Premature Pubarche: A Pragmatic Approach.

Premature pubarche (PP) is a common and usually benign variant of normal puberty most often seen in 5-year-old to 9-year-old children. Some providers routinely order laboratory testing and a bone age to try to rule out other diagnoses including nonclassic congenital adrenal hyperplasia and gonadal or adrenal tumors. I review the natural history of PP and studies which suggest that without clinical features such as rapid growth and progression or genital enlargement, it is unlikely that a treatable condition will be found. Therefore it is recommended that patients with PP not undergo testing unless there are red flags at the time of the initial visit.

Isolated Vaginal Bleeding Before the Onset of Puberty.

Isolated vaginal bleeding before the onset of puberty is a rare presentation of isosexual precocity. In most cases, isolated vaginal bleeding without an abnormal genital examination is self-limited with resolution usually within 1 to 3 episodes. Watchful waiting is appropriate in most patients who do not have persistent bleeding, other signs of puberty, or signs/symptoms of an underlying etiology. Workup for patients with concerning features may include puberty hormone levels and/or transabdominal and transperineal ultrasound.

Females with Breast Development before Three Years of Age.

Breast development in a girl 3 years of age or younger is a commonly encountered scenario. Nearly all of these cases will either regress or fail to progress during follow-up, confirming a diagnosis of premature thelarche (PT). Studies show that these girls will have onset of true puberty and menses at a normal age. The authors present evidence that laboratory testing, particularly basal and gonadotropin hormone-releasing hormone -stimulated gonadotropin levels, will show overlap between girls with PT and the rare patients with the onset of central precocious puberty before age 3, mainly of whom have hypothalamic hamartomas.

Gonadotropin-releasing hormone analog therapies for children with central precocious puberty in the United States.

Gonadotropin-releasing hormone agonists (GnRHa's) are the standard treatment for children with central precocious puberty (CPP). We aim to present data on available GnRHa options with an easy-to-review table and discuss factors that influence treatment selection. Five GnRHa's are currently FDA-approved and prescribed in the US and published data suggest similar safety and efficacy profiles over the first year of treatment. One- and 3-month intramuscular (IM) leuprolide acetate (LA) have long-term safety and efficacy data and allow for flexible dosing. Six-month IM triptorelin pamoate offers a longer duration of treatment, but without long-term efficacy and outcome data. Six-month subcutaneous (SQ) LA combines a SQ route of injection and long duration of action but lacks long-term efficacy and outcome data. The 12-month SQ histrelin acetate implant avoids injections and offers the longest duration of action, but requires a minor surgical procedure with local or general anesthesia. Factors in treatment selection include route of administration, needle size, injection volume, duration of action, and cost. The current GnRHa landscape provides options with varying benefits and risks, allowing physicians and caregivers to select the most appropriate therapy based on the specific needs and concerns of the child and the caregiver. Agents have different advantages and disadvantages for use, with no one agent displaying superiority.

Economic burden of growth hormone deficiency in a US pediatric population.

BACKGROUND: Pediatric growth hormone deficiency (GHD) is a rare disorder of short stature that is currently treated with daily injections of somatropin. In addition to short stature, GHD is associated with other comorbidities such as impaired musculoskeletal development, cardiovascular disease, and decreased quality of life. OBJECTIVE: To analyze somatropin utilization, adherence, and health care costs among children with GHD who had either Medicaid or commercial health insurance. METHODS: Children (aged < 18 years) with a GHD diagnosis between January 1, 2008, and December 31, 2017, were identified in the IBM MarketScan Commercial and Medicaid databases. Patients with at least 12- and 6-month continuous enrollment pre- and postdiagnosis were eligible. Children with GHD were direct matched (1:3) to controls without GHD (or other short stature-related disorders) on age, gender, plan type, region, and race (Medicaid only). Index date was the date of the first GHD diagnosis during the selection window for GHD patients and using random assignment for controls. Patients were followed until the end of continuous database enrollment or December 31, 2018. Baseline comorbidities and medications were measured during the 12 months pre-index, whereas somatropin treatment patterns along with all-cause and GHD-related health care costs were measured during the variable follow-up period. Multivariable modeling was used to compare costs between GHD patients and controls and between somatropin-treated and -untreated GHD patients while adjusting for baseline characteristics. RESULTS: There were 6,820 Medicaid and 14,070 commercial patients with GHD who met the study inclusion criteria. Mean (SD) age at index was 9.5 (4.5) years for Medicaid patients and 11.1 (3.7) years for commercial patients. The majority of patients were male (> 65%), and mean follow-up time for all cases and controls was 3-4 years. Overall, 63.2% of Medicaid and 68.4% of commercial GHD patients were treated with somatropin at some point during follow-up. Among Medicaid GHD patients, the treatment rate was highest among White males and lowest among Black females. Adherence was low as the proportion of days covered was ≥ 80% for only 18.4% of Medicaid patients and 32.3% of commercial patients and 49.1% of treated Medicaid and 24.3% of treated commercial patients discontinued before turning age 13. After adjusting for baseline characteristics, all-cause non-somatropin annualized costs were 5.67 times higher (Δ$19,309) for Medicaid GHD patients and 5.46 times higher (Δ$12,305) for commercial GHD patients than matched non-GHD controls. Adjusted all-cause non-somatropin annualized costs were 0.59 times lower (Δ$14,416) for treated Medicaid patients and 0.69 times lower (Δ$7,650) for treated commercial patients than for untreated patients. CONCLUSIONS: Pediatric GHD presents a significant health care burden, and many patients remain untreated or undertreated. Untreated GHD was associated with higher non-somatropin health care costs than treated GHD. Strategies to optimize treatment and improve adherence may reduce the health care burden faced by these patients. DISCLOSURES: This study was funded by Ascendis Pharma, Inc. Smith and Pitukcheewanont are employed by Ascendis Pharma, Inc. Manjelievskaia, Lopez-Gonzalez, and Morrow are employed by IBM Watson Health, which received funding from Ascendis Pharma, Inc., to conduct this study. Kaplowitz is a paid consultant of Ascendis Pharma, Inc.

Brain MRIs may be of low value in most children diagnosed with isolated growth hormone deficiency.

OBJECTIVES: Brain MRIs are considered essential in the evaluation of children diagnosed with growth hormone deficiency (GHD), but there is uncertainty about the appropriate cut-off for diagnosis of GHD and little data about the yield of significant abnormal findings in patients with peak growth hormone (GH) of 7-10 ng/mL. We aimed to assess the frequency of pathogenic MRIs and associated risk factors in relation to peak GH concentrations. METHODS: In this retrospective multicenter study, charts of patients diagnosed with GHD who subsequently had a brain MRI were reviewed. MRIs findings were categorized as normal, incidental, of uncertain significance, or pathogenic (pituitary hypoplasia, small stalk and/or ectopic posterior pituitary and tumors). Charges for brain MRIs and sedation were collected. RESULTS: In 499 patients, 68.1% had normal MRIs, 18.2% had incidental findings, 6.6% had uncertain findings, and 7.0% had pathogenic MRIs. Those with peak GH<3 ng/mL had the highest frequency of pathogenic MRIs (23%). Only three of 194 patients (1.5%) with peak GH 7-10 ng/mL had pathogenic MRIs, none of which altered management. Two patients (0.4%) with central hypothyroidism and peak GH<4 ng/mL had craniopharyngioma. CONCLUSIONS: Pathogenic MRIs were uncommon in patients diagnosed with GHD except in the group with peak GH<3 ng/mL. There was a high frequency of incidental findings which often resulted in referrals to neurosurgery and repeat MRIs. Given the high cost of brain MRIs, their routine use in patients diagnosed with isolated GHD, especially patients with peak GH of 7-10 ng/mL, should be reconsidered.

Radioactive iodine therapy for pediatric Graves' disease: a single-center experience over a 10-year period.

Introduction Only about 30% of pediatric patients with Graves' hyperthyroidism achieve remission with medical therapy, and therefore radioactive iodine (RAI) therapy is often used as a definitive treatment. Although the goal of RAI is permanent hypothyroidism, this is not consistently achieved. We conducted a chart review to determine the factors associated with the success of RAI. We also tried to determine optimal follow-up post RAI and if there was an optimal L-thyroxine dose that would normalize the hypothyroid state quickly. Methods This is a retrospective chart review of Graves' patients who underwent RAI between 2008 and 2017. We included age, sex, time from diagnosis, thyroid gland size, total dose of I-131 and dose in µCi/g of thyroid tissue. Patients were grouped based on outcome and analyzed using univariate and multivariate logistic regression. Follow-up thyroid levels post RAI and after starting l-thyroxine were analyzed. Results There were 78 ablations including six repeat ablations. Seventy-three percent became hypothyroid, 23% remained overtly or subclinically hyperthyroid, and 4% were euthyroid. Smaller thyroid size (36.5 vs. 47.4 g; p = 0.037) and higher dose of I-131 (242 vs. 212 µCi/g thyroid tissue; p = 0.013) were associated with a higher likelihood of hypothyroidism. Most patients remained hyperthyroid at 1 month post RAI, but by 3 months the majority became hypothyroid. There was no clear L-thyroxine dose that normalized hypothyroidism quickly. Conclusions An I-131 dose close to 250 µCi/g of thyroid tissue has a higher likelihood of achieving hypothyroidism. Testing at 2-3 months after RAI is most helpful to confirm response to RAI.

Update on pediatric hyperthyroidism.

PURPOSE OF REVIEW: This review is intended to highlight recent studies which provide new data on the epidemiology and management of children with hyperthyroidism, including neonates. RECENT FINDINGS: A French study demonstrates differences in age-related trends in incidence of hyperthyroidism in males versus females and suggests the overall incidence may be increasing. New studies confirm the effectiveness and safety of long-term medical therapy (up to 10 years), including from the first randomized trial of short-term versus long-term therapy. Radioiodine ablation (RAI) is the main alternative therapy, though surgery may have some advantages if done in a high-volume center; using higher weight-based doses of I-131 (250 µCI/g thyroid tissue) could increase proportion of patients achieving hypothyroidism and decrease repeat ablations. Maternal or neonatal thyroid-stimulating hormone (TSH) receptor antibodies in children of mothers with Graves' disease, and TSH at 3-7 days of age are good predictors of which neonates will have problems. SUMMARY: More research is needed on the epidemiology of Graves' disease. Long-term medical therapy well past two years should be considered an option in compliant patients to decrease the number who need definitive therapy. For those receiving RAI, a dose of about 250 µCI/g thyroid tissue should result in fewer cases of persistent hyperthyroidism than lower doses.

Clinical and laboratory characteristics and follow up of 62 cases of ketotic hypoglycemia: a retrospective study.

INTRODUCTION: Idiopathic ketotic hypoglycemia (KH) is the most common cause of hypoglycemia in non-diabetic children ages 0.5-6 years old and typically occurs after a period of poor food intake. There are no large studies looking at the value of common laboratory testing in children presenting with KH or how often other diagnoses are made. OBJECTIVES: To examine the clinical presentations and the value of laboratory testing done in a cohort of children clinically diagnosed with KH. METHODS: Billing records were searched from 2008 to 2017 for patients seen by the endocrine service for "hypoglycemia, not otherwise specified". Charts were reviewed to determine age, sex, presenting symptoms and testing ordered at the time of the consult. Through chart reviews after the event and parent phone calls, diagnoses other than idiopathic KH were searched. RESULTS: Of 150 charts reviewed, 62 had sufficient information to make a clinical diagnosis of KH (32 males 30 females, mean age 2.9 years). Most had a history of gastrointestinal illness or prolonged fasting but 29% had no apparent precipitating event. Laboratory testing was quite variable and while low serum CO2 was seen in over half, no routine hormone testing, metabolic testing or supervised fasting resulted in a relevant diagnosis. We identified 4 out of 62 (6.5%) with relevant diagnoses which explained KH, including one child with failure to thrive found to have growth hormone (GH) deficiency and 3 by genetic testing, including one case of GSD type 9α, but all had atypical presentations. CONCLUSIONS: In the typical setting of a healthy 0.5-6 year-old child with an uncomplicated episode of KH following poor food intake and a normal exam including growth, hormonal and metabolic testing can safely be deferred. However, frequent recurrences and atypical features should prompt further investigation. TRIAL REGISTRATION: Not needed for a retrospective chart review study.

Neonatal Thyroid Disease: Testing and Management.

"Thyroid dysfunction that requires prompt diagnosis and treatment often becomes evident in the newborn period because of testing that is done as part of universal newborn screening. Primary congenital hypothyroidism is the most common treatable cause of mental retardation, requiring immediate treatment to prevent abnormal brain development. However, many of the abnormal thyroid test results are less abnormal and difficult to interpret, with a need for repeat testing and careful follow-up before initiation of treatment. Less often, neonatal hyperthyroidism is encountered. This article reviews and discusses management of thyroid dysfunction that may present in the first month after birth."

CHALLENGES OF SECURING GROWTH HORMONE COVERAGE FOR IDIOPATHIC SHORT STATURE: REVIEW OF THE 7-YEAR EXPERIENCE AT ONE INSTITUTION.

OBJECTIVE: Despite U.S. Food & Drug Administration (FDA) approval of growth hormone (GH) for idiopathic short stature (ISS), many providers face challenges obtaining insurance coverage. We reviewed the insurance coverage experience for ISS at our hospital to identify factors predictive of approval or denial. METHODS: We reviewed charts of patients who underwent GH stimulation testing from July 1, 2009, to April 30, 2017, to identify ISS patients (height <-2.25 SD, subnormal predicted adult height (PAH) and peak GH >10 ng/mL). RESULTS: Eighty-seven patients met ISS criteria, of whom 47 (29 male/18 female) had a GH request submitted to insurance. Mean age, height, and growth velocity were 8.6 ± 2.7 years, 2.83 ± 0.4 SD, and 4.4 ± 1.7 cm/year, respectively. Mean PAH based on bone age was -2.50 ± 0.9 SD, equaling 62 inches for males and 58 inches for females. Most had private managed care insurance (74%). Overall, 17/47 (36%) received treatment approval, 7 immediately and 10 more on appeal. There were no differences in age, height SD, growth rate, insurance type, or PAH between the 17 who were approved and the 30 denied. For 21 patients who were treated, a mean increase in 0.6 SD in height was seen after 1 year. CONCLUSION: At our institution, GH coverage requests for ISS included very short children mostly ages 6 to 11, with heights well below -2.25 SD and poor PAH. Only 36% were approved even after appeal. This highlights the challenge in our area to secure GH treatment for a FDA-approved indication. Collaboration between pediatric endocrinologists and insurers focusing on height SD and PAH, may improve cost-effective coverage to deserving short children who meet FDA guidelines for ISS treatment. ABBREVIATIONS: FDA = Food and Drug Administration; GH = growth hormone; IGF-1 = insulin-like growth factor 1; ISS = idiopathic short stature; PAH = predicted adult height.

Low Value of Thyroid Testing in the Pediatric Inpatient Setting.

OBJECTIVES: Our objective was to assess the frequency of pediatric inpatient thyroid testing, frequency of detection of abnormal results, and apparent impact on patient management. METHODS: This is a retrospective study of admissions from July 2015 to June 2016 at a large urban children's hospital. Chart review was conducted on all hospitalized pediatric patients who underwent thyroid testing. We used a normal range of 0.5 to 5.0 µIU/mL for thyroid-stimulating hormone (TSH) and 1.0 to 2.0 ng/dL for free thyroxine (FT4), except for neonates for whom we used the higher reference ranges specified by the hospital laboratory. RESULTS: Thyroid testing occurred in 1202 (5.7%) of 20 907 hospitalizations; 79.3% had combined thyroid function tests (TFTs) with TSH + FT4 being most common, and 20.6% had TSH only. Combined TFTs were ordered routinely by psychiatry and frequently by endocrine, gastrointestinal, cardiology, and neurology services, but many cases had no identified reason for testing. Of the 205 abnormal tests (17.1%), the most common abnormalities in the combined TFTs group were normal FT4 and increased TSH (35.4%) (76% of which were between 5 and 10 µIU/mL), normal FT4 and TSH 0.1 to 0.5 µIU/mL (33.1%), and high FT4 but normal TSH (14.3%). Patients with new-onset type 1 diabetes had borderline low or high TSH in about 20% of cases, but all abnormalities resolved at outpatient follow-up. Overall, 8 patients (0.66%) were started on levothyroxine. CONCLUSIONS: Pediatric inpatient thyroid testing is relatively common at our institution, and although results are often abnormal, they do not point to thyroid disease that has contributed to the reason for hospitalization and do not identify patients in urgent need of starting therapy.

Toward More Targeted and Cost-Effective Gonadotropin-Releasing Hormone Analog Treatment in Girls with Central Precocious Puberty.

The use of gonadotropin-releasing hormone analogs (GnRHa) for the treatment of central precocious puberty (CPP), especially in girls, has increased rapidly in recent years. In the context of a secular trend towards earlier puberty onset, many girls now treated for CPP are healthy children experiencing puberty onset within the early end of the normal range. Justifications for GnRHa treatment include the preservation of adult height (AH) potential and the alleviation of presumed distress of early maturation and menarche. With a case of a family requesting treatment for an 8-year-old girl in early puberty as a background, studies of the effect of untreated CPP and of GnRHa treatment of CPP on AH are reviewed. In addition, the limited evidence relating CPP to significant psychological distress - in part due to early menses, and for the amelioration of such distress by GnRHa treatment - is discussed. Taken together, current information suggests that for girls with mildly early onset of puberty (ages 7-9 years), an informed assent discussion with the family should include the consideration of reassurance and observation for many girls who might otherwise receive 2-4 years of GnRHa treatment for a poorly defined benefit and at a cost of at least $20-30,000 per year.

Partial androgen insensitivity syndrome presenting as pubertal gynecomastia: clinical and hormonal findings and a novel mutation in the androgen receptor gene.

Pubertal gynecomastia is common, can be seen in 65% of the adolescent boys and is considered physiological. It is thought to be due to transient imbalance between the ratio of testosterone and estradiol in the early stages of puberty. It resolves in 1-2 years and requires no treatment. However, more persistent and severe pubertal gynecomastia is less common and can be associated with pathological disorders. These can be due to diminished androgen production, increased estrogen production or androgen resistance. We report a case of persistent pubertal gynecomastia due to partial androgen insensitivity syndrome (PAIS), classical hormone findings and a novel mutation in the androgen receptor (AR) gene. Learning points: Laboratory testing of follicle-stimulating hormone (FSH), leutinizing hormone (LH) and testosterone for pubertal gynecomastia is most helpful in the setting of undervirization. The hormonal finding of very high testosterone, elevated LH and estradiol and relatively normal FSH are classical findings of PAIS. Gynecomastia due to PAIS will not resolve and surgery for breast reduction should be recommended.

Type 1 Diabetes: Urinary Proteomics and Protein Network Analysis Support Perturbation of Lysosomal Function.

While insulin replacement therapy restores the health and prevents the onset of diabetic complications (DC) for many decades, some T1D patients have elevated hemoglobin A1c values suggesting poor glycemic control, a risk factor of DC. We surveyed the stool microbiome and urinary proteome of a cohort of 220 adolescents and children, half of which had lived with T1D for an average of 7 years and half of which were healthy siblings. Phylogenetic analysis of the 16S rRNA gene did not reveal significant differences in gut microbial alpha-diversity comparing the two cohorts. The urinary proteome of T1D patients revealed increased abundances of several lysosomal proteins that correlated with elevated HbA1c values. In silico protein network analysis linked such proteins to extracellular matrix components and the glycoprotein LRG1. LRG1 is a prominent inflammation and neovascularization biomarker. We hypothesize that these changes implicate aberrant glycation of macromolecules that alter lysosomal function and metabolism in renal tubular epithelial cells, cells that line part of the upper urinary tract.

Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies.

BACKGROUND: The growth-promoting effects of IGF-I is mediated through the IGF-I receptor (IGF1R), a widely expressed cell-surface tyrosine kinase receptor. IGF1R copy number variants (CNV) can cause pre- and postnatal growth restriction or overgrowth. METHODS: Whole exome sequence (WES), chromosomal microarray, and targeted IGF1R gene analyses were performed on 3 unrelated children who share features of small for gestational age, short stature, and elevated serum IGF-I, but otherwise had clinical heterogeneity. Fluorescence-activated cell sorting (FACS) analysis of cell-surface IGF1R was performed on live primary cells derived from the patients. RESULTS: Two novel IGF1R CNV and a heterozygous IGF1R nonsense variant were identified in the 3 patients. One CNV (4.492 Mb) was successfully called from WES, utilizing eXome-Hidden Markov Model (XHMM) analysis. FACS analysis of cell-surface IGF1R on live primary cells derived from the patients demonstrated a ∼50% reduction in IGF1R availability associated with the haploinsufficiency state. CONCLUSION: In addition to conventional methods, IGF1R CNV can be identified from WES data. FACS analysis of live primary cells is a promising method for efficiently evaluating and screening for IGF1R haploinsufficiency. Further investigations are necessary to delineate how comparable IGF1R availability leads to the wide spectrum of clinical phenotypes and variable responsiveness to rhGH therapy.

Do 6-8 year old girls with central precocious puberty need routine brain imaging?

BACKGROUND: The subject of whether all girls with central precocious puberty (CPP) require brain imaging is controversial. FINDINGS: A review of the major papers concerning this topic published since 1994 was conducted looking primarily at the frequency of occult intracranial lesions, particularly brain tumors, in girls with CPP. While CNS abnormalities are frequently noted (8-15 %), the proportion of previously unknown findings requiring intervention in 6-8 year old girls is very small, in the range of 0-2 %. CONCLUSION: While MRI should still be done in boys and in girls with onset of puberty younger than age 6 and in boys, ordering an MRI should not be routine in 6-8 year old girls with CPP. Suggestions are made as to how to approach the decision-making process with the parents regarding brain imaging in asymptomatic 6-8 year old girls with CPP.