bluuebunny/crossref_metadata_2025_split huggingface dataset:
ODP397 Small-volume, Subcutaneous, 6-month Leuprolide Acetate Effectively Reduces Growth Velocity to Prepubertal Levels in Children with Central Precocious Puberty
Authors: Klein Karen O , Atkinson Stuart N , Boldt-Houle Deborah M 
Published: November 2022

Abstract

Introduction
Clinical signs of puberty, growth rate, rate of bone maturation, luteinizing hormone concentrations and estimates of change in predicted adult height are the common variables for assessing efficacy of central precocious puberty (CPP) therapies. (1, 2) All clinical and laboratory parameters are essential when interpreting treatment response. (3) Preservation of adult height potential is an important goal of CPP treatment and accelerated growth velocity can contribute to reduced adult height. (4) We present secondary analyses of growth velocity data from the pivotal trial of the first small-volume, long-acting, subcutaneously administered GnRH agonist for central precocious puberty (CPP), approved in 2020. (5) Methods: 62 children (60 girls, 2 boys) with treatment-naïve CPP received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals. We measured standing height with a calibrated stadiometer at Baseline and Weeks 4, 12, 20, 24, 36, 44, and 48. Growth velocity (cm/year) was calculated as a change in height (cm) between visits/((number of weeks between visits)/52).

Results
Mean growth velocity decreased throughout treatment from 10.4 cm/year for the time period from screening to baseline to 6. 0 cm/year for Week 34 to 48. The proportion of children who achieved growth velocity 4-6 cm/year increased 2.5-fold from baseline (10%) to Week 48 (25%).

Conclusions
Subcutaneous leuprolide acetate effectively decreased growth velocity to prepubertal rates in children with CPP. Mean growth velocity from Week 24 to 48 was similar to what is seen in children of the same age without CPP (5.8-6.1 cm/year, depending on sex and race). (6) These data indicate that subcutaneous leuprolide acetate may increase adult height and improve the likelihood of achieving genetic target height range. References Cited 1. Klein KO, et al. Phase 3 trial of a small-volume subcutaneous 6-month duration leuprolide acetate treatment for central precocious puberty. JCEM. 2020. 2. Lee HS, et al. Increased final adult height by gonadotropin-releasing hormone agonist in girls with idiopathic central precocious puberty. PLoS One. 2018. 3. Klein KO, Lee PA. Gonadotropin-releasing hormone (GnRHa) therapy for central precocious puberty (CPP): Review of nuances in assessment of height, hormonal suppression, psychosocial issues, and weight gain, with patient examples. PER. 4. Chen M, Eugster EA. Central Precocious Puberty: Update on Diagnosis and Treatment. Paediatr Drugs. 2015. 5. FENSOLVI® (leuprolide acetate) for injectable suspension, for subcutaneous use [prescribing information]. 2020. 6. Kelly A, et al. Age-based reference ranges for annual height velocity in US children. JCEM. 2014.
Presentation: No date and time listed
ODP399 Growth Hormone Peak did not predict presence of Pituitary Stalk Interruption Syndrome
Authors: Kononowicz Julia , Muhaisen Fadi A , Mitre Naim 
Published: November 2022

Abstract

Background
Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary gland characterized by a triad of the thin or interrupted pituitary stalk, aplasia, or hypoplasia of the anterior pituitary and absent or ectopic posterior pituitary. This can be associated with midline defects and pituitary endocrine deficiencies, ranging from isolated growth hormone deficiency to combined pituitary hormone deficiency. PSIS is a rare entity with an estimated incidence rate of 0.5/1,000,000 births. Clinical case: A 3-year-old neurodevelopmentally appropriate male was initially seen at the PCP office for growth failure. After birth, the patient appeared to have normal growth parameters, as he was in the 61st percentile for length and at the 19th percentile for weight. His growth velocity trended downwards, as he dropped to the 34th percentile at nine weeks old and the 2nd percentile by nine months old. PCP records showed that the patient was at the 10th percentile for height at one year old, but by 18-months, he had fallen below the 1st percentile. His mid-parental height was 175cm, between 25th and 50th percentile. Initial workup showed elevated TSH 9.12 mIU/ml (0.5-4.3 mIU/mL) with negative thyroid antibodies, thus started on 25 mcg of levothyroxine. The screen for systemic disease and inflammatory markers was negative. Insulin-like growth factor 1 (IGF-1) was low at &lt;16 ng/mL (24-148 ng/mL) and insulin-like growth factor binding protein-3 (IGFBP-3) was normal at 1.2mcg/ml (0.7-3.6)A growth hormone (GH) stimulation test was obtained due to suboptimal growth, short stature, and undetectable IGF-1 level. The patient failed his GH stimulation study with a GH peak of 5.1 ng/mL (&gt;10) after clonidine and 2ng/ml (&gt;10) after arginine. A clinical and biochemical diagnosis of GHD was made, an MRI was ordered to evaluate for anatomic cause. Brain MRI showed an ectopic posterior pituitary gland with an absent infundibulum, suggesting PSIS. The patient was started on GH therapy with excellent response. He is currently growing well on a low dose of somatropin, around 0.234mg/kg/week.

Conclusion
PSIS is a congenital pituitary anatomical defect with a heterogeneous presentation. It is typically encountered in infancy and childhood, possibly progressing to panhypopituitarism by adulthood. Diagnosis can be delayed, as brain MRI imaging is not always obtained based on growth hormone peaks. As seen in our patient, the severity of GHD based on peak levels did not adequately predict the presence of brain anomalies. Historically, severe GHD (&lt;5 ng/mL) is strongly associated with brain MRI abnormalities, but GH levels may not suffice to determine the severity of the disease. Based on our findings, we recommend obtaining brain MRI in all patients diagnosed with GHD to identify critical anatomical abnormalities, like PSIS, that require long-term close monitoring of pituitary function.
Presentation: No date and time listed
OR05-3 Utility of Genomic work-up for 46XY Disorder of Sex Development Patients with Severe Hypospadias
Authors: Srivastava Priya 
Published: November 2022

Abstract

Background
Hypospadias is a common human congenital anomaly occurring in ∼1: 200 to 1: 300 live male births in the USA, with an unexplained doubling in incidence over previous decades. Historically, 46XY Differences of Sex Development (DSD) patients, with severe hypospadias have lacked a genetic diagnosis. With the advent of commercially available DSD genomic panels, this is now changing (GeneDX. Neonatal 46 2021, In-vitae 2021). The goal of this study is to review the anatomical characteristics of severe hypospadias that can accurately define patients that have 46XY DSD and to determine the practical utility of performing a genomic workup in these rare 46XY DSD patients with severe hypospadias.Patients: 14 patients seen in disorders of sexual development clinic between 2018–2020 with severe hypospadias defined by an ectopic urethral meatus typically in the scrotum or perineum, an abnormally small glans penis size (&lt;14 mm at maximal width in the first year of life), severe curvature and associated foreskin fusion or penoscrotal transposition were enrolled in the study.

Methods
Patients who met the criteria for 46XY disorder of sexual development and severe hypospadias were offered a genomic work-up in consultation with pediatric genetics. Patients were identified through chart review. Data extracted included karyotype, hypospadias phenotype including stretched penile length at diagnosis, age at genetic diagnosis/genomic workup, gene defect/ pathologic variant, gender identity, and clinical course.Main Outcome Measurements: The main outcome measured was the presence of a genetic mutation that can be linked to the disorder of sexual development. Secondary outcomes measured included gender identity, clinical course, and histological findings if a biopsy was obtained.

Results
Of the 14 patients that underwent genomic analysis, 8 had documented pathologic variants known to cause hypospadias. Pathologic genetic variants include defects in the AR (3), SRD5A2 (1), NR5A1 (2), WT1 (1), and ARTX (1). Five had no evidence of pathologic variants based on the Invitae and GeneDx commercial 46XY DSD panel (see Table 2 for genes tested). One had a genetic variant of unknown significance, FREM2. The patient with WT1 was consequently found to have a Wilms tumor and the patients with SRD5A2 are now undergoing adrenal insufficiency surveillance after their genetic testing.

Conclusions
Patients with 46XY DSD and severe hypospadias can benefit from genetic evaluation as their underlying disorders may unveil mutations that could have potentially life-altering consequences and change surveillance and monitoring.
Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.
OR05-5 Body Mass Index (BMI) as a Predictor of Bone Mineral Density (BMD) in Gender Diverse Youth
Authors: Rodriguez Gonzalez Adriana , Witchel Selma , Pinto Bianca 
Published: November 2022

Abstract

Objective
GnRH agonists (GnRHa), used to prevent development of undesired secondary sex characteristics for gender diverse youth (GDY), may impede pubertal bone mineral accrual increasing the risk for osteopenia/osteoporosis during adulthood. Based on findings of low bone mineral density (BMD) scores (relative to natal sex) prior to GnRHa [1], we hypothesized BMD might be associated with body mass index (BMI) in GDY.Method: To test our hypothesis, we reviewed medical records for 27 GDY; 16 were designated female at birth (DFAB) and 11 were designated male at birth (DMAB). Age at presentation, gender identity, ages at initiation of GnRHa and gender affirming hormone treatment (GAHT), duration of GnRHa treatment prior to GAHT initiation, auxologic parameters including BMI, and lumbar spine BMD obtained from GE lunar IDXa dual-energy X-ray absorptiometry (DEXA) were extracted. Lumbar spine BMD was used for statistical analysis. Statistical analysis was performed with Microsoft Excel Analysis ToolPak. A linear regression model was used to determine significance of BMI and GnRHa as predictors of BMD Z-score using a significance level of 0.05. Legal gender marker was used to determine BMD Z-scores.

Results
BMI ranged from 16.93 kg/m2 to 35.79 kg/m2 (5th to the 99th percentile). DEXA scan results were available for 27 GDY with age range 10-25 years; mean age (±SD) was 17±3 years. BMD of the lumbar spine was obtained from 0-61 months (mean 30 ± 21 months) following initiation of GnRHa. Length of GnRHa treatment prior to GAHT initiation ranged from 0-53 months (mean 14 ± 12 months).Individuals were at different stages of the gender affirmation process including 1) No medical treatments, 2) GnRH agonist only, 3) GAHT only, and 4) combined GnRH agonist and GAHT. Using a linear regression model, length of GnRHa therapy and length of GnRHa without GAHT were not significantly associated with lumbar spine BMD in our sample (p = 0.44 and 0.29, respectively). Using a linear regression model, BMI was a significant positive predictor of higher lumbar bone mineral density (p = 0.03).

Conclusion
Sex hormone exposure during adolescence and young adulthood is essential for bone health. While GnRH agonists lower endogenous sex hormone exposure, in our sample, lower BMD was not associated with total duration of GnRHa therapy or duration of GnRHa treatment prior to GAHT. Rather BMD was positively associated with BMI regardless of gender affirming medical therapies. Limitations include small sample size, retrospective design, and the use of legal gender marker for normative values. The next step will be larger, prospective studies to identify predictors of low BMD in GD youth. This information will guide future management regarding BMD monitoring.References: 1. Lee JY,et al., J Endocr Soc. 2020;4(9): bvaa065.
Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.
OR14-4 Acute sleep disruption does not diminish pulsatile growth hormone secretion in pubertal children
Authors: Amin Rafiul , Faghih Rose T , Genty Jon , Kangarloo Tairmae , Klerman Elizabeth B , Molsberry Samantha , Shaw Natalie D , Calvert Madison 
Published: November 2022

Abstract

Context: Growth hormone (GH) plays a critical role in glucose homeostasis and linear growth during childhood. GH secretion is controlled by multiple neurotransmitters and hormones. Sleep is also a powerful stimulus for GH secretion. In children, GH pulses occur after sleep onset in association with slow-wave sleep (SWS), but it is unclear if undisrupted sleep is required for normal GH secretion. Given the rising incidence of pediatric sleep disorders such as obstructive sleep apnea (OSA) that cause sleep fragmentation, it is critical to determine whether sleep fragmentation during childhood may dysregulate the somatotropic axis.

Objective
To quantify how undisrupted vs fragmented sleep affects GH secretion in children.

Methods
Pubertal subjects (10 M, 9 F; 9.1-14.4 yrs) were randomized to two overnight polysomnographic studies with frequent blood sampling (q10min) to measure GH: fourteen were healthy subjects studied with or without SWS disruption via auditory stimuli (3 sec, 1500 Hz tones, 40-100 dB followed by 18 sec of a 75 dB noise simulating a knock on the door) and five were subjects with OSA studied with or without prescribed continuous positive airway pressure (CPAP); the latter condition was expected to have sleep fragmentation due to untreated OSA. GH pulses were identified using sparse deconvolution. Studies without auditory stimuli or when using CPAP were combined and analyzed as 'undisrupted sleep'. The relationship between GH pulse rate per hour and sleep stage was evaluated using Poisson generalized estimating equations.

Results
In SWS disruption studies, an average of 77.51 ± 13.61 (range 23-190) auditory stimuli were delivered, causing a 40.02 ± 7.78% decrease in SWS in favor of lighter sleep stages. In subjects with OSA, CPAP withdrawal caused a slight increase in the apnea hypopnea index (1.08 ± 0.10 vs. 2.20 ± 1.70 events/hour of sleep, p=0.07) with no change in sleep stage durations. During undisrupted sleep, subjects had an average of 0.91 ± 0.067 GH pulses/hour with a mean pulse amplitude of 10.03 ± 1.00 ng/mL and mean basal secretion rate of 0.26 ± 0.10 ng/ml per min. GH pulses occurred more frequently during SWS (2.3 pulses/hour SWS, amplitude 9.92 ± 2.59 ng/mL) than during any other sleep stage (P &lt; 0.001). Neither form of sleep disruption affected the distribution of GH pulses across sleep stages, GH pulse amplitude and frequency, nor basal GH secretion.

Conclusion
In children, nocturnal GH pulses are temporally associated with SWS. However, neither acute fragmentation of SWS nor nocturnal arousals from OSA altered basal or pulsatile GH secretion, indicating that somatotrophic axis activity is preserved in the face of acute sleep disruption in children.
Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.
OR18-2 Clinical, Hormonal and Genetic Characterization of Familial Central Precocious Puberty
Authors: Argente Jesús , Brito Vinicius , Guimaraes Aline , Latronico Ana Claudia , Leal Andrea , Mendonça Berenice , Montenegro Luciana , Piovesan Maiara , Ramos Carolina , Seraphim Carlos , Tinano Flavia , Canton Ana 
Published: November 2022

Abstract

Context: Familial central precocious puberty (CPP) is a prevalent form (about 27.5%) of precocious puberty. Loss-of-function mutations in two maternally imprinted genes, MKRN3 and DLK1, were identified in families with CPP showing dominant autosomal inheritance with paternal transmission. Maternally transmitted CPP was previously demonstrated in up to 60% of families using pedigree analysis, however, no definitive genetic abnormality has been identified so far.

Objectives
To estimate the prevalence of familial cases in a multiethnic cohort with CPP. To characterize the genetic basis and the mode of inheritance of the affected families. To compare clinical and hormonal features of patients with familial CPP due to different modes of transmission.

Patients and Methods
Clinical and hormonal data were obtained from medical registries of 495 patients with CPP and no brain MRI alterations. Familial CPP was defined as the presence of one or more close relatives with CPP or precocious menarche (≤9 yr). Sanger sequencing of MKRN3 and DLK1 was performed in 427 index cases. Targeted gene panel sequencing was performed in 79 cases, while whole exome sequencing was performed in 101 cases from 36 families

Results
Among 495 index cases, 159 had familial CPP (31%). The mode of transmission of CPP was identified as paternal in 58 (35%), maternal in 59 (38%), indeterminate in 34 (22%), and both maternal and paternal transmission in 8 (5%). Most families with paternal or maternal transmission had 2 generations known to be affected (51 and 77%, respectively). Notably, 67% of index cases with maternally transmitted CPP had their mother affected. In girls with CPP, the median age of thelarche was 6.5 yr in the paternally transmitted group, 6.9 yr in the maternally transmitted group, and 7.3 yr in the indeterminate group (p= 0.547). Median bone age advancement was 2.1, 2.3 and 1.2 yr, respectively (p= 0.013). Basal LH levels were higher in girls with paternally transmitted CPP (p= 0.047). Among those with paternally transmitted CPP, MKRN3 and DLK1 mutations were identified in, respectively, 63.8% and 10.3% of the families.

Conclusions
A significant prevalence (31%) of familial CPP was demonstrated in a multiethnic cohort. Maternally transmitted CPP represented the most frequent form of familial CPP (38%). MKRN3 loss-of-function mutations were responsible for most paternally transmitted CPP cases (63.8%), followed by DLK1 loss-of-function mutations (10.3%).
Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.
RF14 | PSAT114 Conversion from one side of the autoimmune thyroid spectrum to the other: a pediatric clinical challenge
Authors: Almutlaq Nourah , Eugster Erica A , Nebesio Todd D 
Published: November 2022

Abstract

Introduction
Graves disease and Hashimoto thyroiditis represent the two ends of the autoimmune thyroid spectrum. Spontaneous conversion from one to the other is a rare phenomenon, especially in children, and the underlying mechanism is unknown. Changes in the predominance of stimulating versus blocking TSH receptor antibodies (TRAb) has been proposed as a potential etiology.Method: We describe a series of cases of autoimmune thyroid disease in children that converted from one end of the biochemical spectrum to the other Result: Eleven patients of whom 55% were girls and 36% had Down syndrome (DS) were identified. Five (46%) presented with hyperthyroidism (hyper) that spontaneously converted to hypothyroidism (hypo). Four patients (36%) had hypo which converted to hyper while the remaining 2 (18%) presented with Hashitoxicosis (HT) with negative TRAb titers which later converted to hyper. In those who went from hyper to hypo, mean duration of antithyroid drug therapy was 1.8 ± 1.4 years and mean age at initial presentation was 11.0 ± 4.8 years (5-16). Before conversion, all 5 patients had positive TRAb titers with mean of 15.0 ± 4.2 and a mean thyroid peroxidase antibody level of 287.5 ± 389. A period of euthyroidism lasting 2.0 ± 0.8 years was present prior to the development of hypo with a mean TSH of 17.0 ± 25 mU/L (5.8-62). Mean duration of hypo in the second group was 5.0 ± 5.2 years and mean age at initial diagnosis was 6.7 ± 2.8 years (3-10). TSH became suppressed in all 4 patients, TRAb was elevated, and mean free T4 off levothyroxine was 3.3 ± 1.2 ng/dL (2.4-4.6). The two patients with initial HT were 12 ± 2.8 years at diagnosis and converted to hyper after 6.5 ± 0.7 months. Initial mean free T4 was 1.3 ± 0.2 ng/dL and after conversion was 4.6 ± 0.4 ng/dL along with strongly positive TRAb titers (mean of 6.9 ± 6.5). TSH became further suppressed after conversion to hyper (&lt;0.01). More of our patients with DS converted from hypo to hyper than the other direction (75% vs 20%, p=0.01). However, two of them proceeded to have a wavering course between hyper and hypo requiring intensive monitoring and frequent changes in management.

Conclusion
Although oscillating thyroid function in children with autoimmune thyroid disease is uncommon, it is important for parents and providers to be aware of this entity. The natural history of these cases is extremely variable and clinical management is challenging. Our findings suggest that DS may be a risk factor for the phenomenon of vacillating thyroid function in pediatric patients.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:42 p.m. - 12:47 p.m.
RF26 | PMON332 Safety and Efficacy of Treatment with Lonapegsomatropin in Children with Growth Hormone Deficiency at Week 130 in the enliGHten Trial
Authors: Saenger Paul , Nadgir Ulhas , Hofman Paul , Thornton Paul , Chertok Elena D , Aghajanova Elena M , Korpal-Szczyrska Maria , Vlachopapadopoulou Elpis , Malievskiy Oleg , Chaychenko Tetyana , Cappa Marco , Song Wenjie , Mao Meng , Chessler Steven D , Komirenko Allison S , Beckert Michael , Shu Aimee D , Maniatis Aristides K 
Published: November 2022

Abstract

Background
Once-weekly lonapegsomatropin (TransCon hGH) is a long-acting prodrug of somatropin, recently approved for the treatment of pediatric growth hormone deficiency (GHD) by the US FDA. In the pivotal 52-week phase 3 heiGHt trial and the 26-week fliGHt trial, lonapegsomatropin demonstrated safety and efficacy in both treatment-naïve and treatment-experienced children with GHD.

Methods
Results are reported from Week 130 (data snapshot date: September 01, 2021) from the open-label extension trial enliGHten. Upon entry into enliGHten, all participants received lonapegsomatropin via vial/syringe, with subsequent switch to TransCon hGH Auto-Injector when available.

Results
A total of 298 participants (98% of parent trials) continued from the heiGHt or fliGHt trials into enliGHten. At Week 130, 36 participants had completed the trial and 248 participants remain enrolled. The height standard deviation score (SDS) mean (standard deviation [SD]) at Week 130 was -0.64 (0.85) compared with baseline value of -1.56 (0.88) at the start of enliGHten. Participants continued to approach the average parental height SDS mean (SD) of -0.39 (0.77). The annualized height velocity mean (SD) at Week 130 was 9.32 cm/year (0.45). Average IGF-1 SDS mean (SD) at Week 130 was 1.46 (1.18) compared with 0.52 (1.58) at enliGHten baseline. For the 36 participants who had completed the trial, 14 had reached bone age of &gt;14 years (girls) or &gt;16 years (boys), and 24 had completed the study based on investigator judgement that treatment for growth hormone deficiency was no longer necessary. The difference between mean (SD) height SDS at last visit and average parental height SDS was -0.05 (0.75) for the 36 completers, and 61.1% of these participants had met or exceeded the average parental height SDS. The mean (SD) total duration of hGH treatment for participants who completed the trial (including daily treatment and lonapegsomatropin) was 3.53 (0.88) years, and the mean (SD) duration of treatment with lonapegsomatropin was 2.20 (0.66). With continued lonapegsomatropin treatment, the AE profile remained consistent with what was observed in the parent trials, with no new safety signals.

Conclusions
Children and adolescents treated with lonapegsomatropin showed continued improvement of height SDS through their 3rd year of therapy. Lonapegsomatropin continued to demonstrate a safety profile comparable to that of daily somatropin therapy.
Presentation: Monday, June 13, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.