Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Atherosclerosis and associated cardiovascular risk factors originate in childhood; hence, early management of dyslipidaemia is vital. However, hypercholesterolemia remains untreated or undertreated in many youths. We review current therapies, drugs under investigation and consider potential future directions for the management of paediatric dyslipidaemia to highlight the recent evidence and new therapeutic options for future use. RECENT FINDINGS/RESULTS:Cardiovascular disease (CVD) risk factors in childhood, including dyslipidaemia, are associated with CVD risk and clinical CVD events in adulthood. Recent data show that initiation of statin therapy in childhood in children with familial hypercholesterolemia reduces the risk of CVD in adulthood. Several well tolerated and efficacious treatment options have become available in recent times for the management of dyslipidaemia in youth. Many new lipid-lowering drugs are under investigation to widen the available choices. Some of these drugs are now available for use in paediatrics, while some remain targets for future use. SUMMARY/CONCLUSIONS:We review available treatment options for paediatric dyslipidaemia management, discuss potential limitations and propose future directions. We also acknowledge the need for continued research in paediatrics for optimal paediatric dyslipidaemia management.

OBJECTIVES/OBJECTIVE:To evaluate the relationships between adipose tissue distribution, insulin secretion and sensitivity, sleep-disordered breathing, and inflammation in obese adolescents. METHODS:; non-REM sleep duration), and inflammation (high-sensitivity C-reactive protein, hsCRP). RESULTS:Subjects (55% female) were mean (SD) 14.4 (2.1) years, with BMI Z-score of 2.3 (0.4). AHI was >5 in 10 (18%) subjects and 1< AHI ≤5 in 22 (39%). Visceral adipose tissue area (VAT) was positively correlated with OGTT 1 and 2 h insulin and 1 h glucose, and hsCRP (r=0.3-0.5, p≤0.007 for each). VAT was negatively correlated with sensitivity to insulin (r=-0.4, p=0.005) and SpO2 nadir (r=-0.3, p=0.04) but not with other sleep measures. After adjustment for BMI-Z, sex, population ancestry, age, and sleep measures, VAT remained independently associated with insulin measures and 1 h glucose, but no other measures of glycemia. SAT was not associated with measures of glycemia or insulin resistance. CONCLUSIONS:Among adolescents with obesity, visceral adiposity was associated with insulin resistance, SpO2 nadir, and inflammation. The independent association of visceral adiposity with insulin resistance highlights the potential role of VAT in obesity-related chronic disease.

Severe hypertriglyceridemia (HTG) (>885 mg/dL) can be caused by familial partial lipodystrophy type 3 (FPLD3), an autosomal dominant disorder caused by loss of function of the peroxisome proliferator-activated receptor gamma (PPARG), characterized by abnormal distribution of fat and metabolic derangements. This case reports a 16-year-old female (body mass index, 23.5 kg/m2) hospitalized twice for pancreatitis (triglycerides [TG] level >2,200 mg/dL). Her treatment management included bowel rest, insulin infusion, and plasmapheresis. A low-fat diet with 10 g of fat daily and 160 mg of fenofibrate daily decreased fasting TG to 411 mg/dL (range, 0-149 mg/dL). The patient had a normal leptin level. Panel testing of genes that impact TG metabolism revealed a known pathogenic variant in the PPARG gene (c.452A>G p.Tyr151Cys). A second variant detected in this gene, c.1003G>C (p.Val335Leu), is considered benign. Her glycosylated hemoglobin of 6.6% and 2-hour oral glucose tolerance test confirmed type 2 diabetes mellitus (T2DM). This study reports the earliest detection of T2DM in an adolescent with a pathogenic variant of PPARG. PPARG-related FPLD3 should be considered in lean children that present with severe HTG and insulin resistance, and subsequent treatment with proliferator-activated receptor gamma agonists, specifically thiazolidinediones, should be considered.

Suppression of menstruation and/or ovarian function in adolescent girls may be desired for a variety of reasons. Numerous medical options exist. The choice of the appropriate modality for an individual patient depends on several factors based on differences in the efficacy of achieving menstrual suppression as well as in their side effect profiles. Adolescence is also a period of bone mass accrual in girls, and several of these modalities may negatively influence peak bone mass. This review focuses on the efficacy of achieving menstrual suppression and the effect on bone health of the various options through an overview of the current literature and also highlights areas in need of further research.

CONTEXT:Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. AIM:In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. CASES:We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol <145 mg/dL (3.7 mmol/L). If the triglyceride is ≥400 mg/dL (4.5 mmol/L), prescription omega-3 fatty acids and fibrates are considered. In the case of triglyceride >1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. CONCLUSION:Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.

BACKGROUND:Hyperosmolar diabetic ketoacidosis (H-DKA), a distinct clinical entity, is the overlap of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). AIM/OBJECTIVE:We describe the clinical presentation, metabolic aberrations, and associated morbidity/mortality of these cases with H-DKA. We highlight the problem areas of medical care which require particular attention when caring for pediatric diabetes patients presenting with H-DKA. METHODS:In our study we reviewed the literature back to 1963 and retrieved twenty-four cases meeting the criteria of H-DKA: glucose >600 mg/dL, pH < 7.3, bicarbonate <15 mEq/L, and serum osmolality >320 mOsm/kg, while adding three cases from our institution. RESULTS:Average age of presentation of H-DKA was 10.2 years ± 4.5 years in females and 13.3 years ± 4 years in males, HbA1c was 13%. Biochemical parameters were consistent with severe dehydration: serum osmolality = 394.8±55 mOsm/kg, BUN = 48±22 mg/dL, creatinine = 2.81±1.03 mg/dL. Acute kidney injury, present in 12 cases, was the most frequent end-organ complication. CONCLUSION/CONCLUSIONS:Multi-organ involvement with AKI, rhabdomyolysis, pancreatitis, neurological and cardiac issues such as arrhythmias, are common in H-DKA. Aggressive fluid management, insulin therapy and supportive care can prevent acute and long term adverse outcomes in children and adolescents.

BACKGROUND:Unlike medullary thyroid carcinoma in adults, the vast majority of pediatric medullary thyroid carcinoma is hereditary. Pediatric medullary thyroid carcinoma is known to have different genetic alterations driving tumorigenesis, but it is not known if pediatric medullary thyroid carcinoma has different clinicopathologic features. This study aims to identify which pediatric medullary thyroid carcinoma patients might warrant elective neck dissection. METHODS:We selected all patients ages 0 to 19 diagnosed with clinically evident medullary thyroid carcinoma in the National Cancer Database between 2004 to 2016. Clinicopathologic factors, treatments, and outcomes were analyzed and compared between this cohort and adults (ages ≥20) with medullary thyroid carcinoma. RESULTS:One hundred twenty-five pediatric medullary thyroid carcinoma (median age: 13) and 5,086 adult medullary thyroid carcinoma (median age: 57) patients were identified. Pediatric patients had smaller tumors (median diameter: 1.2 cm vs 2.0 cm; P < .001), lower rates of nodal metastases (n = 31, 36.9% vs 1,689, 50.4%; P = .02) but double the incidence of multifocal tumors (n = 70, 59.3%, vs 1,412, 29.9%; P < .001) compared with adults. Multifocal tumors conferred a significantly increased risk of nodal metastases in adult medullary thyroid carcinoma (64.4% vs 43.2%; P < .001) but not pediatric medullary thyroid carcinoma (37.7% vs 35.7%; P = .85). Nodal metastases were more frequent among older children (0-5 years: 0.0%, 6-12: 40.7%, 13-19: 41.7%; P = .04). However, rates of occult nodal metastases were similar between older children (6-19 years: n = 12, 21.4%) and adults (557, 25.8% P = .56). CONCLUSION/CONCLUSIONS:Pediatric medullary thyroid carcinoma has lower rates of lymph node metastases compared with adults. The risk of nodal disease was low among the youngest children, but older children ages 6 to 19 were at considerable risk for occult metastases. These findings could guide clinicians in selecting pediatric patients considered for elective lymph node dissection.

Summary/UNASSIGNED:We describe a case of an infant who presented with clinical features of hyperthyroidism. The child was found to be tachycardic, hypertensive and diaphoretic, she was noted to have poor weight gain and difficulty in sleeping. The child was admitted to the pediatric intensive care unit for care. She was found to have biochemical evidence of hyperthyroidism with positive thyroid stimulating immunoglobulin. She responded well to methimazole and propranolol and had a remarkable recovery. She is the youngest patient to be diagnosed with Graves disease in the English literature, at 12 months of life. Learning points/UNASSIGNED:Hyperthyroidism must always be considered even at very young age, for patient presenting with poor weight gain and hyperdynamic state. Autoimmune diseases are becoming more common in infancy. Craniosynostosis and increased height for age are well-documented consequences of untreated hyperthyroidism in developing children.

BACKGROUND:The diagnosis of hypoglycemia and the use of diazoxide have risen in the last decade. Diazoxide is the only Food and Drug Agency-approved pharmacologic treatment for neonatal hypoglycemia caused by hyperinsulinism (HI). Recent publications have highlighted that diazoxide has serious adverse effects (AEs) such as pulmonary hypertension (2-3%) and neutropenia (15%). Despite its increasing use, there is little information regarding dosing of diazoxide and/or monitoring for AEs. METHODS:We convened a working group of pediatric endocrinologists who were members of the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES) to review the available literature. Our committee sent a survey to its PES members regarding the use of diazoxide in their endocrine practices. Our review of the results concluded that there was substantial heterogeneity in usage and monitoring for AEs for diazoxide among pediatric endocrinologists. CONCLUSIONS:Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized the information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.

BACKGROUND:It is unknown that dysglycemia in obese adolescents has effects on myocardial deformation that are more pronounced when compared to obesity alone. We hypothesized that obesity associated abnormal glucose tolerance (dysglycemia) would have adverse effects on two-dimensional speckle tracking echocardiography derived longitudinal, radial and circumferential strain (LS, RS, CS) compared to age and gender lean controls. We also examined if changes in deformation would be reflected in abnormal ventricular vascular coupling indices (VVI). METHODS:In a prospective cross-sectional design 39 obese adolescents (15.9 ± 1.7 years; 101.5 ± 39 kg; female - 58%) were compared to age and gender matched lean controls (15.7 ± 1.8 yrs, 60 ± 12.8 kg). Based on results from an oral glucose tolerance test (OGTT), obese adolescents were categorized as obese normoglycemic (ONG, n = 25) or obese dysglycemic (ODG, n = 14). Left ventricular (LV) global and average LS, CS, RS and strain rate were measured. LV ejection fraction and mass index were measured and VVI approximated as ratio of arterial elasticity (Ea) and end-systolic elastance (Ees). RESULTS:Adolescents with ODG had significantly (P = 0.005) impaired global LS (- 20.98% ± 2.8%) compared to controls (- 23.01% ± 2.3%). A similar (P = 0.0027) reduction was observed in average LS for adolescents with ODG (18.87% ± 2.5%) compared to controls (20.49% ± 2%). Global CS was also decreased (P = 0.03) in ODG (- 23.95%) compared to ONG (- 25.80). A similar trend was observed in average CS after multivariate regression for BMI and blood pressure. CS correlated with HbA1c in both groups (P = 0.05). VVI had a negative correlation with both LS (r = - 0.4, P = 0.025) and CS rate (r = - 0.36, P = 0.04). CONCLUSIONS:Myocardial strain and strain rate were significantly altered in obese adolescents. Unfavorable subclinical reductions in global and average CS were more pronounced in adolescents with dysglycemia compared to obese adolescents with normoglycemia and controls. These data indicate progressive worsening of subendocardial function across the spectrum of glucose tolerance. Strain rate was predictive of VVI in obese adolescents, suggesting strain rate may be a sensitive marker for cardiac remodeling in abnormal glucose homeostasis states.