bluuebunny/crossref_metadata_2025 huggingface dataset:
7039 Isolated Gonadotropin Deficiency Transmitted From Mother to Daughter Conceived Through Assisted Reproduction Due Newly Identified, Autosomal Dominant Mutation Within the SOX10 Gene
Authors: Bakjaji Shadi , Hoffman Robert Paul
Published: October 2024

Disclosure: S. Bakjaji: None. R.P. Hoffman: None.

Title: Isolated gonadotropin deficiency transmitted from mother to daughter conceived through assisted reproduction due newly identified, autosomal dominant mutation within the SOX10 gene. Objectives: We report a case of genetic isolated gonadotropin deficiency occurring in a mother and in her daughter conceived through assisted reproductive technology using mother’s ovum. Methods Case report Results: The daughter was initially seen at 12 years 0 months for evaluation of short stature and concerns she had not grown in the last year. She was otherwise in good health and reported normal sense of smell. At the time of assessment, her height was 132.6 cm (0.61 percentile; Z=-2.5). The mother had been diagnosed with Kallmann’s syndrome and achieved pregnancy through ovarian stimulation. Her height was 152.4 cm, while the father's height was 177.8 cm. Two male siblings were born at the same time and were in normal health. Physical examination of the daughter was unremarkable. She had Tanner stage 1 pubic hair and Tanner stage 1 breasts. The growth chart displayed a notable deceleration in growth Laboratory results showed normal free T4 of (0.9 ng/dL) with slightly elevated TSH (8.348 uIU/mL), positive thyroid antibodies, normal IGFI at 164 ng/mL (normal range for Tanner I: 54 - 301) and IGFBP-3 at 5.8 ug/mL (2.4 - 8.4 ug/mL). The karyotype was 46 XX. Her peak growth hormone using glucagon-arginine stimulation was 12.8 ng/ml. When no pubertal development was seen over the next 6 months, GnRH stimulation testing revealed baseline LH of 0.04 mIU/ml and a peak of 1.78 and baseline FSH of 0.41 mIU/ml with a peak of 2.83. Bone age was 8 years 4 months.Over the next year her growth velocity was 4.8 cm/year and she remained prepubertal. Genetic testing done identified a new heterozygous sequence variant (c.226G>A) in the SOX10 gene which would lead to replacement of valine by isoleucine at position 76 and was thought to be damaging in silico. This variant was subsequently found to be shared with her mother but not her father. Conclusions: Most Kallmann’s syndrome or genetic isolated gonadotropin deficiency cases are due to autosomal dominant but spontaneous new mutations since infertility is usually present in those with the syndrome. This case emphasizes the importance of genetic counselling regarding inheritance risk when assisted reproduction technology using maternal ovum is used.

Presentation: 6/2/2024
8517 Low Peak GH in Stimulation Tests Among Obese Children; Is it Clinically Meaningful?
Authors: Strich D , Meirman C , Edri S , Gillis D J
Published: October 2024

Disclosure: D. Strich: None. C. Meirman: None. S. Edri: None. D.J. Gillis: None.

Background: Peak growth hormone (GH) levels in stimulation tests are lower in obese subjects. The clinical significance of this finding is unclear. It has been suggested that results of tests should be adjusted for body mass index (BMI). Aims: A. To evaluate the association between GH peak levels and body mass index (BMI ) in a single center. B. To discuss the biological and clinical significance of the findings and make recommendations based on this study and other data from the medical literature. Methods: Peak GH levels and BMI standard deviation scores (BMI-SDS) for a total of 988 tests (Clonidine - 694, Glucagon - 198, Arginine - 96) performed in one center were analyzed. Studies referring to the biology of growth hormone and to the evaluation of GH deficiency were reviewed. Results: In the testing center studied, mean peak GH levels were significantly lower in arginine (p=0.015) and clonidine tests (p=0.018) starting at BMI standard deviation score over 1 compared to below 1 BMI-SDS. The differences still remained significant for a subgroup with peaks below 7.5 ng/dl (p=0.003 and p=0.042 respectively). The proportion of overweight and obese children in our cohort and in similar cohorts of children undergoing stimulation tests was about tenfold lower than in the corresponding general population. In other studies, short obese patients responded better than non-obese to GH treatment and had greater increases both in height and IGF-1. Obese adult patients with low GH peaks had high carotid intima-media thickness compared with non GH deficient obese. Conclusion: Obese children are generally tall and therefore are not referred for testing. Those who are short, tend to have lower peaks than their lean peers in GH stimulation tests and respond better to GH therapy. These patients have biologically significant GH deficiency. We do not recommend "correcting" GH test results for BMI in the decision algorithm for GH therapy.

Presentation: 6/3/2024
7439 Mercury toxicity presenting as Pheochromocytoma
Authors: Ansar Aisha , McNerney Kyle , Marshall Bess Adkins
Published: October 2024

Disclosure: A. Ansar: None. K. McNerney: None. B.A. Marshall: None.

Background: Mercury intoxication is a rare cause of hypertension in children and can mimic other endocrinopathies such as pheochromocytoma. Mercury affects catecholamine metabolism and can cause elevated catecholamine levels, thereby incorrectly suggesting a catecholamine-secreting tumor. Clinical Case: An 8-year-old girl presented to the ED with progressive night sweats, intractable migratory myalgias, hypertension and tachycardia. Patient was in her usual state of health until 2 weeks before presentation when she started to have worsening intermittent pains in her chest, arms, back, and knees. She also experienced restlessness and inability to sleep. On presentation she was hypertensive, with blood pressure of 146/116 mm Hg while calm, heart rate 125 bpm, afebrile. She was anxious, irritable, and seemed uncomfortable. Her skin was dry and rough with a scaly eczematous rash on the arms and legs. She had persistently elevated blood pressure in upper and lower extremities, unremarkable echocardiogram and electrocardiogram, and a normal result on fundoscopic examination. Her initial electrolytes, creatinine, and urinalysis were all normal and remained so on serial evaluations. Urine drug screen was negative. Thyroid function panel showed normal TSH with slightly elevated Free T4 2.28 ng/dL (0.9-1.7), but a normal Free T3 3.9 pg/mL (2.0-4.4) and Free T4 by equilibrium dialysis 1.8 ng/dL (0.8 - 2.0). CT of the chest, abdomen and pelvis was negative and did not show any lesions. Plasma renin activity was 4.6 ng/mL/hour, supine, (<2.0) and plasma aldosterone level < 4.0 ng/dL (< 40 supine) were normal. 24-hour urinary norepinephrine was 90 μg/24h (13-65), epinephrine 37 μg/24h (0.2-10), urine metanephrines 195 μg/24h (18-144), urine normetanephrines 305 μg/24h (29-145), all elevated. Further history taking revealed that patient was taking Ayurvedic supplements prepared by hand by medicinal personnel in India for 3 months prior to presentation. These were stopped 2 weeks prior to her presentation, when she first became symptomatic. Her blood mercury level was 11 ng/mL (n <9), and urinary mercury excretion 67 μg/24 hours (n<10), both obtained 3 weeks after stopping supplementation. She was started on oral chelation therapy with succimer 10 mg/kg/day. Her hypertension was controlled with doxazosin. One week after initiation of therapy, her symptoms improved, and she became normotensive. Her acrodynia and irritability resolved. Urine metanephrine levels will be repeated at upcoming clinic follow up. Conclusion: Mercury toxicity should be considered in the differential of pheochromocytoma to avoid extensive diagnostic testing and morbidity associated with it. Lead, mercury, and arsenic have been detected in traditionally prepared Ayurvedic supplements. A careful history of intake of supplements can be important in cases with unusual symptomatology.

Presentation: 6/3/2024
7814 Non-fasting and Fasting Mixed Meal Tolerance Tests Equally Capture the Triglyceride Response in Participants With and Without MASLD
Authors: Gonzalez Ramirez Lucia A , He Zhulin , Binongo Jose N , Huneault Helaina E , Ramirez Tovar Ana Maria , Welsh Jean A , Vos Miriam B
Published: October 2024

Disclosure: L.A. Gonzalez Ramirez: None. Z. He: None. J.N. Binongo: None. H.E. Huneault: None. A. Ramirez Tovar: None. J.A. Welsh: None. M.B. Vos: Consulting Fee; Self; Boehringer Ingelheim, Prosciento, Target Real World Solutions, Intercept Pharmaceuticals, INC, Novo Nordisk. Grant Recipient; Self; Target Real World Solutions.

Mixed meal tolerance tests (MMTTs) are functional assessments that may identify metabolic dysregulation earlier than fasting tests during the progression to metabolic dysfunction-associated steatotic liver disease (MASLD). Although standards to conduct MMTTs in adults are readily available, the knowledge gap for children is quite large. Furthermore, conducting this type of study in children is challenging because they are less tolerant of long fasting intervals, long periods of testing, and early morning visits that interrupt school attendance. The objective of this study was to assess if conducting an MMTT in a non-fasting state will equally identify variance in the metabolic response of triglycerides (TG) between healthy children and those living with MASLD when compared to a 12-hour fasting MMTT. We collected blood samples every two hours in our 2-day randomized crossover feeding study. During each visit, 9 children with MASLD and 10 healthy controls aged 10 to 18 y underwent 1 standardized MMTT after a 12-hour overnight fasting (breakfast), followed by 2 standardized MMTTs in a non-fasting state (lunch and dinner). Participants were randomized to receive a glucose or fructose beverage at visit 1 and the other at visit 2. For uniformity, we only used data from the glucose beverage visit. We found that TG levels were statistically higher in the MASLD participants when compared to the non-MASLD group at each time point (p= 0.01). The maximum TG metabolic response peak for each MMTT was higher and more delayed in the MASLD group compared to the non-MASLD group. Within groups, postprandial TG level patterns were not significantly different when comparing breakfast, lunch, and dinner. Although TG levels varied throughout the day, the pattern after every meal was similar. These findings suggest that it is possible to identify differences in the TG metabolic response between children living with MASLD and healthy participants in the postprandial state. The results from our study also support the use of non-fasting MMTTs when examining TG metabolism in children, though further research to validate these findings is needed.

Presentation: 6/1/2024
12626 Non-high-density Lipoprotein Cholesterol For Detecting Dyslipidemia Among Korean Adolescents
Authors: Nam H K , Kang E , Rhie Y J , Lee K H
Published: October 2024

Disclosure: H. Nam: None. E. Kang: None. Y. Rhie: None. K. Lee: None.

Objectives: Non-high-density lipoprotein (HDL) cholesterol is an alternative method to assess dyslipidemia. We aimed to assess the validity of non-HDL cholesterol for detecting dyslipidemia among Korean adolescents. Methods: Data for 6,989 adolescents aged 10 to 19 years (3,684 boys and 3,305 girls), were obtained from the Korean National Health and Nutrition Examination Surveys. Dyslipidemia was defined by having one of the followings; total cholesterol ≥200 mg/dL, triglyceride ≥130 mg/dL, low-density lipoprotein (LDL) cholesterol ≥130 mg/dL, or HDL cholesterol <40 mg/dL. Non-HDL cholesterol ≥145 mg/dL was used to detect dyslipidemia based on National Heart, Lung, and Blood Institute 2011. Results: The overall prevalence of dyslipidemia were 27% and 37% among Korean adolescents based on calculated and measured LDL cholesterol level, respectively. The prevalence of non-HDL cholesterol level ≥145 mg/dL were 7.1% and 8.5% in teenage boys and girls, respectively. Dyslipidemia was found in 97.1% and 97.7% of boys and girls with high non-HDL level, respectively. High non-HDL cholesterol level especially detected high measured LDL-cholesterol level with a sensitivity of 96.3%, and a specificity of 96.3%, and a sensitivity of 95.2%, and a specificity of 97.1%, in teenage boys and girls. Using non-HDL cholesterol was more detected high LDL-cholesterol level compared to using total cholesterol alone in teenage boys and girls. Conclusions: Screening dyslipidemia using non-HDL cholesterol level was more useful than using total cholesterol level alone, especially in detecting high LDL cholesterol level. Non-HDL cholesterol was not required fasting and was appeared to be a reliable screening test also in adolescents.

Presentation: 6/1/2024
7685 Outcomes of Low-Risk Differentiated Thyroid Carcinomain a Predominantly Hispanic Pediatric Population
Authors: Delgado E A , Martinez A , Solano N , Baboun D , Alkhoury F , Carrillo-Iregui A , Bustamante Escobar C L
Published: October 2024

Disclosure: E.A. Delgado: None. A. Martinez: None. N. Solano: None. D. Baboun: None. F. Alkhoury: None. A. Carrillo-Iregui: None. C.L. Bustamante Escobar: None.

Background: The American Thyroid Association (ATA) guidelines for the management of low-risk differentiated thyroid carcinoma (DTC) in children, recommend total thyroidectomy and central neck dissection without iodine ablation. Surveillance for recurrence in these patients includes serial TSH-suppressed thyroglobulin levels and thyroid ultrasounds. Iodine ablation is reserved for patients classified as ATA intermediate and high-risk given their risk of persistent cervical disease and distant metastasis, respectively. There is ongoing concern whether withholding Iodine-131 will result in higher rates of disease recurrence among ATA low-risk pediatric patients. To our knowledge this is the first study addressing a predominantly Hispanic pediatric population. Objective: Evaluate the recurrence rate of differentiated thyroid cancer (DTC) in ATA low risk patients since implementing the 2015 ATA pediatric guidelines in a predominantly Hispanic pediatric population. Methods: After obtaining Institutional Review Board approval, we performed a retrospective chart review of patients 19 years and younger, between 2012 and 2023, for DTC. We analyzed demographics, histopathological diagnoses, risk stratification, and post-diagnosis follow up. Results: From a cohort of 63 pediatric patients diagnosed with DTC, a significant majority (n=55, 87%) comprised Hispanic individuals, while non-Hispanic cases represented the minority (n= 8, 13%). The mean age at diagnosis was 14.7 ± 2.6 years. Papillary thyroid carcinoma emerged as the prevailing type in 58 (92%), while 5 (8%) were follicular carcinoma. Among the patients, 12 (20%) were categorized as low risk level and underwent surgery alone. Over a median follow-up period of 2.6 years (IQR 2.97, range 0.94-5.18), 2 out of the 12 (18%) in this low-risk group experienced disease recurrence, with an average time to recurrence of 1.6 ± 0.9 years. Notably, one of the patients had a history of autoimmune thyroiditis. Subsequently, these 2 patients underwent further evaluation and treatment with iodine ablation. Conclusion: In a free-standing hospital with a predominantly Hispanic population, we found a recurrence rate of 18% in patients with ATA low-risk DTC not treated with radioactive iodine. Our rates align closely with those observed in earlier studies, which featured a non-Hispanic population and reported a 24% recurrence rate during the surveillance period. This underscores the crucial role of surveillance in low-risk patients with DTC in a Hispanic pediatric population.

Presentation: 6/1/2024
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

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 >5), elevated plasma renin activity (124 ng/ml/h, NL <58), elevated ACTH (961 pg/ml, NL <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>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>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

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

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

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 (<25), 17OHProgesterone 49 ng/dl (<265), Estradiol 30 pg/ml (<47), LH 17 mIU/ml (0.4 -11.7), Anti Mullerian Hormone 368 ng/ml (<13), Testosterone 629 ng/dl (<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

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 (> 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 > 2 SDS. In this subset, 60% of patients had levels of free IGF-1 in the normal range (< 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 > 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

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

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

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
8151 The Genetic Etiology Is a Relevant Cause of Central Precocious Puberty
Authors: Machado Canton Ana Pinheiro , Seraphim Carlos Eduardo , Montenegro Luciana Ribeiro , Krepsichi Ana Cristina , Mendonca Berenice Bilharinho , Latronico Ana Claudia , Brito Vinicius Nahime
Published: October 2024

Disclosure: A.P. Canton: None. C.E. Seraphim: None. L.R. Montenegro: None. A. Krepsichi: None. B.B. Mendonca: None. A. Latronico: None. V.N. Brito: None.

Background: The etiology of central precocious puberty (CPP) has expanded with the identification of new genetic causes, including the monogenic deficiency of MKRN3 in familial cases. Objectives: To assess the prevalence of CPP causes and the predictors of genetic involvement in this phenotype. Methods: A single-center retrospective cohort study was performed for an etiological survey of patients with CPP. All patients had detailed medical history, deep phenotyping, and brain MRI. Patients with CPP and no pathological brain lesions, previously considered idiopathic forms, were submitted to genetic studies, mainly DNA sequencing studies, genomic microarray, and methylation analysis. Results: We assessed 270 patients (241 girls) with CPP; 50 (18.5%) patients had CPP-related brain lesions, whereas 220 (81.5%) patients had normal brain MRI. Of the latter, 174 (165 girls and 9 boys) were included for genetic studies. Genetic etiologies were identified in 22 patients (20 girls and 2 boys), indicating an overall frequency of genetic CPP of 12.6%, which was higher in boys (22.2%) than in girls (12.1%). The most common genetic defects were MKRN3, DLK1, and MECP2 loss-of-function mutations, followed by 14q32.2 imprinting defects (Temple syndrome). Univariate logistic regression identified positive family history (OR 3.3; 95%CI 1.3-8.3; p=0.01) and associated neurodevelopmental disorders (OR 4.1; 95%CI 1.3-13.5; p=0.02) as clinical predictors of genetic CPP. A novel algorithm for investigating the etiology of CPP was set up, including genetic studies guided by clinical parameters. Conclusion: Distinct genetic causes were identified in 12.6% of CPP patients previously classified as idiopathic, revealing the genetic etiology as a relevant cause of CPP in both sexes. Family history and neurodevelopmental disorders were identified as predictors of genetic CPP, recommending that both factors should be actively investigated in the CPP workup. A novel algorithm for investigating the etiology of CPP can be practice-changing for those who assist children with precocious puberty.

Presentation: 6/2/2024
8170 The Relationship Between SUOX Gene Mutation and Type 1 Diabetes
Authors: Green S , Ilaka-Chibuluzo S
Published: October 2024

Disclosure: S. Green: None. S. Ilaka-Chibuluzo: None.

Isolated Sulfite Oxidase Deficiency (ISOD) is a rare autosomal recessive inborn error of metabolism caused by a missense mutation in the SUOX gene (gene locus 12q13.2). The main sequalae of ISOD is neuro-cognitive developmental delay, microcephaly, muscle spasticity, chronic aspiration, severe scoliosis, and seizures. The sulfite oxidase enzyme catalyzes the final step of the breakdown of methionine and cysteine, sulfur-containing amino acids. Loss of function of SUOX gene causes increased production of reactive oxygen species, decreased activity of TCA cycle, and decreased ATP synthesis within the mitochondria. SUOX gene mutation has been found to be preliminarily linked to Type 1 Diabetes (T1D) through the loss of β cells through altered expression of macrophages and dendritic cells. However, there has not been in-depth analysis between this connection. OS is a seven-year-old male diagnosed with ISOD. He had an uncomplicated gestation and delivery and started having seizure activity of day of life one. The subsequent EEG showed abnormal background activity consistent with burst suppression, but no seizure activity. The MRI of his brain showed diffuse cerebral atrophy and basal ganglia ischemic injury. After numerous genetic screenings, he was found to have a SUOX mutation. During a recent hospitalization in 2023, he was found to have elevated pancreatic enzymes, hyperglycemia, and an elevated hemoglobin a1c, at which point he was diagnosed with T1D.

Presentation: 6/2/2024
6480 Variability in Breast Development in Response to Exogenous Estrogen in Girls
Authors: Kurman T M , Eugster E A
Published: October 2024

Disclosure: T.M. Kurman: None. E.A. Eugster: None.

Intro: Adolescents requiring treatment with exogenous estrogen (E2) include girls with primary and secondary hypogonadism and transfeminine youth. While 17B-estradiol is standard of care, the starting dose and escalation schedule are individualized. To what degree the response to E2 as assessed by breast Tanner stage is correlated with the dose is unknown. Similarly, whether the response to E2 varies depending on the underlying diagnosis has not been systematically analyzed. We aimed to investigate relationships between diagnosis, E2 dose, and breast Tanner staging in adolescent girls. Methods: We conducted a chart review of girls treated with E2 followed at our Pediatric Endocrine clinic between 2008-2022. Inclusion criteria included girls who were prepubertal at baseline and on a single increment of a 25 mcg E2 patch changed 2X/week from initiation of treatment to the first follow up visit. Only transgender girls being treated with a GnRH analog were included. Within each group of patients on the same starting dose, a Kruskal-Wallis test was conducted to evaluate differences in Tanner stage between diagnostic groups. Spearman’s correlation was used to evaluate the relationship between starting dose and Tanner stage. Finally, we evaluated differences within the Turner syndrome (TS) group for girls with monosomy X vs a mosaic karyotype. Results: Of 1,899 medical records, 70 eligible patients were identified. Of these, 33 (47.2%) had TS, 17 (24.3%) had primary ovarian insufficiency (POI), 15 (21.4%) had hypogonadotropic hypogonadism (HH), and 5 (7.1%) were transgender (TG). Twenty-three (32.9%) started on 1/4 patch (6.25 mcg), 29 (41.4%) on 1/2 patch (12.5 mcg) and 18 (25.7%) on a full patch (25 mcg). Girls on other regimens (e.g., 1/8 patch worn only at night) were excluded from analysis. The first f/u visit occurred at a median of 6 months (range 3-12 months). All TG girls were started on 25 mcg E2, which was significantly different compared to the other groups (p=0.002, p=0.005, and p=0.005 for TS, POI, and HH respectively). Breast Tanner stage at the first f/u visit ranged from 1-4 with no significant difference within each dose group based on diagnosis. However, a significant correlation between E2 dose and breast Tanner stage at f/u was seen in girls with HH (r=0.601, p=0.018). No effect of karyotype (monosomy X vs mosaic) on response to E2 in girls with TS was seen. Conclusion: There was striking variability in the starting dose of E2 in the vast majority of patients, highlighting the lack of standardization in clinical management. Interestingly, we found significant individual variability in terms of breast development in response to the initial dose of E2, regardless of diagnosis. Factors responsible for the unpredictable nature of the response to exogenous E2 are unexplored. Our findings provide important and novel prognostic information for patients and providers.

Presentation: 6/1/2024