Reduced prevalence of impaired awareness of hypoglycemia in a population-based clinic sample of youth with type 1 diabetes.

BACKGROUND: Impaired awareness of hypoglycemia (IAH) is associated with an increased risk for severe hypoglycemia (SH). However, reduced rates of SH raise the question as to whether there has been a reduction in IAH. The aim of this study was to determine the change in prevalence of IAH in a population-based cohort of adolescents with Type 1 diabetes (T1D). METHODS: Children older than 12 years with T1D documented their responses to hypoglycemia based on the modified Clarke questionnaire. The prevalence of IAH was also analyzed in a similar population-based cohort using the same questionnaire in 2002. The clinical details of the participants and the number of SH events in the preceding year were determined from the Western Australian diabetes database. RESULTS: The questionnaire was administered to 413 children in 2002 and to 444 children in 2015 with similar baseline characteristics. The prevalence of IAH was 33% in 2002 and 21% in 2015 (P < .001). A lower HbA1c, younger age at diagnosis and longer duration of diabetes correlated with IAH in 2002 but not in 2015. There was a significant decline in the rates of SH in 2015 compared with 2002 (P < .001) despite a reduced HbA1c in 2015. IAH increased the risk of SH in both cohorts (52 vs 16 events/100 patient years in 2002 and 8 vs 2 events/100 patient years in 2015). CONCLUSIONS: Although IAH has reduced, IAH is still prevalent in a substantial minority of adolescents and continues to be associated with an increased risk of SH.

Prediction of congenital hypothyroidism based on initial screening thyroid-stimulating-hormone.

BACKGROUND: In thyroid-stimulating-hormone (TSH)-based newborn congenital hypothyroidism (CH) screening programs, the optimal screening-TSH cutoff level is critical to ensuring that true cases of CH are not missed. Screening-TSH results can also be used to predict the likelihood of CH and guide appropriate clinical management. The purpose of this study is to evaluate the predictive value of various screening-TSH levels in predicting a diagnosis of CH in the Ontario Newborn Screening Program (ONSP). METHODS: The initial screening and follow-up data of 444,744 full term infants born in Ontario, Canada from April 1, 2006 to March 31, 2010 were analyzed. Confirmed CH cases were based on local endocrinologists' report and initiation of thyroxine treatment. RESULTS: There were a total of 541 positive screening tests (~1/822 live births) of which 296 were true positives (~1:1,500 live births). Subjects were further subdivided based on screening-TSH and positive predictive values (PPV) were calculated. Twenty four percent in the 17-19.9 mIU/L range were true positives. In the 17-30 mIU/L range, 29 % were true positives with a significantly higher PPV for those sampled after (43 %) rather than before (25 %) 28 h of age (p < 0.02). Seventy three percent of neonates with an initial screening-TSH of ≥ 30 mIU/L and 97 % of those with ≥ 40 mIU/L were later confirmed to have CH. CONCLUSIONS: Infants with modestly elevated screening positive TSH levels between 17 and 19.9 mIU/L have a significant risk (24 %) of having CH. The very high frequency of true positives in term newborns with initial TSH values ≥ 30mIU/L suggests that this group should be referred directly to a pediatric endocrinologist in an effort to expedite further assessment and treatment. Screen positives with a modestly elevated TSH values (17-19.9 mIU/L) need to be examined in more detail with extended follow-up data to determine if they have transient or permanent CH.

A novel MC4R mutation associated with childhood-onset obesity: A case report.

The melanocortin-4-receptor gene (MC4R) is a key regulator of energy homeostasis, food intake and body weight. MC4R gene mutations are associated with early-onset severe obesity. Most patients are heterozygotes, with some reports of homozygotes and compound heterozygotes. The authors report a case involving an eight-year-old girl with progressive weight gain from infancy, body mass index 44 kg/m(2) (>97th percentile), hyperphagia, hyperinsulinemia and increased linear growth. There was no phenotype of morbid obesity in the parents or sibling. Coding regions and intron-exon boundaries of the genes encoding leptin, leptin receptor, pro-opiomelanocortin and MC4R were analyzed. Two heterozygous coding mutations in the MCR4 gene (S94N and C293R) were detected, of which the second has not been previously reported. The mutations were on opposite chromosomes, confirming compound heterozygosity. The molecular findings and clinical features associated with this novel MC4R mutation are described. The authors emphasize that rare mutations can be found in some patients with severe childhood-onset obesity.

Le gène récepteur de la mélanocortine 4 (MC4R) joue un rôle clé dans le maintien de l'homéostasie énergétique, de la prise alimentaire et du poids corporel. Les mutations du gène MC4R s'associent à une grave obésité à apparition précoce. La plupart des patients sont hétérozygotes, mais il y a certaines descriptions de patients homozygotes et d'hétérozygotes composés. Les auteurs présentent le cas d'une fillette de huit ans ayant une prise de poids progressive depuis la première enfance, un indice de masse corporel de 44 kg/m2 (>97e percentile), une hyperphagie, une hyperinsulinémie et une augmentation de la croissance linéaire. Les parents et la fratrie ne possédaient pas de phénotype d'obésité morbide. Les auteurs ont analysé les régions codantes et les limites intron-exon des gènes codant la leptine, son récepteur, la pro-opiomélanocortine et le MC4R. Ils ont décelé deux mutations en région codante du gène MCR4 (S94N et C293R), la deuxième n'ayant jamais été déclarée auparavant. Les mutations se situaient sur des chromosomes opposés, ce qui confirme leur hétérozygotie composée. Les auteurs décrivent les observations moléculaires et les caractéristiques cliniques associées à cette nouvelle mutation MC4R. Ils soulignent que certains patients ayant une importante obésité qui se manifeste pendant l'enfance peuvent présenter des mutations rares.

Microvascular complications assessment in adolescents with 2- to 5-yr duration of type 1 diabetes from 1990 to 2006.

OBJECTIVE: Microvascular complications occur in adolescents with type 1 diabetes, although guidelines vary as to when screening should commence and prevalence data for those with ≤5-yr duration are limited. We therefore investigated trends in prevalence of early microvascular complications over 17 yr. RESEARCH DESIGN AND METHODS: 819 adolescents (54% female) aged 11-17 yr with 2- to 5-yr diabetes duration were assessed for complications at a tertiary pediatric diabetes clinic between 1990 and 2006. Early retinopathy was detected using seven-field fundal photography, albumin excretion rate (AER) by timed overnight urine collections and peripheral nerve function by thermal/vibration threshold at the foot. Results were analyzed by age, time period of assessment, and duration. RESULTS: Early retinopathy declined from 1990 to 2002 (16-7%, p < 0.01), then remained unchanged until 2006. Early elevation of AER (≥7.5 µg/min) and microalbuminuria (≥20 µg/min) did not change over time, whereas peripheral nerve abnormalities increased (14-28%, p < 0.01). Median hemoglobin A1c improved (8.7-8.2%, p < 0.01), in parallel with increased total daily insulin dose and injections per day (p < 0.01). Body mass index standard deviation score increased over time (0.55-0.79, p < 0.01). In multivariate logistic regression, early retinopathy was associated with earlier time period [odds ratio (OR) 0.68, confidence interval (CI) 0.55-0.85, p < 0.01] and older age (OR 1.19, CI 1.02-1.39, p = 0.03). AER ≥ 7.5 µg/min was associated with older age (1.19, 1.06-1.34, p < 0.01) and longer diabetes duration (OR 1.28, CI 1.02-1.62, p = 0.04) and height-adjusted peripheral nerve abnormalities with later time period (OR 1.26, CI 1.05-1.50, p = 0.01). CONCLUSIONS: Early complications are not uncommon in adolescents with 2- to 5-yr diabetes duration, despite more intensive management in recent years.

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA1c and continuous glucose monitoring over 12 months. RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, N = 1,298] vs. 4.7% [95% CI 3.4-5.9%, N = 1,089], P = 0.035) with lower rates of prior CD screening (6.9% vs. 44.2%, P < 0.0001). Fifty-one participants were randomized to a GFD (N = 27) or GCD (N = 24). No HbA1c differences were seen between the groups (+0.14%, 1.5 mmol/mol; 95% CI -0.79 to 1.08; P = 0.76), although greater postprandial glucose increases (4-h +1.5 mmol/L; 95% CI 0.4-2.7; P = 0.014) emerged with a GFD. CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD.

Angiotensinogen gene T235 variant: a marker for the development of persistent microalbuminuria in children and adolescents with type 1 diabetes mellitus.

AIM: We examined genetic polymorphisms in the renin-angiotensin system (RAS) coding for angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) for angiotensinogen (AGT) M235T and angiotensin II receptor type 1 (AGTR1) A1166C as predictors for the development of microalbuminuria (MA) in children with type 1 diabetes mellitus (T1DM). METHODS: Four hundred fifty-three (215 males, 238 females) T1DM children [median (interquartile range): age, 16.7 years (13.9-18.3); diabetes duration, 6.9 years (3.3-10.8); age at diagnosis, 9.1 years (5.8-11.8)] were followed prospectively from diagnosis until the development of MA (two of three consecutive overnight urine samples with albumin excretion rates of > or =20 and <200 microg/min). Kaplan-Meier survival curves and Cox proportional multivariate model estimated the probability of developing MA and the relative risk for MA among different variables. RESULTS: MA developed in 41 (9.1%) subjects. The frequencies of genotypes were as follows: ACE-II 112 (25%), ACE-ID 221 (49%), and ACE-DD 117 (26%) (n=450); AGT-MM 144 (32%), AGT-MT 231 (51%), and AGT-TT 77 (17%) (n=452); AGTR1-AA 211 (47%), AGTR1-AC 204 (45%), and AGTR1-CC 37 (8%) (n=452). The cumulative risk for the development of MA was higher in ACE-DD versus ACE-ID/II groups (log-rank test, P=.05), and a trend was noticed when AGT-TT was compared to AGT-MT/MM groups (log-rank test, P=.08). AGT-TT polymorphism conferred a fourfold increased risk for MA compared to AGT-MM/MT (hazard ratio=3.8; 95% confidence interval=1.43-10.3; P=.008). INTERPRETATION: Our findings suggest that RAS gene polymorphism at AGT M235T is a strong predictor for early MA in young T1DM subjects.

Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis.

OBJECTIVE: Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor-based overnight predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS: In two age-groups of children with type 1 diabetes (11-14 and 4-10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time <70 mg/dL overnight. RESULTS: Median time at <70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P < 0.001) in 11-14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P < 0.001) in 4-10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 ± 18 vs. 152 ± 19 mg/dL [P < 0.001] and 153 ± 14 vs. 160 ± 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 ± 29 vs. 176 ± 28 mg/dL (P < 0.001) in the 11-14-year-olds and 154 ± 25 vs. 158 ± 22 mg/dL (P = 0.11) in the 4-10-year-olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis. CONCLUSIONS: In 4-14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher.

Plantar fascia thickness is longitudinally associated with retinopathy and renal dysfunction: a prospective study from adolescence to adulthood.

AIM: The aim was to study the longitudinal relationship between plantar fascia thickness (PFT) as a measure of tissue glycation and microvascular (MV) complications in young persons with type 1 diabetes (T1DM). METHODS: We conducted a prospective longitudinal cohort study of 152 (69 male) adolescents with T1DM who underwent repeated MV complications assessments and ultrasound measurements of PFT from baseline (1997-2002) until 2008. Retinopathy was assessed by 7-field stereoscopic fundal photography and nephropathy by albumin excretion rate (AER) from three timed overnight urine specimens. Longitudinal analysis was performed using generalized estimating equations (GEE). RESULTS: Median (interquartile range) age at baseline was 15.1 (13.4-16.8) years, and median follow-up was 8.3 (7.0-9.5) years, with 4 (3-6) visits per patient. Glycemic control improved from baseline to final visit [glycated hemoglobin (HbA1c) 8.5% to 8.0%, respectively; p = .004]. Prevalence of retinopathy increased from 20% to 51% (p < .001) and early elevation of AER (>7.5 µg/min) increased from 26% to 29% (p = .2). A greater increase in PFT (mm/year) was associated with retinopathy at the final assessment (ΔPFT 1st vs. 2nd-4th quartiles, χ(2) = 9.87, p = .02). In multivariate GEE, greater PFT was longitudinally associated with retinopathy [odds ratio (OR) 4.6, 95% confidence interval (CI) 2.0-10.3] and early renal dysfunction (OR 3.2, CI 1.3-8.0) after adjusting for gender, blood pressure standard deviation scores, HbA1c, and total cholesterol. CONCLUSIONS: In young people with T1DM, PFT was longitudinally associated with retinopathy and early renal dysfunction, highlighting the importance of early glycemic control and supporting the role of metabolic memory in MV complications. Measurement of PFT by ultrasound offers a noninvasive estimate of glycemic burden and tissue glycation.

Impaired awareness of hypoglycemia in a population-based sample of children and adolescents with type 1 diabetes.

OBJECTIVE: To determine the prevalence and clinical associations of impaired awareness of hypoglycemia in a population-based sample of children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: A validated questionnaire was administered to 656 patients with type 1 diabetes over a 6-month period to determine hypoglycemia awareness status. Case ascertainment was 79% of the clinic population. The rate of severe hypoglycemia was determined by data collected prospectively in the preceding year. RESULTS: Impaired awareness of hypoglycemia was present in 29% of patients. Patients with impaired awareness of hypoglycemia had an earlier onset of diabetes (P < 0.001), were younger (P < 0.001), and had lower mean levels of A1C since diabetes onset (P = 0.006) and at their last visit (P = 0.001). The overall rate of severe hypoglycemia was 24.5 episodes per 100 patient-years in the preceding year. The severe hypoglycemia rate was higher in those with impaired awareness of hypoglycemia (37.1 vs. 19.3 episodes per 100 patient-years, P < 0.001). Among patients aged <6 years (n = 46), 59% of care providers reported impaired awareness of hypoglycemia, and the rate of severe hypoglycemia was significantly higher in those reporting impaired awareness (33.3 vs. 52 episodes per 100 patient-years, P = 0.02). More patients with recurrent hypoglycemia reported impaired awareness of hypoglycemia (47 vs. 28%, P = 0.03). CONCLUSIONS: A significant proportion of children and adolescents with type 1 diabetes have impaired awareness of hypoglycemia. Screening for impaired awareness is an important component of routine diabetes care and can identify patients at increased risk of a severe hypoglycemic event.

Plantar fascia thickness, a measure of tissue glycation, predicts the development of complications in adolescents with type 1 diabetes.

OBJECTIVE: Direct measurement of collagen glycation requires skin biopsy, which is invasive. We hypothesized that measurement of plantar fascia thickness (PFT) by ultrasound is an alternative index of tissue glycation and a marker of microvascular disease. RESEARCH DESIGN AND METHODS: This was a prospective longitudinal study of microvascular complications in 344 adolescents with type 1 diabetes, whose PFT was assessed by ultrasound at baseline. Retinopathy was assessed by seven-field fundal photography, albumin excretion rate (AER) measured from three consecutive timed overnight urine specimens, autonomic neuropathy by pupillometry and cardiovascular tests, and peripheral neuropathy by vibration and thermal thresholds. Longitudinal analysis was performed using generalized estimating equations with baseline PFT, duration, and A1C as explanatory variables. RESULTS: At first assessment, median (interquartile range) age was 15.1 (13.5-17.2) years and diabetes duration was 8.5 (6.0-11.5) years. Median follow up was 3.2 (2.1-4.5) years with a median of 4 (2-13) complications assessments per patient. In multivariate analysis, baseline PFT (abnormal in 132 subjects, 38%) predicted subsequent development of retinopathy (odds ratio 2.4 [95% CI 1.1-5.0]), elevated AER (2.24 [1.05-5.11]), peripheral neuropathy (2.3 [1.2-4.41]), and autonomic neuropathy (4.94 [2.46-9.91]). Limited joint mobility was present in only 4%. CONCLUSIONS: PFT is a significant predictor of the subsequent development of complications in type 1 diabetes, suggesting that glycation and oxidation of collagen in soft tissues may be independent risk factors for microvascular complications.

Association between p.Leu54Met polymorphism at the paraoxonase-1 gene and plantar fascia thickness in young subjects with type 1 diabetes.

OBJECTIVE: In type 1 diabetes, plantar fascia, a collagen-rich tissue, is susceptible to glycation and oxidation. Paraoxonase-1 (PON1) is an HDL-bound antioxidant enzyme. PON1 polymorphisms have been associated with susceptibility to macro- and microvascular complications. We investigated the relationship between plantar fascia thickness (PFT) and PON1 gene variants, p.Leu54Met, p.Gln192Arg, and c.-107C>T, in type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a cross-sectional study of 331 adolescents with type 1 diabetes (162 male and 169 female). PFT was assessed by ultrasound, PON1 was assessed by genotyping with PCR and restriction fragment-length polymorphism, and serum PON1 activity was assessed by rates of hydrolysis of paraoxon and phenylacetate. RESULTS: Median (interquartile range) age was 15.4 (13.5-17.3) years, and diabetes duration was 7.6 (4.9-10.6) years. The distribution of p.Leu54Met genotypes was LL 135 (40.8%), ML 149 (45%), and MM 47 (14.2%). PFT was abnormal (>1.7 mm) in 159 adolescents (48%). In multivariate analysis, predictors of abnormal PFT were ML/LL versus MM p.Leu54Met polymorphism (odds ratio 3.84 [95% CI 1.49-9.82], P = 0.005); BMI (percentile) (1.02 [1.01-1.03], P = 0.007); systolic blood pressure (percentile) (1.01 [1.00-1.02], P = 0.03); and male sex (3.29 [1.98-5.46], P < 0.001). CONCLUSIONS: Thickening of the plantar aponeurosis occurs predominantly in overweight and male adolescents with type 1 diabetes. The MM genotype at PON1 p.Leu54Met is associated with a reduced risk of abnormal PFT.

Mosaicismo cromossômico para Síndrome de Turner com defiiênci estrutural do cromossomo X em forma de anel: a propósito de um caso / The chromosomal mosaicism for Turner's syndrome with structural deficiency of the X chromossome in ring shape: case report

Relata-se um caso de diagnóstico da síndrome de Turner pela análise citogenética onde se obteve o resultado de um mosaicismo cromossômico com a formação de um cromossomo em anel. Uma menina de 9 anos, apresentando velocidade de crescimento abaixo da normalidade, com características fenotípicas leves, convergentes à síndrome de Turner, foi submetida à realização da análise cromossômica, obtendo-se quatro linhagens celulares distintas 46,XX/46,Xr(X)/45,X/45,r(X). Além de divulgar os achados citogenéticos raros, o trabalho objetiva evidenciar a importância da citogenética na confirmação das síndromes cromossômicas.