Inspiring New Science to Guide Healthcare in Turner Syndrome: Rationale, design, and methods for the InsighTS Registry.

Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) Registry is a national, multicenter registry for individuals with Turner syndrome (TS) designed to collect and store validated longitudinal clinical data from a diverse cohort of patients with TS. Herein, we describe the rationale, design, and approach used to develop the InsighTS registry, as well as the demographics of the initial participants to illustrate the registry's diversity and future utility. Multiple stakeholder groups have been involved from project conceptualization through dissemination, ensuring the registry serves the priorities of the TS community. Key features of InsighTS include recruitment strategies to facilitate enrollment of participants that appropriately reflect the population of individuals with TS receiving care in the US, clarity of data ownership and sharing, and sustainability of this resource. The registry gathers clinical data on diagnosis, treatment, comorbidities, health care utilization, clinical practices, and quality of life with the goal of improving health outcomes for this population. Future directions include multiple patient-centered clinical-translational research projects that will use the InsighTS platform. This thorough and thoughtful planning will ensure InsighTS is a valuable and sustainable resource for the TS community for decades to come.

Diagnosis and Management of Aortic Dissection in a Pediatric Patient With Turner Syndrome: A Simulation.

Aortic dissection is exceedingly rare in the pediatric population. However, it is much more common among children and adolescents with certain underlying syndromes, including Turner syndrome. Furthermore, aortic dissection carries significant mortality without prompt diagnosis and management. Therefore, pediatric emergency providers should know how to recognize and treat pediatric aortic dissection in a patient with Turner syndrome. We designed this simulation for pediatric emergency medicine fellows. A simulated adolescent female patient with a known history of Turner syndrome presents with chest pain, tachycardia, and hypertension. Participants must order and interpret the appropriate diagnostics, diagnose aortic dissection, and manage aortic dissection adequately. This simulation was completed by six pediatric emergency medicine fellows and one pediatric resident. After completing the simulation, six participants (85.7%) provided anonymous feedback on a five-point Likert scale (one = strongly disagree, five = strongly agree). Feedback was positive, and participants agreed that the case content was relevant to their clinical practice and that the event will improve their clinical practice. This simulation encourages participants to recognize and manage pediatric aortic dissection in patients with Turner syndrome. Participants felt that the simulation was relevant and will improve their clinical practice.

Cardiovascular Manifestations of Turner Syndrome: Phenotypic Differences Between Karyotype Subtypes.

Turner syndrome (TS) is a genetic disorder presenting in phenotypic females with total or partial monosomy of the X chromosome. Cardiovascular abnormalities are common, including congenital heart defects (CHD) and aortic dilation. Although mosaic TS is suspected to have less severe phenotype as compared to non-mosaic TS, differences in cardiovascular manifestations between karyotypes are not well studied. This is a single-center retrospective cohort study including patients with TS seen from 2000 to 2022. Demographic data, chromosomal analysis, and imaging were reviewed. Karyotypes were categorized as monosomy X (45X), 45X mosaicism, isochromosome Xq, partial X deletions, ring X (r(X)), TS with Y material, and others. Prevalence of CHD and aortic dilation were compared between monosomy X and other subtypes using Pearson's chi-square test and Welch two-sample t-test. We included 182 TS patients with median age 18 (range 4-33) years. CHD was more common in monosomy X as compared with others (61.4% vs. 26.8%, p < 0.001), including bicuspid aortic valve (44.3% vs. 16.1%, p < 0.001), partial anomalous pulmonary venous return (12.9% vs. 2.7%, p = 0.023), persistent left superior vena cava (12.9% vs. 1.8%, p = 0.008), and coarctation of the aorta (20.0% vs. 4.5%, p = 0.003). Cardiac surgery (24.3% vs. 8.9%, p = 0.017) was more prevalent in the monosomy X group. There was no statistically significant difference for presence of aortic dilation (7.1% vs 1.8%, p = 0.187). Although CHD and need for cardiac surgery are more common in TS with monosomy X as compared to others, all TS subtypes may have similar risk of developing aortic dilation. All TS patients should have similar cardiovascular surveillance testing to monitor for aortic dilation.

Scoliosis and Kyphosis Prevalence in Turner Syndrome: A Retrospective Review at a Pediatric Tertiary Care Medical Center.

BACKGROUND: The prevalence of major coronal and sagittal spinal curves (scoliosis and kyphosis) in Turner syndrome (TS) is not well established due to limited reporting. The relationship between growth hormone (GH) therapy and its effect on TS spinal curve incidence is also not well established. METHODS: A retrospective chart review of 306 TS patients from 2007 to 2021 evaluated major coronal and sagittal spinal curves, progression of the curve, and treatment with GH. Statistical significance (defined as P <0.05) between curvature rates and curve progression was compared between GH-treated patients and non-GH-treated patients using a χ 2 or Fisher exact test when appropriate. RESULTS: Thirty-seven of 306 (12%) TS patients had a radiographically relevant spinal deformity. Twenty-seven of 37 (73%) had mild; 4 of 37 (11%) had moderate, and 6 of 37 (16%) had severe curves. Of those with severe, 4 underwent spinal fusion, 1 was treated with bracing, and 1 was braced before a cardiovascular-related death. Regarding GH use among TS patients, 190 of 306 (62%) used GH versus 116 of 306 (38%) who did not. Of those with a spinal curve, 24 of 37 (65%) used GH compared with 13 of 37 (35%) who did not. On univariate analysis, GH therapy was not a risk factor for the diagnosis of a major spinal curve, a more severe degree of the curve at the time of diagnosis, or spinal curve progression ( P >0.05 for all). CONCLUSIONS: This is the largest single institution retrospective review of a TS cohort known to the authors assessing spinal curve prevalence and relation to GH treatment and demonstrates a TS spinal curve rate of 12% (37/306). Four of six (11%) TS patients with a severe curve underwent corrective spine fusion. There was no relationship between the use of GH and the presence of a spinal curve or curve progression. Further study is warranted to determine risk factors for curve progression. LEVEL OF EVIDENCE: Level III. CLINICAL RELEVANCE: This retrospective case series serves to review and address the prevalence of spinal deformity in TS patients and whether GH impacts worsening deformity.

Ocular findings in pediatric turner syndrome.

OBJECTIVE: Turner syndrome (TS) is associated with abnormalities across several organ systems, including the visual system. There is a relative paucity of literature describing ophthalmic manifestations of TS. We sought to investigate eye manifestations in our cross-sectional population of pediatric TS patients. METHODS: All patients managed by the TS program of a tertiary children's hospital were identified. Patients with documentation of at least one eye exam were included for analysis. Chart review was retrospectively performed to identify all documented ocular abnormalities as well as patient demographics, including TS karyotype. Statistical analysis was performed to identify any association between karyotype and ocular abnormality. RESULTS: A total of 187 patients with TS were identified. The mean age of the cohort was 14.3 ± 7.2 years. Ametropia was the most common ocular abnormality, occurring in 79 patients (42%), followed by strabismus in 25 (13%). Of the patients with strabismus, 17 had exotropia and 8 had esotropia, with only 2 patients requiring surgical intervention. Posterior segment abnormalities were identified in five patients without accompanying visual deficits. Two patients had ocular tumors: one with retinoblastoma and one with retinal astrocytic hamartoma. There was no association between TS karyotype and occurrence of ocular abnormalities. CONCLUSION: Ophthalmic manifestations of TS were common, particularly ametropia and strabismus. Management of strabismus was conservative in the vast majority of patients. Ocular manifestations were not associated with TS karyotype. Early screening and routine ophthalmic evaluation of patients with TS is needed to prevent progression of potentially vision-threatening abnormalities.

Identification of clinical factors related to antibody-mediated immune response to the subfornical organ.

OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.

Is Gadolinium Contrast Necessary for Pituitary MRI in the Evaluation of Pediatric Short Stature and Growth Hormone Deficiency?

INTRODUCTION: Short stature is a common concern that necessitates pediatric endocrinology evaluation. Growth hormone deficiency (GHD) is a commonly considered etiology. Brain and pituitary magnetic resonance imaging (MRI) with gadolinium-based contrast agents (GBCAs) is the most widely used imaging in assessing patients with GHD. Given the significant strides made in MRI technology, the need for contrast material should be reassessed. METHOD: We performed a retrospective review of healthy patients with short stature and/or GHD who underwent brain and pituitary MRI with and without contrast to assess the added value of contrast administration. RESULTS: 227/318 identified patients underwent growth hormone (GH) stimulation testing; 28 (12.3%) with normal GH response and 62 (27.3%) with severe GHD. We found a low incidence of sellar and suprasellar pathologies. When comparing noncontrast and contrast MRI, we found perfect agreement in detecting abnormal posterior pituitary bright spots (kappa:1.0) and substantial agreement in detecting pars intermedia cysts and posterior superior sellar cysts (kappa: 0.74 and 0.71, respectively). Initially, only moderate agreement was found in detecting infundibular abnormalities (kappa: 0.51), although a revised noncontrast MRI protocol with high-resolution 3D images enabled visualization of the infundibulum. CONCLUSION: The MRI evaluation of healthy patients with short stature and/or isolated GHD may be completed without the use of GBCAs. The slight overestimation of pituitary stalk interruption by noncontrast images can be overcome by adding newer high-resolution sequences.

Turner Syndrome with Y Chromosome: Spontaneous Thelarche, Menarche, and Risk of Malignancy.

STUDY OBJECTIVE: Girls with Turner syndrome with Y-chromosome material (TS + Y) are assumed to have nonfunctional gonads with increased tumor risk, therefore prophylactic gonadectomy is recommended at diagnosis. In this study we aimed to determine rates of spontaneous thelarche (ST) and spontaneous menarche (SM), and prevalence of gonadal tumor and malignancy in girls with TS + Y, to further inform discussions about gonadectomy. DESIGN: Retrospective review of clinical and pathology data. SETTING: Multicenter study involving 4 United States children's hospitals. PARTICIPANTS: Patients included those with a genetically proven diagnosis of TS + Y and phenotypically female genitourinary exam. INTERVENTIONS: Demographic characteristics, pubertal development, and gonadal pathology data were abstracted from clinical records. Data for ST were analyzed for patients aged 13 years and older and SM for patients older than 15 years. MAIN OUTCOME MEASURES: ST, SM, prevalence of gonadal tumor, and malignancy. RESULTS: Forty-four patients met inclusion criteria. Nineteen patients were 13 years or older; 8/19 (42%) had ST and reached Tanner stages 2-4 and 2 (11%) had normal ovarian pathology. Nineteen patients were 15 years or older; 2/19 (11%) had SM. Thirty-seven patients underwent gonadectomy; 35 had available pathology results. Gonadoblastoma was identified in 35/7 patients (19%), 1 in situ germ cell neoplasia, and 1 dysgerminoma (3%). One patient with bilateral gonadoblastoma had ST and SM. CONCLUSION: In this multicenter cohort, 42% of girls with TS + Y entered puberty spontaneously and 11% had SM, supportive of gonadal function. Risk of tumor was similar to previous reports. To achieve informed decision-making, discussions about gonadectomy should incorporate potential for gonadal function and tumor risk.

Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.

AIMS/HYPOTHESIS: Maternal type 2 diabetes during pregnancy and gestational diabetes are associated with childhood adiposity; however, associations of lower maternal glucose levels during pregnancy with childhood adiposity, independent of maternal BMI, remain less clear. The objective was to examine associations of maternal glucose levels during pregnancy with childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. METHODS: The HAPO Study was an observational epidemiological international multi-ethnic investigation that established strong associations of glucose levels during pregnancy with multiple adverse perinatal outcomes. The HAPO Follow-up Study (HAPO FUS) included 4832 children from ten HAPO centres whose mothers had a 75 g OGTT at ~28 weeks gestation 10-14 years earlier, with glucose values blinded to participants and clinical caregivers. The primary outcome was child adiposity, including: (1) being overweight/obese according to sex- and age-specific cut-offs based on the International Obesity Task Force (IOTF) criteria; (2) IOTF-defined obesity only; and (3) measurements >85th percentile for sum of skinfolds, waist circumference and per cent body fat. Primary predictors were maternal OGTT and HbA1c values during pregnancy. RESULTS: Fully adjusted models that included maternal BMI at pregnancy OGTT indicated positive associations between maternal glucose predictors and child adiposity outcomes. For one SD difference in pregnancy glucose and HbA1c measures, ORs for each child adiposity outcome were in the range of 1.05-1.16 for maternal fasting glucose, 1.11-1.19 for 1 h glucose, 1.09-1.21 for 2 h glucose and 1.12-1.21 for HbA1c. Associations were significant, except for associations of maternal fasting glucose with offspring being overweight/obese or having waist circumference >85th percentile. Linearity was confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally consistent associations for boys and girls. CONCLUSIONS/INTERPRETATION: Exposure to higher levels of glucose in utero is independently associated with childhood adiposity, including being overweight/obese, obesity, skinfold thickness, per cent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes are associated with greater childhood adiposity; this may have implications for long-term metabolic health.

Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): Maternal Gestational Diabetes Mellitus and Childhood Glucose Metabolism.

OBJECTIVE: Whether hyperglycemia in utero less than overt diabetes is associated with altered childhood glucose metabolism is unknown. We examined associations of gestational diabetes mellitus (GDM) not confounded by treatment with childhood glycemia in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. RESEARCH DESIGN AND METHODS: HAPO Follow-up Study (FUS) included 4,160 children ages 10-14 years who completed all or part of an oral glucose tolerance test (OGTT) and whose mothers had a 75-g OGTT at ∼28 weeks of gestation with blinded glucose values. The primary predictor was GDM by World Health Organization criteria. Child outcomes were impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes. Additional measures included insulin sensitivity and secretion and oral disposition index. RESULTS: For mothers with GDM, 10.6% of children had IGT compared with 5.0% of children of mothers without GDM; IFG frequencies were 9.2% and 7.4%, respectively. Type 2 diabetes cases were too few for analysis. Odds ratios (95% CI) adjusted for family history of diabetes, maternal BMI, and child BMI z score were 1.09 (0.78-1.52) for IFG and 1.96 (1.41-2.73) for IGT. GDM was positively associated with child's 30-min, 1-h, and 2-h but not fasting glucose and inversely associated with insulin sensitivity and oral disposition index (adjusted mean difference -76.3 [95% CI -130.3 to -22.4] and -0.12 [-0.17 to -0.064]), respectively, but not insulinogenic index. CONCLUSIONS: Offspring exposed to untreated GDM in utero are insulin resistant with limited ß-cell compensation compared with offspring of mothers without GDM. GDM is significantly and independently associated with childhood IGT.

Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): Maternal Glycemia and Childhood Glucose Metabolism.

OBJECTIVE: This study examined associations of maternal glycemia during pregnancy with childhood glucose outcomes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. RESEARCH DESIGN AND METHODS: HAPO was an observational international investigation that established associations of maternal glucose with adverse perinatal outcomes. The HAPO Follow-up Study included 4,832 children ages 10-14 years whose mothers had a 75-g oral glucose tolerance test (OGTT) at ∼28 weeks of gestation. Of these, 4,160 children were evaluated for glucose outcomes. Primary outcomes were child impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Additional outcomes were glucose-related measures using plasma glucose (PG), A1C, and C-peptide from the child OGTT. RESULTS: Maternal fasting plasma glucose (FPG) was positively associated with child FPG and A1C; maternal 1-h and 2-h PG were positively associated with child fasting, 30 min, 1-h, and 2-h PG, and A1C. Maternal FPG, 1-h, and 2-h PG were inversely associated with insulin sensitivity, whereas 1-h and 2-h PG were inversely associated with disposition index. Maternal FPG, but not 1-h or 2-h PG, was associated with child IFG, and maternal 1-h and 2-h PG, but not FPG, were associated with child IGT. All associations were independent of maternal and child BMI. Across increasing categories of maternal glucose, frequencies of child IFG and IGT, and timed PG measures and A1C were higher, whereas insulin sensitivity and disposition index decreased. CONCLUSIONS: Across the maternal glucose spectrum, exposure to higher levels in utero is significantly associated with childhood glucose and insulin resistance independent of maternal and childhood BMI and family history of diabetes.

Turner Syndrome Systematic Review: Spontaneous Thelarche and Menarche Stratified by Karyotype.

BACKGROUND: Girls with Turner syndrome (TS) have a high incidence of primary ovarian insufficiency. Recent data show rates of spontaneous thelarche (ST) of 38% and spontaneous menarche (SM) of 15-16%, with higher rates in those with mosaicism. SUMMARY: We systematically reviewed the literature for evidence regarding rates of ST and SM in TS and evaluated rates based on the type of chromosomal mosaicism. We searched MEDLINE via PubMed, Embase, and the Cochrane Database of Controlled Trials. Reference lists were screened. Studies reporting outcomes of ST and SM in girls with TS, diagnosed by genetic analysis, were included. Data was collected regarding study design, cohort type, cohort age, the number of participants with ST and SM, the individual age at diagnosis of ST and SM, the mean age of patients with ST and SM, sample size, the number of participants with secondary amenorrhea, and karyotype. Key Messages: In total 2,699 patients were assessed for ST and 2,890 for SM from 43 articles. Overall the rates of ST were 32% (95% CI 26.4-38.9) and SM 20.8% (95% CI 19.3-22.4). Girls with X monosomy had the lowest rates of ST (i.e., 13%; 95% CI 8.7-19.7) and SM (i.e., 9.1%; 95% CI 7.3-11.3). Girls with 45,X/47,XXX had the highest rates of ST (i.e., 88.1%; 95% CI 62-97.1) and SM (i.e., 66.2%; 95% CI 49.3-79.6). CONCLUSIONS: Rates of ST and SM differ by karyotype in TS. When counseling patients, the karyotype should strongly influence discussions regarding pubertal development and the future reproductive potential.

Association of Gestational Diabetes With Maternal Disorders of Glucose Metabolism and Childhood Adiposity.

Importance: The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear. Objective: To examine associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years' postpartum. Design, Setting, and Participants: The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016). Exposures: Gestational diabetes was defined post hoc using criteria from the International Association of Diabetes and Pregnancy Study Groups consisting of 1 or more of the following 75-g oral glucose tolerance test results (fasting plasma glucose ≥92 mg/dL; 1-hour plasma glucose level ≥180 mg/dL; 2-hour plasma glucose level ≥153 mg/dL). Main Outcomes and Measures: Primary maternal outcome: a disorder of glucose metabolism (composite of type 2 diabetes or prediabetes). Primary outcome for children: being overweight or obese; secondary outcomes: obesity, body fat percentage, waist circumference, and sum of skinfolds (>85th percentile for latter 3 outcomes). Results: The analytic cohort included 4697 mothers (mean [SD] age, 41.7 [5.7] years) and 4832 children (mean [SD] age, 11.4 [1.2] years; 51.0% male). The median duration of follow-up was 11.4 years. The criteria for GD were met by 14.3% (672/4697) of mothers overall and by 14.1% (683/4832) of mothers of participating children. Among mothers with GD, 52.2% (346/663) developed a disorder of glucose metabolism vs 20.1% (791/3946) of mothers without GD (odds ratio [OR], 3.44 [95% CI, 2.85 to 4.14]; risk difference [RD], 25.7% [95% CI, 21.7% to 29.7%]). Among children of mothers with GD, 39.5% (269/681) were overweight or obese and 19.1% (130/681) were obese vs 28.6% (1172/4094) and 9.9% (405/4094), respectively, for children of mothers without GD. Adjusted for maternal body mass index during pregnancy, the OR was 1.21 (95% CI, 1.00 to 1.46) for children who were overweight or obese and the RD was 3.7% (95% CI, -0.16% to 7.5%); the OR was 1.58 (95% CI, 1.24 to 2.01) for children who were obese and the RD was 5.0% (95% CI, 2.0% to 8.0%); the OR was 1.35 (95% CI, 1.08 to 1.68) for body fat percentage and the RD was 4.2% (95% CI, 0.9% to 7.4%); the OR was 1.34 (95% CI, 1.08 to 1.67) for waist circumference and the RD was 4.1% (95% CI, 0.8% to 7.3%); and the OR was 1.57 (95% CI, 1.27 to 1.95) for sum of skinfolds and the RD was 6.5% (95% CI, 3.1% to 9.9%). Conclusions and Relevance: Among women with GD identified by contemporary criteria compared with those without it, GD was significantly associated with a higher maternal risk for a disorder of glucose metabolism during long-term follow-up after pregnancy. Among children of mothers with GD vs those without it, the difference in childhood overweight or obesity defined by body mass index cutoffs was not statistically significant; however, additional measures of childhood adiposity may be relevant in interpreting the study findings.

Refractory hypoglycemia in a pediatric patient with desmoplastic small round cell tumor.

Background Tumor-induced hypoglycemia is a rare and serious complication that is usually a consequence of either excessive insulin secretion (insulinoma) or because of non-islet cell tumor hypoglycemia (NICTH). NICTH is a rare phenomenon seen most often in adult patients. It is associated with different tumor types. Here, we report the first case to the best of our knowledge in the literature of a pediatric patient with NICTH associated with desmoplastic small round cell tumor (DSRT). Case presentation This is a 15-year-old girl who presented with symptomatic hypoglycemia and abdominal mass. She required an intravenous glucose infusion rate as high as 9 mg/kg/min in addition to glucose containing oral supplements in order to maintain her blood glucose above 60 mg/dL. Computed tomography (CT) scan of the chest, abdomen and pelvis showed multiple hepatic lesions with an intraperitoneal soft tissue mass which subsequently was diagnosed as DSRT. When the blood glucose was 45 mg/dL, the insulin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels were suppressed with an appropriate elevation of cortisol. Subsequently, an insulin-like growth factor-2 (IGF-2) level was sent and the IGF-2:IGF-1 ratio was found to be elevated >10 consistent with NICTH. After the first dose of chemotherapy, hypoglycemia improved, and she was weaned off glucose containing fluids. Conclusions NICTH should be considered in all cancer patients regardless of their age with refractory hypoglycemia.

New-onset diabetes mellitus after heart transplantation in children - Incidence and risk factors.

Diabetes mellitus is a recognized complication of SOT in adults and is associated with decreased graft and patient survival. Little is known about NOD in pediatric HT recipients. We aimed to characterize the incidence and describe risk factors for development of NOD after HT in children. Children who developed diabetes after HT were identified from the OPTN database. Demographic and clinical data before and after transplant were compared between patients with and without NOD. A total of 2056 children were included, 56% were male, 54% were Caucasian, and 62% had cardiomyopathy prior to HT. NOD developed in 219 children (11%) after HT. The incidence of NOD was 2.4, 9.0, and 10.4% at one, five, and 10 yr after HT, respectively. Obesity (HR: 4.32), dialysis prior to transplant (HR: 2.38), African American race (HR: 1.86), transplant before year 2000 (HR: 1.82), female gender (HR: 1.68), and older age at transplant (HR: 1.28) were independent predictors of NOD. The major modifiable risk factor for NOD is obesity, imparting the maximum hazard. Improved surveillance for diabetes in high-risk patients and specific prevention and intervention strategies are imperative in this population.

Squamosal Suture Craniosynostosis Due to Hyperthyroidism Caused by an Activating Thyrotropin Receptor Mutation (T632I).

BACKGROUND: Congenital hyperthyroidism can be a cause of failure to thrive, hyperactivity, developmental delay, and craniosynostosis during infancy. Most commonly, the condition occurs in the setting of maternal autoimmune thyroid disease. Rarely, congenital hyperthyroidism can also occur secondary to activating mutations within the thyrotropin (TSH) receptor. PATIENT FINDINGS: A Hispanic male infant presented at age 6 months with severe thyrotoxicosis. At the time of presentation he was being evaluated for squamosal suture synostosis and he was noted to have significant developmental delays. SUMMARY: The patient's thyrotoxicosis was initially treated with antithyroid medication, and he subsequently underwent craniosynostosis repair leading to neurodevelopmental improvement. DNA from the patient and his parents was submitted for mutational analysis of exons 9 and 10 of the TSH receptor. He was found to carry a monoallelic transition 1895C>T in exon 10 that resulted in the substitution of threonine at position 632 by isoleucine (T32I). This mutation resulted in constitutive activation of the TSH receptor. Neither parent carried this mutation indicating that the child has acquired a de novo germline mutation. CONCLUSIONS: We report the first case of squamosal suture craniosynostosis in a patient with non-autoimmune hyperthyroidism. Squamosal suture craniosynotosis is rare, often has a subtle presentation, and should be considered in all patients with this condition because prompt treatment of hyperthyroidism and craniosynotosis repair can lead to normalization of neurodevelopment.

Persistent apparent pancreatic ß-cell defects in premenarchal PCOS relatives.

CONTEXT: Polycystic ovary syndrome confers an increased risk for type 2 diabetes in affected women as early as adolescence. First-degree relatives (FDRs) of affected women are at increased risk for associated reproductive and metabolic phenotypes. OBJECTIVE: We sought to prospectively assess insulin sensitivity and secretion and to measure reproductive hormone levels using sensitive techniques. DESIGN, SETTING, AND PARTICIPANTS: Twelve premenarchal FDR girls and 10 control girls of comparable age, Tanner stage, and body mass index were studied at an academic medical center. INTERVENTIONS: Frequently sampled intravenous glucose tolerance tests and oral glucose tolerance tests were performed. MAIN OUTCOME MEASURES: Reproductive hormone levels, lipid profiles, glucose tolerance, and frequently sampled iv glucose tolerance test parameters of insulin sensitivity and secretion were investigated. RESULTS: Disposition index (DI), insulin secretion corrected for insulin sensitivity, was decreased in FDR compared with control girls at baseline (P = .01), independent of dysglycemia. Decreases in DI persisted in FDR girls during the 2-year follow-up (P = .003). T levels were increased (P = .02) in FDR compared with control girls at baseline, but this difference did not persist because T levels increased in control girls. CONCLUSIONS: DI is decreased in peripubertal FDR girls, and this decrease persists as puberty progresses. These findings suggest that ß-cell dysfunction is an early defect in glucose homeostasis preceding decompensation in glucose tolerance in FDR girls. T levels were increased in FDR girls earlier than previously reported, but these changes did not persist, suggesting an earlier onset of pubertal increases in glandular androgen secretion in FDR girls.

Do static and dynamic insulin resistance indices perform similarly in predicting pre-diabetes and type 2 diabetes?

AIMS: We designed a study to compare the predictive power of static and dynamic insulin resistance indices for categorized pre-diabetes (PDM)/type 2 diabetes (DM). METHODS: Participants included 1134 adults aged 18-60 years old with normal glucose at baseline who completed both baseline and 6-years later follow-up surveys. Insulin resistance indices from baseline data were used to predict risk of PDM or DM at follow-up. Two static indices and two dynamic indices were calculated from oral glucose tolerance test results (OGTT) at baseline. Area under the receiver operating characteristic curve (AROC) analysis was used to estimate the predictive ability of candidate indices to predict PDM/DM. A general estimation equation (GEE) model was applied to assess the magnitude of association of each index at baseline with the risk of PDM/DM at follow-up. RESULTS: The dynamic indices displayed the largest and statistically predictive AROC for PDM/DM diagnosed either by fasting glucose or by postprandial glucose. The bottom quartiles of the dynamic indices were associated with an elevated risk of PDM/DM vs. the top three quartiles. However, the static indices only performed significantly to PDM/DM diagnosed by fasting glucose. CONCLUSIONS: Dynamic insulin resistance indices are stronger predictors of future PDM/DM than static indices. This may be because dynamic indices better reflect the full range of physiologic disturbances in PDM/DM.

Association of adiposity trajectories with insulin sensitivity and glycemic deterioration: a longitudinal study of rural Chinese twin adults.

OBJECTIVE: To evaluate associations between adiposity trajectories over time and insulin sensitivity and glucose deterioration in a Chinese twin cohort. RESEARCH DESIGN AND METHODS: This study focused on 341 males and 292 females aged 20-50 years at baseline who had physical clinical examinations and oral glucose tolerance test at two time points with an average of 6 years apart. BMI, waist circumference, percent body fat (PBF), and percent trunk fat (PTF) trajectories were classified into five track groups based on age- and sex-specific tertiles at each visit. We calculated the odds of the insulin sensitivity index((0,120)) [ISI((0,120))] or glycemic deterioration at follow-up among five defined trajectories (tertile(baseline) → tertile(follow-up)) using generalized estimate equation models. Additionally, we applied structural equation models to examine genetic and environmental influences on adiposity, adiposity change over time (ACO), ISI((0,120)), and the interrelationships among them. RESULTS: Participants with stable adiposity (BMI, waist circumference, PBF, and PTF) in the highest tertile or shifting to the highest tertile tended to have the lowest ISI((0,120)) at follow-up or experience glycemic deterioration. Genetic factors exerted the major influence on adiposity, but environmental factors unique to each twin contributed more strongly to ISI and ACO. Correlations between adiposity/ACO and insulin sensitivity were mainly due to environmental influences. CONCLUSIONS: When adiposity stays or becomes high, insulin sensitivity falls and risk of glycemic deterioration rises. Additionally, we found that genetic factors exerted the major influence on adiposity, while environmental factors played the principal role for ACO and insulin sensitivity.

Tracking blood glucose and predicting prediabetes in Chinese children and adolescents: a prospective twin study.

We examined the tracking of blood glucose, the development of prediabetes, and estimated their genetic contributions in a prospective, healthy, rural Chinese twin cohort. This report includes 1,766 subjects (998 males, 768 females) aged 6-21 years at baseline who completed a 6-year follow-up study. Oral glucose tolerance test was performed for all subjects at both baseline and follow-up. We found that subjects with low fasting plasma glucose (FPG) or 2 h post-load glucose (PG) levels at baseline tended to remain at the low level at follow-up. Subjects in the top tertile of baseline plasma glucose tended to have a higher risk of developing prediabetes at follow-up compared to the low tertile: in males, 37.6% vs. 27.6% for FPG and 37.2% vs. 25.7% for 2hPG, respectively; in females, 31.0% vs. 15.4% for FPG and 28.9% vs. 15.1% for 2 h PG, respectively. Genetic factors explained 43% and 41% of the variance of FPG, and 72% and 47% for impaired fasting glucose for males and females, respectively; environmental factors substantially contribute to 2hPG status and impaired glucose tolerance. In conclusion, in this cohort of healthy rural Chinese children and adolescents, we demonstrated that both FPG and 2hPG tracked well and was a strong predictor of prediabetes. The high proportion of children with top tertile of blood glucose progressed to prediabetes, and the incidence of prediabetes has a male predominance. Genetic factors play more important role in fasting than postload status, most of which was explained by unique environmental factors.