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The article examines the unnecessary routine endocrinologic evaluations for adolescent boys with gynecomastia. Topics discussed include the various causes of gynecomastia in this age group, the low incidence of pathological conditions underlying the condition, and the potential benefits of reducing healthcare costs and alleviating patient and parental anxiety by minimizing unnecessary referrals and testing.

Introduction: Newborn screening for congenital adrenal hyperplasia (CAH) has been in place in the USA for over 20 years. However, not all patients with classic CAH are diagnosed as neonates. Our aim was to characterize patients with classic CAH who were missed on the newborn screen (NBS) in Indiana and determine if discriminating features were present that might have led to earlier detection. Methods: Medical records of children diagnosed with classic CAH due to 21-hydroxylase deficiency seen at Riley Hospital for Children in Indiana between January 2005 and December 2020 were reviewed. Patient characteristics, visit information, and laboratory results were collected. Statistical analysis was performed using SPSS version 28. Results: A total of 64 patients were identified of whom 12 (19%) were missed on the NBS. Mean age at diagnosis was 21.7 months (range: 2–74 months), 67% were girls and 66% had salt-wasting CAH. Eight (67%) presented with clinical evidence of hyperandrogenism, including clitoromegaly (n = 7), posterior labial fusion (n = 5), and pubic hair (n = 2). Screening was pursued due to a family history of CAH in the remaining 4. Genetic confirmation was present in 50%. There was no history of antenatal steroid exposure in any of the missed patients. No differences were seen with regard to sex, ethnicity, gestational age, birth weight, type of CAH, or serum 17-hydroxyprogesterone (17OHP) level at diagnosis in patients who were missed compared with those diagnosed on the NBS (14,948 ng/dL vs. 16,701 ng/dL, p = 0.74). However, the mean testosterone level at diagnosis was lower in patients who were missed compared with those who were diagnosed earlier (68 ± 60.28 ng/dL vs. 196.2 ± 206.0 ng/dL, p = 0.02). A positive family history of CAH was present in 42% of the missed patients. The timing of the NBS collection was not different between the two groups, p = 0.36. Conclusion: Nearly one-fifth of our patients with classic CAH were missed on the NBS. No specific features were identified that distinguished these children from those who were detected at birth. It is critical to maintain a high index of suspicion for CAH in order to recognize these patients as early as possible so as to avoid adverse effects and potential life-threatening adrenal crises. [ABSTRACT FROM AUTHOR]

A retrospective review of gender-affirming hormone therapy was conducted in 101 transgender boys followed in the pediatric endocrine clinic. Eighty-seven percent were postmenarchal at the initial visit. Of the 44% prescribed gonadotropin-releasing hormone analogs (GnRHas), insurance coverage was denied in 34% and an average of 4.5 months elapsed before treatment could be started in the remainder. Patients prescribed GnRHas were younger than those who were not, 13.7±2.1 versus 15.5±2.0 years, p<0.001. Continued menstrual bleeding was reported by patients receiving testosterone alone at doses ranging from 50 to 200 mg every 2 weeks. [ABSTRACT FROM AUTHOR]

Background: Androgen blockers are an essential part of gender affirming care in post-pubertal transfeminine patients. Bicalutamide is a highly potent androgen receptor blocker that is used primarily in adults. We aimed to review our experience with the use of bicalutamide in transgender adolescents who were assigned male at birth. Methods: A retrospective review of medical records of transfeminine patients treated with bicalutamide during an 8-year period was conducted. Results: Forty patients, aged 15.5 ± 1.55 years were identified, of whom 21 (53%) were started on bicalutamide alone and 19 were started concurrently on estrogen. In patients on bicalutamide alone, 90.4% reported breast development at their first follow up visit, which occurred at a median of 7.1 months. Patients were treated for 29.4 ± 18.2 months. No episodes of liver toxicity related to bicalutamide were seen. Conclusions: Although these results are preliminary, bicalutamide appears to be a safe option for androgen blockade in transgender girls. [ABSTRACT FROM AUTHOR]

The article presents the case study of 26-month-old girl with rapid growth, clitoromegaly, and abnormal laboratory findings. Topics include biochemical profile did not indicate congenital adrenal hyperplasia (CAH) and that an endocrine referral was not needed; and physical examination revealed complete posterior labial fusion, a prominent clitoris, and a urogenital sinus.

Introduction: Hypothyroidism-induced rhabdomyolysis without precipitating factors is extremely rare, particularly in pediatric patients. We describe a previously healthy adolescent boy who came to our institution with vague symptoms and was found to have rhabdomyolysis secondary to hypothyroidism due to Hashimoto thyroiditis. We also summarize previously published cases in children and adolescents. Case Presentation: A 16-year-old boy presented to the emergency department at Riley Hospital for Children with a 2-week history of bilateral eye and lip swelling, fatigue, and slowing of speech initially attributed to angioedema. His laboratory studies were significant for acute kidney injury secondary to rhabdomyolysis. Additional evaluation revealed profound primary hypothyroidism and positive TPO antibodies. Although his free T4 was undetectable, his TSH was only 32.2 mcU/mL. He received IV hydration and thyroid replacement, and his symptoms improved after several months of treatment. Discussion: Rhabdomyolysis without any risk factors is very rare, especially in children. Our patient was not on any medications, had no family history of neuromuscular disorders, and no history of trauma, infection, or strenuous exercise. The reason behind the disproportionately mild elevation of TSH in the setting of an undetectable free T4 is unclear. Conclusion: It is important for clinicians to be aware that rhabdomyolysis may be a presenting sign of severe hypothyroidism, as delay in diagnosis and treatment can be detrimental. [ABSTRACT FROM AUTHOR]

Background: Testicular adrenal rest tumors (TARTs) increase the risk of infertility in males with classic congenital adrenal hyperplasia (CAH). There is no consensus regarding at what age screening testicular ultrasounds should begin and how often they should be repeated. Furthermore, it is unknown whether patients and parents are aware of the significance of TARTs. Objective: The objective of the study was to investigate awareness, concern, and screening rates for TARTs in males with classic CAH. Methods: Males with CAH and parents completed an online questionnaire from 2019 to 2020. Responses to questions about TARTs were analyzed. Fisher's exact test was used to determine statistical significance. Results: Of 123 responders, 14 were males with CAH (range 16–54 years) and 109 were parents of males with CAH (son's age range infancy to 37 years). Of all responders, 74% were concerned about the possibility of TARTs, 48% had discussions about TARTs with their endocrinologist, and 42% were aware of possible infertility in males with CAH. There was no difference between responses provided by affected males and parents for these topics (p ≥ 0.08). Among male responders with CAH, 93% had at least one testicular ultrasound, and 77% had undergone more than one. Among parent responders, 30% of their sons had at least one testicular ultrasound, and 61% had more than one. The frequency, total number, and age when the first testicular ultrasound was obtained were inconsistent in both groups. Fifty percent of male responders with CAH and 11% of sons were referred to a urologist for evaluation. Conclusions: Although most responders were concerned about TARTs, less than half recalled discussing this issue with their endocrinologist, and less than half were aware of the possibility of infertility. Although TARTs are most often treated medically, several responders were referred to a urologist. Standardized patient education and consensus guidelines are needed for the surveillance and management of TARTs in males with classic CAH. [ABSTRACT FROM AUTHOR]

Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis.. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function. [ABSTRACT FROM AUTHOR]

The histrelin implant has been used to treat central precocious puberty (CPP) for more than 15 years. Although approved for annual use, limited published reports suggest that a single implant is efficacious well beyond a year. Our objective was to report our long-term experience using a single histrelin implant for more than 12 months in children with CPP. We performed a retrospective study of 170 children with central precocious puberty treated with a single histrelin implant for more than 1 year. Implants were left in situ for an average of 24 months. Pubertal development regressed or remained stable in the vast majority of patients and biochemical suppression was maintained. No correlation between time since an implant was placed and complications such as implant breakage or a second incision was seen. A single histrelin implant provides excellent pubertal suppression well beyond a year. Extended use of a single histrelin implant should be considered standard of care in children with CPP. [ABSTRACT FROM AUTHOR]

Spanning from bench to bedside, the history of normal and precocious puberty is characterized by a series of remarkable advances that have illuminated reproductive physiology and profoundly impacted clinical care. Early recognition of the hypothalamic and pituitary control of ovarian and testicular function led to the identification of GnRH as the key driver of pubertal onset. Decades later, discovery of the kisspeptin system further refined our understanding of human reproductive neuroendocrinology. Development of long-acting analogs of GnRH revolutionized the treatment of precocious puberty worldwide and ushered in the current era of an ever-expanding therapeutic armamentarium. Identification of monogenic etiologies of precocious puberty has further illustrated the exquisite complexity that comprises neurosecretory modulation of the hypothalamic GnRH neuron and may well lead to exciting novel targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Three times daily (TID) hydrocortisone (HC) is recommended as the optimal glucocorticoid regimen in growing children with congenital adrenal hyperplasia (CAH). However, a variety of other treatment schemes are used in the clinical setting. Objective: The aim of this study was to determine whether there are clinical differences between children being treated with TID HC versus those receiving other glucocorticoid regimens. Furthermore, we sought to determine whether there was evidence of a deleterious effect on growth in children receiving treatment with alternate regimens. Methods: Medical records of children followed in our pediatric endocrinology outpatient clinic for classic CAH secondary to 21-hydroxylase deficiency during the last 10 years were reviewed. Variables analyzed included sex, age at the most recent visit, glucocorticoid type, frequency and dose (mg/m2/day), height z-score, BMI z-score, ethnicity, most recent bone age, growth velocity z-score, and provider's impression of compliance (good or poor). Results: Of 104 children (51% boys) with CAH, 50 (48%) were on TID HC, 43 (41%) were on prednisone or prednisolone, and 5 (5%) were on dexamethasone. An additional 6 (6%) were on HC administered either 2 or 4 times daily. No differences were seen between TID HC and alternate regimen groups with respect to sex, height z-score, BMI z-score, ethnicity, provider assessment of compliance, ratio of bone age to chronologic age, or growth velocity. The average height z-score was −0.40 ± 1.31 in the TID HC group compared to −0.87 ± 1.33 in the alternate regimen group (p = 0.075). Patients receiving TID HC were younger (p = 0.027) and on a lower glucocorticoid dose (p = 0.001) than those on alternate regimens. Conclusions: Less than half of our patients with CAH were receiving TID HC. Reassuringly, growth parameters and other indices of disease control were equivalent between patients on conventional HC dosing and other therapeutic approaches. These results suggest that a range of glucocorticoid treatment regimens may be equally viable in children with CAH. [ABSTRACT FROM AUTHOR]

Background: Prolactinomas are rare in children and adolescents. As in adults, dopamine agonists (DAs) are the treatment of choice in the majority of patients. However, at what point children should be taken off of therapy and what the recurrence risk of hyperprolactinemia is following treatment withdrawal is not well described. Objective: Our objective was to systematically review our experience with DA treatment withdrawal in children and adolescents with prolactinomas. Methods: A retrospective review of patients followed for prolactinomas during the last 12 years was conducted. Variables analyzed included age, gender, initial serum prolactin levels, tumor characteristics, cabergoline dose, and results of treatment withdrawal. Clinical characteristics of patients who met eligibility criteria for DA withdrawal were compared with those who did not. Patients who underwent surgery were excluded. Results: Of 47 patients identified, 42 were included in the study. Of those, DA withdrawal was attempted in 13 (31%) and was initially successful in 3 (21%). Patients who did not meet eligibility criteria for treatment withdrawal had higher baseline prolactin levels (p = 0.018) as well as larger (p = 0.03) and more invasive (p = 0.002) tumors. Conclusions: Less than half of our patients were eligible for DA treatment withdrawal and less than one-fourth achieved remission of hyperprolactinemia following cessation of therapy. This suggests that the overall recurrence rate of prolactinomas in pediatric patients may be higher than has been reported in adults. [ABSTRACT FROM AUTHOR]

Short stature is one of the most common reasons for referral to pediatric endocrinologists. The vast majority of short children do not have growth hormone (GH) deficiency or another pathologic process that is interfering with normal growth. While GH has been approved in the US for several etiologies of non-GH deficient short stature, its high cost and need for daily injections represent barriers for many families. Alternative agents for the management of short stature include the use of gonadotropin releasing hormone analogs (GnRHas) to delay puberty, and aromatase inhibitors (AIs) in boys to postpone epiphyseal fusion. The results of studies employing GnRHas as either monotherapy or combined with GH are mixed, and there is a dearth of rigorously designed clinical trials that have followed patients to adult height. While AIs have been found to result in modest increases in adult height in some studies, important questions about their long-term safety exist. The C-type natriuretic peptide analog vosoritide is an experimental agent that is emerging as a potential treatment for a few specific conditions including achondroplasia, although its efficacy in attenuating disproportionality is as yet unproven. While each of these therapeutic strategies holds promise, none are currently considered standard of care and several important questions remain. These include the impact of these interventions on quality of life as well as long-term outcomes. [ABSTRACT FROM AUTHOR]

Introduction: In the randomized "Toddler Turner" study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters. Methods: Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups. Results: The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>−2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = −0.30; p = 0.016]). No new safety concerns arose. Conclusion: Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood. [ABSTRACT FROM AUTHOR]

Background: A random ultrasensitive luteinizing hormone (LH) (LH-ICMA) ≥0.3 mIU/L is highly accurate in confirming a diagnosis of central precocious puberty (CPP). However, a prepubertal value does not exclude the diagnosis. The clinical differences between patients with CPP who have a pubertal versus prepubertal LH-ICMA have not been clearly defined. Furthermore, there is minimal information regarding the utility of this test in boys with CPP. The objective of this study was to analyze differences between patients diagnosed with CPP who had a pubertal versus prepubertal LH-ICMA, including a cohort of boys. Methods: A retrospective chart review of children diagnosed with CPP within the last 10 years who had a baseline LH-ICMA obtained was performed. Variables analyzed included sex, age, ethnicity, bone age, BMI, etiology, Tanner stage (TS), testicular volume, and menarchal status. Results: Of 27 boys and 126 girls who qualified for the study, the LH-ICMA was pubertal in 87% and prepubertal in 13%. Girls with a pubertal LH-ICMA had higher baseline estradiol concentrations (p < 0.001) and more advanced breast development (p = 0.015) compared to girls with a prepubertal LH-ICMA. Of girls with a prepubertal LH-ICMA, 74% had at least TS 3 breast development and 1 was post-menarchal. The LH-ICMA was pubertal in 96% of the boys with CPP in this study. Conclusions: The LH-ICMA can be prepubertal even in girls with advanced development. To our knowledge, ours is the largest cohort of boys in whom the accuracy of a random LH-ICMA has been reported. [ABSTRACT FROM AUTHOR]

Context: Gonadotropin-releasing hormone agonists (GnRHas) are standard of care for central precocious puberty (CPP). A 6-month subcutaneous injection has recently been approved by the Food and Drug Administration.Objective: Determine efficacy, pharmacokinetics, and safety of 6-month 45-mg subcutaneous leuprolide acetate for CPP.Design: Phase 3 multicenter, open-label, single-arm study.Setting: 25 sites in 6 countries.Subjects: 64 GnRHa-naïve children with CPP (age: 7.5 ± 0.1 years) received study drug: 59 completed the study.Intervention(s): 2 doses of 45-mg subcutaneous leuprolide acetate (0.375 mL) at 0 and 24 weeks; children were followed for 48 weeks.Main Outcome Measure(s): Percentage of children with serum luteinizing hormone (LH) <4 IU/L 30 minutes following GnRHa stimulation at week 24.Results: 54/62 (87%) children achieved poststimulation LH <4 IU/L at week 24; 49/56 (88%) girls and 1/2 boys maintained peak LH <4 IU/L at week 48. Mean growth velocity decreased from 8.9 cm/year at week 4 to 6.0 cm/year at week 48. Mean bone age was advanced 3.0 years beyond chronological age at screening and 2.7 years at week 48. Breast pubertal stage regressed or was stable in 97% of girls and external genitalia development regressed in both boys. Adverse events were mild and did not cause treatment discontinuation.Conclusions: A small volume of 45-mg subcutaneous leuprolide acetate administered at a 6-month interval effectively suppressed pubertal hormones and stopped or caused regression of pubertal progression. This long-acting GnRHa preparation of leuprolide acetate is a new, effective, and well-tolerated therapy for children with CPP. [ABSTRACT FROM AUTHOR]

Long-acting analogs of GnRH (GnRHas) have been the gold-standard treatment of central precocious puberty (CPP) worldwide and have an enviable track record of safety and efficacy. Recent years have witnessed much growth in the availability of longer-acting and sustained-release forms of GnRHas. Although all available agents appear promising, limited long-term follow-up and/or comparative data are available. In this review, important issues pertaining to the treatment of children with CPP are discussed. In addition to an assessment of the newer extended-release GnRHa formulations, a delineation of factors essential in determining which children should be treated is offered. Outstanding uncertainties in clinical management are highlighted and areas in need of future research identified. Literature searches for this review were performed in PubMed and OVID, with a focus on English-language publications using the terms "central precocious puberty" and "treatment." [ABSTRACT FROM AUTHOR]

Introduction: Precocious puberty (PP) is one of the most common reasons for referral to pediatric endocrinologists. Gonadotropin-releasing hormone analogs (GnRHas) are the gold standard for the treatment of central precocious puberty (CPP) and have an impressive record of safety and efficacy. However, ongoing refinements in diagnosis and management continue to lead to important advancements in clinical care. Areas covered: The aim of this review is to cover current considerations and controversies regarding the diagnosis of CPP, as well as new findings in regards to etiology and treatment modalities. Expert opinion: There is emerging evidence of monogenic etiologies of CPP and significant progress in the expansion of newer formulations of GnRHas. Despite these exciting developments, areas of uncertainty in the diagnosis and treatment of CPP remain. While long-term outcomes of patients treated for CPP are encouraging, only short-term follow-up is available with respect to the newer extended release GnRHa preparations, and how they compare with historically used formulations is unknown. A particular shortage of information exists pertaining to CPP in boys and regarding the psychological implications of PP in girls, and more research is needed. Continued investigation will yield new insights into the underlying genetics and optimal treatment strategies for CPP. [ABSTRACT FROM AUTHOR]

The article discusses a study that determines the incidence of true hypoglycemia in patients referred to a tertiary outpatient pediatric endocrinology clinic for evaluation of presumed abnormally low blood sugars. The study was approved by the Indiana University Institutional Review Board. The database search revealed 178 patients with ICD-9 codes consistent with hypoglycemia. A bar graph is presented that shows percentage of different symptoms reported by patients referred for hypoglycemia.

Background: We sought to determine the frequency with which genital exams (GEs) are performed in children with disorders of sex development (DSD) and ambiguous genitalia (AG) during routine visits to the pediatric endocrine clinic. Methods: Medical records of children with DSD and AG seen at one large academic center since 2007 were reviewed. Data analyzed included diagnosis, sex of rearing, age, initial or follow up visit, number of individuals present and sex of the pediatric endocrinologist. Repeated measures analysis was performed to evaluate associations between GEs and patient/physician factors. Results: Eighty-two children with DSD and AG who had a total of 632 visits were identified. Sex of rearing was female in 78% and the most common diagnosis was congenital adrenal hyperplasia (CAH) (68%). GEs were performed in 35.6% of visits. GEs were more likely in patients with male sex of rearing (odds ratio [OR] 17.81, p = 0.006), during initial vs. follow-up visits (OR 5.99, p = 0.012), and when the examining endocrinologist was female (OR 3.71, p = 0.014). As patients aged, GEs were less likely (OR 0.76, p < 0.0001). Conclusions: GEs were performed in approximately onethird of clinic visits in children with DSD and AG. Male sex of rearing, initial visits and female pediatric endocrinologist were associated with more frequent GEs. [ABSTRACT FROM AUTHOR]

Background: To determine whether psychological characteristics of girls with variations of early puberty and their mothers change over time and with treatment in girls with central precocious puberty (CPP). Methods: Girls with CPP, premature adrenarche (PA), and early normal puberty (ENP) completed psychological assessments at baseline and after 1 year along with their mothers. All girls with CPP were treated with GnRH analogs. Psychological effects of group and time were examined using 2 x 3 mixed ANOVAs. Results: Sixty-two subjects aged 7.5 ± 1.4 years (range 4.8-10.5) were enrolled, of whom 36 (15 with CPP, 8 with PA, and 13 with ENP) completed 1-year follow-up assessments. Psychological measures were normal in all girls. No significant group differences were found for any measure of girls' psychological functioning at either time point. However, across all groups there was change over time with a decrease in perceived physical competence (p < 0.001) and an increase in perceived maternal acceptance (p = 0.001). Conclusion: No abnormalities in psychological functioning were found among girls with variations of early puberty, and all groups were in the normal range. Our results are largely reassuring regarding concerns of adverse psychological consequences of early puberty in girls. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine the extent of post-treatment weight gain that occurs in pediatric patients in the first year following radioactive iodine (RAI) therapy for Graves disease (GD) and its relationship to clinical characteristics. Methods: A retrospective chart review of patients receiving RAI therapy for GD between 1998-2015 was performed. Change in BMI SDS (ΔBMI SDS) from baseline to one year after treatment was determined. We also investigated whether individual clinical and/or biochemical factors were associated with the weight trajectory in these patients. Results: One hundred fifty seven patients aged 12.7 ± 3 years (80% girls) were included in the analysis. Average ΔBMI SDS was 0.70 ± 0.71 (p < 0.001) at 1 year. Patients with weight loss at presentation had a greater ΔBMI SDS than those without (0.92 vs 0.56, p = 0.005), whereas no association was seen with gender, pubertal status, use of antithyroid drugs, history of ADHD, or Down syndrome. Baseline BMI SDS was negatively correlated with ΔBMI SDS, with a stronger correlation in males. From baseline to 1 year, the proportion of overweight and obese patients increased from 9.6% to 18.5% and from 6.4% to 21%, respectively. In a subset of 81 patients, a positive correlation was noted between time to euthyroidism and ΔBMI SDS, particularly in boys. Conclusions: The number of our patients in the overweight category doubled and the number in the obese category more than tripled in the first year following RAI treatment for GD. Anticipatory guidance regarding this important issue is badly needed. [ABSTRACT FROM AUTHOR]

Background: Little is known about the comparative effects of different glucocorticoids on the adrenal and growth hormone (GH) axes in children with congenital adrenal hyperplasia (CAH). We sought to compare the effects of hydrocortisone (HC), prednisone (PDN), and dexamethasone (DEX) in children with classic CAH and to investigate a potential role of pharmacogenetics. Methods: Subjects were randomly assigned to three sequential 6-week courses of HC, PDN, and DEX, each followed by evaluation of adrenal hormones, IGF-1, GH, and body mass index (BMI). Single nucleotide polymorphism (SNP) analysis of genes in the glucocorticoid pathway was also performed. Results: Nine prepubertal subjects aged 8.1 ± 2.3 years completed the study. Mean ACTH, androstenedione, and 17-hydroxyprogesterone (17-OHP) values were lower following the DEX arm of the study than after subjects received HC (p ≤ 0.016) or PDN (p ≤ 0.002). 17-OHP was also lower after HC than PDN (p < 0.001). There was no difference in IGF-1, GH, or change in BMI. SNP analysis revealed significant associations between hormone concentrations, pharmacokinetic parameters, and variants in several glucocorticoid pathway genes (ABCB1, NR3C1, IP013, GLCCI1). Conclusions: DEX resulted in marked adrenal suppression suggesting that its potency relative to hydrocortisone and prednisone was underestimated. SNPs conferred significant differences in responses between subjects. Although preliminary, these pilot data suggest that incorporating pharmacogenetics has the potential to eventually lead to targeted therapy in children with CAH. [ABSTRACT FROM AUTHOR]

Background: Limited information is available regarding baseline characteristics of children and adolescents with gender dysphoria (GD). The purpose of this retrospective study was to describe baseline characteristics of pediatric patients referred for GD. Methods: A retrospective chart review of pediatric patients with GD referred to the pediatric endocrine clinic between 2002 and 2017 was conducted. Body mass index (BMI) percentiles and z-scores were calculated based on height and weight at the initial visit. Results: Seventy-eight patients aged 14.9±2.37 years were identified. Of these, affirmed gender was more often male than female (63% vs. 37%, p=0.024). Although no difference was seen in average BMI z-scores between female to male (FTM) and male to female (MTF) patients, approximately 50% were overweight or obese. A higher incidence of anxiety was present in FTM compared with MTF youth (p=0.05). Fifty-six patients were referred in January 2014 or later, of whom 27% had a history of early expression of GD compared with 55% of those seen prior to 2014 (p=0.061). Conclusions: The high prevalence of overweight in TG youth at baseline represents a potential risk for adverse health consequences. There appears to be a change in the age of first manifestation of GD over time. [ABSTRACT FROM AUTHOR]

Central precocious puberty (CPP) is characterized by the same biochemical and physical features as normally timed puberty but occurs at an abnormally early age. Most cases of CPP are seen in girls, in whom it is usually idiopathic. In contrast, ~50 % of boys with CPP have an identifiable cause. The diagnosis of CPP relies on clinical, biochemical, and radiographic features. Untreated, CPP has the potential to result in early epiphyseal fusion and a significant compromise in adult height. Thus, the main goal of therapy is preservation of height potential. The gold-standard treatment for CPP is gonadotropin-releasing hormone (GnRH) analogs (GnRHa). Numerous preparations with a range of delivery systems and durations of action are commercially available. While the outcomes of patients treated for CPP have generally been favorable, more research about the psychological aspects, optimal monitoring, and long-term effects of all forms of GnRHa treatment is needed. Several potential therapeutic alternatives to GnRHa exist and await additional investigation. [ABSTRACT FROM AUTHOR]

The Region 4 Midwest Genetics Collaborative, made up of seven regional states (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, and Wisconsin), brought together pediatric endocrinologists, state laboratory experts, public health follow-up specialists, and parents of children with congenital hypothyroidism (CH) to identify the three-year follow-up management and education patterns of primary care clinicians and pediatric endocrinologists in the care of children diagnosed with CH by state newborn screening (NBS) programs. Among a number of challenges, each state had different NBS methods, data systems, public health laws, and institutional review board (IRB) requirements. Furthermore, the diagnosis of CH was complicated by the timing of the NBS sample, the gestational age, weight, and co-morbidities at delivery. There were 409 children with CH identified through NBS in 2007 in the seven state region. The clinician of record and the parents of these children were invited to participate in a voluntary survey. Approximately 64 % of clinician surveys were collected with responses to questions relating to treatment, monitoring practices, educational resources, genetic counseling, and services provided to children with confirmed CH and their families. Nearly one-quarter (24 %) of parents surveyed responded to questions relating to treatment, education, genetic counseling, resources, and services they received or would like to receive. De-identified data from six of the seven states were compiled for analysis, with one state being unable to obtain IRB approval within the study timeline. The data from this collaborative effort will improve state follow-up programs and aid in developing three-year follow-up guidelines for children diagnosed with CH. To aid in the facilitation of similar public health studies, this manuscript highlights the challenges faced, and focuses on the pathway to a successful multi-state public health endeavor. [ABSTRACT FROM AUTHOR]

Background: Concerns about psychological distress are often used to justify treatment of girls with precocious puberty, but there is little evidence to support these concerns. The extent to which psychological problems are associated with central precocious puberty (CPP) compared with other forms of early puberty in girls has likewise not been established. Methods: Girls presenting with untreated CPP, premature adrenarche (PA) or early normal puberty (ENP) were recruited from our pediatric endocrine clinic along with their mothers. Child psychological adjustment was assessed by child self-report and parent report. Parent self-reported personality, anxiety, and depression were also assessed. Differences between groups were explored using one-way ANOVA and Dunnett's T3 test. Results: Sixty-two subjects (aged 7.5 ± 1.4 years, range 4.8-10.5) were enrolled, of whom 19 had CPP, 22 had PA, and 21 had ENP. Girls with ENP were significantly older (8.9 ± .9 years) than girls with CPP (6.9 ± 1.1 years, p < .001) and PA (6.6 ± 1.0 years, p < .001). Girls with PA had significantly higher BMI z-scores (1.7 ± .8) than girls with CPP (1.1 ± .6, p = .01) and ENP (1.2 ± .6, p = .04). More girls with PA and ENP were from racial minorities (47% and 50% respectively) than girls with CPP (32%). No group differences were found for any child measure of psychological adjustment. However, mothers of girls with PA scored significantly higher than mothers of girls with ENP on one measure of depression (p = .04) and stress (p = .01). Conclusions: While mothers of girls with PA report increased psychological distress on some measures, no differences in psychological adjustment were found at baseline amongst the girls themselves. Whether these results will change as puberty progresses in the PA and ENP groups or with treatment of CPP is unknown. Long-term prospective studies are needed in order to further investigate psychological correlates of early puberty in girls. [ABSTRACT FROM AUTHOR]

Primary adrenal insufficiency (AI) in children usually presents with non-specific symptoms such as fatigue, nausea, vomiting, and anorexia. Here, we report an unusual case of a 15 year old girl who presented with acute mental status change and was ultimately diagnosed with AI due to autoimmune polyglandular syndrome type II (APS2). Central nervous system imaging revealed a cerebral infarction. To our knowledge, the constellation of APS2, stroke and acute mental status change has not been previously reported. We review the literature with regard to the presentation of AI as well as the association between vasculitis and APS2. [ABSTRACT FROM AUTHOR]

Objectives. The aims of this study were to determine the frequency at which spurious diagnoses and unnecessary treatment occurs prior to the diagnosis of Graves disease (GD) and to evaluate the economic consequences of these events. Methods. Retrospective chart review of children diagnosed with GD. Results. A total of 76 children (61 girls) aged 11.9 ± 3.8 years were identified. In all, 17 (22.4%) were referred to other subspecialists prior to diagnosis of GD. Six were hospitalized, and 2 visited emergency rooms. A total of 15 (19.7%) underwent nonthyroid-related studies. Estimated cost of testing and procedures ranged from $49 to $14 000. Twelve (15.8%) were diagnosed with attention deficit/hyperactivity disorder, and 16 (21.1%) were started on medications for other conditions prior to diagnosis of GD. Conclusions. Evaluation and treatment for presumed other disorders are common in children with GD. A high index of suspicion for hyperthyroidism by primary care providers may help to avoid clinical detours that may be costly and delay diagnosis. [ABSTRACT FROM PUBLISHER]

Fibrous dysplasia (FD) is sometimes accompanied by extraskeletal manifestations that can include any combination of café-au-lait macules, hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, hyperthyroidism, growth hormone excess, FGF23-mediated renal phosphate wasting, and/or Cushing syndrome, as well as other less common features. The combination of any of these findings, with or without FD, is known as McCune-Albright syndrome (MAS). The broad spectrum of involved tissues and the unpredictable combination of findings owe to the fact that molecular defect is due to dominant activating mutations in the widely expressed signaling protein, Gsa, and the fact these mutations arises sporadically, often times early in development, prior to gastrulation, and can distribute across many or few tissues. The complexity can be mastered by a systematic screening of potentially involved tissues and cognizance that the pattern of involved tissues is established, to some degree, in utero. Thorough testing allows the clinician to establish, often times at presentation, the full extent of the disease, and importantly as well what tissues are unaffected. Treatment and follow-up can then be focused on affected systems and a meaningful prognosis can be offered to the patient and family. The authors outline screening and treatment strategies that allow for effective management of the extraskeletal manifestations of FD. [ABSTRACT FROM AUTHOR]

Background: Severe acquired hypothyroidism often results in significant height deficit due to rapid bone age advancement following treatment. Whether gradual correction of hypothyroidism and/or adjunctive growth-promoting therapies (GPTs) augment final adult height (FAH) is controversial. Objective: To investigate time to euthyroidism, pace of bone age advancement (ΔBA/ΔCA), and impact of GPTs on FAH. Methods and patients: Retrospective review of 21 children (10.1 ± 3.0 years) with profound hypothyroidism. Results: Baseline bone age standard deviation score (SDS) was -4.1 ± 1.8, whereas height SDS was -3.0 ± 1.1. Average time to euthyroidism was 9.7 months (2.3 - 33.7 months). Average ΔBA/ΔCA was 2.3 ± 0.9. Six of 13 patients at FAH received GPTs. No correlation was found between time to euthyroidism and rate of skeletal maturation. No difference in height outcome was seen between those who received GPTs and those who did not. Conclusions: Neither time to euthyroidism nor use of GPTs significantly affected height potential in our patients. [ABSTRACT FROM AUTHOR]

Context: No randomized, controlled, prospective study has evaluated the effect of growth hormone (GH) on the rates of middle ear (ME) disease and hearing loss in girls with Turner syndrome (TS). Design: A 2-year, prospective, randomized, controlled, open-label, multicenter, clinical trial ('Toddler Turner Study'; August 1999 to August 2003) was carried out. Setting: The study was conducted at 11 US pediatric endocrine centers. Subjects: Eighty-eight girls with TS, aged 9 months to 4 years, were enrolled. Intervention: The interventions comprised recombinant GH (50 μg/kg/day, n = 45) or no treatment (n = 43) for 2 years. Main Outcome Measures: The outcome measures included occurrence rates of ear-related problems, otitis media (OM) and associated antibiotic treatments, tympanometric assessment of ME function and hearing assessment by audiology. Results: At baseline, 57% of the girls (mean age = 1.98 ± 1.00 years) had a history of recurrent OM, 33% had undergone tympanostomy tube (t-tube) insertion and 27% had abnormal hearing. There was no significant difference between the treatment groups for annual incidence of OM episodes (untreated control: 1.9 ± 1.4; GH-treated: 1.5 ± 1.6, p = 0.17). A quarter of the subjects underwent ear surgeries (mainly t-tube insertions) during the study. Recurrent or persistent abnormality of ME function on tympanometry was present in 28-45% of the girls without t-tubes at the 6 postbaseline visits. Hearing deficits were found in 19-32% of the girls at the annual postbaseline visits. Most of these were conductive deficits, however, 2 girls had findings consistent with sensorineural hearing loss, which was evident before 3 years of age. Conclusions: Ear and hearing problems are common in infants and toddlers with TS and are not significantly influenced by GH treatment. Girls with TS need early, regular and thorough ME monitoring by their primary care provider and/or otolaryngologist, and at least annual hearing evaluations by a pediatric audiologist. [ABSTRACT FROM AUTHOR]

The treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is complex. In addition to disease control, important therapeutic goals are themaintenance of normal growth and the acquisition of normal reproductive function.Here, data regarding final adult height (FH) in patients with CAH will be reviewed. Additional difficulties associated with CAH, including risks of obesity and hypertension, will be discussed. Information about fertility and reproductive outcomes in men and women with CAH will also be summarized. Although the treatment of each child with CAH needs to be individualized, close medical followup and laboratory monitoring along with good compliance can often result in positive clinical outcomes. [ABSTRACT FROM AUTHOR]

Patients with rare and complex diseases such as congenital adrenal hyperplasia (CAH) often receive fragmented and inadequate care unless efforts are coordinated among providers. Translating the concepts of the medical home and comprehensive health care for individuals with CAH offers many benefits for the affected individuals and their families. This manuscript represents the recommendations of a 1.5 day meeting held in September 2009 to discuss the ideal goals for comprehensive care centers for newborns, infants, children, adolescents, and adults with CAH. Participants included pediatric endocrinologists, internal medicine and reproductive endocrinologists, pediatric urologists, pediatric surgeons, psychologists, and pediatric endocrine nurse educators. One unique aspect of this meeting was the active participation of individuals personally affected by CAH as patients or parents of patients. Representatives of Health Research and Services Administration (HRSA), New York-Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), and National Newborn Screening and Genetics Resource Center (NNSGRC) also participated. Thus, this document should serve as a "roadmap" for the development phases of comprehensive care centers (CCC) for individuals and families affected by CAH. [ABSTRACT FROM AUTHOR]

Objective: To compare glycemic control, body mass index (BMI), neurocognitive function, and parenting stress for preschool-aged diabetic children randomized to treatment either with continuous subcutaneous insulin infusion (CSII) or with intensive insulin injection therapy (IIT). Methods: Children <5 yr of age diagnosed with type 1 diabetes mellitus for at least 12 months were randomized to either CSII (n = 21) or IIT (n = 21) for 6 months. After 6 months, the IIT group began CSII therapy and the CSII group continued on pumps. Hemoglobin A1c (HbA1c) and BMI percent were collected at baseline, 3, 6, 9, and 12 months. Neurocognitive assessments (Developmental Test of Visual–Motor Integration and Stanford–Binet Intelligence Scale: Fourth Edition) were administered to children, and parenting and child behavior assessments (Parenting Stress Index and Child Behavior Checklist) were completed by parents and at baseline, 6, and 12 months. Results: Thirty-five children completed the study. Mean HbA1c decreased significantly over the study period (8.9% ± 0.6 vs. 8.5% ± 0.7, p = 0.006). Initiation of CSII resulted in an HbA1c decrease of 0.4% after 3 months (p = 0.002); however, in the CSII first group, the HbA1c at 12 months was not significantly different from study start (8.8% ± 0.6 vs. 8.5% ± 0.6; p = 0.4). There were no significant changes in BMI%, neurocognitive, parenting, and child behavior measures between groups. Conclusion: Initiation of CSII vs. continuing IIT does not significantly influence HbA1c, BMI, neurocognitive, or parenting stress parameters in a research study setting. [ABSTRACT FROM AUTHOR]

The article discusses the case of a child with Down syndrome who was diagnosed with congenital hypothyroidism due to left thyroid hemiagenesis and later developed Graves' disease. Increased thyroid stimulating hormone (TSH) was shown on the repeat newborn screen done on the patient. Issues on thyroid hemiagenesis, autoimmune hyperthyroidism, and thyroid disease in children with Down syndrome are discussed.

Background: Peripheral precocious puberty (PPP) results from sex steroid exposure by a process other than activation of the hypothalamic-pituitary-gonadal axis. It is much less common than central precocious puberty and may be congenital or acquired. Causes of PPP range from well-characterized genetic mutations to those conditions without a known etiology (idiopathic). Medical evaluation and treatment of affected children is guided by the presenting features and ultimate diagnosis. Conclusions: Carefully executed and collaborative multicenter investigations are essential to expand our knowledge of the underlying pathophysiology, optimal therapy and ultimate outcomes in children with PPP. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. Gonadotropin releasing hormone analogs (GnRHas) are standard of care for central precocious puberty (CPP). The histrelin subcutaneous implant is safe and effective in the treatment of CPP for one year. Objective. The study evaluates a second year of therapy in children with CPP who received a new implant after one year of treatment. Methods. A prospective one-year study following an initial 12-month treatment period was conducted. Results. Thirty-one patients (29 girls) aged 7.7 ± 1.5 years received a second implant. Eighteen were naïve to GnRHa therapy at first implantation. Peak LH declined from0.92±0.58 mIU/mL at 12 months to 0.51 ± 0.33 mIU/mL at 24 months (P < .0001) in naïve subjects, and from 0.74 ± 0.50 mIU/mL at 12 months to 0.45 ± 0.35 mIU/mL at 24 months (P = .0081) in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months (P = .0001). Minor implant site reactions occurred in 61%, while minor difficulties with explantation occurred in 32.2% of subjects. Conclusion. The histrelin implant demonstrates profound hypothalamic-pituitary-gonadal axis suppression when a new implant is placed for a second year of treatment. Prospective follow-up of this therapeutic modality for the treatment of CPP is needed. [ABSTRACT FROM AUTHOR]

The article discusses a study which aimed to investigate the incidence of thyroid stimulating immunoglobulin (TSI) negativity in children and adolescents diagnosed with Graves' disease (GD). The study also aims to determine whether any aspects of the disease were different in patients with TSI negative versus TSI positive GD. Charts of children with GD seen in a pediatric endocrinology clinic over the past five years were reviewed in this study. The study concluded that in patients with GD, the finding of a negative TSI titer usually creates diagnostic uncertainty.

The most common cause of congenital adrenal hyperplasia is 21-hydroxylase deficiency (21 OHD). The prevalence of hypertension (HTN) in children with 21 OHD is unknown, and HTN has not been reported to be a component of this disorder. As children with 21 OHD are at risk of developing obesity, we hypothesized that an elevated body mass index (BMI) would be a predictive factor in the development of HTN. A retrospective chart review of children with 21 OHD seen in our pediatric endocrine clinics for the past 21 yr was performed. Ninety-one children with 21 OHD were identified (54% female). Of these children, six (6.6%) had HTN, and five (5.6%) had essential HTN, which was defined as HTN of unknown etiology. Elevated body mass index was not a determining factor in the development of HTN. Children with 21 OHD do appear to have a higher prevalence of HTN when compared to historical reports of pediatric populations. The coexistence of HTN with a salt-wasting state and mineralocorticoid deficiency in some children with 21 OHD is paradoxical and of unclear etiology. [ABSTRACT FROM AUTHOR]