 1 was highest in the GHD group at 11.68 cm/year (n= 62, sd = 5.93), followed by ISS at 9.41cm/year (n = 52, sd = 4.34). The mean first year HV of those who had received chemotherapy (n= 5, mean = 5.48, sd = 1.92) or had Turner syndrome (n= 24, mean = 7.20, sd = 2.15) was significantly lower than both the GHD and ISS groups. GH peak during a GH stimulation test at baseline was not correlated to the first year height velocity while on GH treatment. However there was a negative linear correlation between baseline IGF1 level and first year height velocity (Spearman’s rho = 0.312216, p-value= 0.01516). Age at GH initiation was negatively correlated with height velocity during GH treatment. Height velocity over time decreased sharply from year 1 to year 3, and became stable for the remaining years of GH therapy. For the entire group, HV for years 1-5 was 9.81 (sd=4.83), 7.40 (sd=2.89), 6.29 (sd=2.38), 5.92 (sd=2.56), 5.66 (sd=2.51). There is no significant correlation between GH dose and height velocity response after adjusting for diagnosis. CONCLUSION: In our population, the response to GH therapy was consistent with those reported in the literature. Response to GH therapy was not associated with GH peak on stimulation but rather to baseline IGF-1 level and age at initiation. Although peak GH to stimulation is required to obtain public funding for GH therapy, these findings demonstrate that GH stimulation test results may not indicate which patients may benefit the most from GH therapy. Follow-up until final adult height will allow us to have a better understanding of the efficacy of GH therapy in patients with both GHD and nGHD conditions.

]]>
<![CDATA[SAT-109 Utilizing Pituitary Volume (PV) and the Growth Hormone Stimulation Test (GHST) to Jointly Define the Etiology of Short Stature (SS): An Improved Diagnostic Criteria for Growth Hormone Treatment]]> https://www.researchpad.co/article/elastic_article_6827 Background: We have previously shown that short children have significantly reduced PVs. In this study, we further define the etiology of SS in a larger cohort of siblings (SBs). Objective: To further investigate the efficacy of PV as an indicator of poor growth. Patients and Methods:Methods: The database of a peds endo center was queried for SBs aged 6–18 yrs who underwent a GHST and subsequent MRI between 2013–19. Their MRI results were compared to randomly selected normal controls (NCs) aged 6–18 yrs seen at a neuroradiology center between 2010–16. Patients with MRI abnormalities were excluded. PVs were calculated using the ellipsoid formula (LxWxH/2). Our previous ROC curve analysis has defined 215.02mm3 and 315.00mm3 as cutoffs for small PVs in prepubertal and pubertal (PB) SBs, respectively (RSP). Growth hormone levels <10 ng/ml or >10 ng/ml diagnosed patients as growth hormone deficient (GHD) or idiopathic short stature (ISS), RSP. Patients: 77 SBs of 37 families were compared to 170 NCs. SBs <11 yrs and >11 yrs were considered pre-PB and PB, RSP. Results: The mean (MN) and median (MD) ages of SBs were 11.6 ± 2.2 and 11.9 yrs, RSP, and the MN and MD ages of the NCs were 12.6 ± 3.4 and 13.2 yrs, RSP. The difference (DIF) in MN age was significant (SG) (p<0.05). The pre-PB SBs and pre-PB NCs had MN and MD ages of 9.3 ± 1.2 and 9.7 yrs, RSP and 8.6 ± 1.4 and 8.6 yrs, RSP. The DIF in MN pre-PB age was SG (p<0.05). The PB SBs and PB NCs had MN and MD ages of 13.0 ± 1.4 and 12.7 yrs, RSP and 14.7 ± 1.9 and 14.6 yrs, RSP. The DIF in MN PB age was not SG (p<0.05).

The MN and MD PVs for SBs (n=77) were 220.1 ± 94.0 and 204mm3, RSP. The MN and MD PVs for NCs (n=170) were 364.0 ± 145.2 and 346.0mm3, RSP. The DIF in MN PVs was SG (p <0.001). Stratified by age, the MN and MD PVs for SBs ages 6–11 yrs (n=29) were 166.1 ± 46.8 and 160mm3, RSP, and the MN and MD PVs for NCs ages 6–11 yrs (n=58) were 246.8 ± 63.7 and 241.6mm3, RSP. The DIF in MN PV was SG (p <0.001). The MN and MD PVs for SBs >11 yrs (n=48) were 252.7 ± 100.5 and 227mm3, RSP and the MN and MD PVs for NCs >11 yrs (n=112) were 424.6 ± 138.4 and 403.3mm3, RSP. The DIF in MN PV was SG (p <0.001). 86% of pre-PB SBs had small PVs, while 93% were GHD. 79% of PB SBs had small PVs, while 79% of PB SBs were GHD. 81.8% of all SBs had small PVs, while 84.4% were GHD. When combined, GHST and PV identify the etiology for SS in 96.1% of subjects. Discussion: The GHST recognized the etiology for SS in 84.4% of the SBs, while PV identified 81.8%. Using both criteria together, the etiology for SS was identified in 96.1% of the SBs. 3 of the 4 pre-PB SBs, who did not meet the PV cutoff had PVs within 10% of the cutoff. Conclusion: We have shown that PV is not inferior to the GHST in the diagnosis of SS. Combining the GHST and PV defines the etiology of SS in 96.1% of patients. Jointly, the GHST and PV should be considered the new gold standard for identifying children who qualify for GH therapy. This criteria will significantly diminish the number of patients diagnosed with ISS.

]]>
<![CDATA[SAT-103 Extrauterine Growth Restriction (EUGR) in Preterm Infants: Incidence, Risk Factors, Nutrition, Auxological and Neurological Outcome.A Retrospective Study from 2010 to 2016]]> https://www.researchpad.co/article/elastic_article_6716 EUGR is still a serious problem in very low birth weight preterm infants. The gradual improvement in neonatal intensive care has allowed the survival of newborns with increasing low weight and gestational age, with a higher incidence of major nutritional problems and diseases (Goldenberg 2008). EUGR was defined as growth parameters ≤ 10° centile at discharge, compared to the expected intrauterine growth for post-menstrual age. Recently EUGR was defined, in a dynamic way, as the reduction in anthropometric parameters z-score between birth and discharge >1SD (Griffin 2016). Aims of our study were to evaluate: the incidence of EUGR, the nutritional intake, the main risk factors, the auxological and neurological outcome. We enrolled 346 newborns admitted to our NICU from 2010 to 2016 with gestational age (GA) at birth < 30 weeks and/or birth weight <1500 gr. Infants with malformations or syndromes were excluded. The incidence of EUGR was 73.1% for weight, 66.3% for length and 39.3% for head circumference. We observed a decrease in SD mainly during the first 14 days of life. From two weeks to discharge, no significant catch-up growth was observed. Risk factors for EUGR were: male gender, reduced GA (p=0.000), low birth weight (p=0.000), lower minimum weight achieved (p=0.000), more time to recover birth weight (p=0.000), lower growth rate per day (p=0.001), longer period of total parenteral nutrition (p=0.008), later onset of minimal enteral feeding (p=0.006), later achievement of the full enteral feeding (p=0.000), cesarean section (p=0.006), incomplete corticosteroid prophylaxis (p=0.025), postnatal steroids use (p=0.000), mechanical ventilation (p=0.000), pulmonary bronchodysplasia (p= 0.000), leukomalacia (p=0.06), patent ductus arteriosus (p=0.000), retinopathy of prematurity (p= 0.008), late onset sepsis (p= 0.09). In 197 patients post-discharge clinical follow up at 1, 3 and 24 months of correct age (CA) was performed. Around 88% of all our sample showed normal neurological development. 12% at 1 and 3 months had abnormal general movements (both writhing and fidgety movements) or absent (p = 0.001). At 24 months CA patients with abnormal/absent fidgety movements had neurological disabilities and 83% were EUGR. At 24 months, 17% had weight <10th centile and all were EUGR. 25% showed an overgrowth (weight >75th centile) with a probably increased risk of metabolic disease later in life. The incidence of EUGR increased over the years due to the augmentation in preterm births with lower GA. The first 14 days of life were a critical period and nutrition is known to be mandatory to promote newborns’ growth (Asbury 2019). The EUGR condition negatively affected the neurological (Chien 2018) and auxological (Takayanagi 2018, Wood 2018) outcome of preterm infants and the early recognition of this condition is extremely important in order to implement a careful and prolonged follow-up.

]]>
<![CDATA[SAT-086 Pituitary Volume as a Diagnostic Measure for Determining the Etiology of Short Stature in Children: Receiver Operating Characteristic Curve Analysis and Cutoff Values]]> https://www.researchpad.co/article/elastic_article_6446 Background: It is speculated that pituitary volume (PV) is a marker of chronic growth hormone (GH) secretion. In previous studies, we determined that children with GH deficiency (GHD) and idiopathic short stature (ISS) had significantly smaller PVs than normal controls (NCs). Cutoff values for small PVs are needed to improve the clinical utility of PV in determining children who qualify for GH therapy.

Objective: To define the cutoff between pathologic and nonpathologic PV in prepubertal and pubertal children with short stature (SS).

Patients and Methods: The SS group was selected from the database of a pediatric endocrinology center, which was queried for siblings (SBs) aged 6–18 yrs who underwent a GH stimulation test and MRI between 2013–2019. All 77 SBs had SS, defined as 2 SDs below mean height for age, subnormal growth velocity for at least 6 months, or predicted height at least 2 inches discrepant from midparental height. The NC group was selected from the database of a neuroradiology center; these NCs consisted of 170 randomly selected subjects aged 6–18 yrs. Patients with MRI abnormalities were excluded. PVs were calculated using the ellipsoid formula (LxWxH/2). ROC curve analysis was utilized to generate cutoff values. The diagnosis of short stature was the dependent variable and PV was the independent variable. The PV with the highest Youden index was selected as the definitive cutoff for a small PV.

Results: The mean (MN) and median (MD) age of SBs was 11.6 ±2.2 and 11.9 yrs, respectively, and the MN and MD age of the NCs was 12.6 ±3.4 and 13.2 yrs, respectively. The MN and MD age of prepubertal SBs (n=29) and NCs (n=58) were 9.3 ±1.2 and 9.7, and 8.6 ±1.4 and 8.6 yrs, respectively. The MN and MD age of pubertal SBs (n=48) and NCs (n=112) were 13.0 ±1.4 and 12.7, and 14.7 ±1.9 and 14.6 yrs, respectively. The difference in MN age between SBs and NCs was significant (p<0.05). For prepubertal subjects, sensitivity was 86.21% and specificity was 68.97%. The distance to corner was 0.3396, and the highest Youden index was 0.5517, corresponding to a PV of 215.02 mm3. The Area Under the Curve (AUC) was 0.8395 with a standard error of 0.0426 (p<0.001). For pubertal subjects, sensitivity was 81.25% and specificity was 79.46%. The distance to corner was 0.2781, and the highest Youden index was 0.6071, corresponding to a PV of 315.0 mm3. The AUC was 0.8460 with a standard error of 0.0337 (p<0.001).

Conclusion: To our knowledge, we present the first study on the sensitivity and specificity of PV in determining the etiology of SS. Our data suggest that prepubertal patients with a PV<215.02 mm3 and pubertal patients with a PV<315.00 mm3 have small pituitary glands. Statistically calculated cutoffs are necessary to accurately diagnose pituitary hypoplasia and should be utilized to determine the etiology of SS. Future studies should include children with Tanner staging and height SDs to generate more accurate PV cutoffs.

]]>
<![CDATA[SAT-087 Identifying Distinct Facial Dysmorphology in Youth with Congenital Adrenal Hyperplasia Using Deep Learning Techniques]]> https://www.researchpad.co/article/elastic_article_6064 Purpose: Classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency affects 1:15,000 newborns and involves adrenal insufficiency and androgen excess. These hormone abnormalities are evident as early as 7 weeks’ gestation and persist throughout pregnancy. Structural brain abnormalities are also known to occur in CAH, with abnormalities of brain and facial structure occurring together in conditions such as fetal alcohol spectrum disorder and holoprosencephaly. As well, sex differences in facial morphology are well described in healthy individuals. Thus, we aimed to study facial features using artificial intelligence in CAH youth. Methods: We studied frontal images of the face in 57 youth with severe salt-wasting CAH (60% female; 9.4±5.5y), and 38 controls (47% female, 9.7±5.1y), acquired with an iPad v12.1. We included 32 additional controls (43% female; 4-19y) from a publicly available face image dataset (1). Applying deep learning techniques, we converted 2-D facial photos to mathematical descriptors in order to differentiate features between groups. For a given test image, our pipeline output was a predicted “CAH score” between [0,1]. Due to our small dataset, we employed K-fold cross validation to train and test our deep neural network. At each of the K-9 folds, 88% of data (468 control and 531 CAH images) were used to train the network, with the remaining data (55 control and 63 CAH images) used to test the trained network. Test results were validated in terms of area under the curve (AUC) of receiver operating characteristic curves (generated from predicted CAH scores of test subjects), to analyze true and false positive rates. Our pipeline automatically detected face-bounding boxes and 68 facial landmarks (dlib toolkit) which were then used to compute 27 Euclidean (linear) facial features (2,3). We performed between group analyses of features with t-tests. Results: The averaged AUC of nine folds was 0.83±0.14, representing strong predictive power as a proxy to correlating facial dysmorphology with CAH. Predicted CAH scores were different between control (0.24±0.33) and CAH (0.69±0.37; p<0.0001) youth. Thirteen of 27 facial features were different between controls and CAH (p<0.05 for all) including 3 of 6 features related to sexual dimorphism. We also produced heat (i.e., saliency) maps showing the effect of CAH on facial features, and 2D t-SNE plot visualization of features showing well-defined separation between CAH and control group clusters. Conclusions: Utilizing deep learning, we have shown that CAH youth have facial features that can reliably distinguish them from controls. Further study is merited in regard to the etiology of affected facial morphology in CAH, and associations with disease severity, and/or brain and behavior abnormalities. (1) Masi I et al. Int J Comput Vis 2019. (2) Whitehouse AJ et al. Proc Biol Sci 2015. (3) Lefevre CE et al. Evol Hum Behav 2013

]]>
<![CDATA[SAT-107 Improved Adult Height in Brazilian Turner Syndrome Patients Treated with Growth Hormone]]> https://www.researchpad.co/article/Ne3cf24d2-ed5b-4a74-9f7c-163067507cd1 <![CDATA[SAT-091 First Report of Disease-Specific Patient-Reported Outcomes from a Randomized Phase 2 Trial of Once-Weekly Somapacitan vs Daily GH in Children with GHD]]> https://www.researchpad.co/article/Nc88872b3-02ba-4d7a-b294-204ece1a0678 <![CDATA[SAT-LB15 24-Month Efficacy and Safety of Once Weekly and Every Other Week Administration of GX-H9, Hybrid FC-Fused Long-Acting Human Growth Hormone: A Phase 2 Study in Children With Growth Hormone Deficiency]]> https://www.researchpad.co/article/Nee1e29fb-8781-4d44-af2e-6a45d52c574d <![CDATA[SAT-LB18 A Randomized Controlled Trial of Vosoritide in Children With Achondroplasia]]> https://www.researchpad.co/article/N6aa9d9bc-59db-430b-97bf-6d44dbc1a84d <![CDATA[SAT-092 Positive Effect of an Early Start of Growth Hormone Therapy on Auxology and Metabolic Parameters in Children with Prader Willi Syndrome]]> https://www.researchpad.co/article/Ne65689ad-0bb5-46ce-b554-b6194e424574