Pheochromocytoma and paraganglioma are rare in the pediatric population occurring in approximately 1 in 50,000 children. While some cases are sporadic, they have commonly been associated with syndromes such as von Hippel-Lindau, multiple endocrine neoplasia types IIa and IIb, neurofibromatosis type 1, and hereditary pheochromocytoma-paraganglioma syndromes. In children less than 18 years of age approximately 60% of pheochromocytomas and paragangliomas are associated with a germline mutation. We present an 11-year-old child with an abdominal paraganglioma related to a succinate dehydrogenase subunit B gene mutation whose father had a previously resected abdominal paraganglioma and was found to carry the same mutation. In addition, we review the etiology, genetics, diagnostic approach, and challenges of preoperative management of secretory pheochromocytomas and paragangliomas in children.

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Gamma aminobutyric acid(GABA) is synthesized by glutamate decarboxylase(GAD) in β-cells. Regarding Type 1 diabetes(T1D), animal/islet-cell studies found that GABA promotes insulin secretion, inhibits α-cell glucagon and dampens immune inflammation, while GAD immunization may also preserve β-cells. We evaluated the safety and efficacy of oral GABA alone, or combination GABA with GAD, on the preservation of residual insulin secretion in recent-onset T1D. Herein we report a single-center, double-blind, one-year, randomized trial in 97 children conducted March 2015 to June 2019(NCT02002130). Using a 2:1 treatment:placebo ratio, interventions included oral GABA twice-daily(n = 41), or oral GABA plus two-doses GAD-alum(n = 25), versus placebo(n = 31). The primary outcome, preservation of fasting/meal-stimulated c-peptide, was not attained. Of the secondary outcomes, the combination GABA/GAD reduced fasting and meal-stimulated serum glucagon, while the safety/tolerability of GABA was confirmed. There were no clinically significant differences in glycemic control or diabetes antibody titers. Given the low GABA dose for this pediatric trial, future investigations using higher-dose or long-acting GABA formulations, either alone or with GAD-alum, could be considered, although GABA alone or in combination with GAD-alum did nor preserve beta-cell function in this trial.

Objectives This study examined the natural history of the proinsulin to c-peptide (PI:C) ratio and its correlation with residual β-cell function in childhood new-onset type 1 diabetes (T1D). Reputedly, this ratio is a biomarker of β-cell endoplasmic reticulum (ER) stress. Over the first year of T1D, the temporal trend in fasting and nutrient-stimulated PI data is limited. Methods PI was a secondary pre-planned analysis of our one year, randomized, double-blind, placebo-controlled gamma aminobutyric acid (GABA) trial in new-onset T1D. Of the 99 participants in the primary study, aged 4-18 years, 30 were placebo. This study only involved the 30 placebo patients; all were enrolled within 5 weeks of T1D diagnosis. A liquid mixed meal tolerance test was administered at baseline visit, 5 and 12 months for determination of c-peptide, PI, glucose, and hemoglobin A1C. Results Both the fasting (p=0.0003) and stimulated (p=0.00008) PI:C ratios increased from baseline to 12 months, inferring escalating β-cell ER stress. The baseline fasting PI correlated with the fasting change in c-peptide at 12 months (p=0.004) with a higher PI correlating with a greater decline in c-peptide. Patients with an insulin adjusted A1C > 9% (hence, not in remission) had higher fasting PI:C ratios. Younger age at diagnosis correlated with a higher PI:C ratio (p=0.04). Conclusion Children with new-onset T1D are undergoing progressive β-cell ER stress and aberrant proinsulin processing as evidenced by increasing PI:C ratios. Moreover, the PI:C ratio reflects a more aggressive β-cell onslaught the younger the age as well as diminished glycemic control.