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.

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

Thyroid dermopathy and acropachy in pediatric patients.

The extrathyroid manifestations of Graves disease (GD) include thyroid orbitopathy, dermopathy, and acropachy. Thyroid dermopathy (TD), also known as pretibial myxedema, classically presents as nonpitting edema or plaquelike lesions on the pretibial region, while thyroid acropachy (TA) is seen in cases of severe TD, characterized by soft tissue swelling and clubbing of fingers and toes, as well as a periosteal reaction of the bones of the hands and feet. Both TD and TA are rare manifestations of thyroid disease and uncommonly reported in pediatric patients. Our aim was to increase awareness of dermatological manifestations associated with pediatric GD and review the literature of pediatric thyroid dermopathy as well as report a case of acropachy in a child.

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.

In congenital hypothyroidism, an initial L-thyroxine dose of 10-12 µg/kg/day is sufficient and sometimes excessive based on thyroid tests 1 month later.

BACKGROUND: Current guidelines recommend an initial L-thyroxine (L-T4) dose of 10-15 µg/kg/day for the treatment of congenital hypothyroidism (CH). We analyzed our data for the treatment outcome at 1 month after we noted a frequent overtreatment even at the lower end of this dose range. METHODS: A 3-year chart review of 55 patients with confirmed CH was performed. The patients were divided to three groups based on L-T4 dose: Group 1 (6-9.9 µg/kg), Group 2 (10-11.9 µg/kg), and Group 3 (12-15 µg/kg). Overtreatment was defined as T4>16 µg/dL/free T4>2.3 ng/dL±thyroid-stimulating hormone (TSH) <0.5 µIU/L and undertreatment was defined as TSH>6 µIU/L at 1 month. RESULTS: At 1 month, 45.8%, 37.5%, and 16.6% in Group 1, 30%, 55%, and 15% in Group 2, and 0%, 75%, and 25% in Group 3 had target labs, overtreatment, and undertreatment, respectively. CONCLUSIONS: An initial L-T4 dose of 10-11.9 µg/kg for TSH>100 µIU/L and 8-10 µg/kg for TSH<100 µIU/L at diagnosis met and often exceeded the target thyroid levels at 1 month. More frequent overtreatment was seen when >12 µg/kg was given.

Update on Pediatric Hyperthyroidism.

Typical symptoms which should lead to suspicion of hyperthyroidism are unintentional weight loss, tachycardia, and palpitations, heat intolerance, and hyperactivity. It is diagnosed by suppressed thyroid-stimulating hormone (TSH) with elevated thyroid hormone (TH) levels. Graves' disease (GD) due to antibodies stimulating the TSH receptor is the leading cause, and first-line treatment is with methimazole (MMI). Emerging data suggest MMI treatment, up to 8 years is effective and safe in improving the rate of remission. Radioactive iodine (RAI) and thyroidectomy offer definitive treatment and induce permanent hypothyroidism. Thyroid storm is a life-threatening condition with systemic decompensation and hyperpyrexia. Neonates of mothers with current or past GD are at risk for neonatal hyperthyroidism (NH). Appropriate identification and follow-up of at-risk neonates will reduce complications.

Evaluation and follow-up of clinically euthyroid children with normal free T4 and suppressed TSH.

AIM: Although subnormal TSH between 0.1-0.4 mIU/L is fairly common and benign, suppression of TSH to < 0.1 mIU/L with normal free T4 is less common and more worrisome. We have conducted a retrospective chart review of a collection of such cases and have summarized the features and outcome on follow up. METHODS: We studied 23 consecutive patients referred from 2005-07 to our pediatric endocrine clinic with TSH < 0.1 mIU/L and free T4 in the range of 0.8-2 ng/dl. We collected historical, clinical and laboratory data, and analyzed their outcome. RESULTS: The natural evolutions of these subjects were separated into 4 groups. Group 1, 14 subjects, (61%) became euthyroid within a mean of 3.7 months. Group 2, 4 subjects, (17%) became hypothyroid within a mean of 2.8 months. Group 3, 2 subjects (9%) progressed to overt hyperthyroidism. Group 4, 3 subjects (13%) had persistently suppressed TSH, 8-14 months after initial testing, of which one had a multinodular goiter and had a thyroidectomy. Elevated thyroid peroxidase antibody (TPO) was seen in 54.5% of those tested. CONCLUSION: Only 2/23 in our series became overtly hyperthyroid. Substantial number of subjects had a short period of transient TSH suppression that resolved spontaneously. Markers suggestive of autoimmune thyroid disease were consistently seen in group 2 and less so in others. It is prudent to observe such cases in the short term with serial follow up TSH, free T4 and T3, and to reserve further testing and treatment for those who become symptomatic or do not resolve.

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.

Shared leadership in a medical division of an academic hospital.

PURPOSE: The purpose of this paper is to describe a successful model of shared medical leadership within an academic division of an urban children's hospital. DESIGN/METHODOLOGY/APPROACH: Experience and outcomes were tracked over a three-year period during which two physicians shared the role of interim division chief of pediatric endocrinology and diabetes, resulting in a working model of shared leadership. FINDINGS: An evolutionary trajectory occurred over three years in which the strengths of the leaders were combined to optimize decision making in a complex medical division. Improvements in team satisfaction and additional positive outcomes were achieved. PRACTICAL IMPLICATIONS: Benefits of and challenges tackled by the strategic approach to shared leadership are identified to inform other medical institutions, particularly those with many team members or combined programs that include strong clinical and research components. ORIGINALITY/VALUE: Little has been written within medical literature regarding shared leadership. The shared leadership model described in this paper can be implemented by others in a complex academic setting and will hopefully lead to more robust divisions.

Utilizing serum bicarbonate instead of venous pH to transition from intravenous to subcutaneous insulin shortens the duration of insulin infusion in pediatric diabetic ketoacidosis.

Background Standard therapy of diabetic ketoacidosis (DKA) in pediatrics involves intravenous (IV) infusion of regular insulin until correction of acidosis, followed by transition to subcutaneous (SC) insulin. It is unclear what laboratory marker best indicates correction of acidosis. We hypothesized that an institutional protocol change to determine correction of acidosis based on serum bicarbonate level instead of venous pH would shorten the duration of insulin infusion and decrease the number of pediatric intensive care unit (PICU) therapies without an increase in adverse events. Methods We conducted a retrospective (pre/post) analysis of records for patients admitted with DKA to the PICU of a large tertiary care children's hospital before and after a transition-criteria protocol change. Outcomes were compared between patients in the pH transition group (transition when venous pH≥7.3) and the bicarbonate transition group (transition when serum bicarbonate ≥15 mmol/L). Results We evaluated 274 patient records (n=142 pH transition group, n=132 bicarbonate transition group). Duration of insulin infusion was shorter in the bicarbonate transition group (18.5 vs. 15.4 h, p=0.008). PICU length of stay was 3.2 h shorter in the bicarbonate transition group (26.0 vs. 22.8 h, p=0.04). There was no difference in the number of adverse events between the groups. Conclusions Transitioning patients from IV to SC insulin based on serum bicarbonate instead of venous pH led to a shorter duration of insulin infusion with a reduction in the number of PICU therapies without an increase in the number of adverse events.

Plasma midkine concentrations in healthy children, children with increased and decreased adiposity, and children with short stature.

BACKGROUND: Midkine (MDK), one of the heparin-binding growth factors, is highly expressed in multiple organs during embryogenesis. Plasma concentrations have been reported to be elevated in patients with a variety of malignancies, in adults with obesity, and in children with short stature, diabetes, and obesity. However, the concentrations in healthy children and their relationships to age, nutrition, and linear growth have not been well studied. SUBJECTS AND METHODS: Plasma MDK was measured by immunoassay in 222 healthy, normal-weight children (age 0-18 yrs, 101 boys), 206 healthy adults (age 18-91 yrs, 60 males), 61 children with BMI ≥ 95th percentile (age 4-18 yrs, 20 boys), 20 girls and young women with anorexia nervosa (age 14-23 yrs), and 75 children with idiopathic short stature (age 3-18 yrs, 42 boys). Body fat was evaluated by dual-energy X-ray absorptiometry (DXA) in a subset of subjects. The associations of MDK with age, sex, adiposity, race/ethnicity and stature were evaluated. RESULTS: In healthy children, plasma MDK concentrations declined with age (r = -0.54, P < 0.001) with values highest in infants. The decline occurred primarily during the first year of life. Plasma MDK did not significantly differ between males and females or between race/ethnic groups. MDK concentrations were not correlated with BMI SDS, fat mass (kg) or percent total body fat, and no difference in MDK was found between children with anorexia nervosa, healthy weight and obesity. For children with idiopathic short stature, MDK concentrations did not differ significantly from normal height subjects, or according to height SDS or IGF-1 SDS. CONCLUSIONS: In healthy children, plasma MDK concentrations declined with age and were not significantly associated with sex, adiposity, or stature-for-age. These findings provide useful reference data for studies of plasma MDK in children with malignancies and other pathological conditions.

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.

The influence of acoustic transmit parameters on the destruction of contrast microbubbles in vitro.

In this study, the destruction of the contrast agent Sonazoid (GE Healthcare, Oslo, Norway) was measured in vitro as a function of centre frequency (2-3 MHz), acoustic amplitude (0.66-1.6 MPa), pulse length (2-16 cycles) and PRF (0.5-8.0 kHz). Up to 82% of microbubbles were destroyed after exposure to a single 1.6 MPa acoustic pulse (16 cycles, 2.5 MHz and PRF of 1.0 kHz), while at a low amplitude of 0.66 MPa, fractional destruction increased gradually from 0 to 40% after exposure to 9 (identical) pulses. Fractional destruction increased from approximately 8 to 66% as pulse length was changed from 2 to 16 cycles following exposure to a single 2.5 MHz, 1.3 MPa pulse. As the PRF was increased from 0.5 to 8.0 kHz, shorter exposure time intervals (from 4.8 to 1.2 ms) were needed to achieve the same fractional destruction of 80%. Conversely, as the transmit frequency was increased from 2 to 3 MHz the fractional destruction decreased (by more than half within the first 3 pulses). The influence of changes in acoustic pressure and duty cycle on the destruction of Sonazoid microbubbles was highly statistically significant (p < or = 0.01) with a threshold around 0.67 MPa for a duty cycle of 0.0064. In conclusion, the fractional destruction increases with the duty cycle and the acoustic pressure amplitude and decreases with ultrasonic transmit frequency. Better understanding of the influence of the ultrasound transmit parameters on the destruction of contrast microbubbles should help improve existing contrast-assisted imaging modalities and may help develop new techniques for better use of contrast agents.

Children with hyperthyroidism younger than age 7 require higher mg/kg doses of methimazole to normalize free T4 compared to older children.

BACKGROUND: Hyperthyroidism is much less common in children <7 years vs. older children and less well studied. It was our impression that the youngest patients needed a higher weight-based dose of methimazole (MMI) to achieve euthyroidism. OBJECTIVES: To compare the mean MMI dose needed to normalize free T4 in younger (<7 years) vs. older children and the time taken to normalize free T4. METHODS: Based on chart review (2004-2012), patients were divided into groups based on age at diagnosis: <7 years (n=13), 7-12 years (n=30) and >12 years (n=40). Follow-up visits were reviewed until free T4 normalized. RESULTS: The mean dose of MMI (mg/kg/day) needed to normalize free T4 was 0.71 (±0.29) in the <7 group, significantly higher vs. the two older groups: 0.50 (±0.22) and 0.44 (±0.24). Months taken to achieve a euthyroid state was significantly longer in children <7 (6.23±3.91) vs. the older groups (3.10±2.12 and 3.18±2.86 months). CONCLUSION: Hyperthyroid children diagnosed before age 7 required higher initial doses of MMI and took a longer time to become euthyroid than older patients. Clinicians should consider starting with higher weight-based MMI doses when treating younger patients to more rapidly normalize free T4.

Checking In: A Pilot of a Physician-Delivered Intervention to Increase Parent-Adolescent Communication About Blood Glucose Monitoring.

Low-cost, translatable interventions to promote adherence in adolescents with type 1 diabetes are needed. This study evaluated a brief physician-delivered intervention designed to increase parent-adolescent communication about blood glucose monitoring. Thirty adolescent-parent dyads completed baseline questionnaires and received the physician-delivered intervention. Participants completed follow-up questionnaires at 12 weeks; HbA1c and glucometer data were abstracted from medical charts. Parent-reported conflict surrounding diabetes management decreased from pre- to postintervention. Participants who reported adhering to the intervention plan (n = 15) demonstrated an increase in blood glucose monitoring frequency and trends in improved HbA1c and parental diabetes collaboration from pre- to postintervention. Participants and physicians reported overall satisfaction with the program. Results demonstrate initial feasibility as well as a trend toward improvement in diabetes-specific health indicators for parent-adolescent dyads who adhered to program components. Frequent joint review of glucometer data can be a useful strategy to improve type 1 diabetes-related health outcomes and parent-adolescent communication.

Transient Pseudohypoaldosteronism due to Urinary Tract Infection in Infancy: A Report of 4 Cases.

Hyponatremia with hyperkalemia in infancy is an uncommon but life-threatening occurrence. In the first weeks of life, this scenario is often associated with aldosterone deficiency due to salt-wasting congenital adrenal hyperplasia. However, alternative diagnoses involving inadequate mineralocorticoid secretion or action must be considered, particularly for infants one month of age or older. We report four infants who presented with profound hyponatremia accompanied by urinary tract infection, ultimately leading to the diagnosis of transient pseudohypoaldosteronism. Our cases provide support for the idea that the renal tubular resistance to aldosterone is due to urinary tract infection itself rather than to underlying urinary tract anomalies typically found in these infants. Awareness of this condition is important so that serum aldosterone, urine sodium, and urine cultures may be obtained immediately in any infant presenting with hyponatremia and hyperkalemia in whom a diagnosis of congenital adrenal hyperplasia was not found. Adequate replacement with intravenous saline and antibiotic therapy is sufficient to correct sodium levels over 24-48 hours.

Limitation and withdrawal of intensive therapy at the end of life: practices in intensive care units in Mumbai, India.

OBJECTIVE: To describe the practices in intensive care units in Mumbai hospitals regarding limitation and withdrawal of care at the end of life. DESIGN: Review of prospectively collected data. SETTINGS: Intensive care units of four major hospitals (two private tertiary referral general hospitals, one mixed public and private cancer referral hospital, and one large public hospital). PATIENTS: Hospital and intensive care unit patients who died during the study period. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We measured the percentage of hospital deaths occurring inside and outside intensive care units and the incidence of withholding intubation, withholding other therapy, and withdrawing therapy for deaths in the intensive care unit. The proportion of hospital deaths that occurred in an intensive care unit was 14% in the cancer hospital, 23% in the public hospital, and 58-73% in the two private hospitals (chi-square test for trends, p < .0001). Of the 143 deaths that occurred in intensive care unit, limitation of care occurred in 49 patients. Twenty-five percent of these patients were not intubated terminally, 67% were initially intubated and ventilated but failed to recover and subsequently had no further escalation of therapy, and 8% had withdrawal of therapy. Therapy was limited in 19% of deaths in the public hospital intensive care unit (odds ratio, 0.44; 95% confidence interval, 0.2-0.97) vs. 40%, 41%, and 50% of deaths in the other three intensive care units. CONCLUSIONS: Therapy is limited in a significant proportion of intensive care unit patients. Significant differences in the practice of limitation of therapy exist between public and private hospitals. Lack of access to a limited number of intensive care unit beds, especially in the public hospital, may constitute implicit limitation of care.