A self-guided curriculum on endocrinology standard of care for gender diverse youth, including ethical considerations.

Objective: While the field of pediatric endocrinology, and the American Board of Pediatrics, continues expanding training to include gender-affirming care, many pediatric endocrinology fellowship programs do not have formal curriculum for this patient population. Members of the Pediatric Endocrine Society (PES) that have a special interest in transgender health designed a curriculum based on Endocrine Society practice guidelines to expand the knowledge of gender affirming care for medical trainees' and faculty. Methods: PES members designed a 5-part self-guided educational module series with embedded knowledge questions. Uniquely, medical ethical reflections were included within each module. Participants completed baseline demographic and baseline and follow-up knowledge surveys. Results: Most participants were pediatric endocrinology fellows and 44 % percent (n = 21) completed all study components, including the follow up knowledge survey. Knowledge question data analysis demonstrated knowledge gained in medical management of pubertal youth and surgical interventions. Conclusion: This is the first medical education curriculum in gender-affirming care created by pediatric endocrinologists grounded in the Endocrine Society practice guidelines. This study demonstrates medical knowledge gained in caring for gender diverse youth and is the first to incorporate ethical considerations for this patient population. While initially designed for pediatric endocrinology trainees and faculty, this curriculum may be of great utility for any provider interested in caring for gender diverse youth.

Growth hormone as a rescue treatment in maple syrup urine disease with lessons from pediatric burn literature, case report and brief literature review.

Maple Syrup Urine Disease (MSUD) is a rare inherited disorder of branched chain amino acid metabolism characterized by cerebral edema and death in uncorrected metabolic crisis. It is conventionally treated with intensive nutritional therapy to prevent and correct metabolic crisis. This paper reports the use of growth hormone as a pharmacologic rescue agent in the case of an 11-year-old male with MSUD and metabolic crisis refractory to standard interventions. The initiation of short courses of growth hormone correlated with corrected mental status, resolution of metabolic acidosis, and improvement in plasma leucine levels on two occasions during an admission to the pediatric intensive care unit. This is the first known case report of the use of growth hormone in MSUD since contemporary dietary management became available. The discussion includes a literature review of the use of growth hormone in inherited diseases of amino acid metabolism and a brief discussion of protein anabolic pharmacotherapeutic agents shown to improve net protein balance in pediatric burn patients. We propose that growth hormone and other protein anabolic agents may be valuable adjuvants to standard therapy in children with inherited metabolic disease.

Duplication 6q24: More Than Just Diabetes.

Chromosome 6q24-related transient neonatal diabetes mellitus is characterized by intrauterine growth restriction and low birth weight, with neonatal hyperglycemia resolving by 18 months and an increased risk for type 2 diabetes in adulthood. Molecularly, it is caused by overexpression of the 6q24 imprinted chromosomal region due to a duplication, uniparental disomy, or abnormal methylation. Conventional testing for this condition analyzes methylation patterns at the 6q24 locus but does not evaluate for the presence of other surrounding chromosomal abnormalities. We report a female with a history of neonatal hyperglycemia due to a paternally inherited duplication at chromosomal location 6q24. She subsequently presented to the pediatric genetics clinic at 15 months of age with developmental delay and abnormal balance. Microarray analysis identified a larger 14 Mb chromosomal duplication from 6q24 to 6q25.2, consistent with a diagnosis of duplication 6q syndrome. This case highlights the clinical importance of pursuing further genetic evaluation in patients diagnosed with chromosome 6q24-related neonatal hyperglycemia via targeted methylation-specific multiplex ligation-dependent probe amplification analysis identifying a duplication in this region. Early identification and intervention can improve developmental outcomes for patients with larger chromosome 6q duplications.

Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents with obesity and type 2 diabetes.

The incidence of type 2 diabetes is increasing more rapidly in adolescents than in any other age group. We identified and compared metabolite signatures in obese children with type 2 diabetes (T2D), obese children without diabetes (OB), and healthy, age- and gender-matched normal weight controls (NW) by measuring 273 analytes in fasting plasma and 24-hour urine samples from 90 subjects by targeted LC-MS/MS. Diabetic subjects were within 2 years of diagnosis in an attempt to capture early-stage disease prior to declining renal function. We found 22 urine metabolites that were uniquely associated with T2D when compared to OB and NW groups. The metabolites most significantly elevated in T2D youth included members of the betaine pathway, nucleic acid metabolism, and branched-chain amino acids (BCAAs) and their catabolites. Notably, the metabolite pattern in OB and T2D groups differed between urine and plasma, suggesting that urinary BCAAs and their intermediates behaved as a more specific biomarker for T2D, while plasma BCAAs associated with the obese, insulin resistant state independent of diabetes status. Correlative analysis of metabolites in the T2D signature indicated that betaine metabolites, BCAAs, and aromatic amino acids were associated with hyperglycemia, but BCAA acylglycine derivatives and nucleic acid metabolites were linked to insulin resistance. Of major interest, we found that urine levels of succinylaminoimidazole carboxamide riboside (SAICA-riboside) were increased in diabetic youth, identifying urine SAICA-riboside as a potential biomarker for T2D.

The Glucose Control Resistance Scale

Objective: While past research found family conflict, disordered eating, body image concerns and anxious self-doubts may affect adolescent diabetic glucose control, available measures of adherence mainly focus on management tasks. The current study aimed to combine measures of emotional distress and beliefs with decisions concerning management in a new measure of resistance to treatment adherence: the 12-item Glucose Control Resistance Scale (GCRS). Methods: Participants included 135 adolescents and their parents from a pediatric diabetes clinic. Family conflict, body image concerns, anxious self-doubts and glucose control resistance were assessed. Results: Factor analysis identified 12 items, with loadings of ≥0.40, which were used to form the GCRS. The scale had adequate reliability and there was a significant correlation between child and parent GCRS scores. One factor, family conflict, was significantly related to hemoglobin A1c (HbA1c) levels, but a set of four factors explained a total of 12% of the variance in HbA1c levels. Of the demographic variables considered (gender, number of parents at home, age, body mass index z-score), only gender was significantly associated with adolescent perceptions of family conflict. Conclusion: The GCRS may allow diabetic care teams to better understand the origin of family conflict perceptions and the motivational beliefs that modify behavior and contribute to independent self-management and glucose control. Each question was designed to be meaningful in interventions by addressing common items of resistance to adherence and impulsive management decisions. The GCRS may be used by providers as an initial short screening survey on an annual or semi-annual basis.

Mutational Analysis in Pediatric Thyroid Cancer and Correlations with Age, Ethnicity, and Clinical Presentation.

BACKGROUND: Well-differentiated thyroid cancer (WDTC) incidence in pediatrics is rising, most being papillary thyroid carcinoma (PTC). The objective of the study was to assess the prevalence of different mutations in pediatric WDTC and correlate the genotype with the clinical phenotype. METHODS: This is a single-center retrospective study. Thyroid tissue blocks from 42 consecutive pediatric WDTC patients who underwent thyroidectomy between 2001 and 2013 were analyzed at Quest Diagnostics for BRAF(V600E), RAS mutations (N,K,H), and RET/PTC and PAX8/PPARγ rearrangements, using validated molecular methods. Thyroid carcinomas included PTC, follicular thyroid carcinoma (FTC), and follicular variant of PTC (FVPTC). RESULTS: Thirty-nine samples (29 females) were genotyped. The mean age at diagnosis was 14.7 years (range 7.9-18.4 years), and most were Hispanic (56.4%) or Caucasian (35.9%). The mean follow-up period was 2.9 years. Mutations were noted in 21/39 (53.8%), with both BRAF(V600E) (n = 9), and RET/PTC (n = 6) detected only in PTC. Mutations were detected in 2/5 FTC (PAX8/PPARγ and NRAS) and 3/6 FVPTC cases (PAX8/PPARγ). Of 28 PTC patients, 57.1% had mutations: 32.1% with BRAF(V600E), 21.4% with RET/PTC, and 3.6% with NRAS. Of patients with BRAF(V600E), 77.8% were Hispanic and 88.9% were >15 years, while all RET/PTC-positive patients were ≤15 years (p = 0.003). Tumor size, lymph node involvement, and distant metastasis at diagnosis (or soon after (131)I ablation) did not vary significantly based on the mutation. CONCLUSIONS: BRAF(V600E) was the most common mutation, especially in older and Hispanic adolescents. A larger, ethnically diverse pediatric cohort followed long term will enable the genotypic variability, clinical presentation, and response to therapy to be better assessed.

Haplotype analysis of the promoter region of phosphodiesterase type 8B (PDE8B) in correlation with inactivating PDE8B mutation and the serum thyroid-stimulating hormone levels.

BACKGROUND: Human phosphodiesterase (PDE) type 8B (PDE8B) is located at 5q14.1 and is known as the PDE with the highest affinity to cAMP. We recently described a family with bilateral micronodular adrenocortical disease that was apparently caused by an inactivating PDE8B mutation (H305P). As a result of a genome-wide study, a strong association between six polymorphic variants in the PDE8B promoter and serum levels of the thyroid-stimulating hormone (TSH) has been recently reported. Despite an extended analysis of the regions surrounding 5q14.1, no other potential genetic variants that could be responsible for the associated TSH levels were found. METHODS: In this study, we genotyped by polymerase chain reaction the described six polymorphic variants in the PDE8B promoter in the family with micronodular adrenocortical disease and inactivating PDE8B mutation and analyzed their correlation with individual TSH values in the family members. RESULTS: We observed complete segregation between the reported association and individual TSH values in the family we studied. Haplotype analysis showed that the haplotype associated with the high TSH levels is different from the one that segregated with H305P, suggesting that the mutation most probably has arisen on an allele independent of the high TSH-associated allele. CONCLUSIONS: The proposed mechanism by which PDE8B may influence TSH levels is through control of cAMP signaling. Our analysis revealed separate segregation of an inactivating PDE8B allele from the high-TSH-allele and showed low TSH levels in persons who carry an inactivating PDE8B allele. These data suggest that, indeed, PDE8B may be involved in regulation of TSH levels.

Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors.

Inactivating germline mutations in phosphodiesterase 11A (PDE11A) have been implicated in adrenal tumor susceptibility. PDE11A is highly expressed in endocrine steroidogenic tissues, especially the testis, and mice with inactivated Pde11a exhibit male infertility, a known testicular germ cell tumor (TGCT) risk factor. We sequenced the PDE11A gene-coding region in 95 patients with TGCT from 64 unrelated kindreds. We identified 8 nonsynonymous substitutions in 20 patients from 15 families: four (R52T, F258Y, G291R, and V820M) were newly recognized, three (R804H, R867G, and M878V) were functional variants previously implicated in adrenal tumor predisposition, and one (Y727C) was a known polymorphism. We compared the frequency of these variants in our patients to unrelated controls that had been screened and found negative for any endocrine diseases: only the two previously reported variants, R804H and R867G, known to be frequent in general population, were detected in these controls. The frequency of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (P = 0.0002), present in 19% of the families of our cohort. Most variants were detected in the general population, but functional studies showed that all these mutations reduced PDE activity, and that PDE11A protein expression was decreased (or absent) in TGCT samples from carriers. This is the first demonstration of the involvement of a PDE gene in TGCT, although the cyclic AMP signaling pathway has been investigated extensively in reproductive organ function and their diseases. In conclusion, we report that PDE11A-inactivating sequence variants may modify the risk of familial and bilateral TGCT.