Jeanie B. Tryggestad

Obese Children Have Higher Arterial Elasticity Without a Difference in Endothelial Function: The Role of Body Composition

The childhood obesity epidemic is expected to increase cardiovascular disease risk, but the impact of obesity on vascular function in children is not fully understood. The purpose of this study was to determine the effect of obesity and maturation on vascular function in normal weight (BMI: 25–75 percentile) and obese (BMI: ≥95 percentile) children ages 8–18 years old. Large and small artery elasticity (LAEI and SAEI, respectively), measured by diastolic radial pulsewave contour analysis, and reactive hyperemia index (RHI), measured by peripheral arterial tonometry, were obtained, along with anthropometric and biochemical outcomes, in 61 normal weight and 62 obese children. SAEI and LAEI increased with age and were 30% and 18% higher, respectively, in obese children (P < 0.01). In contrast, reactive hyperemia increased with age in the normal weight group but did not differ between groups. Multivariate modeling was used to select variables that explained differences in vascular outcomes. The best model for LAEI in normal weight children was height alone (r2 = 0.49), whereas for obese children the best model included height + fat mass (r2 = 0.40). For SAEI, there were no significant models for normal weight children, but for obese children the best model included lean mass + fat mass (r2 = 0.36). Obese children had greater lean and fat mass, and more advanced Tanner stages than their normal weight peers. The increased elasticity observed in obese children appears to reflect accelerated growth and maturation without affecting vascular reactivity measured by reactive hyperemia. Longitudinal follow up will be essential in determining effects on future vascular disease risk.

Complications and comorbidities of T2DM in adolescents: findings from the TODAY clinical trial

With the rise in childhood obesity, type 2 diabetes mellitus (T2DM) has been recognized to occur in adolescents with increasing frequency. Although much is known about T2DM in adults, few studies have examined the treatment and complications of T2DM in youth. The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study was designed to evaluate the efficacy of various treatments and provided a unique opportunity to study the disease progression and appearance of complications in a pediatric cohort with recent onset of the disease. In the TODAY study, hypertension was present in 11.6% of the population at baseline and increased to 33.8% by the end of the study. Prevalence of high-risk LDL-cholesterol rose from 4.5% at baseline to 10.7% at the end of the study. Microalbuminuria was found in 6.3% of the cohort at baseline and increased to 16.6%. Retinopathy was not assessed upon entry into TODAY, but was present in 13.9% of the TODAY cohort at the end of the study. Experience to date indicates that these complications and comorbidities are similar to those seen in adults, but occur on an accelerated timeline. The early manifestation of diabetes complications in youth-onset T2DM suggests that this group will be burdened with the tangible consequences of cardiovascular disease, nephropathy, and retinopathy in the third and fourth decades of life. It is hoped that through an early, aggressive approach to treatment and prevention, we may be able to curb the onset and progression of these potentially devastating outcomes.

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

A model of delivering multi-disciplinary care to people with 46 XY DSD

In 2006, a consensus statement was jointly produced by the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society of Paediatric Endocrinology (ESPE) concerning the management of disorders of sex development (DSD) [1]. A recommendation provided by this consensus was that evaluation and long-term care for people affected by DSD should be performed at medical centers with multi-disciplinary teams experienced in such conditions. Here we provide our teams interpretation of the 2006 consensus statement recommendations and its translation into a clinical protocol for individuals affected by 46 XY DSD with either female, or ambiguous, genitalia at birth. Options for medical and surgical management, transitioning of care, and the use of mental health services and peer support groups are discussed. Finally, we provide preliminary data to support the application of our model for delivering multi-disciplinary care and support to patients and their families.

An Evidence-Based Model of Multidisciplinary Care for Patients and Families Affected by Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

In 2002 a consensus statement pertaining to the management of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency was jointly produced by the Lawson Wilkins Pediatric Endocrine Society and the European Society of Pediatric Endocrinology. One of the recommendations of this consensus was that centers should maintain multidisciplinary teams for providing care and support to these patients and their families. However, the specifics for how this should be accomplished were not addressed in the original consensus statement. Here we interpret and translate the 2002 consensus statement recommendations into medical, surgical and mental health protocols. Additionally, we provide preliminary evidence that such protocols result in improved care and support for patients and families.

Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat

BACKGROUND The treatment of familial hyperchylomicronemia presenting in early childhood with episodes of pancreatitis has been ineffective, and affected patients remain at risk for pancreatitis. OBJECTIVE To report on the effect of orlistat in siblings with severe inherited hyperchylomicronemia and to assess posttreatment lipoprotein concentrations and composition. METHODS Serial observations of plasma lipid levels and hospitalizations after treatment with orlistat and lipoprotein studies on a single fasting posttreatment sample. RESULTS The affected siblings inherited a lipoprotein lipase gene mutation from each of their parents: a novel mutation from their father (c.542G > C, p.G181R) and a known missense mutation from their mother (c.644G > A, p.G215E). When the boy presented to us at age 9 years of age and his sister at age 7 years, we found that addition of orlistat, a pancreatic lipase inhibitor, at a dose of 120 mg given before three low-fat meals a day was effective in reducing episodes of pancreatitis in the boy and in maintaining the triglyceride at lower levels in both children. During treatment, the children were observed to have elevations in apolipoprotein (apo)B, low-density lipoprotein particle concentration, abnormal apoB-containing subclasses, and deficiencies in apoA-I and apoA-II-containing lipoproteins, changes consistent with continuing increased cardiovascular risk. CONCLUSION The data support the need for more effective long-term treatments that not only prevent pancreatitis but also offset cardiovascular risk. Orlistat can be considered effective in augmenting the effect of a low-fat diet and reducing risk for pancreatitis.

Oxidized HDL and LDL in adolescents with type 2 diabetes compared to normal weight and obese peers.

OBJECTIVE Obesity and type 2 diabetes mellitus (T2DM) are associated with oxidative stress. Oxidative damage of high-density lipoprotein (oxHDL) leads to a dysfunctional molecule, potentially a mediator and/or marker of cardiometabolic disease. We tested the hypothesis that circulating concentration of oxHDL is higher in obese (Ob) or T2DM adolescents compared to normal-weight (NW) peers. METHODS In 37 NW, 38 Ob, and 42 T2DM adolescents, ages 11-18 y, fasting concentrations of HDL and LDL cholesterol, oxHDL, oxidized low-density lipoprotein (oxLDL), and myeloperoxidase (MPO) were measured. RESULTS Compared to the NW group, oxHDL in the Ob group was not different, but was 65% higher (p < 0.01) in the T2DM group. Within the T2DM group oxHDL was higher in boys than in girls, but this sex difference was not evident in NW or Ob groups. OxLDL was 23% higher in Ob (p = 0.02), and 56% higher in T2DM (p < 0.01) versus NW and did not differ between boys and girls. MPO was not different between NW and Ob but was 88% (p < 0.02) higher in T2DM compared to NW. Contrary to our hypothesis MPO and insulin resistance (HOMA-IR) were not correlated with oxHDL. OxHDL was positively associated with oxLDL and lean body mass while oxLDL was positively associated with apolipoprotein B, triglycerides, HOMA-IR and trunk fat. CONCLUSIONS The higher concentrations of oxHDL and oxLDL, along with higher MPO in children with T2DM reflect higher oxidative stress compared with obesity alone and potentially increased cardiovascular disease risk in youth with T2DM.

Pigment epithelium-derived factor (PEDF) varies with body composition and insulin resistance in healthy young people.

CONTEXT Pigment epithelium-derived factor (PEDF) was recently implicated as a metabolic regulatory protein because plasma concentration was increased in obese or insulin resistant adults. To our knowledge, circulating PEDF values in children have not been reported. Because PEDF is a predictor of metabolic health in adults, it may have a similar impact on metabolic profiles in children. OBJECTIVE The objective of the study was to determine whether PEDF in normal-weight (NW) and overweight/obese (OW) children and young adults varies with age, sex, or body composition or is associated with clinical markers of metabolic disease. SETTING Volunteers were tested at the University of Oklahoma Health Sciences Center. PARTICIPANTS Ninety-one NW (8-30 yr old) and 105 OW (8-35 yr old) males and females participated in the study. MAIN OUTCOME MEASURES Body composition, blood pressure, arterial compliance, fasting plasma PEDF, glucose, insulin, (used for homeostasis model assessment of insulin resistance), triglycerides, cholesterol (total, low density lipoprotein, and high density lipoprotein), and C-reactive protein. RESULTS PEDF was 60% higher in the OW vs. NW participants but did not differ between males and females. PEDF was positively correlated with body mass, body mass index, fat and lean mass, fasting insulin, and homeostasis model assessment of insulin resistance in both the NW and OW groups. Multiple regression models revealed that fat and lean mass were significant predictors of circulating PEDF levels independent of age, sex, and body mass index category. CONCLUSIONS Plasma PEDF is elevated in OW youth and is positively associated with insulin resistance. These findings suggest that PEDF may play a role in the development of cardiometabolic dysfunction in youth.

Arterial compliance is increased in children with type 2 diabetes compared with normal weight peers but not obese peers.

We reported that obesity was associated with increased arterial compliance in children, possibly due to accelerated vascular maturation. Here, we explored the additional burden of type 2 diabetes (T2DM) on vascular function in children.

Hypogonadotropic hypogonadism presenting with arhinia: A case report

IntroductionArhinia, congenital absence of the nose, is a rare malformation. We present the third reported case of arhinia accompanied by hypogonadism and demonstrate that this is due to gonadotropin deficiency.Case presentationA 13-year-old Caucasian boy with congenital arhinia presented for evaluation of delayed puberty and micropenis. We examined genes known to be associated with hypogonadotropic hypogonadism for mutations and performed a chromosomal microarray to assess copy number variation.ConclusionNo mutations in KAL1, FGFR1, PROK2, PROKR2, FGF8, CHD7 and GnRHR were identified in our patient and there were no copy number variations observed that would explain the phenotype. Though studies are limited in such patients, we suggest that hypogonadotropic hypogonadism is associated with arhinia and that the two entities likely result from a common genetic cause that affects early nasal development and gonadotropin-releasing hormone neuron formation or migration.