Obesity in children with congenital adrenal hyperplasia in the Minnesota cohort: importance of adjusting body mass index for height-age.

OBJECTIVES: To evaluate obesity and overweight in children with congenital adrenal hyperplasia (CAH) and associations with glucocorticoids, fludrocortisone and disease control. Adjusting body mass index-for-height-age (BMIHA ) percentile is proposed to correct misclassification of obese/overweight status in CAH children with advanced bone age and tall-for-age stature. DESIGN: Longitudinal. PATIENTS: One hundred and ninety-four children with CAH seen from 1970 to 2013: 124 salt wasting (SW); 70 simple virilizing (SV); 102 females. MEASUREMENTS: Body mass index (BMI) end-points were overweight (85-94 percentile) and obese (≥95 percentile). RESULTS: Approximately 50% of the children had at least one BMI measurement ≥95 percentile and about 70% had at least one ≥85 percentile. Using BMIHA percentiles, obesity incidence decreased slightly in SW children (47-43%) and markedly in SV children (50-33%); however, overweight status was not reduced. Only 6% of SW and 1% of SV children were persistently obese (≥3 clinic visits) when BMIHA was applied, whereas overweight status persisted in 35% of SW and 33% of SV children. Most obesity or overweight when using BMIHA occurred before age 10 and there was no association with hydrocortisone (HC) or fludrocortisone dosing. Adiposity rebound for SW children occurred by 3·3 years and in SV females by age 3·8 years, over a year earlier than the adiposity rebound for healthy children. CONCLUSION: Children with CAH are at higher risk for early onset obesity and overweight with or without using BMIHA but rates of persistent obesity were lower than previously reported. Careful HC dosing during early childhood is needed to prevent increased weight gain and an early adiposity rebound.

Predominance of DR3 in Somali children with type 1 diabetes in the twin cities, Minnesota.

BACKGROUND: Minnesota is home to the largest Somali population in USA, and pediatric diabetes teams are seeing increasing numbers of Somali children with diabetes. OBJECTIVE: To assess the immune basis of diabetes in Somali children in the Twin Cities, Minnesota. METHODS: A total of 31 Somali children ≤19 yr were treated for type 1 diabetes (T1D) at the University of Minnesota Masonic Children's Hospital and Children's Hospitals and Clinics of Minnesota underwent analysis of human leukocyte antigen (HLA) alleles (n = 30) and diabetes autoantibodies [glutamic acid decarboxylase (GAD65), islet antigen 2 (IA-2), zinc transporter 8 (ZnT8); n = 31]. HLA alleles were analyzed in 49 Somalis without diabetes (controls). Anti-transglutaminase autoantibodies (TGA) for celiac disease were also measured. RESULTS: In Somali children with T1D aged 13.5 ± 5 yr (35% female, disease duration 6.5 ± 3.6 yr), the most common HLA allele was DRB1*03:01 (93%, compared with 45% of Somali controls), followed by DRB1*13:02 (27%). There was a relatively low frequency of DR4 (13%). Controls showed a similar pattern. All 31 participants were positive for at least one diabetes autoantibody. Insulin antibodies were positive in 84% (all were on insulin). Excluding insulin antibodies, 23 (74%) subjects tested positive for at least one other diabetes autoantibody; 32% had 1 autoantibody, 32% had 2 autoantibodies, and 10% had 3 autoantibodies. GAD65 autoantibodies were found in 56% of subjects, IA-2 in 29%, and ZnT8 in 26%. Four (13%) were TGA positive. CONCLUSION: The autoantibody and HLA profiles of Somali children with diabetes are consistent with autoimmune diabetes. Their HLA profile is unique with an exceptionally high prevalence of DRB1*03:01 allele and relative paucity of DR4 alleles compared with African Americans with T1D.

Hypertension in children with congenital adrenal hyperplasia.

OBJECTIVES: Estimates of high blood pressure (BP) incidence in children with congenital adrenal hyperplasia (CAH) vary widely; risk factors are poorly understood. We estimated incidence of hypertension by CAH subtype and sex, and assessed its association with body mass index, hydrocortisone and fludrocortisone. DESIGN: Longitudinal. PATIENTS: Chart review of 180 paediatric CAH patients (120 salt wasting; 60 simple virilizing; 93 females) seen from 1970 to 2013. MEASUREMENTS: High BP was diagnosed by diastolic or systolic blood pressure measurement ≥95th percentile for age, sex and height; hypertension was diagnosed with high BP on at least three clinic visits. RESULTS: Children with classic CAH who received fludrocortisone had a significantly higher rate of hypertension (55% vs 31%) than those who did not. Hypertension incidence was higher in salt-wasting CAH (58%) than in simple-virilizing CAH (35%). Hypertension first occurred before age 5 years in 91% of salt-wasting males and 50% of cases in salt-wasting females; most simple-virilizing cases occurred during ages 10-18 years. Rates of hypertension were higher in children who had three or more measurements with 17-OHP < 400 ng/dl (12·12 nmol/l), and this difference was significant in salt-wasting males. Children on fludrocortisone who had three or more readings of 17-OHP < 400 ng/dl (12·12 nmol/l) had a significantly higher rate of hypertension than those who did not. Hydrocortisone dose was not associated with hypertension. CONCLUSION: Children with CAH are at higher risk for hypertension than the general paediatric population, and incidence differs by sex and CAH subtype. Hypertension was higher in children on fludrocortisone and who were oversuppressed.

The relation of peripubertal and pubertal growth to final adult height in children with classic congenital adrenal hyperplasia.

OBJECTIVES: To determine the relationships between peripubertal and pubertal timing and growth, along with glucocorticoid exposure, to the reduced final adult height seen in patients with congenital adrenal hyperplasia (CAH). STUDY DESIGN: Chart review of 104 children with classic CAH (41 males: 28 salt-wasting, 13 simple-virilizing; 63 females: 38 salt-wasting, 25 simple-virilizing) were selected from a cohort from 3 medical institutions in Minnesota. Triple logistic modeling of longitudinal data was performed to determine patterns of peripubertal and pubertal growth. RESULTS: Hydrocortisone dose was similar between subtypes and during all growth periods. Simple-virilizing boys (P < .01) and girls (P < .01) were diagnosed later than their salt-wasting counterparts. Height at take-off SDS was reduced for patients with salt-wasting (boys: P < .01; girls: P < .01), and bone age at take-off SDS was more advanced for patients with simple-virilizing (boys: P < .01; girls: P = .05). Bone age at pubertal onset SDS was advanced for all patients, but more so for boys and girls with simple-virilizing. Although all patients had reduced final adult height SDS, this was more pronounced in patients with salt-wasting. CONCLUSION: Reduced final adult height SDS in patients with salt-wasting vs simple-virilizing may be attributable in part to a later age of diagnosis and resultant less prolonged exposure to hydrocortisone. This finding suggests that duration of hydrocortisone treatment in the peripubertal period, independent of the hydrocortisone dose, may affect final adult height in patients with CAH.

Understanding Cultural Beliefs in Families of Somali Children with Diabetes in the Twin Cities, Minnesota.

Describe cultural beliefs related to diabetes in Minnesota Somali children with type 1 diabetes (T1D), and compare their diabetes control to that of non-Somali children with diabetes. A cross-sectional study involving Somali children ≤ 19 years with T1D at the University of Minnesota Masonic Children's Hospital and Children's Hospitals and Clinics of Minnesota. A survey was administered to parents of all participants and to children aged ≥ 12 years. Data were collected by history and from the medical record. Twenty-five Somali children participated, with 24 parent-child pairs (2 siblings). Mean participant age was 12.2 ± 5.2 (36% female). Seventy-one percent of parents indicated the child was "the same as before" other than having to do diabetes cares. Families were coping well, and the child was not treated differently than siblings. Performance of routine cares was described as the hardest part about having diabetes, but this was not related to traditional culture or religion. One notable exception was difficulty performing carbohydrate counting on Somali foods. Respondents were appreciative of the education provided by the diabetes team. Less than 10% used herbal supplements in addition to insulin. Mean HbA1c in Somali children was higher than the overall pediatric clinic average, 9.5 ± 1.6 % versus 8.8 ± 1.6 (p = 0.01). The difference was largely due to adolescent patients. The majority of Somali families cope well with diabetes and have a positive attitude towards the diabetes education. Glycemic control in adolescents is worse than in non-Somali peers. There is a need for culture-specific dietary instruction materials.

Impact of hydrocortisone on adult height in congenital adrenal hyperplasia-the Minnesota cohort.

OBJECTIVE: To estimate the impact of the average daily dose of hydrocortisone (HC) on the amount of growth attained in children with congenital adrenal hyperplasia (CAH). The effect of glucocorticoid therapy on adult height (AH) in children with CAH has yet to be elucidated. STUDY DESIGN: Triple-logistic models estimating components of growth and maturation were fitted to longitudinal records of 104 patients with classic CAH from 3 pediatric medical centers in Minnesota between 1955 and 2012. A total of 3664 clinical encounters were examined. Random-effects longitudinal models with time-related covariates were used to estimate the effect of HC therapy on linear growth. RESULTS: The predicted AH z-score (-0.7) was similar between the sexes and among CAH subtypes. The mean growth period HC dose was 18.9 ± 5.6 mg/m(2)/day. In the final regression model, HC dose was negatively associated with predicted AH, with each mg/m(2)/day increase in average growth period HC dose predicting a 0.37-cm decrease in AH (P < .004). CONCLUSION: This study has quantified the fractional reduction in predicted final AH with an incremental increase in HC dose. These findings have important clinical implications in the decision making balance between HC replacement dose and adrenal androgen suppression in children with CAH.

Can incorporating molecular testing improve the accuracy of newborn screening for congenital adrenal hyperplasia?

BACKGROUND: Single-tier newborn screening (NBS) for CAH using 17-hydroxyprogesterone (17OHP) measured by fluoroimmunoassay (FIA) in samples collected at 24-48 hours produces a high false-positive rate (FPR). 2nd tier steroid testing can reduce the FPR and has been widely implemented. We investigated the accuracy of an alternative multi-tier CAH NBS protocol that incorporates molecular testing of the CYP21A2 gene and reduces the 1st tier 17OHP cutoff to minimize missed cases. METHODS: Created a Minnesota-specific CYP21A2 pathogenic variants panel; develop a rapid, high-throughput multiplex, allele-specific-primer-extension assay; perform 1-year retrospective analysis of Minnesota NBS results comparing metrics between a conventional steroid-based two-tier protocol and a molecular-based multi-tier NBS protocol, applied post-hoc. RESULTS: CYP21A2 gene sequencing of 103 Minnesota families resulted in a Minnesota-specific panel of 21 pathogenic variants. Centers for Disease Control and Prevention (CDC) created a molecular assay with 100% accuracy and reproducibility. Two-tier steroid-based screening of 68,659 live births during 2015 resulted in 2 false negatives (FNs), 91 FPs, and 1 true positive (TP). A three-tier protocol with a lower 1st-tier steroid cutoff, 2nd-tier 21-variant CYP21A2 panel and 3rd-tier CYP21A2 sequencing would have resulted in 0 FNs, 52 FPs and 3 TPs. CONCLUSIONS: Incorporation of molecular testing could improve the accuracy of CAH NBS, although some distinct challenges of molecular testing may need to be considered before implementation by NBS programs.

A picture is worth a thousand words: A culturally-tailored video-based approach to diabetes education in Somali families of children with type 1 diabetes.

Objectives: Type 1 diabetes (T1D) is highly prevalent in Somali immigrant children and hemoglobin A1c (HbA1c) levels are elevated in this population compared to non-Hispanic Whites. Current self-management diabetes education has not been tailored to this population. We aimed to improve delivery of T1D education to Somali immigrants by developing and testing a culturally-appropriate video-based curriculum. Methods: This cross-sectional study involved Somali youth ≤ 19 years with T1D followed at two pediatric tertiary centers in Minnesota. Ten Somali-language T1D education videos were developed (∼60 min for total program) based on core ADA curriculum and tailored to address cultural concerns and misconceptions. A diabetes knowledge questionnaire was administered to parents of all participants and to children aged ≥12 years. Pre- and post-educational session questionnaire mean scores were compared using a paired t-test to assess knowledge improvement immediately post-video education (primary endpoint) and retention at 3 months (secondary endpoint). HbA1c was measured pre- and 6 months post education (exploratory endpoint). Results: Twenty-two Somali parents of 22 children participated (mean age 12.3 ± 4 years; 36 % female), 12 children ≥12 years. Diabetes knowledge scores significantly improved immediately post-video education compared to baseline (p = 0.012). This improvement persisted 3 months later (p = 0.0008). There was no significant change in mean HbA1c from baseline at 6 months post education (9.0 ± 1.5 % vs 9.3 ± 1.9; p = 0.6). Conclusion: Culturally and linguistically tailoring diabetes education materials to African immigrants and delivering it audio-visually could improve effectiveness of diabetes education and increase knowledge and retention compared to simply translating standard diabetes education materials. The effect on HbA1c needs further study with a larger sample size.

A picture-based carbohydrate-counting resource for Somalis.

Objective Carbohydrate counting is essential for effective management of type 1 diabetes (T1D). Somali diet-specific carbohydrate-counting references are lacking, creating an additional barrier to effective diabetes control. We developed a picture-based carbohydrate-counting resource for Somalis with T1D. Methods Traditional Somali foods were selected using a variety of methods. Serving sizes and carbohydrate calculations were tabulated using the United States Department of Agriculture National Nutrient Database for Standard Reference. Carbohydrate contents of home-prepared foods were calculated by measuring the total yield and total carbohydrates of ingredients in the recipe divided by the number of servings to be consumed. When available, recipes were used for food preparation and analysis for more accurate carbohydrate estimation. Results Photographs of prepared Somali foods were compiled into a PDF file. While introductions are written in text, the resource is primarily picture-based to bypass limited literacy. The resource is shared free of charge via the following link: http://journals.sagepub.com/doi/suppl/10.1177/0300060517718732 . The link will be updated annually with new information. Conclusion There is a necessity to tailor educational materials to address the needs of Somalis with diabetes. We have created a picture-based nutrition resource for carbohydrate counting of traditional Somali foods and have made this freely available to individuals worldwide.

Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations.

Tpit is a T box transcription factor important for terminal differentiation of pituitary proopiomelanocortin-expressing cells. We demonstrated that human and mouse mutations of the TPIT gene cause a neonatal-onset form of congenital isolated ACTH deficiency (IAD). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency. This clinical entity was not previously well characterized because of the small number of published cases. Since identification of the first TPIT mutations, we have enlarged our series of neonatal IAD patients to 27 patients from 21 unrelated families. We found TPIT mutations in 17 of 27 patients. We identified 10 different TPIT mutations, with one mutation found in five unrelated families. All patients appeared to be homozygous or compound heterozygous for TPIT mutations, and their unaffected parents are heterozygous carriers, confirming a recessive mode of transmission. We compared the clinical and biological phenotype of the 17 IAD patients carrying a TPIT mutation with the 10 IAD patients with normal TPIT-coding sequences. This series of neonatal IAD patients revealed a highly homogeneous clinical presentation, suggesting that this disease may be an underestimated cause of neonatal death. Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy.

Combination therapy with sitagliptin and lansoprazole in patients with recent-onset type 1 diabetes (REPAIR-T1D): 12-month results of a multicentre, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Type 1 diabetes results from autoimmune destruction of pancreatic ß cells. Findings from preclinical studies suggest that dipeptidyl peptidase-4 inhibitors and proton-pump inhibitors might enhance ß-cell survival and regeneration. We postulated that sitagliptin and lansoprazole would preserve ß-cell function in patients with recent-onset type 1 diabetes. METHODS: We did a double-blind, placebo-controlled, phase 2 trial (REPAIR-T1D). Participants aged 11-36 years, diagnosed with type 1 diabetes within the past 6 months were recruited from Sanford Health Systems (Sioux Falls, SD, USA; Fargo, ND, USA), Children's Hospitals and Clinics of Minnesota (St Paul, MN, USA), and Rady Children's Hospital (San Diego, CA, USA). Participants were randomly assigned (2:1) to receive oral sitagliptin (100 mg for participants ≥18 years, 50 mg for those <18 years) and lansoprazole (60 mg for participants ≥18 years, 30 mg for those <18 years) or matched placebo for 12 months. Randomisation was done by a blocked randomisation process (blocks of three and six), with separate streams for younger (<18 years) and older (≥18 years) participants, and males and females. All participants and personnel remained masked until after the completion of the final 12 month visit, at which time data were unmasked to the analysis team. The primary endpoint was C-peptide response to a mixed meal challenge at 12 months measured as 2 h area under curve. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01155284. FINDINGS: Between Sept 21, 2010, and May 29, 2012, 46 participants were randomly assigned to the treatment group and 22 to the placebo group; of whom 40 participants in the treatment group and 18 in the placebo group completed the 12-month treatment. At 12 months, the mean change in C-peptide area under curve was -229 pmol/L (95% CI -316 to -142) for the treatment group and -253 pmol/L (-383 to -123) for the placebo group; this difference was not significant (p=0·77). No adverse or serious adverse events were probably or definitely related to the study treatment. INTERPRETATION: Although the expected change in the primary endpoint was not achieved, not all participants had increases in glucagon-like peptide-1 and gastrin concentrations that were expected with treatment. Although participants did not have adverse events related to study drugs, the study is not powered to address safety definitively. Further trials including these drugs might be warranted, but should be designed to ensure appropriate selection of participants and increases in these intermediary hormones. FUNDING: Sanford Research and JDRF.