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Initially provided as an alternative to evaluation of serum analytes and nuchal translucency for the assessment of pregnancies at high risk of trisomy 21, cell-free DNA screening for fetal aneuploidy, also referred to as noninvasive prenatal screening, can now also screen for fetal sex chromosome anomalies such as monosomy X as early as 9 to 10 weeks of gestation. Early identification of Turner syndrome, a sex chromosome anomaly resulting from the complete or partial absence of the second X chromosome, allows medical interventions such as optimizing obstetrical outcomes, hormone replacement therapy, fertility preservation and support, and improved neurocognitive outcomes. However, cell-free DNA screening for sex chromosome anomalies and monosomy X in particular is associated with high false-positive rates and low positive predictive value. A cell-free DNA result positive for monosomy X may represent fetal Turner syndrome, maternal Turner syndrome, or confined placental mosaicism. A positive screen for monosomy X with discordant results of diagnostic fetal karyotype presents unique interpretation and management challenges because of potential implications for previously unrecognized maternal Turner syndrome. The current international consensus clinical practice guidelines for the care of individuals with Turner syndrome throughout the lifespan do not specifically address management of individuals with a cell-free DNA screen positive for monosomy X. This study aimed to provide context and expert-driven recommendations for maternal and/or fetal evaluation and management when cell-free DNA screening is positive for monosomy X. We highlight unique challenges of cell-free DNA screening that is incidentally positive for monosomy X, present recommendations for determining if the result is a true-positive, and discuss when diagnosis of Turner syndrome is applicable to the fetus vs the mother. Whereas we defer the subsequent management of confirmed Turner syndrome to the clinical practice guidelines, we highlight unique considerations for individuals initially identified through cell-free DNA screening.

Liver disease in children with Turner Syndrome (TS) is poorly understood relative to associated growth, cardiac and reproductive complications. This study sought to better characterize hepatic abnormalities in a large national cohort of youth with TS.Using electronic health record data from PEDSnet institutions, 2145 females with TS were matched to 8580 females without TS on eight demographic variables. Outcomes included liver enzymes (AST and ALT) stratified as normal, 1-2 times above the upper limit of normal (ULN), 2-3 times ULN and 3 times ULN, as well as specific liver disease diagnoses.Fifty-eight percent of youth with TS had elevated liver enzymes. Patients with TS had higher odds of enzymes 1-2 times ULN (OR: 1.7, 95% CI: 1.4-1.9), 2-3 times ULN (OR: 2.7, 95% CI: 1.7-3.3) and 3 times ULN (OR: 1.7, 95% CI: 1.3-2.2). They also had higher odds of any liver diagnosis (OR: 2.4, 95% CI: 1.7-3.3), fatty liver disease (OR: 1.9, 95% CI: 1.1-3.2), hepatitis (OR: 3.7, 95% CI: 1.9-7.1), cirrhosis/fibrosis (OR: 5.8, 95% CI: 1.3-25.0) and liver tumour/malignancy (OR: 4.8, 95% CI: 1.4-17.0). In a multinomial model, age, BMI and presence of cardiovascular disease or diabetes significantly increased the odds of elevated liver enzymes in girls with TS.Youth with TS have higher odds for elevated liver enzymes and clinically significant liver disease compared with matched controls. These results emphasize the need for clinical screening and additional research into the aetiology and treatment of liver disease in TS.Turner Syndrome, a chromosomal condition in which females are missing the second sex chromosome, is often associated with short stature, infertility and cardiac complications. Liver abnormalities are less well described in the literature. In this study, nearly 60% of youth with TS have elevated liver enzymes. Furthermore, patients with TS had a diagnosis of liver disease more often than patients without TS. Our results support the importance of early and consistent liver function screening and of additional research to define mechanisms that disrupt liver function in paediatric TS females.

Context Hypothalamic obesity is a rare, treatment-resistant form of obesity. In preliminary studies, the hypothalamic hormone oxytocin (OXT) has shown promise as a potential weight loss therapy. Objective To determine whether 8 weeks of intranasal OXT (vs 8 weeks of placebo) promotes weight loss in children, adolescents, and young adults with hypothalamic obesity. Methods This randomized, double-blind, placebo-controlled, crossover pilot trial (NCT02849743), conducted at an outpatient academic medical center, included patients aged 10 to 35 years with hypothalamic obesity from hypothalamic/pituitary tumors. Participants received intranasal OXT (Syntocinon, 40 USP units/mL, 4 IU/spray) vs excipient-matched placebo, 16 to 24 IU 3 times daily at mealtimes. Weight loss attributable to OXT vs placebo and safety (adverse events) were assessed. Results Of 13 individuals randomized (54% female, 31% pre-pubertal, median age 15.3 years, IQR 13.3-20.6), 10 completed the entire study. We observed a nonsignificant within-subject weight change of −0.6 kg (95% CI: −2.7, 1.5) attributable to OXT vs placebo. A subset (2/18 screened, 5/13 randomized) had prolonged QTc interval on electrocardiography prior to screening and/or in both treatment conditions. Overall, OXT was well-tolerated, and adverse events (epistaxis and nasal irritation, headache, nausea/vomiting, and changes in heart rate, blood pressure, and QTc interval) were similar between OXT and placebo. In exploratory analyses, benefits of OXT for anxiety and impulsivity were observed. Conclusion In this pilot study in hypothalamic obesity, we did not detect a significant impact of intranasal OXT on body weight. OXT was well-tolerated, so future larger studies could examine different dosing, combination therapies, and potential psychosocial benefits.

The potential for fertility in Turner syndrome has improved in recent years. Understanding of associated risks and approaches is important for the care of girls and women with this condition. This review focuses on reproductive health, fertility options and appropriate counselling for women with Turner syndrome and their families.Women with Turner syndrome have rapidly declining ovarian function beginning in utero . Therefore, counselling regarding fertility concerns should begin at a young age and involve discussion of options, including ovarian tissue cryopreservation, oocyte preservation and use of nonautologous oocytes. Clinical guidance on fertility management and pregnancy risk assessment based on karyotype, associated comorbidities and fertility is still not fully data driven. Realistic expectations regarding reproductive options and associated outcomes as well as the need for multidisciplinary follow-up during pregnancy are crucial to the ethical and safe care of these patients.Fertility care in women with Turner syndrome is evolving as current management techniques improve and new approaches are validated. Early counselling and active management of fertility preservation is critical to ensure positive and well tolerated reproductive outcomes.

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 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.

Many individuals with brain tumors affecting the hypothalamus and pituitary gain weight excessively after tumor treatment. There is currently no FDA-approved treatment for this condition, which is called hypothalamic obesity. In animals and in some preliminary studies in humans, the hypothalamic hormone oxytocin impacts metabolism, and may be deficient in individuals with hypothalamic obesity. Therefore, we performed a randomized, double-blind, placebo-controlled, cross-over trial to test the effects of 8 weeks of intranasal administration of oxytocin as compared to placebo on body weight in children, adolescents, and young adults (ages 10- Presentation: No date and time listed

The use of recombinant human growth hormone (rhGH) in children and adolescents has expanded since its initial approval to treat patients with severe GH deficiency (GHD) in 1985. rhGH is now approved to treat several conditions associated with poor growth and short stature. Recent studies have raised concerns that treatment during childhood may affect morbidity and mortality in adulthood, with specific controversies over cancer risk and cerebrovascular events. We will review 3 common referrals to a pediatric endocrinology clinic, followed by a summary of short- and long-term effects of rhGH beyond height outcomes. Methods to mitigate risk will be reviewed. Finally, this information will be applied to each clinical case, highlighting differences in counseling and clinical outcomes. rhGH therapy has been used for more than 3 decades. Data are largely reassuring, yet we still have much to learn about pharmaceutical approaches to growth in children and the lifelong effect of treatment.

Objective: Mutations in hepatocyte nuclear factor 1B (HNF1B), are often identified based on a history of renal disease and diabetes mellitus, but other endocrine manifestations including dyslipidemia and hyperparathyroidism have not been well-defined in the literature. Given HNF1B-MODY is rare, there have been few case series defining the disease spectrum. This study analyzes the clinical characteristics of HNF1B-related endocrine disorders in 9 pediatric patients identified at a single pediatric tertiary care center. Methods: Data was collected through the Atypical Diabetes Registry and Biorepository at the Children’s Hospital of Philadelphia. Results: Of the 9 pediatric patients with HNF1B mutations or deletions, 7/9 (78%) have diabetes mellitus, 8/9 (89%) have renal disease, 8/9 (89%) have dyslipidemia, and 5/9 (55%) have hyperparathyroidism. Over half (55%) initially presented with diabetes mellitus, while the remaining 45% were diagnosed either based on family history or a genetic workup secondary to renal disease. No patients presented with diabetic ketoacidosis and only two presented with ketosis. Of the 4/9 with previously identified HNF1B-mutations, two have subsequently developed diabetes mellitus. Lipid profiles demonstrated: 7/9 with total cholesterol >170 mg/dL, 8/9 with triglycerides >100 mg/dL, 3/9 with LDL > 110 mg/dL and 3/9 with HDL < 40 mg/dL. In regards to calcium homeostasis, 55% have an elevated PTH (>65 pg/mL) with high-normal calcium levels. Autism spectrum disorder was diagnosed in 3/9 patients (2 with 17q12 deletion and 1 with HNF1B mutation). Conclusion: This study represents one of the largest series of pediatric patients with HNF1B-MODY at a single center. The majority of patients have had progressively declining beta-cell function resulting in diabetes mellitus. Nearly all had elevated lipids with hypertriglyceridemia predominating. Over half of the patients had elevated PTH levels preceding the decline in renal function concerning for primary hyperparathyroidism. Disclosure M. E. Craven: None. V. Bamba: None. A. C. Calabria: None. S. E. Pinney: None.

Hypocalcemia has been reported in ~50% of patients 22q11.2DS and calcium regulation is known to play a role in neuronal development and synaptic plasticity. Because calcium ions play a role in neuronal function and development, we hypothesized that hypocalcemia would be associated with adverse effects on full scale IQ index (FSIQ) in patients with 22q11.2DS. A retrospective chart review cataloguing the presence or absence of hypocalcemia in 1073 subjects with a laboratory confirmed chromosome 22q11.2 deletion evaluated at the Children's Hospital of Philadelphia was conducted. 852/1073 patients had an endocrinology evaluation with laboratory confirmed calcium levels. 466/852 (54.7%) had a diagnosis of hypocalcemia. 265/1073 subjects ranging from 0 to 51 years of age had both calcium levels measured and a neuropsychological evaluation yielding a FSIQ. The mean FSIQ for 146/265 patients with hypocalcemia was 77.09 (SD = 13.56) and the mean FSIQ for 119/265 patients with normocalcemia was 77.27 (SD = 14.25). The distribution of patients with intellectual disability (ID) (FSIQ69), borderline IQ (FSIQ 70-79), and average IQ (FSIQ80) between the hypocalcemic and normocalcemic groups was not statistically significant (χ2 = 0.2676, p = 0.8748). Neonatal hypocalcemic seizures were not found to be associated with ID. We found no difference in FSIQ between the hypocalcemic and non-hypocalcemic patients with 22q11.2DS. As our findings differ from a previous report in adult subjects, we speculate that this may reflect a potential benefit from early treatment of hypocalcemia and may support early 22q11.2 deletion detection in order to offer prompt diagnosis and subsequent treatment of hypocalcemia.

Background: Previous case reports have suggested a possible association of congenital hyperinsulinism with Turner syndrome. Objective: We examined the clinical and molecular features in girls with both congenital hyperinsulinism and Turner syndrome seen at The Children’s Hospital of Philadelphia (CHOP) between 1974 and 2017. Methods: Records of girls with hyperinsulinism and Turner syndrome were reviewed. Insulin secretion was studied in pancreatic islets and in mouse islets treated with an inhibitor of KDM6A, an X chromosome gene associated with hyperinsulinism in Kabuki syndrome. Results: Hyperinsulinism was diagnosed in 12 girls with Turner syndrome. Six were diazoxide-unresponsive; 3 had pancreatectomies. The incidence of Turner syndrome among CHOP patients with hyperinsulinism (10 of 1,050 from 1997 to 2017) was 48 times more frequent than expected. The only consistent chromosomal anomaly in these girls was the presence of a 45,X cell line. Studies of isolated islets from 1 case showed abnormal elevated cytosolic calcium and heightened sensitivity to amino acid-stimulated insulin release; similar alterations were demonstrated in mouse islets treated with a KDM6A inhibitor. Conclusion: These results demonstrate a higher than expected frequency of Turner syndrome among children with hyperinsulinism. Our data suggest that haploinsufficiency for KDM6A due to mosaic X chromosome monosomy may be responsible for hyperinsulinism in Turner syndrome.

Background Over 95% of girls with Turner syndrome (TS) who lack all or part of the X chromosome will experience premature ovarian insufficiency and will require estrogen replacement therapy to initiate and maintain puberty. However, the optimal protocol that mimics physiologic puberty while preserving growth potential is not yet known. Current recommendations to start with low dose estrogen increased incrementally over two to three years will typically result in thelarche within six months and menarche after an average of two years. Here we present three patients with TS who experienced rapid progression of puberty, with menarche occurring shortly after initiating the lowest dose of transdermal estrogen. Our institutional review board deemed this retrospective case series exempt from the need for IRB approval. Case Three 12-year-old females with mosaic TS (Table 1) presented for pubertal induction. On exam, the patients had tanner stage I breasts and pubic hair. Labs were consistent with ovarian insufficiency with elevated levels of follicle stimulating hormone (FSH) and undetectable levels of estradiol. They were each started on estradiol 14 ucg transdermal patch weekly for pubertal induction and experienced menarche within five months. Breast and pubic hair progressed to tanner stage II and III. Cases 1 and 2 subsequently had regular monthly menses with moderate flow. The dose of their transdermal estradiol patch was decreased by half to 7 ucg weekly. Case 3 developed heavy, irregular bleeding, which caused her to stop using the transdermal estrogen patch. Four months later, she reinstated estrogen use with half of her prior dose at 7 ucg weekly. At one year follow up, all three cases continued with the ultra low dose estradiol 7 ucg transdermal patch weekly without further episodes of vaginal bleeding. On imaging bone age was within normal limits. Comments These cases highlight the importance of starting estrogen replacement therapy at the lowest available dose in girls with Turner syndrome. Given the possible advancement of bone age with pubertal levels of estrogen, rapid progression to menarche could further impair the final growth potential in these patients who are already susceptible to short stature. Thus girls with TS should be monitored closely when initiating estrogen therapy and should be re-evaluated if they experience vaginal bleeding with low dose therapy.

Objective: To describe the range of insulin-like growth factor-I (IGF-I) z-score values (IGF-Iz) and growth hormone (GH) dose adjustments in pre-pubertal patients with GH deficiency (GHD) treated with GH in a single tertiary care center. Methods: This is a retrospective review of GH-treated patients of ages ≤9 years with GHD, seen in an endocrinology clinic in 2013-2014. Patient demographics and pre-treatment anthropometrics, GH treatment duration, IGF-Iz, and GH dosage (mg/kg/week) were extracted. Multipredictor linear regression was used to evaluate the associations between IGF-Iz and GH dosage and subject gender, race, insurance type, age, and clinical characteristics. Logistic regression was used to calculate the odds ratio of direction of GH dose adjustment (decrease/no change versus increase) and IGF-Iz category based on patient clinical characteristics, accounting for provider random effect. Results: Forty-one percent (57/139) of IGF-Iz were outside the “normal” range of between -2 and +2 standard deviation; the majority of IGF-Iz beyond the “normal” range (93%) were supraphysiologic [>+2 standard deviation score (SDS)]. Of the IGF-Iz >+2, 10/53 (18%) were followed by a GH dose increase and 30/53 (57%) had no dose change. Patient clinical characteristics and demographics did not significantly increase the odds of being in the IGF-Iz >+2 SDS category or having a dose increase in multipredictor logistic regression models. Conclusion: GH dosages and IGF-Iz varied, without significant patient clinical predictors. IGF-Iz was frequently supraphysiologic, and these levels often did not prompt a reduction in GH dose, likely influenced by a variety of factors. Our study emphasizes the need for better understanding of long-term safety and efficacy of maintaining supraphysiologic levels of IGF-Iz.

Background Children with congenital adrenal hyperplasia (CAH) because of 21 hydroxylase deficiency (21OHD) are at risk for early or precocious puberty and a short adult height compared to population means and midparental height. The effect of histrelin in suppressing puberty and improving growth in these children has not been reported. Methods Retrospective cohort analysis of all patients (age ≤ 20) at our institution who underwent histrelin implantation between 2008 and 2017. Treated patients with CAH (classic and nonclassic forms of 21OHD) were identified and their growth data analyzed. Results Fifteen children with CAH were treated with histrelin for a median of 3 years (range 2–5; age at first implantation 7.7 ± 1.5 years). Bone age (BA) to chronologic age (CA) decreased from 1.57 ± 0.4 to 1.25 ± 0.25 (P < .01), while predicted adult height (PAH) increased by 7.1 ± 6.6 cm (P < .01). A subgroup of 10 children reached adult height. Similar changes in BA/CA and PAH were observed with therapy (P = .02). Adult height z improved compared to pretreatment PAH z (–1.42 ± 0.9 vs. –1.96 ± 1.1 respectively, P < .01), but remained lower than midparental height z (P = .01). Conclusion In this retrospective cohort study of children with CAH due to 21OHD and early or precocious puberty, histrelin implantation resulted in a decrease in BA progression compared to CA and an improvement in PAH. In the subgroup who completed growth, adult height remained significantly lower than midparental. These results need to be confirmed with prospective controlled studies.

To address knowledge gaps about Turner syndrome (TS) associated disease mechanisms, the Turner Syndrome Society of the United States created the Turner Syndrome Research Registry (TSRR), a patient-powered registry for girls and women with TS. More than 600 participants, parents or guardians completed a 33-item foundational survey that included questions about demographics, medical conditions, psychological conditions, sexuality, hormonal therapy, patient and provider knowledge about TS, and patient satisfaction. The TSRR platform is engineered to allow individuals living with rare conditions and investigators to work side-by-side. The purpose of this article is to introduce the concept, architecture, and currently available content of the TSRR, in anticipation of inviting proposals to utilize registry resources.

Previous case reports have suggested a possible association of congenital hyperinsulinism with Turner syndrome.We examined the clinical and molecular features in girls with both congenital hyperinsulinism and Turner syndrome seen at The Children's Hospital of Philadelphia (CHOP) between 1974 and 2017.Records of girls with hyperinsulinism and Turner syndrome were reviewed. Insulin secretion was studied in pancreatic islets and in mouse islets treated with an inhibitor of KDM6A, an X chromosome gene associated with hyperinsulinism in Kabuki syndrome.Hyperinsulinism was diagnosed in 12 girls with Turner syndrome. Six were diazoxide-unresponsive; 3 had pancreatectomies. The incidence of Turner syndrome among CHOP patients with hyperinsulinism (10 of 1,050 from 1997 to 2017) was 48 times more frequent than expected. The only consistent chromosomal anomaly in these girls was the presence of a 45,X cell line. Studies of isolated islets from 1 case showed abnormal elevated cytosolic calcium and heightened sensitivity to amino acid-stimulated insulin release; similar alterations were demonstrated in mouse islets treated with a KDM6A inhibitor.These results demonstrate a higher than expected frequency of Turner syndrome among children with hyperinsulinism. Our data suggest that haploinsufficiency for KDM6A due to mosaic X chromosome monosomy may be responsible for hyperinsulinism in Turner syndrome.

Turner syndrome (TS) is a genetic condition occurring in females resulting from the loss of part or all of one of the X chromosomes. The two hallmark features of Turner syndrome include short stature and primary ovarian insufficiency. In addition, Turner syndrome can involve multiple healthcare issues including cardiac and renal anomalies, autoimmune disorders, hearing loss, ophthalmologic issues, bone anomalies, dermatologic issues and psychosocial and educational concerns. The presenting signs of Turner syndrome can vary markedly, leading to delayed or even missed diagnosis. Early identification of TS allows for appropriate screening and surveillance evaluations and more timely treatment intervention. This article will provide an overview of the healthcare issues common to patients with TS, treatments available and the screening and surveillance testing that is recommended.

Background: Turner syndrome (TS) is associated with an increased risk of cardiovascular disease. Non-high-density lipoprotein cholesterol (non-HDL-C) is a convenient measure of atherogenicity (normal concentration Methods: A retrospective chart review was used to obtain demographics, body composition, genetic reports, and lipid profiles in females with TS. Results: Lipid profiles were assessed in 158 females (mean age 13.6 years). Mean non-HDL-C was 118.9 mg/dL (±32.0); the prevalence of high non-HDL-C (≥144 mg/dL) was 17.7% (n = 28). In TS females aged 8–17 years (n = 46), the prevalence of high non-HDL-C was 23.9% (95% CI 11.1–36.7; n = 11) between 2011 and 2012, compared to 9.2% (95% CI 5.6–14.1) in females of the same age in the general population reported in the National Health and Nutrition Examination Survey (NHANES) dataset (p < 0.005). Body mass index (BMI) accounted for only 6% of variance in non-HDL-C values (β coefficient = 1.31, p < 0.05). Conclusions: Children and adolescents aged 8–17 years with TS appear to have a greater prevalence of adverse non-HDL-C levels compared to the general adolescent population. The prevalence of high non-HDL-C was not fully explained by BMI.

PURPOSE OF REVIEW: Description of recent studies evaluating growth and inhaled corticosteroids. RECENT FINDINGS: Corticosteroids are the gold standard of asthma maintenance treatment, but effects on growth remain controversial. This is a review of recent research in this area, which has focused on medications causing less adrenal suppression as well as alternative regimens for chronic illness such as asthma. SUMMARY: The use of newer corticosteroids and regimens shows short-term evidence of minimal growth effects without worsening of asthma control.

Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk.

Cardiovascular disease is a leading cause of morbidity and mortality. Early identification and treatment of risk factors that accelerate this condition are paramount to preventing disease. To this effect, the National Heart Lung and Blood Institute (NHLBI), endorsed by the American Academy of Pediatrics, issued updated pediatric guidelines for cardiovascular risk reduction in 2011. Integration of these guidelines into pediatric practice may lessen cardiovascular morbidity.In addition to reviewing the NHLBI guidelines, a detailed literature search was performed on PubMed for clinical studies published between 2010 and 2013. Key search terms included "pediatric dyslipidemia/hyperlipidemia," "cardiovascular disease," "atherosclerosis," "familial hypercholesterolemia," "hypertriglyceridemia," and "diabetes." Additional citations from these publications were also reviewed. Final publications were selected for their relevance to the topic.These guidelines contain several important recommendations relative to lipid management, including screening all children with nonfasting non-high-density lipoprotein-cholesterol at ages 9-11 years, incorporation of aggressive lifestyle changes to meet cholesterol targets, and initiation of statin therapy for those with low-density lipoprotein-cholesterol elevation. In addition, both type 1 and type 2 diabetes are now considered high-risk conditions and have stringent cholesterol targets. The primary aim is early identification of children with familial hypercholesterolemia; however, these recommendations have met with some controversy. The purpose of this update is to summarize these recent lipid guidelines, present the relevant controversies, highlight common cholesterol disorders, and discuss dyslipidemia specific to the pediatric diabetes population.Identification and treatment of youth with dyslipidemia is of paramount importance to the reduction of future cardiovascular disease. Increasing the comprehension and application of the newest NHLBI guidelines is critical to improving cardiovascular outcomes.

Patients with Turner syndrome (TS) require close medical follow-up and management for cardiac abnormalities, growth and reproductive issues. This review summarizes current controversies in this condition, including: 1) the optimal genetic testing for Turner syndrome patients, particularly with respect to identification of Y chromosome material that may increase the patient's risk of gonadoblastoma and dysgerminoma, 2) which patients should be referred for bilateral gonadectomy and the recommended timing of such referral, 3) options for assisted reproduction in these patients and associated risks, 4) the increased risk of mortality associated with pregnancy in this population, and 5) how best to assess and monitor cardiovascular risks., Highlights • Patients with non-mosaic TS must be tested for cryptic Y chromosome material. • Y chromosome material increases gonadoblastoma risk, so gonadectomy is recommended. • Cardiac MRI is preferred to echocardiogram for detecting cardiac anomalies in TS. • TS increases risk of cardiovascular anomalies and death, particularly in pregnancy. • TS is a relative contraindication to reproduction; cardiac anomalies are absolute.

Sib-pair linkage analyses were used to search for linkage to a set of chromosome 19 and 21 marker loci in two sets of families with Alzheimer's disease. The advantage of this technique is that no assumption is made about the mode of inheritance of the disease. Some mild suggestions of linkage were found in early-onset families for a chromosome 21 marker and in a set of late-onset families for a chromosome 19 marker

Sib-pair linkage analysis was used to screen a large pedigree, ascertained through four members with hypercholesterolemia, for evidence of linkage between 12 quantitative traits and 15 genetic marker loci. Traits were analyzed on the untransformed, natural log and square root-transformed scales. After adjusting for multiple tests, there is a suggestion of linkage between height and the Kidd blood group on chromosome 18 and between VLDL cholesterol, and possibly triglyceride, and KM on chromosome 2

Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C.

Sub-analysis of interaction terms in multivariable models for delta cortisol. Description: Separate analysis of groups with significant interaction terms in multivariable models. This displays multivariable models of weight, BSA, and height for the group exposed to exogenous glucocorticoids only. (DOC 31 kb)

Sub-analysis of interaction terms in multivariable models for peak cortisol. Description: Separate analysis of groups with significant interaction terms in multivariable models. This displays multivariable models of weight, BSA, and height for the group exposed to exogenous glucocorticoids only. (DOC 32 kb)

Background Corticotropin-Releasing Hormone (CRH) testing is used to evaluate suspected adrenocorticotropic hormone (ACTH) deficiency, but the clinical characteristics that affect response in young children are incompletely understood. Our objective was to determine the effect of age and body size on cortisol response to CRH in children at risk for ACTH deficiency referred for clinical testing. Methods Retrospective, observational study of 297 children, ages 30 days – 18 years, undergoing initial, clinically indicated outpatient CRH stimulation testing at a tertiary referral center. All subjects received 1mcg/kg corticorelin per institutional protocol. Serial, timed ACTH and cortisol measurements were obtained. Patient demographic and clinical factors were abstracted from the medical record. Patients without full recorded anthropometric data, pubertal assessment, ACTH measurements, or clear indication for testing were excluded (number remaining = 222). Outcomes of interest were maximum cortisol after stimulation (peak) and cortisol rise from baseline (delta). Bivariable and multivariable linear regression analyses were used to assess the effects of age and size (weight, height, body mass index (BMI), body surface area (BSA), BMI z-score, and height z-score) on cortisol response while accounting for clinical covariates including sex, race/ethnicity, pubertal status, indication for testing, and time of testing. Results Subjects were 27 % female, with mean age of 8.9 years (SD 4.5); 75 % were pre-pubertal. Mean peak cortisol was 609.2 nmol/L (SD 213.0); mean delta cortisol was 404.2 nmol/L (SD 200.2). In separate multivariable models, weight, height, BSA and height z-score each remained independently negatively associated (p

Sub-analysis of interaction terms in multivariable models for delta cortisol. Description: Separate analysis of groups with significant interaction terms in multivariable models. This displays multivariable models of weight, BSA, and height for the group exposed to exogenous glucocorticoids only. (DOC 31 kb)

Sub-analysis of interaction terms in multivariable models for peak cortisol. Description: Separate analysis of groups with significant interaction terms in multivariable models. This displays multivariable models of weight, BSA, and height for the group exposed to exogenous glucocorticoids only. (DOC 32 kb)