Publications by authors named "Bradley S Miller"

71 Publications

Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I.

JIMD Rep 2021 Mar 8;58(1):89-99. Epub 2020 Dec 8.

Department of Pediatrics The Lundquist Institute at Harbor-UCLA Medical Center Torrance California USA.

Background: Orthopedic disease progresses in mucopolysaccharidosis type I (MPS I), even with approved therapies and remains a major factor in persistent suffering and disability. Novel therapies and accurate predictors of response are needed. The primary objective of this study was to identify surrogate biomarkers of future change in orthopedic disease.

Methods: As part of a 9-year observational study of MPS I, range-of-motion (ROM), height, pelvic radiographs were measured annually. Biomarkers in year 1 were compared to healthy controls. Linear regression tested for associations of change in biomarkers over the first year with change in long-term outcomes.

Results: MPS I participants (N = 19) were age 5 to 16 years and on average 6.9 ± 2.9 years post treatment initiation. Healthy controls (N = 51) were age 9 to 17 years. Plasma IL-1β, TNF-α, osteocalcin, pyridinolines, and deoxypyridinolines were higher in MPS than controls. Within MPS, progression of hip dysplasia was present in 46% to 77%. A 1 pg/mL increase in IL-6 was associated with -22°/year change in ROM (-28 to -15; < .001), a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -0.024 Z-score/year change in height Z-score (-0.043 to -0.005; = .016), and a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -2.0%/year change in hip dysplasia measured by Reimers migration index (-3.8 to -0.1; = .037).

Conclusions: Inflammatory cytokines are high in MPS I. IL-6 and PYD were associated with progression in joint contracture, short stature, and hip dysplasia over time. Once validated, these biomarkers may prove useful for predicting response to treatment of skeletal disease in MPS I.
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http://dx.doi.org/10.1002/jmd2.12190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932872PMC
March 2021

Usefulness and Potential Pitfalls of Long-Acting Growth Hormone Analogs.

Front Endocrinol (Lausanne) 2021 24;12:637209. Epub 2021 Feb 24.

Department of Medicine, VA Palo Alto Health Care System and Stanford University School of Medicine, Palo Alto, CA, United States.

Daily recombinant human GH (rhGH) is currently approved for use in children and adults with GH deficiency (GHD) in many countries with relatively few side-effects. Nevertheless, daily injections can be painful and distressing for some patients, often resulting in non-adherence and reduction of treatment outcomes. This has prompted the development of numerous long-acting GH (LAGH) analogs that allow for decreased injection frequency, ranging from weekly, bi-weekly to monthly. These LAGH analogs are attractive as they may theoretically offer increased patient acceptance, tolerability, and therapeutic flexibility. Conversely, there may also be pitfalls to these LAGH analogs, including an unphysiological GH profile and differing molecular structures that pose potential clinical issues in terms of dose initiation, therapeutic monitoring, incidence and duration of side-effects, and long-term safety. Furthermore, fluctuations of peak and trough serum GH and IGF-I levels and variations in therapeutic efficacy may depend on the technology used to prolong GH action. Previous studies of some LAGH analogs have demonstrated non-inferiority compared to daily rhGH in terms of increased growth velocity and improved body composition in children and adults with GHD, respectively, with no significant unanticipated adverse events. Currently, two LAGH analogs are marketed in Asia, one recently approved in the United States, another previously approved but not marketed in Europe, and several others proceeding through various stages of clinical development. Nevertheless, several practical questions still remain, including possible differences in dose initiation between naïve and switch-over patients, methodology of dose adjustment/s, timing of measuring serum IGF-I levels, safety, durability of efficacy and cost-effectiveness. Long-term surveillance of safety and efficacy of LAGH analogs are needed to answer these important questions.
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http://dx.doi.org/10.3389/fendo.2021.637209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943875PMC
February 2021

PATRO children, a multi-center, non-interventional study of the safety and effectiveness of Omnitrope (somatropin) treatment in children: update on the United States cohort.

J Pediatr Endocrinol Metab 2021 Apr 26;34(4):431-440. Epub 2021 Feb 26.

Sandoz Inc., Princeton, NJ, USA.

Objectives: Omnitrope (somatropin, Sandoz Inc.) is one of several recombinant human growth hormones (rhGH) approved in the United States (US) for use in pediatric indications, including growth hormone deficiency (GHD) and idiopathic short stature (ISS). We report data on the effectiveness and safety of Omnitrope in the US cohort of the PATRO Children (international, longitudinal, non-interventional) study.

Methods: All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope are given according to country-specific prescribing information.

Results: By September 2018, 294 US patients were recruited; the two largest groups were GHD (n=193) and ISS (n=62). Across all indications, HSDS improvement (ΔHSDS) from baseline at three years was +1.0 (rhGH-naïve, +1.2; pre-treated, +0.7). In pre-pubertal patients, ΔHSDS from baseline at three years was +0.94 (rhGH-naïve, +1.3; pre-treated, +0.7). Following three years of treatment, ΔHSDS from baseline was +1.3 in rhGH-naïve GHD patients and +1.1 in rhGH-naïve ISS patients. In pre-pubertal rhGH-naïve patients, ΔHSDS from baseline was +1.3 and +1.2 in GHD and ISS patients, respectively. Overall, 194 patients (66.0%) experienced adverse events (AEs; n=886 events); most were of mild-moderate intensity. Five patients (1.7%) had AEs that were suspected to be treatment-related (n=5 events). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No AEs of diabetes mellitus or hyperglycemia were reported.

Conclusions: Omnitrope appears to be well tolerated and effective in the majority of patients, without evidence of an increased risk of developing unexpected AEs, diabetes mellitus, or new malignancies during treatment.
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http://dx.doi.org/10.1515/jpem-2020-0360DOI Listing
April 2021

Long-term safety of growth hormone treatment in childhood: Two large observational studies NordiNet ® IOS and ANSWER.

J Clin Endocrinol Metab 2021 Feb 11. Epub 2021 Feb 11.

Thomas Jefferson University, Philadelphia, Pennsylvania, United States.

Context: GH treatment has a generally good safety profile; however, concerns of increased mortality risk in adulthood have been raised.

Objective: Assessing the long-term safety of GH treatment in clinical practice.

Design: Two multicenter longitudinal observational studies: NordiNet® International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA).

Setting: Data collected from 676 clinics.

Patients: Pediatric patients treated with GH, classified into three risk groups based on diagnosis.

Intervention: Daily GH treatment.

Main Outcome Measures: Incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to the GH dose.

Results: The combined studies comprised 37,702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130,476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (e.g. with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with >1 AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = 0.0029 and P = 0.0003, respectively) and the non-SGA subgroup (P = 0.0022 and P = 0.0015, respectively), and for SAEs in the intermediate- and high-risk groups (P = 0.0017 and P = 0.0480, respectively).

Conclusions: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group.
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http://dx.doi.org/10.1210/clinem/dgab080DOI Listing
February 2021

Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome.

Horm Res Paediatr 2020 13;93(6):380-395. Epub 2021 Jan 13.

Pediatric Endocrinology, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota, USA.

Introduction: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS).

Objective: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice.

Methods: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years' height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data.

Results: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, -2.76 (1.03); GH dose, 41.6 (11.1) µg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was -1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was -1.51 (0.60) (154.90 [3.21] cm) in females and -1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ -2. Adverse drug reactions and GH-unrelated serious adverse events (n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred.

Conclusions: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ -2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.
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http://dx.doi.org/10.1159/000512429DOI Listing
January 2021

Adult growth hormone deficiency: Optimizing transition of care from pediatric to adult services.

Growth Horm IGF Res 2021 Feb 10;56:101375. Epub 2020 Dec 10.

Novo Nordisk Inc., Plainsboro, NJ, United States of America. Electronic address:

Objective: Most patients with childhood-onset growth hormone deficiency (CO-GHD) receive treatment with exogenous growth hormone (GH) to facilitate the attainment of their full potential adult height. Recent evidence suggests that continuing GH administration during the transition period between the end of linear growth and full adult maturity is necessary for proper body composition and bone and muscle health, and may also have beneficial effects on metabolic parameters, bone mineral density, and quality of life. The timing of this transition period coincides with the transfer of care from a pediatric to an adult endocrinologist, creating the potential for a care gap as a consequence of losing the patient to follow-up.

Design: An advisory board comprising both pediatric and adult endocrinologists was assembled to address current clinical unmet needs and to collaborate on a structured transitional plan for optimal management of patients with CO-GHD.

Insights/conclusion: The advisors suggest collaborative, multidisciplinary approaches to ensure continuity of care; ongoing testing and monitoring of GHD status into adulthood; and a clearly structured protocol that includes practical guidance for clinicians to establish best practices for transitioning older adolescents with persistent CO-GHD to adult care.
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http://dx.doi.org/10.1016/j.ghir.2020.101375DOI Listing
February 2021

Height outcomes in children with growth hormone deficiency and idiopathic short stature treated concomitantly with growth hormone and aromatase inhibitor therapy: data from the ANSWER program.

Int J Pediatr Endocrinol 2020 6;2020:19. Epub 2020 Oct 6.

Novo Nordisk Inc, Plainsboro, NJ USA.

Background: Treatment of children with growth hormone deficiency (GHD) or idiopathic short stature (ISS) using GH is only effective for bone growth prior to epiphyseal fusion. Aromatase inhibitor therapy (AIT) blocks estrogen production, thereby delaying epiphyseal fusion. The current study analyzed baseline characteristics and longitudinal data of male patients with GHD or ISS who were treated with GH and concomitant AIT.

Methods: Data were obtained from the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program, which collected efficacy and safety data of patients treated with Norditropin®. A longitudinal cohort approach compared patient characteristics, including chronologic age, bone age, and height standard deviation score (HSDS), in GH-treated males before and after AIT initiation.

Results: A total of 142 GH-naïve patients with GHD ( = 115) or ISS ( = 27) with mean (± SD) baseline chronological ages of 12.10 ± 3.00 and 10.76 ± 3.07 years, respectively, were analyzed. The majority were classified at advanced Tanner stages II to V. Patients with GHD had mean HSDS of - 1.97 ± 0.78 at baseline and - 0.99 ± 0.88 prior to AIT initiation, while corresponding values for patients with ISS were - 2.15 ± 0.72 and - 1.04 ± 0.79, respectively. In patients evaluated after 2 years of concomitant AIT, mean HSDS had decreased to - 0.40 ± 1.16 and - 0.65 ± 0.52 for patients with GHD and ISS, respectively. Patients with GHD had a mean bone age/chronological age ratio (BA/CA) of 0.91 ± 0.11 at baseline and 0.97 ± 0.10 prior to AIT initiation, while corresponding values for patients with ISS were 0.85 ± 0.16 and 0.99 ± 0.10, respectively. In patients evaluated after 2 years of concomitant AIT, mean BA/CA values were 0.95 ± 0.10 and 0.96 ± 0.06 for patients with GHD and ISS, respectively.

Conclusions: In this real-world analysis, use of AIT with GH in males appeared to be associated with ongoing growth over 2 years, and AIT likely augmented growth potential as indicated by continued HSDS increase with decreased BA/CA after AIT initiation.

Trial Registration: This trial was sponsored by Novo Nordisk and is registered with ClinicalTrials.gov (NCT01009905). Registered November 11, 2009; retrospectively registered.
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http://dx.doi.org/10.1186/s13633-020-00089-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537098PMC
October 2020

Development of Tanner Stage-Age Adjusted CDC Height Curves for Research and Clinical Applications.

J Endocr Soc 2020 Sep 17;4(9):bvaa098. Epub 2020 Jul 17.

Rollins School of Public Health, Emory University, Atlanta, Georgia.

Background And Objective: Variations in normal pubertal development, pubertal disorders, and race/ethnicity can lead to differences in growth patterns and timing that are not captured by the Centers for Disease Control and Prevention (CDC) height-for-chronological age (CA) charts. Therefore, we sought to develop new Tanner stage-adjusted height-for-age (TSA) charts accounting for these differences.

Study Design: Population-based Tanner staging and anthropometric data for 13 358 children age 8 to 18 years from 3 large US national surveys: National Health Examination Surveys (NHES cycle III); the Hispanic Health and Nutrition Examination Surveys (HHANES) and the third National Health and Nutrition Examination Surveys (NHANES III) were analyzed. TSA semi-parametric models with additive age splines were used to develop smoothed TSA curves accounting for maturation stage and calendar age.

Results: As expected, the TSA curves did not track along the respective percentile curves for the CDC 2000 CA curves. We generated race/ethnicity-nonspecific and race/ethnicity-specific TSA charts stratified by sex and plotted against the CDC 2000 CA curves to account for the pubertal status differences between these models. An online calculator to adjust height for pubertal status was created.

Conclusions: TSA charts provide a much-needed tool to assess and manage linear growth for US children over the course of puberty. These tools may be useful in clinical management of children with pubertal timing variations.
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http://dx.doi.org/10.1210/jendso/bvaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426000PMC
September 2020

Phase 3 Trial of a Small-volume Subcutaneous 6-Month Duration Leuprolide Acetate Treatment for Central Precocious Puberty.

J Clin Endocrinol Metab 2020 10;105(10)

Nemours Children's Health System, Jacksonville, Florida.

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.
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http://dx.doi.org/10.1210/clinem/dgaa479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442270PMC
October 2020

Pubertal recalibration of cortisol-DHEA coupling in previously-institutionalized children.

Horm Behav 2020 09 17;125:104816. Epub 2020 Jul 17.

Institute of Child Development, University of Minnesota - Twin Cities, United States of America.

As a period of heightened plasticity, puberty may provide a window of opportunity for recalibration of the hypothalamic-pituitary-adrenal (HPA) axis to current conditions. Our group has recently documented evidence for pubertal recalibration of HPA axis reactivity among children internationally adopted as infants from institutions into supportive, well-resourced homes. As a first step at examining potential mechanisms by which puberty may facilitate recalibration of the HPA axis, the current study assessed whether previously-institutionalized (PI) children differed from non-adopted (NA) comparison children in levels of the adrenal steroid hormone dehydroepiandrosterone (DHEA) and in its intra-individual covariation (coupling) with cortisol by adrenal pubertal stage. In an accelerated longitudinal design, 7- to 15-year-olds completed up to 3 annual assessments, which included nurse-conducted pubertal staging and the Modified Trier Social Stress Test for Children (TSST-M). Adrenal (pubic hair) rather than gonadal pubertal stage scores were used in the analysis. Paired salivary cortisol-DHEA samples were available at 60-80 min post-TSST-M. NA and PI children did not differ in DHEA levels, which were higher among children at more advanced pubertal stages (averaged across the sessions) for both groups. For NA children, post-stressor cortisol and DHEA were positively coupled across sessions at all average adrenal pubertal stages. For PI children who were, on average, at earlier adrenal pubertal stages, post-stressor cortisol and DHEA were not coupled, but PI children who were at later pubertal stages demonstrated positive cortisol-DHEA coupling similar to that of the NA children. We suggest that these findings provide insights into processes which may underlie pubertal recalibration of the HPA axis.
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http://dx.doi.org/10.1016/j.yhbeh.2020.104816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543053PMC
September 2020

Early characteristics of bone deficits in children with Fontan palliation.

Cardiol Young 2020 Apr 20;30(4):468-475. Epub 2020 Feb 20.

Department of Pediatrics, Emory University, Atlanta, GA, USA.

Background: This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation.

Methods: We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children's hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls.

Results: All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences -30.13 mg/cm3 (p = 0.041), -0.31 mm (p = 0.043), and -6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were -0.46 ± 1.1 and -0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex.

Conclusions: In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.
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http://dx.doi.org/10.1017/S1047951120000293DOI Listing
April 2020

Adult growth hormone deficiency: clinical advances and approaches to improve adherence.

Expert Rev Endocrinol Metab 2019 11 13;14(6):419-436. Epub 2019 Nov 13.

Division of Pediatric Endocrinology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

: There have been significant clinical advances in the understanding of the diagnosis and benefits of long-term recombinant human growth hormone (rhGH) replacement in adults with GH deficiency (GHD) since its approval in 1996 by the United States Food and Drug Administration.: We searched PubMed, Medline, CINAHL, EMBASE and PsychInfo databases between January 2000 and June 2019 for published studies evaluating adults with GHD. We reviewed the data of the oral macimorelin test compared to the GHRH plus arginine and the insulin tolerance tests that led to its approval by the United States FDA and European Medicines Agency for adult diagnostic testing. We summarize the clinical advances of long-term benefits of rhGH therapy and the potential effects of GH receptor polymorphisms on individual treatment responsiveness. We identify that non-adherence and discontinuation rates are high and recommend strategies to support patients to improve adherence. We also provide an overview of several long-acting GH (LAGH) preparations currently under development and their potential role in improving treatment adherence.: This article summarizes recent clinical advances in rhGH replacement therapy, the biological and molecular aspects that may influence rhGH action, and offers practical strategies to enhance adherence in adults with GHD.
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http://dx.doi.org/10.1080/17446651.2019.1689119DOI Listing
November 2019

Pubertal stress recalibration reverses the effects of early life stress in postinstitutionalized children.

Proc Natl Acad Sci U S A 2019 11 11;116(48):23984-23988. Epub 2019 Nov 11.

Division of Pediatric Endocrinology, Department of Pediatrics, University of Minnesota, 8952D, MB671 East Building, 2450 Riverside Ave., Minneapolis, MN 55454

Nonhuman animal models reveal that the hypothalamic-pituitary-adrenocortical (HPA) axis calibrates to the harshness of the environment during a sensitive period in infancy. Humans exposed to depriving institutional care in infancy show reduced HPA axis responsivity, even years after they are placed in supportive, well-resourced families. This study examined whether puberty opens a window of opportunity to recalibrate the HPA axis toward more typical reactivity when children shift from harsh deprived conditions in infancy into supportive conditions in childhood and adolescence. Participants ( = 129 postinstitutionalized, 68.2% female; = 170 comparison, 52.4% female) completed 3 annual sessions beginning at ages 7 to 15 ( = 11.28, SD = 2.31). Each session assessed pubertal stage via nurse examination and cortisol reactivity to the Trier social stress test for children. The linear mixed-effects model controlling for sex and between-individual differences in pubertal stage showed a significant group by pubertal stage interaction: within-individual increases in pubertal stage were associated with increases in cortisol stress reactivity for postinstitutionalized youth but not nonadopted comparison youth. This study indicates that pubertal development reopens a window of opportunity for the HPA axis to recalibrate based on significant improvements in the supportiveness of the environment relative to that in infancy. The peripubertal period may be an important time in development where the caregiving environment has a substantial impact on the HPA axis and, perhaps, other stress-mediating systems. Future research is needed to examine the mechanisms of recalibration and whether HPA recalibration impacts physical and psychological health.
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http://dx.doi.org/10.1073/pnas.1909699116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883847PMC
November 2019

Long-Acting Growth Hormone Preparations - Current Status and Future Considerations.

J Clin Endocrinol Metab 2020 06;105(6)

Departments of Neuroendocrinology and Neurosurgery, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine, Phoenix, Arizona.

Context: Long-acting GH (LAGH) preparations are currently being developed in an attempt to improve adherence. The profile of GH action following administration of LAGH raises practical questions about clinical monitoring and long-term safety and efficacy of these new therapeutic agents.

Methods: Recent literature and meeting proceedings regarding LAGH preparations are reviewed.

Results: Multiple LAGH preparations are currently at various stages of development, allowing for decreased GH injection frequency from daily to weekly, biweekly, or monthly. Following administration of LAGH, the serum peak and trough GH and IGF-I levels vary depending upon the mechanism used to prolong GH action. Randomized, controlled clinical trials of some LAGH preparations have reported non-inferiority compared with daily recombinant human GH (rhGH) for improved growth velocity and body composition in children and adults with GH deficiency (GHD), respectively. No significant LAGH-related adverse events have been reported during short-term therapy.

Conclusion: Multiple LAGH preparations are proceeding through clinical development with some showing promising evidence of short-term clinical efficacy and safety in children and adults with GHD. The relationship of transient elevations of GH and IGF-I following administration of LAGH to efficacy and safety remain to be elucidated. For LAGH to replace daily rhGH in the treatment of individuals with GHD, a number of practical questions need to be addressed including methods of dose adjustment, timing of monitoring of IGF-I, safety, efficacy, and cost-effectiveness. Long-term surveillance of efficacy and safety of LAGH preparations will be needed to answer these clinically relevant questions.
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http://dx.doi.org/10.1210/clinem/dgz149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755139PMC
June 2020

Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective.

Horm Res Paediatr 2019 12;92(1):1-14. Epub 2019 Sep 12.

Pediatric Endocrinology Division, Children's Hospital, University of Bonn, Bonn, Germany.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.
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http://dx.doi.org/10.1159/000502231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979443PMC
April 2020

Hypothalamic hamartomas and inner ear diverticula with X-linked stapes gusher syndrome - new associations?

Pediatr Radiol 2020 01 22;50(1):142-145. Epub 2019 Aug 22.

Department of Radiology, University of Minnesota, Minneapolis, MN, USA.

X-linked stapes gusher syndrome is a genetic form of deafness with distinct radiographic features on temporal bone CT. Hypothalamic hamartoma is a congenital glioneuronal anomaly of the hypothalamus. We report a potential association between these two rare anomalies that, to our knowledge, has not been reported. Two brothers presented with sensorineural hearing loss and almost identical inner ear and hypothalamic abnormalities, consistent with a diagnosis of X-linked stapes gusher syndrome and hypothalamic hamartoma. Genetic testing revealed identical mutations in the POU3F4 gene associated with X-linked stapes gusher syndrome. Furthermore, multiple vestibular diverticula were seen in both brothers, which have also not been reported with X-linked stapes gusher syndrome. This case suggests that POU3F4 mediated X-linked stapes gusher syndrome may also lead to multiple vestibular diverticula and hypothalamic hamartoma and, therefore, brain magnetic resonance imaging (MRI) could be considered in patients presenting with these inner ear findings.
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http://dx.doi.org/10.1007/s00247-019-04497-zDOI Listing
January 2020

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

Pediatr Res 2020 01 21;87(1):104-111. Epub 2019 Aug 21.

University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.

Background: Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.

Methods: This 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.

Results: The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.

Conclusions: Laronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made.
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http://dx.doi.org/10.1038/s41390-019-0541-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960090PMC
January 2020

Treatment of Children With GH in the United States and Europe: Long-Term Follow-Up From NordiNet® IOS and ANSWER Program.

J Clin Endocrinol Metab 2019 10;104(10):4730-4742

Thomas Jefferson University, Philadelphia, Pennsylvania.

Context: Understanding real-world prescribing of GH may help improve treatment of eligible patients.

Objective: Overall: to assess real-world effectiveness and safety of GH (Norditropin). This analysis: to compare clinical characteristics of GH-treated children in the United States and Europe.

Design: The American Norditropin Studies: Web-Enabled Research Program (ANSWER; 2002 to 2016, United States) and the NordiNet International Outcome Study (NordiNet IOS; 2006 to 2016, Europe) were multicenter longitudinal observational cohort studies.

Setting: Data were recorded in 207 (United States) and 469 (Europe) clinics.

Participants: Patients with GH deficiency, Turner syndrome, Noonan syndrome, idiopathic short stature, Prader-Willi syndrome, or born small for gestational age, who commenced GH treatment aged <18 years.

Intervention: GH was prescribed by treating physicians according to local practice.

Main Outcomes Measures: Baseline data and drug doses were recorded. Data on effectiveness and safety were collected.

Results: ANSWER had 19,847 patients in the full analysis set (FAS; patients with birthdate information and one or more GH prescription) and 12,660 in the effectiveness analysis set (EAS; GH-naive patients with valid baseline information). NordiNet IOS had 17,711 (FAS) and 11,967 (EAS). Boys accounted for 69% (ANSWER) and 57% (NordiNet IOS). Treatment start occurred later than optimal to improve growth. The proportion of boys treated was generally larger, children were older at treatment start, and GH doses were higher in the United States vs Europe. No new safety signals of concern were noted.

Conclusions: In most indications, more boys than girls were treated, and treatment started late. Earlier diagnosis of GH-related disorders is needed. The data support a favorable benefit-risk profile of GH therapy in children.
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http://dx.doi.org/10.1210/jc.2019-00775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812718PMC
October 2019

The p52 isoform of SHC1 is a key driver of breast cancer initiation.

Breast Cancer Res 2019 06 15;21(1):74. Epub 2019 Jun 15.

Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

Background: SHC1 proteins (also called SHCA) exist in three functionally distinct isoforms (p46SHC, p52SHC, and p66SHC) that serve as intracellular adaptors for several key signaling pathways in breast cancer. Despite the broad evidence implicating SHC1 gene products as a central mediator of breast cancer, testing the isoform-specific roles of SHC1 proteins have been inaccessible due to the lack of isoform-specific inhibitors or gene knockout models.

Methods: Here, we addressed this issue by generating the first isoform-specific gene knockout models for p52SHC and p66SHC, using germline gene editing in the salt-sensitive rat strain. Compared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. Rats were dosed with 7,12-dimethylbenz(a)anthracene (DMBA) by oral gavage to induce mammary tumors, and progression of tumor development was followed for 15 weeks. At 15 weeks, tumors were excised and analyzed by RNA-seq to determine differences between tumors lacking p66SHC or p52SHC.

Results: Compared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. These data, combined with p52SHC being the predominant isoform that is upregulated in human and rat tumors, provide the first evidence that p52SHC is the oncogenic isoform of Shc1 gene products in breast cancer. Compared with WT tumors, 893 differentially expressed (DE; FDR < 0.05) genes were detected in p52SHC KO tumors compared with only 18 DE genes in the p66SHC KO tumors, further highlighting that p52SHC is the relevant SHC1 isoform in breast cancer. Finally, gene network analysis revealed that p52SHC KO disrupted multiple key pathways that have been previously implicated in breast cancer initiation and progression, including ESR1 and mTORC2/RICTOR.

Conclusion: Collectively, these data demonstrate the p52SHC isoform is the key driver of DMBA-induced breast cancer while the expression of p66SHC and p46SHC are not enough to compensate.
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http://dx.doi.org/10.1186/s13058-019-1155-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570928PMC
June 2019

The History of Noonan Syndrome.

Authors:
Bradley S Miller

Pediatr Endocrinol Rev 2019 May;16(Suppl 2):424-427

Division of Endocrinology, University of Minnesota Masonic Children's Hospital, 2450 Riverside Avenue, Minneapolis, Minnesota 55454, USA, E-mail:

Early in her career, Jacqueline Noonan, a pediatric cardiologist, recognized that a number of children with valvular pulmonary stenosis had similar facial features. Dr. Noonan reported the clinical characteristics of this condition including short stature, hypertelorism, ptosis, mild mental retardation, undescended testes, and skeletal malformations. Further characterization of Noonan Syndrome led to the development of clinical criteria for the diagnosis of the condition. Identification of the first genetic cause of Noonan Syndrome, mutation of ptpn11 was reported in 2001. Multiple subsequent genes have been identified as causes of Noonan Syndrome and the related Rasopathies.
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http://dx.doi.org/10.17458/per.vol16.2019.m.historynoonanDOI Listing
May 2019

Establishing the incidence and timing of hypoglycemia at a residential diabetes camp.

Diabetes Res Clin Pract 2019 May 2;151:146-151. Epub 2019 Apr 2.

Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, United States; Division of Pediatric Endocrinology, University of Minnesota, Minneapolis, MN 55454, United States. Electronic address:

Aims: To establish the incidence and timing of hypoglycemia at a week-long residential diabetes camp for children. We hypothesized that hypoglycemia would occur more frequently during the first two days of camp and following evening all-camp games.

Methods: 225 children (mean age 12.0 ± 2.3 years, 56% female, mean hemoglobin A1c 8.4% [71.6 mmol/mol]) had blood glucose (BG) levels obtained before meals, at bedtime, and as needed to detect hypoglycemia. Insulin adjustments were made by medical staff according to camp protocol and at the discretion of medical staff during camper check-in.

Results: Mild hypoglycemia (BG 50-69 mg/dL [3.9 mmol/L]) occurred ≥ 1 time in 90% of campers while 43% had ≥ 1 episode of BG < 50 mg/dL (2.8 mmol/L). No episodes of hypoglycemia requiring glucagon occurred. More campers experienced ≥ 1 overnight hypoglycemia event during the first 48 hours of camp compared to later in the week (p = 0.01). Evening all-camp games did not impact hypoglycemia rates overnight.

Conclusions: Nocturnal hypoglycemia occurred more frequently during the first two nights, establishing this period as high risk and supporting implementation of a standard protocol to lower insulin doses. Rates of hypoglycemia were unaffected by all-camp games, indicating current practices are effective at minimizing hypoglycemia.
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http://dx.doi.org/10.1016/j.diabres.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687467PMC
May 2019

Emergency management of adrenal insufficiency in children: advocating for treatment options in outpatient and field settings.

J Investig Med 2020 01 28;68(1):16-25. Epub 2019 Feb 28.

Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota, USA.

Adrenal insufficiency (AI) remains a significant cause of morbidity and mortality in children with 1 in 200 episodes of adrenal crisis resulting in death. The goal of this working group of the Pediatric Endocrine Society Drug and Therapeutics Committee was to raise awareness on the importance of early recognition of AI, to advocate for the availability of hydrocortisone sodium succinate (HSS) on emergency medical service (EMS) ambulances or allow EMS personnel to administer patient's HSS home supply to avoid delay in administration of life-saving stress dosing, and to provide guidance on the emergency management of children in adrenal crisis. Currently, hydrocortisone, or an equivalent synthetic glucocorticoid, is not available on most ambulances for emergency stress dose administration by EMS personnel to a child in adrenal crisis. At the same time, many States have regulations preventing the use of patient's home HSS supply to be used to treat acute adrenal crisis. In children with known AI, parents and care providers must be made familiar with the administration of maintenance and stress dose glucocorticoid therapy to prevent adrenal crises. Patients with known AI and their families should be provided an Adrenal Insufficiency Action Plan, including stress hydrocortisone dose (both oral and intramuscular/intravenous) to be provided immediately to EMS providers and triage personnel in urgent care and emergency departments. Advocacy efforts to increase the availability of stress dose HSS during EMS transport care and add HSS to weight-based dosing tapes are highly encouraged.
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http://dx.doi.org/10.1136/jim-2019-000999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996103PMC
January 2020

Growth hormone therapy in children; research and practice - A review.

Growth Horm IGF Res 2019 02 26;44:20-32. Epub 2018 Dec 26.

New York University Winthrop Hospital, 101 Mineola Boulevard, Mineola, NY 11201, USA. Electronic address:

Short stature remains the most common reason for referral to a pediatric Endocrinologist and its management remains a challenge. One of the main controversies is the diagnosis of idiopathic short stature and the role of new technologies for genetic investigation of children with inadequate growth. Complexities in management of children with short stature includes selection of who should receive interventions such as recombinant human growth hormone, and how should this agent dose be adjusted during treatment. Should anthropometrical data be the primary determinant or should biochemical and genetic data be used to improve growth response and safety? Furthermore, what is considered a suboptimal response to growth hormone therapy and how should this be managed? Treatment of children with short stature remains a "hot" topic and more data is needed in several areas. These issues are reviewed in this paper.
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http://dx.doi.org/10.1016/j.ghir.2018.12.004DOI Listing
February 2019

Rituximab treatment for isolated IgG4-related hypophysitis in a teenage female.

Endocrinol Diabetes Metab Case Rep 2018 28;2018. Epub 2018 Dec 28.

Division of Rheumatology, Department of Pediatrics.

IgG4-related hypophysitis is an important diagnostic consideration in patients with a pituitary mass or pituitary dysfunction and can initially present with headaches, visual field deficits and/or endocrine dysfunction. Isolated IgG4-related pituitary disease is rare, with most cases of IgG4-related disease involving additional organ systems. We report the case of a teenage female patient with isolated IgG4-related hypophysitis, diagnosed after initially presenting with headaches. Our patient had no presenting endocrinologic abnormalities. She was treated with surgical resection, prednisolone and rituximab with no further progression of disease and sustained normal endocrine function. This case, the youngest described patient with isolated IgG4-related hypophysitis and uniquely lacking endocrinologic abnormalities, adds to the limited reports of isolated pituitary disease. The use of rituximab for isolated pituitary disease has never been described. While IgG4-related hypophysitis has been increasingly recognized, substantial evidence concerning the appropriate treatment and follow-up of these patients is largely lacking. Learning points: IgG4-related hypophysitis most often occurs in the setting of additional organ involvement but can be an isolated finding. This diagnosis should therefore be considered in a patient presenting with pituitary abnormalities. Most patients with IgG4-related hypophysitis will have abnormal pituitary function, but normal functioning does not exclude this diagnosis. Corticosteroids have been the mainstay of therapy for IgG4-related disease, with other immunosuppressive regimens being reserved for refractory cases. Further research is needed to understand the effectiveness of corticosteroid-sparing regimens and whether there is utility in using these agents as first-line therapies.
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http://dx.doi.org/10.1530/EDM-18-0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311468PMC
December 2018

Monitoring rhGH Safety: rhGH Registries, SAGhE and Future Needs.

Pediatr Endocrinol Rev 2018 Sep;16(Suppl 1):150-161

Oregon Health and Science University, Portland, Oregon, USA, STAT5, LLC, United States.

The safety of growth hormone (GH) therapy in children has been studied extensively. The identification of Creutzfeldt-Jacob disease in individuals who received pituitary-derived GH led to heightened surveillance for safety issues related to recombinant human GH (rhGH). An excellent safety profile of rhGH has been demonstrated in large Phase IV registries comprising > 600,000 patient-years of rhGH exposure and long-term safety cohorts of adults treated with GH as children. Increased mortality risk has been reported but eliminated when corrected for small size at birth. Increased risk of mortality from cerebrovascular disease has been reported but interpretation of these events remains difficult due to the lack of appropriate control groups and a lack of replication of these findings in other studies. The advent of new long-acting growth hormone (LAGH) products provides an opportunity for the development of cohorts of individuals receiving LAGH replacement therapy for continued long-term safety studies.
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http://dx.doi.org/10.17458/per.vol16.2018.mr.monitoringrhghsafetyDOI Listing
September 2018

Endothelin receptor A and p66Shc regulate spontaneous Ca oscillations in smooth muscle cells controlling renal arterial spontaneous motion.

FASEB J 2019 02 10;33(2):2636-2645. Epub 2018 Oct 10.

Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Adaptor protein p66Shc is overexpressed in smooth muscle cells of renal resistance vessels of hypertensive salt-sensitive rats and is involved in the regulation of renal vascular tone. We applied 2-photon laser scanning fluorescence microscopy to analyze spontaneous dynamic fluctuations in intracellular calcium concentrations ([Ca]) in smooth muscle cells embedded in the walls of freshly isolated renal resistance arteries. The amplitude, number of events, and frequency of spontaneous [Ca] oscillations triggered by endogenously released endothelin-1 were recorded in smooth muscle cells of the renal arteries. Endothelin receptor A antagonist BQ123 dramatically reduced the amplitude and frequency of spontaneous Ca events, producing marked inhibition of renal vessels spontaneous motion. Spontaneous Ca fluctuations in smooth muscle cells of p66Shc knockout (p66ShcKO) rats had significantly higher amplitude than in control rats. The frequency of spontaneous [Ca] oscillations did not change in p66ShcKO rats, suggesting that p66Shc expression did not affect endothelin-1 release from resident endothelial cells. Acute application of endothelin-1 revealed significantly elevated production of the total [Ca] in p66ShcKO rats. Spontaneous cytosolic Ca oscillations in smooth muscle cells of renal vessels mediate their spontaneous motion via the endothelin-1/endothelin receptor A pathway. p66Shc decreases the amplitude of individual changes in [Ca], which mitigates the spontaneous motion of renal vessels.-Palygin, O., Miller, B. S., Nishijima, Y., Zhang, D. X., Staruschenko, A., Sorokin, A. Endothelin receptor A and p66Shc regulate spontaneous Ca oscillations in smooth muscle cells controlling renal arterial spontaneous motion.
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http://dx.doi.org/10.1096/fj.201800776RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338658PMC
February 2019

Adrenoleukodystrophy: Guidance for Adrenal Surveillance in Males Identified by Newborn Screen.

J Clin Endocrinol Metab 2018 11;103(11):4324-4331

Pediatric Endocrine Unit, Massachusetts General Hospital for Children and Harvard Medical School, Boston, Massachusetts.

Context: Adrenoleukodystrophy (ALD) is a peroxisomal disorder associated with neurologic decompensation and adrenal insufficiency. Newborn screening for ALD has recently been implemented in five states with plans to expand to all 50 states in the United States. Adrenal insufficiency ultimately develops in most males with ALD, but the earliest age of onset is not well established.

Objective: These clinical recommendations are intended to address screening for adrenal insufficiency in boys identified to have ALD by newborn screen.

Participants: Seven members of the Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee, with clinical experience treating children with ALD and adrenal insufficiency, and a pediatric endocrinologist and laboratory director were selected to be on the working committee.

Consensus Process: The authors comprised the working group and performed systematic reviews of the published literature regarding adrenal insufficiency and ALD. The recommendations were reviewed and approved by the larger Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee and then by the Pediatric Endocrine Society Board of Directors.

Conclusions: There is limited literature evidence regarding monitoring of evolving adrenal insufficiency in male infants and children with ALD. The recommendations suggest initiating assessment of adrenal function at diagnosis with ALD and regular monitoring to identify boys with adrenal insufficiency in a timely manner and prevent life-threatening adrenal crisis. These recommendations are intended to serve as an initial guide, with the understanding that additional experience will inform future guidelines.
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http://dx.doi.org/10.1210/jc.2018-00920DOI Listing
November 2018

Inactivation of p66Shc Decreases Afferent Arteriolar K Channel Activity and Decreases Renal Damage in Diabetic Dahl SS Rats.

Diabetes 2018 11 21;67(11):2206-2212. Epub 2018 Aug 21.

Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI

Increased expression of adaptor protein p66Shc has been associated with progression of diabetic nephropathy. Afferent arteriolar dilation and glomerular hyperfiltration in diabetes are due to increased K channel availability and activity. Hyperglycemia was induced in Dahl salt-sensitive (SS) rats in a model of diabetes induced by streptozotocin (STZ). Renal injury was evaluated in SS rats and genetically modified SS rats either lacking p66Shc (p66Shc knockout [p66ShcKO]) or expressing p66Shc mutant (p66Shc-S36A). Afferent arteriolar diameter responses during STZ-induced hyperfiltration were determined by using the juxtamedullary nephron technique. Albuminuria and glomerular injury were mitigated in p66ShcKO and p66Shc-S36A rats with STZ-induced diabetes. SS rats with STZ-induced diabetes had significantly increased afferent arteriolar diameter, whereas p66ShcKO and p66Shc-S36A rats did not. SS rats with STZ-induced diabetes, but not p66ShcKO or p66Shc-S36A rats with STZ-induced diabetes, had an increased vasodilator response to the K channel activator pinacidil. Likewise, the K inhibitor glibenclamide resulted in a greater decrease in afferent arteriolar diameter in SS rats with STZ-induced diabetes than in STZ-treated SS p66ShcKO and p66Shc-S36A rats. Using patch-clamp electrophysiology, we demonstrated that p66ShcKO decreases K channel activity. These results indicate that inactivation of the adaptor protein p66Shc decreases afferent arteriolar K channel activity and decreases renal damage in diabetic SS rats.
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http://dx.doi.org/10.2337/db18-0308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198347PMC
November 2018

Effect of Adjusting for Tanner Stage Age on Prevalence of Short and Tall Stature of Youths in the United States.

J Pediatr 2018 10 10;201:93-99.e4. Epub 2018 Jul 10.

Pediatric Endocrinology, University of Minnesota Masonic Children's Hospital, Minneapolis, MN.

Objective: To evaluate the extent to which pubertal timing alters the classification of extremes of attained stature across race-ethnicity groups of youths in the US.

Study Design: We performed analyses of height and Tanner staging data of 3206 cross-sectional national sample of youths ages 8-18 years (53% male, n = 1606), 72% of whom were non-Hispanic white, 9% Mexican American, and 19% non-Hispanic black . Specialized growth models were used to derive Tanner-stage-age-adjusted z scores (TSA). The prevalence of shortness (<-1SD) and tallness (≥+1SD) status was quantified using TSA.

Results: Highly variable patterns of prevalence of shortness and tallness via chronologic age height z score (CA) were observed in results stratified by race-ethnicity and sex. Tallness CA prevalence was high among non-Hispanic white and non-Hispanic black male youths relative to Mexican American (40.0%-43.3% vs 20.5%) with a similar pattern in female youths. In both sexes, this pattern was eliminated with TSA, with Mexican American youth becoming statistically not different from their non-Hispanic white and non-Hispanic black peers.

Conclusions: Differences in timing of puberty between race-ethnicity groups affects estimated prevalence of shortness and tallness of attained height that remains uncaptured with CA. Adjustment for pubertal development might help isolate crucial determinants of attained stature and other aspects of body composition that may be most responsive to intervention programs in populations. The curves developed by adjusting for pubertal status may help the clinician avoid misclassification of children with early and late pubertal development.
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http://dx.doi.org/10.1016/j.jpeds.2018.05.051DOI Listing
October 2018

The slope of cortisol from awakening to 30 min post-wake in post-institutionalized children and early adolescents.

Psychoneuroendocrinology 2018 10 15;96:93-99. Epub 2018 Jun 15.

Institute of Child Development, University of Minnesota 51 E. River Rd., Minneapolis, MN 55455, USA. Electronic address:

This study examined the association between early life adversity, in the form of early rearing in an institution (orphanage), and the slope of cortisol in the first thirty minutes after waking in 277 children, aged 7 through 15 years old, who had either been adopted between 6 and 60 months of age into well-resourced homes in the United States or born into similar homes. The adopted youth were divided at the median (age 16 months) into those adopted earlier (earlier-adopted, EA) and later (later-adopted, LA). The purpose of this study was to examine the post-waking slope in cortisol in post-institutionalized youth, predicting that it would be blunted, especially in later-adopted youth, when compared to the non-adopted (NA) youth. A secondary goal was to examine whether there would be some evidence of less blunting of the first 30 min of the cortisol awakening response among the children further along in pubertal development (i.e., Pubertal Recalibration Hypothesis). Pubertal stage was determined by nurse exam. Salivary cortisol was assessed at 0 and 30-min post-awakening on three days. The results showed that LA children had a blunted wake-30 min cortisol slope relative to NA and EA children. Neither the age by group nor pubertal stage by group analyses were significant. However, the majority of the sample were in early stages of puberty (56% in stages 1 & 2), thus the power was low for detecting such an interaction. This is the first year of a cohort-sequential longitudinal study examining early experiences and pubertal influences on the HPA axis, so it will be important to re-examine this question as the sample ages.
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http://dx.doi.org/10.1016/j.psyneuen.2018.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459437PMC
October 2018