Safety and Efficacy of Lonapegsomatropin in Children With Growth Hormone Deficiency: enliGHten Trial 2-Year Results.

PURPOSE: The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone lonapegsomatropin in children with growth hormone deficiency. METHODS: Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the United States switched to the TransCon hGH Auto-Injector when available. Endpoints were long-term safety, annualized height velocity, pharmacodynamics [insulin-like growth factor-1 SD score (SDS) values], and patient- and caregiver-reported assessments of convenience and tolerability. RESULTS: Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through week 104 in treatment-naïve subjects from the heiGHt trial (-2.89 to -1.37 for the lonapegsomatropin group; -3.0 to -1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (-1.42 at fliGHt baseline to -0.69 at week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle. CONCLUSIONS: Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the second year of therapy without excess advancement of bone age.

Switching to Weekly Lonapegsomatropin from Daily Somatropin in Children with Growth Hormone Deficiency: The fliGHt Trial.

INTRODUCTION: The phase 3 fliGHt Trial evaluated the safety and tolerability of once-weekly lonapegsomatropin, a long-acting prodrug, in children with growth hormone deficiency (GHD) who switched from daily somatropin therapy to lonapegsomatropin. METHODS: This multicenter, open-label, 26-week phase 3 trial took place at 28 sites across 4 countries (Australia, Canada, New Zealand, and the USA). The trial enrolled 146 children with GHD, 143 of which were previously treated with daily somatropin. All subjects received once-weekly lonapegsomatropin 0.24 mg human growth hormone/kg/week. The primary outcome measure was safety and tolerability of lonapegsomatropin over 26 weeks. Secondary outcome measures assessed annualized height velocity (AHV), height standard deviation score (SDS), and IGF-1 SDS at 26 weeks. RESULTS: Subjects had a mean prior daily somatropin dose of 0.29 mg/kg/week. Treatment-emergent adverse events (AEs) reported were similar to the published AE profile of daily somatropin therapies. After switching to lonapegsomatropin, the least-squares mean (LSM) AHV was 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS changed from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). Among switch subjects, the LSM for average IGF-1 SDS was sustained at Weeks 13 and 26, representing an approximate 0.7 increase from baseline (prior to switching from daily somatropin therapy). Patient-reported outcomes indicated a preference for weekly lonapegsomatropin among both children and their parents. CONCLUSIONS: Lonapegsomatropin treatment outcomes were as expected across a range of ages and treatment experiences. Switching to lonapegsomatropin resulted in a similar AE profile to daily somatropin therapy.

A Web-Delivered Multicomponent Intervention for Adolescents with Poorly Controlled Type 1 Diabetes: A Pilot Randomized Controlled Trial.

Background: Type 1 diabetes is associated with significant mortality and economic cost. Management of type 1 diabetes involves completing multiple daily adherence behaviors, and many adolescents struggle with self-management and show poor glycemic control. Purpose: The purpose was to conduct an unblinded pilot randomized controlled parallel-group study of a web-delivered multicomponent intervention targeting self-monitoring of blood glucose, working memory, and parent supervision of diabetes care among adolescents with type 1 diabetes. Intervention components included high magnitude incentives for adolescents and parents, motivational and cognitive behavioral therapy and working memory training for adolescents, and training in contingency contracting for parents. Methods: Adolescents (N = 114) with poorly controlled type 1 diabetes were screened, and N = 61 were randomized using minimum likelihood allocation to usual care (usual care, N = 31) or to a 25-week/15-session web-delivered intervention (WebRx, N = 30). Results: At the end of treatment, adolescents in WebRx had higher self-monitoring of blood glucose (d = 0.58) (primary outcome), better visual spatial working memory (d = 0.48) and inhibition (d = 0.98), and lower HbA1c (d = 0.45) than those in usual care. WebRx parents reported more frequent review of the adolescent's glucometer (d = 1.30) and reduced family conflict (d = 0.56). Between-condition differences were maintained 6 months later in self-monitoring of blood glucose (d = 0.42), visual spatial working memory (d = 0.76), family conflict (d = 0.50), and HbA1c (d = 0.44). Conclusions: Results showing sustained effects on self-monitoring of blood glucose and HbA1c support moving forward with a larger trial to test this innovative web-delivered and multicomponent intervention. ClinicalTrials.gov Number (NCT01722643).

Low serum alkaline phosphatase activity due to asymptomatic hypophosphatasia in a teenage girl.

OBJECTIVE: The case report details an unusual presentation of a teenage patient with hypophosphatasia. PATIENT AND METHODS: A 17 year-old female patient presented to endocrinology for the evaluation of fatigue and possible adrenal insufficiency. In the course of her clinical evaluation she was noted to have a low serum alkaline phosphatase activity. Relatively few conditions are associated with a low serum alkaline phosphatase including Wilson's disease, hypophosphatasia, pernicious anemia and untreated hypothyroidism. RESULTS: Laboratory testing for hypothyroidism were unrevealing, as were the results for vitamin B12 and vitamin D. Testing for Wilson's disease revealed a ceruloplasmin concentration of 165 mg/L (Reference Interval, 160-450 mg/L), however sequencing of the ATP7B gene revealed no deleterious mutations. Measurement of serum pyridoxal phosphate and urine phosphoethanolamine for the diagnosis of hypophosphatasia revealed concentrations of 541.5 nmol/L (reference interval: 29.6-295.5) and 707 mmol/mol creatinine (reference interval: <778 mmol/mol creatinine), respectively, consistent with a diagnosis of hypophosphatasia. CONCLUSIONS: Hypophosphatasia was initially considered an unlikely diagnosis for this patient given her lack of characteristic skeletal abnormalities. This diagnosis of hypophosphatasia in this case was complicated by a serum ceruloplasmin concentration at the lower end of the reference interval leading to the genetic testing for Wilson's disease.

Pilot Study of a Web-Delivered Multicomponent Intervention for Rural Teens with Poorly Controlled Type 1 Diabetes.

Objective. The purpose of this study was to examine the feasibility and effectiveness of a web-delivered multicomponent behavioral and family-based intervention targeting self-regulation and self-monitoring of blood glucose levels (SMBG) and glycemic control (HbA1c) in teens with type 1 diabetes (T1DM) living in rural US. Methods. 15 teens with poorly controlled T1DM participated in a 25-week web-delivered intervention with two phases, active treatment (weekly treatment sessions and working memory training program) and maintenance treatment (fading of treatment sessions). Results. Almost all (13 of 15) participants completed at least 14 of 15 treatment sessions and at least 20 of 25 working memory training sessions. SMBG was increased significantly at end of active and maintenance treatment, and HbA1c was decreased at end of active treatment (p's ≤ 0.05). Executive functioning improved at end of maintenance treatment: performance on working memory and inhibitory control tasks significantly improved (p's ≤ 0.02) and parents reported fewer problems with executive functioning (p = 0.05). Improvement in inhibitory control was correlated with increases in SMBG and decreases in HbA1c. Conclusions. An innovative web-delivered and multicomponent intervention was feasible for teens with poorly controlled T1DM and their families living in rural US and associated with significant improvements in SMBG and HbA1c.

Pituitary tumors in childhood.

PURPOSE OF REVIEW: This review focuses on recently published literature on pituitary tumors in children with special focus on craniopharyngioma and prolactinoma. Although most pituitary masses are benign neoplasms, they are associated with high morbidity and mortality related to their proximity to vital neurologic structures including the optic chiasm, hypophysis and hypothalamus, resulting in disruption of pituitary hormone secretion. RECENT FINDINGS: The role of Wingless/ß-beta catenin signaling and aryl hydrocarbon receptor-interacting protein mutations in pituitary tumor formation has been recognized. There is general agreement on optimal treatment of prolactinomas, although duration of medical therapy in children deserves more specific attention. Advances in imaging, medical, surgical and radiotherapy techniques have greatly increased survival rates for all pituitary tumors, but high recurrence rates after attempted complete resection and high progression rates after incomplete resection of craniopharyngioma remain troublesome. Long-term morbidity and late mortality of all pituitary tumors have become better appreciated with recent focus placed on severe obesity. A trend toward a more multidisciplinary approach for craniopharyngioma, including radiotherapy and chemotherapy, particularly when tumor burden involves the hypothalamus, continues. SUMMARY: A vast amount of literature has been recently published, focusing on the management and long-term sequelae of all pituitary tumors in children. Craniopharyngioma remains the most challenging mass arising within sellar and parasellar areas, and optimal treatment continues to be hotly debated. Recognizing the rarity of pediatric pituitary tumors, the field would greatly benefit from more prospective multicenter trials, as well as from standardization of the assessment of preoperative function and post-treatment outcomes.

The effect of cinnamon on A1C among adolescents with type 1 diabetes.

OBJECTIVE: The purpose of this study was to determine the effect of cinnamon on glycemic control in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Using a prospective, double-blind, placebo-controlled design, 72 adolescent type 1 diabetic subjects were treated in an outpatient setting with cinnamon (1 g/day) or an equivalent-appearing placebo for 90 days. A1C, total daily insulin intake, and adverse events were recorded and compared between groups. RESULTS: There were no significant differences in final A1C (8.8 vs. 8.7, P = 0.88), change in A1C (0.3 vs. 0.0, P = 0.13), total daily insulin intake, or number of hypoglycemic episodes between the cinnamon and placebo arms. CONCLUSIONS: Cinnamon is not effective for improving glycemic control in adolescents with type 1 diabetes.

Gizmos and gadgets in diabetes care: new tools for sweet kids.

Diabetes care has become more complex as we strive to help children with diabetes achieve and maintain tight glycemic control. The technologic advances described herein have provided the means for safer, more convenient, and more effective diabetes care.

Lack of mutations in CYP2D6 and CYP27 in patients with apparent deficiency of vitamin D 25-hydroxylase.

Activation of vitamin D requires hepatic 25-hydroxylation and renal 1alpha-hydroxylation. Defects in renal P450c1alpha are well-described, but few patients with defective vitamin D 25-hydroxylation are reported. The cytochrome P450 enzymes CYP2D6 and CYP27 are potential 25-hydroxylases. We sequenced both genes in two reported families with hepatic 25-hydroxylase deficiency and found no mutations. 25-Hydroxylation occurs in both mitochondria and microsomes. The existence genes encoding distinct enzymes would provide genetic redundancy, explaining the rarity of apparent vitamin D 25-hydroxylase deficiency.

Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome.

OBJECTIVES: To identify and study adults (21 years or older) who have a 46,XY karyotype and presented as infants or children with genital ambiguity, including a small phallus and perineoscrotal hypospadias, reared male or female. METHODS: Participants were classified according to the cause underlying their intersex condition based on review of medical and surgical records. Long-term medical and surgical outcome was assessed with a written questionnaire and physical examination. Long-term psychosexual development was assessed with a written questionnaire and semistructured interview. RESULTS: Thirty-nine (72%) of 54 eligible patients participated. The cause underlying genital ambiguity of participants included partial androgen insensitivity syndrome (n = 14; 5 men and 9 women), partial gonadal dysgenesis (n = 11; 7 men and 4 women), and other intersex conditions. Men had significantly more genital surgeries (mean: 5.8) than women (mean: 2.1), and physician-rated cosmetic appearance of the genitalia was significantly worse for men than for women. The majority of participants were satisfied with their body image, and men and women did not differ on this measure. Most men (90%) and women (83%) had sexual experience with a partner. Men and women did not differ in their satisfaction with their sexual function. The majority of participants were exclusively heterosexual, and men considered themselves to be masculine and women considered themselves to be feminine. Finally, 23% of participants (5 men and 4 women) were dissatisfied with their sex of rearing determined by their parents and physicians. CONCLUSIONS: Either male or female sex of rearing can lead to successful long-term outcome for the majority of cases of severe genital ambiguity in 46,XY individuals. We discuss factors that should be considered by parents and physicians when deciding on a sex of rearing for such infants.