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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Quantitative Differences in the Urinary Proteome of Siblings Discordant for Type 1 Diabetes Include Lysosomal Enzymes.

Individuals with type 1 diabetes (T1D) often have higher than normal blood glucose levels, causing advanced glycation end product formation and inflammation and increasing the risk of vascular complications years or decades later. To examine the urinary proteome in juveniles with T1D for signatures indicative of inflammatory consequences of hyperglycemia, we profiled the proteome of 40 T1D patients with an average of 6.3 years after disease onset and normal or elevated HbA1C levels, in comparison with a cohort of 41 healthy siblings. Using shotgun proteomics, 1036 proteins were identified, on average, per experiment, and 50 proteins showed significant abundance differences using a Wilcoxon signed-rank test (FDR q-value ≤ 0.05). Thirteen lysosomal proteins were increased in abundance in the T1D versus control cohort. Fifteen proteins with functional roles in vascular permeability and adhesion were quantitatively changed, including CD166 antigen and angiotensin-converting enzyme 2. α-N-Acetyl-galactosaminidase and α-fucosidase 2, two differentially abundant lysosomal enzymes, were detected in western blots with often elevated quantities in the T1D versus control cohort. Increased release of proteins derived from lysosomes and vascular epithelium into urine may result from hyperglycemia-associated inflammation in the kidney vasculature.

Clinical characteristics of children referred for signs of early puberty before age 3.

BACKGROUND: Signs of puberty in very young children are often benign, but the evaluation needed and follow-up are controversial. OBJECTIVES: The study had three objectives: 1) to analyze the frequency of diagnoses in children <3 years referred for early puberty; 2) to examine the usefulness of lab testing; and 3) to identify red flags indicating a more serious diagnosis. METHODS: Charts of all children younger than age 3 referred for early puberty between 7/09 and 6/13 were reviewed. RESULTS: Of 275 patients, 156 (57%) were diagnosed with premature thelarche (PT), 69 (25%; 56 F/13M) with genital hair of infancy (GHI) and 37 (13%, all F) with both (GHI/PT). Six patients had axillary odor only. Four patients had more serious diagnoses, one each with congenital adrenal hyperplasia (CAH), non-classical CAH, McCune-Albright syndrome and central precocious puberty (CPP). Diagnoses did not change in those who returned for follow-up. Hormone tests revealed that none of the PT patients had elevation of both luteinizing hormone (LH) and estradiol, and half of the GHI patients tested had mildly elevated DHEA-S but normal testosterone and 17-OH progesterone. CONCLUSIONS: Very few children referred for puberty at <3 years appear to have a serious underlying diagnosis, and progression of PT to CPP was not identified in this series. Hormone testing is unlikely to be helpful in typical cases of PT, GHI or both, and many such cases may be followed in the primary care setting after initial clinical evaluation.

Benign vaginal bleeding in 24 prepubertal patients: clinical, biochemical and imaging features.

OBJECTIVE: Premature menarche is an uncommon, benign condition characterized by isolated or recurrent menstrual bleeding in the absence of secondary sexual characteristics. METHODS: We performed an observational retrospective study to further characterize the clinical, biochemical and imaging features of benign prepubertal vaginal bleeding (BPVB). Out of 1037 girls evaluated for precocious puberty over a 5-year period, 24 girls with BPVB were identified based on ≥1 episodes of vaginal bleeding, Tanner I or non-progressive Tanner II breast development, and lack of physical findings suggesting genital infection, trauma or foreign body. RESULTS: Age at presentation ranged from 3 years 2 months to 9 years 11 months. Ten patients (42%) had one episode of vaginal bleeding, six (25%) had two episodes and eight patients (33%) had three or more. First bleeding episode lasted 3 days (range; 1-30 days). Six girls had intermittent spotting for up to 1 year. No breast development was noted in 19 (79%) patients. Minimal breast was present in five girls; early pubic hair was present in 2. LH and FSH were prepubertal; estradiol was >20 pg/mL in two girls. Pelvic ultrasound, performed in 11 patients, showed pre-pubertal uterus and ovaries without adnexal masses. CONCLUSION: Isolated prepubertal vaginal bleeding is typically benign and self-limited, in the absence of sexual precocity signs or other vaginal pathology. Laboratory and imaging studies are generally unrevealing.

In children with premature adrenarche, bone age advancement by 2 or more years is common and generally benign.

BACKGROUND: Premature adrenarche (PA) is often associated with bone age (BA) advanced by ≥2 years, which increases the concern for underlying pathology, but the frequency and clinical significance of this is unknown. Our objective was to identify the proportion of PA patients with very advanced BA and normal BA and compare the clinical characteristics of the two groups. METHODS: Charts of 427 patients aged 5-9 years, referred for early puberty over a 2-year period, were reviewed for clinical diagnosis, growth, parental heights, hormone levels and BA. We divided the PA patients into three separate groups based on degree of BA advancement. Predicted adult heights (PAH) were calculated and compared to mid-parental target height (TH). RESULTS: Of 427 patients, 266 (62%) had PA (82% female). Of the 121 with BA, 30.6% had very advanced BA (≥2 years) and this group was taller (Ht SD+1.72 vs. +0.72, p<0.00001) and had higher BMI (SD+1.70 vs. +0.99, p<0.001) than patients with BA advanced by <1 year, but hormone levels were quite similar. Mean PAH was slightly less than TH for patients with very advanced BA, but there were no girls with PAH <60 inches 152.4 cm or boys with PAH <65 inches 165.1 cm in height. CONCLUSIONS: Very advanced BA is common in PA, and patients were significantly taller and more overweight than their peers. The impact of advanced BA on PAH appears to be minor. We question the need for ordering a BA in patients with PA, and suggest that extensive testing is unnecessary simply because of advanced BA.

Characteristics of children with the best and poorest first- and second-year growth during rhGH therapy: data from 25 years of the Genentech national cooperative growth study (NCGS).

BACKGROUND: Models assessing characteristics contributing to response to recombinant human growth hormone (rhGH) response rarely address growth extremes in both years 1 and 2 or examine how children track from year to year. Using National Cooperative Growth Study (NCGS) data, we determined characteristics contributing to responsiveness to rhGH and the pattern of change from years 1 to 2. PATIENTS AND METHODS: Height velocity standard deviation score (HV SDS) for 2 years for prepubertal children with idiopathic GH deficiency (IGHD) (n = 1899) and idiopathic short stature (ISS) (n = 1186) treated with similar doses for two years were computed. Group 1 = HV SDS < -1; 2 = HV SDS -1 to +1; 3 = HV SDS > +1. RESULTS: For IGHD, mean age was 7.5 years and similar in all groups. Year 1 HV SDS was associated with greater body mass index (BMI) SDS, lower pre-treatment HV, baseline height SDS, greater target height SDS minus height SDS, and lower maximum stimulated GH (P <0.0001). Year 2, 172/271 (73%) in group 1 moved to either group 2 (n = 156) or 3 (n = 16). Year 2 HV SDS was associated with greater year 1 HV SDS (r = 0.045, P <0.0001), greater BMI SDS, taller parents and lower peak GH.For ISS, year 1 HV SDS was associated with greater BMI SDS and lower pre-treatment HV (P ≤0.0001). 109/169 (64%) in group 1 moved to group 2 (n = 90) or group 3 (n = 19). Greater year 2 HV SDS was related to year 1 HV SDS (r = 0.27, P <0.0001). CONCLUSION: For IGHD, multiple characteristics contributed to best first-year response but for ISS, best first-year HV SDS was associated only with BMI SDS and inversely with pre-treatment HV. For both GHD and ISS, year 1 HV SDS was not a strong enough predictor of year 2 HV SDS to use first-year HV alone to determine GH continuation.

Characteristics of children with type 1 diabetes and persistent suboptimal glycemic control.

OBJECTIVE: This study aims to determine the relationship between the duration of persistent poor glycemic control in type 1 diabetes mellitus (T1DM) children and the likelihood of subsequent improvement. METHODS: A retrospective cohort study was conducted on T1DM patients aged 6-18 years, followed for at least six visits at Children's National Medical Center (Washington, DC) with at least one hemoglobin A1c (HbA1c) ≥ 10% after the first year since the initial visit (n=151). Medical records of patients with subsequently improved glycemic control were reviewed (n=39). RESULTS: Patients aged 12-18 years, females, and Medicaid patients were twice as likely to be in persistently poor control as patients aged 6-11 years, males, and privately insured patients, respectively. Each additional visit with HbA1c ≥ 10% and one percentage point increase in the mean HbA1c reduced the likelihood of subsequent improvement by 20% and 50%, respectively. Of the 39 patients with improved control, only 5 (13%) sustained their improvement for ≥ 2 years. Multiple contributing factors for improved control were identified, but no one factor explained improved control in > 25% of patients. CONCLUSION: This study suggests that the longer the duration of poor control, the more difficult it is to reverse the underlying factors of poor diabetes management. Strategies to improve regular clinic attendance along with reinforcement of changes which resulted in improved control are critical. Adolescents, females, and Medicaid patients in particular should be targeted for sustained intervention.