Child Health Needs and the Pediatric Endocrinology Workforce: 2020-2040.

The pediatric endocrinology (PE) workforce in the United States is struggling to sustain an adequate, let alone optimal, workforce capacity. This article, one of a series of articles in a supplement to Pediatrics, focuses on the pediatric subspecialty workforce and furthers previous evaluations of the US PE workforce to model the current and future clinical PE workforce and its geographic distribution. The article first discusses the children presenting to PE care teams, reviews the current state of the PE subspecialty workforce, and presents projected headcount and clinical workforce equivalents at the national, census region, and census division level on the basis of a subspecialty workforce supply model through 2040. It concludes by discussing the educational and training, clinical practice, policy, and future workforce research implications of the data presented. Data presented in this article are available from the American Board of Pediatrics, the National Resident Matching Program, and the subspecialty workforce supply model. Aging, part-time appointments, and unbalanced geographic distribution of providers diminish the PE workforce capacity. In addition, limited exposure, financial concerns, and lifestyle perceptions may impact trainees. Additional workforce challenges are the subspecialty's increasingly complex cases and breadth of conditions treated, reliance on international medical graduates to fill fellowship slots, and high relative proportion of research careers. The recent limitations on pediatric endocrinologists providing gender-affirming care may also impact the geographic distribution of the subspecialty's workforce. Deliberate actions need to be taken now to continue serving the needs of children.

The Incidence of Erosive Esophagitis as a Complication of Pediatric Diabetic Ketoacidosis.

INTRODUCTION: Gastrointestinal (GI) symptoms commonly occur during diabetic ketoacidosis (DKA) and typically resolve with treatment. However, GI complications can persist after DKA resolves. The incidence of upper GI bleeding during DKA in adults has been described, with erosive esophagitis one of the most common lesions. The incidence of GI bleeding or erosive esophagitis in children with DKA has not been previously reported. We performed a retrospective chart review of DKA admissions in children 0 to <18 years with type 1 diabetes mellitus (T1DM) at a pediatric hospital between January 2009 and July 2016. Among 395 episodes of DKA over 7.5 years, erosive esophagitis occurred during two DKA admissions (0.5%) and there were no episodes of GI bleeding. Case presentations. Both episodes of erosive esophagitis occurred in adolescent males with known T1DM who presented with severe DKA. Both developed odynophagia after resolution of DKA and were readmitted for DKA recurrence. Upper endoscopy for both patients showed erosive esophagitis. Biopsies were negative for infection, though candida was found during one patient's endoscopy. Both had resolution of their esophagitis symptoms with medication management; neither has had recurrence. CONCLUSION: Erosive esophagitis, a rare complication of pediatric DKA, can manifest with odynophagia or substernal chest pain. This complication can lead to DKA recurrence, likely due to increased insulin resistance from inflammation and pain and from reduced oral intake and insulin administration. Patients with odynophagia associated with DKA should be monitored closely to allow timely evaluation and treatment of esophagitis.

Pediatric Diabetic Ketoacidosis With Hyperosmolarity: Clinical Characteristics and Outcomes.

OBJECTIVE: Studies of hyperglycemic emergencies with hyperosmolality, including hyperglycemic hyperosmolar state (HHS) and "mixed presentation" with features of diabetic ketoacidosis (DKA) and HHS, are lacking in children. Objectives were to determine the incidence of DKA, HHS, and mixed presentation in a pediatric population, to characterize complications, and to assess accuracy of associated diagnosis codes. METHODS: Retrospective cohort study of 411 hyperglycemic emergencies in pediatric patients hospitalized between 2009 and 2014. Hyperglycemic emergency type was determined by biochemical criteria and compared to the associated diagnosis code. RESULTS: Hyperglycemic emergencies included: 333 DKA, 54 mixed presentation, and 3 HHS. Altered mental status occurred more frequently in hyperosmolar events ( P<.0001), and patients with hyperosmolarity had 3.7-fold greater odds of developing complications compared to those with DKA ( P = .0187). Of those with DKA, 98.5% were coded correctly. The majority (81.5%) of mixed DKA-HHS events were coded incorrectly. Events coded incorrectly had 3.1-fold greater odds of a complication ( P = .02). CONCLUSION: A mixed DKA-HHS presentation occurred in 13.8% of characterized hyperglycemic emergencies, whereas HHS remained a rare diagnosis (0.8%) in pediatrics. Hyperosmolar events had higher rates of complications. As treatment of hyperosmolarity differs from DKA, its recognition is essential for appropriate management. ABBREVIATIONS: AMS = altered mental status; DKA = diabetic ketoacidosis; EMR = electronic medical record; HHS = hyperglycemic hyperosmolar state; ICD-9 = International Classification of Diseases, Ninth Revision; ISPAD = International Society of Pediatric and Adolescent Diabetes; NODM = new-onset diabetes mellitus; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

Pediatric Diabetes Outpatient Center at Rhode Island Hospital: The impact of changing initial diabetes education from inpatient to outpatient.

BACKGROUND: This study compared outcomes and costs for new-onset Type 1 diabetes mellitus (T1DM) patients educated at the outpatient versus inpatient settings. METHODS/DESIGN: Retrospective study examining the following variables: 1) hemoglobin A1c (HbA1c), 2) severe hypoglycemia, 3) admissions for diabetic ketoacidosis (DKA) or ER visits, and 4) healthcare cost. RESULTS: 152 patients with new-onset T1DM from September 2007-August 2009. There were no differences between outpatient group (OG) and inpatient group (IG) in mean HbA1c levels at 1, 2 and 3 years post-diagnosis (OG 8%, 8.5%, 9.3%; IG 8.3%, 8.9%, 9%, p=0.51). Episodes of severe hypoglycemia, DKA, and ER visits were not different between the two groups. Mean total hospital costs for OG and pure OG were significantly less than IG (OG: $2886 vs. IG: $4925, p<0.001), (pure OG: $1044 vs. IG: $4925, p<0.0001). CONCLUSION: Our study demonstrates that outpatient- based pediatric diabetes education lowers healthcare cost without compromising medical outcomes. [Full article available at http://rimed.org/rimedicaljournal-2017-02.asp].

Efficacy of growth hormone therapy in Kearns-Sayre syndrome: the KIGS experience.

Kearns-Sayre syndrome (KSS) is characterized by external ophthalmoplegia, retinal pigmentation and cardiac conduction defects due to mitochondrial DNA (mtDNA) deletions. Short stature and growth hormone (GH) deficiency have been reported in KSS, but data on GH treatment is limited. We describe the clinical presentation, phenotype evolution, and response to GH in a patient with KSS and report data on eight additional KSS patients from the KIGS database. Our patient with KSS and GH deficiency achieved a final adult height at -0.8 SDS. In the KIGS database GH treatment resulted in mean improvement in height from -3.9 to -2.9 SDS in patients with KSS. Two patients did not show growth improvement. Our data shows improvement in height SDS in our patient and mixed results in eight additional patients from the KIGS database after treatment with GH. Heterogeneity in responsiveness may relate to presence of GH deficiency or severity of underlying mitochondrial dysfunction.

Severe Hypertriglyceridemia due to a novel p.Q240H mutation in the Lipoprotein Lipase gene.

BACKGROUND: Lipoprotein Lipase (LPL) deficiency is a rare autosomal recessive disorder with a heterogeneous clinical presentation. Several mutations in the LPL gene have been identified to cause decreased activity of the enzyme. FINDINGS: An 11-week-old, exclusively breastfed male presented with coffee-ground emesis, melena, xanthomas, lipemia retinalis and chylomicronemia. Genomic DNA analysis identified lipoprotein lipase deficiency due to compound heterozygosity including a novel p.Q240H mutation in exon 5 of the lipoprotein lipase (LPL) gene. His severe hypertriglyceridemia, including xanthomas, resolved with dietary long-chain fat restriction. CONCLUSIONS: We describe a novel mutation of the LPL gene causing severe hypertriglyceridemia and report the response to treatment. A review of the current literature regarding LPL deficiency syndrome reveals a few potential new therapies under investigation.

Rare complications of pediatric diabetic ketoacidosis.

The incidence of type 1 diabetes (T1D) among youth is steadily increasing across the world. Up to a third of pediatric patients with T1D present with diabetic ketoacidosis, a diagnosis that continues to be the leading cause of death in this population. Cerebral edema is the most common rare complication of diabetic ketoacidosis in children. Accordingly, treatment and outcome measures of cerebral edema are vastly researched and the pathophysiology is recently the subject of much debate. Nevertheless, cerebral edema is not the only sequela of diabetic ketoacidosis that warrants close monitoring. The medical literature details various other complications in children with diabetic ketoacidosis, including hypercoagulability leading to stroke and deep vein thrombosis, rhabdomyolysis, pulmonary and gastrointestinal complications, and long-term memory dysfunction. We review the pathophysiology, reported cases, management, and outcomes of each of these rare complications in children. As the incidence of T1D continues to rise, practitioners will care for an increasing number of pediatric patients with diabetic ketoacidosis and should be aware of the various systems that may be affected in both the acute and chronic setting.

Screening and Treatment of Common Lipid Disorders in Adolescents.

Cardiovascular disease remains a substantial health care burden in the adult population, the roots of which begin in childhood. Universal screening for dyslipidemia in all children and adolescents has been implemented to identify cases of FH that are otherwise missed by conventional screening because untreated FH can result in early CVD and untimely death. Recommendations for medical therapy did not change with the 2011 NHLBI guidelines. LDL levels targeted for therapy usually are elevated because of primary genetic disorders such as FH. Although these recommendations remain controversial, the benefit of universal screening and subsequent treatment of high-risk patients far outweighs the risk of not screening, although more investigation is warranted to understand the long-term outcomes of CVD risk in youth.

Glycemic control in familial vs. sporadic type 1 diabetes patients over 5 years.

BACKGROUND: Studies have shown that familial type 1 diabetes patients (FTID) have less severe metabolic derangement at presentation compared to sporadic patients (ST1D), but data on long-term metabolic control are lacking. OBJECTIVE/HYPOTHESIS: (1) FT1D will have less severe presentation and better HbA1c over 5 years compared to ST1D; (2) HbA1c in the offspring will correlate with parent HbA1c in parent-offspring group; and (3) HbA1c of the second affected sibling (SP2) will correlate with the first affected sibling (SP1) in sib-pairs. METHODS: Cohort of 33 parent-offspring and 19 sib-pairs; controls included 33 sporadic subjects matched by age, sex, ethnicity, puberty, and insulin regimen. Paired t-test and Pearson's correlation were used for statistical analysis. RESULTS: At diagnosis, mean age in FT1D vs. matched ST1D (7.7±4.9 vs. 7.6±4.5 years), mean HbA1c (9.6% vs. 10.7%), HCO3 (21 vs. 18 meq/L), glucose (428 vs. 463 mg/dL) and pH (7.35 vs. 7.36; p=ns) were not different. At 5 years, HbA1c (8.9% vs. 8.8%; p=0.81), clinic visits (12 vs. 12.5, p=0.68) and emergency room visits (0.48 vs. 0.24, p=0.10) were not different. In affected siblings, only HCO3 was different (SP1:18 vs. SP2: 24 meq/L; p<0.01). HbA1c for SP2 correlated positively with SP1 (r=0.67, p<0.01). Offspring HbA1c correlated positively with affected parents (9.3% vs. 8.6%, r=0.57, p=0.18) but was not significant. CONCLUSION: Metabolic control at diagnosis and at 5 years was similar in FT1D and ST1D. In sib-pairs, the second affected sibling had milder clinical presentation compared to the first affected sibling.

Developmental genes targeted for epigenetic variation between twin-twin transfusion syndrome children.

BACKGROUND: Epigenetic mechanisms are thought to be critical in mediating the role of the intrauterine environment on lifelong health and disease. Twin-twin transfusion syndrome (TTTS) is a rare condition wherein fetuses share the placenta and develop vascular anastomoses, which allow blood to flow between the fetuses. The unequal flow results in reciprocal hypo- and hypervolemia in the affected twins, striking growth differences and physiologic adaptations in response to this significant stressor. The donor twin in the TTTS syndrome can be profoundly growth restricted and there is likely a nutritional imbalance between the twins. The consequences of TTTS on fetal programming are unknown. This condition can now be effectively treated through the use of fetal laparoscopic procedures, but the potential for lifelong morbidity related to this condition during development is apparent. As this condition and the resulting uteroplacental discordance can play a role in the epigenetic process, we sought to investigate the DNA methylation profiles of childhood survivors of TTTS (n = 14). We focused on differences in both global measures and genome-wide CpG specific DNA methylation between donor and recipient children in this pilot study in order to generate hypotheses for further research. RESULTS: We identified significant hypomethylation of the LINE1 repetitive element in the peripheral blood of donor children and subtle variation in the genome-wide profiles of CpG specific methylation most prominent at CpG sites which are targets for polycomb group repressive complexes. CONCLUSIONS: These preliminary results suggest that coordinated epigenetic alterations result from the intrauterine environment experienced by infants with TTTS and may, at least in part, be responsible for downstream health conditions experienced by individuals surviving this condition.

IGF-I attenuates FFA-induced activation of JNK1 phosphorylation and TNFα expression in human subcutaneous preadipocytes.

OBJECTIVE: Free fatty acids (FFAs) are increased in visceral fat and contribute to insulin resistance through multiple mechanisms, including c-Jun N-terminal kinase (JNK) activation and expression of TNFα. Given that insulin-like growth factor-1 (IGF-1)-mediated proliferation is impaired in omental compared to subcutaneous (SC) preadipocytes, we investigated IGF-I anti-inflammatory action in preadipocytes from SC and omental adipose tissue. DESIGN AND METHODS: Preadipocytes isolated from abdominal SC and omental fat of obese subjects were studied in primary culture. Cells were exposed to FFAs with or without IGF-I pretreatment followed by analysis of cytokine expression and JNK phosphorylation. Lentivirus infection was used to express a constitutively active AKT (myr-AKT) in omental preadipocytes. RESULTS: FFAs increased the expression of tumor necrosis factor (TNF)α, interleukin (IL)-6, and monocyte chemotactic protein (MCP)-1 in SC and omental preadipocytes. IGF-I pretreatment reduced FFA-induced JNK1 phosphorylation and TNFα expression in SC but not omental preadipocytes. Treatment with the JNK1/2 inhibitor SP600125 reduced FFA-induced expression of TNFα. FFAs and MALP-2, a specific TLR2/6 ligand, but not specific ligands for TLR4 and TLR1/2, increased JNK1 phosphorylation. IGF-I completely inhibited MALP-2-stimulated phosphorylation of JNK1. Expression of myr-AKT in omental preadipocytes inhibited FFA-stimulated JNK1 phosphorylation. CONCLUSIONS: IGF-I attenuated FFA-induced JNK1 phosphorylation and TNFα expression through activation of AKT in human subcutaneous but not omental preadipocytes.

Growth hormone deficiency and central precocious puberty in Klinefelter syndrome: report of a case and review of KIGS database.

Growth hormone deficiency (GHD) and central precocious puberty (CPP) have each, individually, been described in patients with Klinefelter syndrome. However, the combination of GHD, CPP, and Klinefelter syndrome has never been reported. We described a Klinefelter syndrome patient who developed GHD at age 2 10/12 years and CPP at 8 6/12 years. Despite CPP, GnRH agonist therapy was not initiated because of his excellent predicted adult height. At 11 8/12 years, his height was 164.6 cm, close to his mid-parental target height of 165 cm. We report an additional nine patients with Klinefelter syndrome and GHD from the Pfizer International Growth Study (KIGS) database, none of whom had CPP. We conclude that the combination of GHD and CPP is very rare in Klinefelter syndrome and that CPP is unlikely to compromise final adult height.

EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic ß-cells.

BACKGROUND: Postnatal expansion of the pancreatic ß-cell mass is required to maintain glucose homeostasis immediately after birth. This ß-cell expansion is regulated by multiple growth factors, including glucose, insulin, insulin-like growth factor (IGF-1) and epidermal growth factor (EGF). These mitogens signal through several downstream pathways (AKT, ERK, STAT3, and JNK) to regulate the survival and proliferation of ß-cells. Survivin, an oncofetal protein with both pro-proliferative and anti-apoptotic properties, is a known transcriptional target of both IGF-1 and EGF in cancer cells. Here, we analyzed the effects of the ß-cell mitogens IGF-1 and EGF on survivin regulation in the established pancreatic ß-cell model cell lines, MIN6 and INS-1 and in primary mouse islets. RESULTS: In pancreatic ß-cells, treatment with glucose, insulin, or EGF increased survivin protein levels at early time points. By contrast, no significant effects on survivin were observed following IGF-1 treatment. EGF-stimulated increases in survivin protein were abrogated in the presence of downstream inhibitors of the Raf-1/MEK/ERK pathway. EGF had no significant effect on survivin transcription however it prolonged the half-life of the survivin protein and stabilized survivin protein levels by inhibiting surviving ubiquitination. CONCLUSIONS: This study defines a novel mechanism of survivin regulation by EGF through the Raf-1/MEK/ERK pathway in pancreatic ß-cells, via prolongation of survivin protein half-life and inhibition of the ubiquitin-mediated proteasomal degradation pathway. This mechanism may be important for regulating ß-cell expansion after birth.

IGF-I activation of the AKT pathway is impaired in visceral but not subcutaneous preadipocytes from obese subjects.

Obesity morbidity is associated with excess visceral adiposity, whereas sc adipose tissue is much less metabolically hazardous. Human abdominal sc preadipocytes have greater capacity for proliferation, differentiation, and survival than omental preadipocytes. IGF-I is a critical mediator of preadipocyte proliferation, differentiation, and survival through multiple signaling pathways. We investigated IGF-I action in primary cultures of human preadipocytes isolated from sc and omental adipose tissue of obese subjects. IGF-I-stimulated DNA synthesis was significantly lower in omental compared with sc preadipocytes. IGF-I phosphorylation of the IGF-I receptor and the ERK pathway was comparable in sc and omental cells. However, omental preadipocytes had decreased insulin receptor substrate (IRS)-1 protein associated with increased IRS-1-serine(636/639) phosphorylation and degradation. IGF-I-stimulated phosphorylation of AKT on serine(473) but not threonine(308) was decreased in omental cells, and activation of downstream targets, including S6Kinase, glycogen synthase kinase-3, and Forkhead box O1 was also impaired. CyclinD1 abundance was decreased in omental cells due to increased degradation. Over-expression of IRS-1 by lentivirus in omental preadipocytes increased IGF-I-stimulated AKT-serine(473) phosphorylation. The mammalian target of rapamycin (mTOR)-Rictor complex regulates phosphorylation of AKT-serine(473) in 3T3-L1 adipocytes, but knockdown of Rictor by lentivirus-delivered short hairpin RNA in sc preadipocytes did not affect AKT-serine(473) phosphorylation by IGF-I. These data reveal an intrinsic defect in IGF-I activation of the AKT pathway in omental preadipocytes from obese subjects that involves IRS-1 but probably not mTOR-Rictor complex. We conclude that impaired cell cycle regulation by AKT contributes to the distinct growth phenotype of preadipocytes in visceral fat of obese subjects.

Autoimmune polyglandular syndrome Type 3 and growth hormone deficiency.

The simultaneous occurrence of prepubertal Graves' disease, type 1 Diabetes Mellitus (DM), and Growth hormone deficiency (GHD) is uncommon. GHD has been reported in Autoimmune Polyglandular Syndrome (APS) Type 1 and Type 2 but not in APS Type 3. We report a 3-yr-old boy who presented simultaneously with type 1 DM and Graves' disease. After he developed urticarial rash to Propylthiouracil and Methimazole with persistent thyrotoxicosis, he received 8 millicuries of (131)I at 5 yr of age. We diagnosed GHD at age 8 yr 8 months because of growth deceleration (from 95 to 25%) and abnormal growth rate (3 cm/yr) despite euthyroidism, fair glycemic control, and normal weight gain. Both insulin-like growth factor (IGF) 1 (90 ng/mL; normal 113-261 ng/mL) and IGFBP3 (1.3 mcg/mL; normal 2.1-4.2 mcg/mL) levels were low and peak growth hormone level measured by RIA was 5.2 ng/mL after L-Dopa and insulin tolerance test. The rest of his pituitary functions and magnetic resonance imaging of the pituitary gland were normal. Growth hormone treatment (0.3 mg/kg/wk) was administered at 8 yr 9 months until near final adult height (FAH). Near FAH (172 cm) was close to midparental target height of 180 cm. GHD may be a component of all APS even though it is rare. Growth in treated children with Graves' disease should be followed closely as catch down growth below genetic height potential may be a harbinger of underlying GHD.