bluuebunny/crossref_metadata_2025_split huggingface dataset:
12625 P450 Side-chain Cleavage Enzyme Deficiency - A Rare Cause Of Congenital Adrenal Hyperplasia And A Newly Described Genetic Variant
Authors: Tabatabai Ideen , Meeks Naomi , Rapp Michele , Slater Brady , Barker Jennifer Marie 
Published: October 2024

Abstract
Disclosure: I. Tabatabai: None. N. Meeks, MD: None. J.M. Barker: None.
Background: P450 side-chain cleavage enzyme (P450scc) is responsible for the first step in steroidogenesis, converting cholesterol to pregnenolone after cholesterol has been transported into inner mitochondria by StAR. Deficiency in P450scc was first described in 2001 as a cause of primary adrenal insufficiency (PAI) and since then only 40-50 cases have been reported in literature. Clinical Case: A previously healthy 4 month old female born at 36-week gestation presented with 1 week of fatigue, refusal of oral feeds and weight loss. Labs were notable for severe hyponatremia (119 mEq/L), hyperkalemia (6.6 mEq/L), and non-anion gap metabolic acidosis (Bicarbonate 13). Genital exam was normal, newborn screens were normal, and there was no family history of glucocorticoid or mineralocorticoid defects. Further labs revealed hyperreninemic hypoaldosteronism and primary adrenal insufficiency with low aldosterone (2.1 ng/ml, NL &gt;5), elevated plasma renin activity (124 ng/ml/h, NL &lt;58), elevated ACTH (961 pg/ml, NL &lt;48), normal Cortisol on assays not done by mass spectrometry, undetectable 17-OHP, and normal Corticosterone, 11-desoxycortisol, androstenedione, DHEA-S, total testosterone, TSH and T4. She was started on fludrocortisone and kayexalate, then maintenance hydrocortisone was added. ACTH, renin, and electrolytes normalized in the following months and kayexalate was discontinued. She remains on Hydrocortisone and Fludrocortisone and is growing well with normal developmental milestones.A C.A.H. genetic panel revealed two heterozygous mutations in CYP11A1, the gene responsible for P40scc. The first is a known pathogenic loss-of-function mutation (c.835del). The second is a new variant of unknown significance not yet seen in genetic registries, causing a Serine to Leucine shift (c.293C&gt;T). Parent testing showed only a heterozygous c.835del mutation in the mother. Inheritance hypotheses for the new variant include a de novo mutation, paternal germline mosaicism, or a trans-acting gene variant on a different chromosome. Karyotype confirmed 46XX. This was done as p450scc deficiency in XY can cause under-virilization and sex reversal. Conclusion: P450scc deficiency, while rare, is a cause of PAI that is missed by newborn screens which flag elevated 17-OHP, as the deficiency is higher up and all downstream steroid metabolites (i.e. 17-OHP) will not be elevated. Differentiation between StAR and P450scc deficiency can only be done by genetic testing. As this patient is heterozygous for both variants, enzyme function assays of p450scc which are limited to research settings will help determine pathogenicity of this c.293C&gt;T variant and to quantify the degree of enzyme function.
Presentation: 6/1/2024
8265 Premature Ovarian Insufficiency in Pediatric Cancer Patients: a 10-Year Rady Children's Hospital Experience
Authors: Robinson Miranda , Meller Leo , Patterson Mary Elizabeth 
Published: October 2024

Abstract
Disclosure: M. Robinson: None. L. Meller: None. M.E. Patterson: None.
Objective: To highlight the occurrence of premature ovarian insufficiency in cancer patients treated at a children’s hospital and to determine which patient characteristics or treatment modalities are associated with ovarian failure and subsequent recovery of ovarian function. Study design: A retrospective chart review. Setting: Rady Children’s Hospital San Diego. Subjects and Methods: Between August 2011 and August 2021, the cases of 36 patients with cancer and ovarian failure were reviewed. Data collected included type of cancer, age at diagnosis, types of chemotherapy used in treatment, whether a bone marrow transplant or radiation was part of the treatment plan, peak FSH value and age when this occurred, peak AMH value, whether GnRHa treatment was used, type of hormone replacement therapy used, and whether there was recovery of ovarian function. Results: The most common type of cancer identified in this group of patients was acute lymphoblastic leukemia (ALL) (13, 36.1%). The mean age of diagnosis was 8.5 ± 4.3 years and the mean age of peak FSH value was 12.6 ± 2.8 years. Nearly all patients (97.2%) were treated with alkylating agents as part of their chemotherapy regimen and 72.2% received some form of radiation. Most patients (26, 72.2%) also received some form of hormone therapy, most commonly transdermal hormone therapy (13, 36.1%) or oral contraceptive pill (10, 27.8%), and 15.8% of patients were treated with the GnRHa Lupron. Fertility planning was offered or discussed in 36.1% of patients. Ten patients (27.8%) were noted to have some degree of recovery in their ovarian function. Age at diagnosis and type of cancer treatment were significant predictors of recovery in multivariate regression modeling. Specifically, each year older in age was associated with a 30% decrease in odds of recovery (OR: 0.7, CI: 0.5-0.95, P = 0.035), and treatment with an alkylating agent without transplant was associated with a 3-fold increase in odds of recovery (OR: 3, CI:2.7-564, P = 0.007). Conclusion: This retrospective review demonstrates that, while uncommon, POI can occur in pediatric cancer survivors, emphasizing the importance of educating patients on the potential long-term effects of cancer treatment and routine surveillance for these complications. This study also confirmed that recovery of ovarian function is possible in these patients, especially when diagnosed at a younger age, so continued monitoring is essential.
Presentation: 6/3/2024
7063 Serum Alkaline Phosphatase Level as a Marker for Progressive Central Precocious Puberty
Authors: Figueredo V M , Seeherunvong T 
Published: October 2024

Abstract
Disclosure: V.M. Figueredo: None. T. Seeherunvong: None.
Background: Precocious puberty is typically associated with a speed up in growth, risk of premature growth plate closure and reduced adult height. Serum alkaline phosphatase (ALP) is a biochemical indicator of bone turnover and studies have shown greater serum ALP levels in pubertal individuals compared to prepubertal controls. We examined serum ALP levels among children with various form of early puberty. We investigated whether serum ALP levels were significantly different between children with premature thelarche or premature adrenarche compared to those with central precocious puberty (CPP). Methods: We conducted a retrospective chart review of patients with early pubertal development attending a pediatric endocrinology clinic between 2017 and 2023. Information on height, weight, serum ALP levels and bone age was obtained. Patients were considered to have CPP based on the results on a GnRH test. Patients with diagnosis of premature adrenarche or premature thelarche were included as controls. This study was approved by Institutional Review Board (IRB). Analysis of data was performed using IBM SPSS Statistics version 29.0.1.0 (171). Results: Among 72 patients included in the study, 22 patients had progressive CPP whereas 50 patients had premature adrenarche or premature thelarche. The prevalence of abnormally elevated serum ALP levels was greater among patients with CPP (22.7%) than among patients with premature adrenarche or premature thelarche (6%). Using logistic binomial regression analysis, serum ALP levels were significantly elevated (p=0.042) in subjects with progressive CPP compared to patients with premature adrenarche or premature thelarche. Both groups had similar BMI values. BMI z-scores and advanced bone age were positively correlated. BMI (p=0.08) and advanced bone age were not significantly different (p=0.12) in the group with CPP compared with the group comprising patients with either premature adrenarche or premature thelarche. Conclusion: These findings suggest that serum ALP levels are helpful as a tool to help distinguish CPP from premature adrenarche or premature thelarche in the evaluation of patients with initial early pubertal development.
Presentation: 6/1/2024
6942 Should there be a consensus statement about managing Inguinal Hernia In females? A Case of Delayed Diagnosis in Complete Androgen Insensitivity Syndrome (CAIS)
Authors: Echetebu S 
Published: October 2024

Abstract
Disclosure: S. Echetebu: None.
Introduction: Androgen Insensitivity Syndrome is usually due to a missense mutation that encodes part of the androgen receptor. More than 50% of females with CAIS present with inguinal hernias (4:1 female to male ratio). Previous CAIS studies have estimated the incidence of CAIS to be 0.8% to 2.4% in girls with inguinal hernias. 90% of the girls with CAIS will undergo inguinal hernia repair during childhood. The prevalence of germ cell tumors is estimated as 0.8% therefore, post-pubertal gonadectomy is now the recommended therapy for individuals with CAIS. Clinical Case: We present a case of a 15-year-old patient with primary amenorrhea who underwent bilateral inguinal hernia repair at the age of 5 weeks and was raised as a female. Initial ultrasound imaging at the age of 14 years revealed an absent uterus and complex hemorrhagic cysts of the ovaries. Further laboratory results revealed 46 XY chromosomal analysis, confirming her diagnosis of CAIS. Her laboratory values are: FSH 6.0 mIU/ml (1.0 to 18.6), Prolactin 15.6 ng/mL (&lt;25), 17OHProgesterone 49 ng/dl (&lt;265), Estradiol 30 pg/ml (&lt;47), LH 17 mIU/ml (0.4 -11.7), Anti Mullerian Hormone 368 ng/ml (&lt;13), Testosterone 629 ng/dl (&lt;55 ). Upon our review of her past medical records from a different hospital, the operation note reports that her gonads resembled testes. Gonads were relocated in the abdomen without follow-up or consultation with an endocrinologist. Upon receiving her new diagnosis, the patient experienced significant emotional distress. As a result, both the patient and her family received psychological counseling and were referred to a genetic counselor to assess any potential risks for her younger sister. There is currently no consensus on the management of females with inguinal hernias in the available literature. It is widely accepted to perform gonadectomy. Currently, researchers at NIH are conducting an observational study on the benefits of additional delays in gonadectomy. Although most surgeons are familiar with this condition, it would be beneficial for families and patients to have an early diagnosis and provide appropriate education regarding future sexual encounters and fertility concerns. Conclusion: We propose to initiate a consensus statement for pediatricians, surgeons, and endocrinologists to perform systematic genetic testing in females with inguinal hernia. Such testing may include either a buccal mucosal smear, karyotype, or skin biopsy in all females with inguinal hernias. If the family chooses to delay orchiectomy, it is recommended that during hernioplasty, the testes should be repositioned in a location that allows for easy monitoring using annual imaging. By adopting this methodology, we can increase awareness about the effects of diagnosis and foster discussions among healthcare professionals regarding suitable management options.
Presentation: 6/3/2024
9282 Silver - Russell Syndrome and Free Insulin-like Growth Factor-1 Measurements
Authors: Oude Engberink Raoul David , van den Bogert Valesca , IJsselstijn Linda , van den Berg Sjoerd Adrianus Antonius , van der Kaay Danielle Christine Maria 
Published: October 2024

Abstract
Disclosure: R.D. Oude Engberink: None. V. van den Bogert: None. L. IJsselstijn: None. S.A. van den Berg: None. D.C. van der Kaay: None.
Introduction: Silver - Russell syndrome (SRS) is a congenital condition characterized by prenatal and postnatal growth retardation. An underlying genetic cause is identified in approximately 60% of patients clinically diagnosed with SRS. The 2 main genetic alterations are loss of methylation of chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (UPD(7)mat). Patients benefit from early and appropriate growth hormone (GH) treatment. However, GH treatment in SRS patients is associated with high levels (&gt; 2 SDS) of immunoreactive Insulin-like Growth Factor-1 (IGF-1). As a result, clinicians often lower the GH dose, resulting in a suboptimal effect on growth, body composition and quality of life. There has been increased interest in measuring free IGF-1 in these conditions. Theoretically, the unbound fraction of IGF - i.e. the fraction that is readily dissociable from IGF binding proteins - is the biologically active fraction. Measurement of free IGF-1 might better reflect IGF-1 bioavailability and may be of benefit in optimizing GH treatment. Objective and methods: We explored levels of free IGF-I versus immunoreactive (total) IGF-1 in 22 SRS patients on GH treatment. Immunoreactive IGF-1 was measured on a routine immunochemistry analyzer (IDS-iSYS) and free IGF-1 was measured manually using a two-site antibody method (AnshLabs). Results: In this group of 22 SRS patients the mean immunoreactive IGF-1 was +1.96 +/- 0.48 SDS and the mean GH dose was 0.84 +/- 0.24 mg/m2/d. Subdividing into SDS categories, 45% of patients had an immunoreactive IGF-1 &gt; 2 SDS. In this subset, 60% of patients had levels of free IGF-1 in the normal range (&lt; 2 SDS). Further stratification into the underlying molecular defect showed that 11p15 LOM was associated with a more pronounced discrepancy between the level of immunoreactive IGF-1 (+2.64 SDS) and free IGF-1 (+0.25 SDS). Conclusion: In the majority of SRS patients on GH treatment, immunoreactive IGF-1 levels exceeded &gt; 2 SDS, whereas free IGF-1 levels were within normal range. Measurement of free IGF-1 could provide clinicians with an additional tool to determine the dose of GH in SRS patients. Ongoing research will reveal the full potential of free IGF-1 measurements in disorders that affect the GH - IGF-1 axis.
Presentation: 6/3/2024
7267 Study of the effect of GnRHa on BMI in girls with central precocious puberty
Authors: Lin L , Ouyang L , Yang F 
Published: October 2024

Abstract
Disclosure: L. Lin: None. L. Ouyang: None. F. Yang: None.
Background: In recent years, childhood obesity has garnered increasing attention. Although a correlation between obesity and central precocious puberty has been established, the underlying mechanisms remain incompletely understood. Gonadotropin-releasing hormone analogues are currently a common clinical intervention for treating CPP. Previous studies have predominantly focused on the enhancement of height following treatment. However, there is limited research on the impact of treatment on BMI, with some studies presenting conflicting results. Our study aims to assess the efficacy of GnRHa and investigate whether GnRHa treatment influences BMI. Methods: This study adopted an observational and retrospective design, enlisting a cohort of girls diagnosed with CPP. The study cohort was categorized into normal weight, overweight, and obese groups according to BMI values recorded at the initial diagnosis. Changes in clinical parameters, encompassing height, weight, BMI, bone age, and hematological markers, were systematically analyzed for the entire study population and subgroups at initial diagnosis, 12 months, and 24 months. Disparities in clinical parameters across various groups of girls were meticulously compared. Results: At the initial diagnosis, the prevalence of obesity among girls with CPP was noted to be 26.5%. After 1 and 2 years of treatment, this prevalence decreased to 18.8% and 15.4%, respectively. In the overall cohort of girls with CPP, the BMI-SDS at baseline, one-year treatment, and two-year treatment were 0.9 (0.2-2.1), 1.0 (0.3-1.6), and 0.8 (0.1-1.3), respectively (p=0.407). Upon categorizing the study population based on BMI and conducting intragroup comparisons, the BMI-SDS for the normal weight group at baseline, after one year of treatment, and after two years of treatment were 0.3±0.5, 0.4±0.6, and 0.3±0.6, respectively (p=0.576). The BMI-SDS for the overweight group at baseline, after one year of treatment, and after two years of treatment were 1.5±0.2, 1.4±0.5, and 1.2±0.2, respectively (p=0.046). The BMI-SDS for the obese group at baseline, after one year of treatment, and after two years of treatment were 2.9±0.9, 2.6±1.4, and 2.3±1.2, respectively (p=0.106). Conclusion: In our study cohort, there was a high detection rate of obesity among girls with CPP, and the use of GnRHa did not contribute to an increase in the incidence of overweight and obesity among CPP girls. Furthermore, GnRHa treatment did not result in an elevation of BMI-SDS in girls with CPP. The anthropometric measurements in various groups after treatment aligned with current research findings.
Presentation: 6/1/2024
9267 Targeting IGF-I to Growth Plate Cartilage Augments Therapeutic Effects on Skeletal Growth and Reduces Hypoglycemic Effects in Mice
Authors: Tailor Krishma , Stowe Tim , van Ree Janine , Ventura Brit , van Deursen Jan , O’Brien Robert , Baron Jeffrey , Lui Julian 
Published: October 2024

Abstract
Disclosure: K. Tailor: None. T. Stowe: None. J. Ree: None. B. Ventura: None. J. Deursen: None. R. O'Brien: None. J. Baron: None. J. Lui: None.
Recombinant human growth hormone (GH) is commonly used to treat short stature in children but has limited efficacy in severe, non-GH-deficient conditions, such as skeletal dysplasias, and has adverse off-target effects. Because short stature is the result of reduced growth plate chondrogenesis, we hypothesized that targeting chondrogenic growth factors specifically to the growth plate might augment the therapeutic skeletal effect while diminishing adverse effects on non-target tissues. Toward this end, we previously developed fusion proteins conjugating insulin-like growth factor-1 (IGF-1) with a single-chain human monoclonal antibody fragment (ScFv) targeting matrillin-3 (1), a protein specifically expressed in cartilage matrix, and demonstrated increased on-target therapeutic efficacy at the growth plate and decreased off-target effects in a GH-deficient (lit) mouse model (2). In the current study, we established a second GH-deficiency model by administration of a GH antagonist, pegvisomant (PEG), in C57BL/6 wild-type male mice. Alternate-day injection of pegvisomant at 40 mg/kg for 7 days reduced body weight, serum IGF-1 levels, and growth plate height in mice. Using this model, we found that once-daily SQ administration of cartilage-targeted IGF-I (named CV1574-1) for five days increased body weight and growth plate height greater than an equimolar dose of IGF-I itself administered twice daily. Hypoglycemia is an adverse effect of recombinant IGF-1 treatment. Therefore, we also monitored blood glucose levels after a single SQ injection of CV1574-1 and found that this fusion protein showed a reduced hypoglycemic effect compared to injection of IGF-I itself. Lastly, to gain mechanistic insight into the role of matrillin-3 targeting on therapeutic efficacy, we assessed the ability of CV1574-1 to induce pAKT signaling in vitro. Transient exposure to CV1574-1 caused more prolonged induction of pAKT signal in wild-type rat chondrosarcoma (RCS) cells compared to matrillin-3-knockout RCS cells, suggesting that matrillin-3 targeting extends the duration of IGF-1 receptor activation. To summarize, the current findings demonstrate that CV1574-1, a fusion protein that targets IGF-1 to cartilage, improves efficacy at the growth plate, reduces hypoglycemic effects, and, in vitro, prolongs receptor activation. Our study provides further evidence that cartilage-targeted therapy has the potential to provide new pharmacological approaches for the treatment of childhood linear growth disorders, including skeletal dysplasias and growth failure due to systemic disease. Reference:(1) Cheung et al. Pharma Res 2015, 32(7):2439-49.(2) Lui et al. Molecular Therapy 2019, 27(3):673-680
Presentation: 6/3/2024
6371 Conditional Deletion Of Nr5a1 In Sox9-cre Mice Impairs Adrenal Development
Authors: Ikeda Yayoi , Tagami Ayako , Ishizuka Kyoko , Maekawa Mamiko 
Published: October 2024

Abstract
Disclosure: Y. Ikeda: None. A. Tagami: None. K. Ishizuka: None. M. Maekawa: None.
The adrenal cortex is a major tissue that produces steroidogenic hormones necessary for regulating body homeostasis. Nuclear receptor subfamily 5, group A, member 1 (Nr5a1, SF-1, or Ad4BP) plays a crucial role in the regulation of adrenal and gonadal development, function and maintenance. SRY-related HMG-box gene 9 (Sox9) is upregulated by interaction of SRY with NR5A1, and leads the supporting cell precursors in XY gonads to differentiate into Sertoli-lineage cells at the initiation of testis differentiation. We previously generated Sox9-cre-Nr5a1flox/flox conditional knockout (cKO) mice, and showed that the loss of Nr5a1 in the gonads of XY Sox9-cre-Nr5a1flox/flox cKO mice abrogated the testicular pathway at embryonic day (E) 12.5–E13.5 to result in postnatal male-to-female gonadal sex reversal (1). Here, we investigated adrenal development of the Sox9-cre-Nr5a1flox/flox cKO mice. In mammals, after separation from the common adrenogonadal primordium, the adrenal primordium, which is formed dorsomedial to the gonadal primordium, begins to develop around E11.5. Double-immunostaining for NR5A1 and SOX9 revealed the presence of cells expressing both NR5A1 and SOX9 in the adrenal primordium of both sexes at E11.5 but not at E12.5. At E12.5, the number of NR5A1+ adrenocortical cells in Sox9-cre-Nr5a1flox/flox cKO mice markedly decreased compared with Nr5a1+/+ mice, and apoptotic cells, which were immunolabelled for active caspase 3, were detected in the area of the adrenal primordium in Sox9-cre-Nr5a1flox/flox cKO mice but not in Nr5a1+/+ mice, indicating that NR5A1- and SOX9-immunoreactive adrenocortical cells in Sox9-cre-Nr5a1flox/flox cKO mice were extinguished by apoptosis due to the activation of the Sox9-cre transgene. At E13.5–postnatal day 20, Sox9-cre-Nr5a1flox/flox cKO adrenals were hypoplastic associated with reduced number of NR5A1-immunoreactive adrenocortical cells, and only a few medullary cells immunolabelled for tyrosine hydroxylase, a marker of chromaffin cell precursors, were infiltrated into the adrenal primordium. Our findings suggest that sufficient number of adrenal cortical progenitors at the earliest stage of adrenal development are required for the subsequent adrenal development. In 8-week-old, Sox9-cre-Nr5a1flox/flox cKO adrenals were smaller in size compared with Nr5a1+/+ adrenals, but showed relatively normal organization with the medulla surrounded by the cortex. However, unlike XY Nr5a1+/+ adrenals, cells immunolabelled for the X-zone marker 20αHSD were observed at the junction between the cortex and medulla in XY Sox9-cre-Nr5a1flox/flox cKO adrenals, probably due to the sex reversal of the XY gonads, since androgen induces regression of the X-zone. Reference: (1) Ikeda et al., Sci Rep. 2021 Feb 24;11(1):4486.
Presentation: 6/2/2024