Using trend arrows in continuous glucose monitoring systems for insulin adjustment in clinical practice: Brazilian Diabetes Society Position Statement.

This manuscript reports the Brazilian Diabetes Society Position Statement for insulin adjustments based on trend arrows observed in continuous glucose monitoring systems. The Brazilian Diabetes Society supports the utilization of trend arrows for insulin dose adjustments in patients with diabetes on basal-bolus insulin therapy, both with multiple daily insulin doses or insulin pumps without closed-loop features. For those on insulin pumps with predictive low-glucose suspend feature, we suggest that only upward trend arrows should be used for adjustments. In this paper, tables for insulin adjustment based on sensitivity factors are provided and strategies to optimize the use of trend arrows in clinical practice are discussed.

Early age at menarche: a risk factor for overweight or obesity in patients with type 1 diabetes living in urban areas?

AIMS: Determine the relationship between age at menarche, glycemic control and cardiovascular risk factors in patients with type 1 diabetes living in urban areas. METHODS: This was a multicenter cross-sectional study conducted in 20 cities in four Brazilian geographic regions. Data were obtained from 1527 female patients, 59.3% Caucasians, aged 25.1 ± 10.6 years. Diabetes duration was 11.4 ± 8.1 years. Age at menarche was stratified in four groups: 8-11 (group 1, early menarche), 12 (group 2), 13 (group 3) and 14-18 years (group 4, late menarche). RESULTS: The mean age at menarche was 12.7 ± 1.7 years without difference among geographical regions, economic status, level of care and ethnicity. BMI had an inverse correlation with age at menarche (r=-0.14, p<0.001). No significant difference was observed among the four groups for blood pressure, lipid profile and diabetes-related chronic complications. Logistic regression analysis showed that early age at menarche, 8-11 years (odds ratio (ORs) 1.77 [1.30-2.41], p<0.001) and duration of diabetes [ORs 1.01 (1.00-1.03), p=0.02], were related to greater risk of patients' overweight or obesity; adherence to diet [ORs 0.78 (0.60-0.93), p=0.01], physical activity [ORs 0.75 (0.94-0.94), p=0.01], and lower insulin dose (U/kg) [ORs 0.54 (0.59-0.90), p=0.001] were related to lower risk for overweight or obesity. CONCLUSIONS: Early menarche occurred in 23.4% of women with type 1 diabetes living in Brazilian urban areas and was strongly associated with overweight/obesity in pubertal/adult life. Further studies are warranted to establish the relationship between early menarche, glycemic control and cardiovascular risk factors.

First two years' response to growth hormone treatment in very young preterm small for gestational age children.

BACKGROUND: Growth hormone (GH) is a therapeutic option for small for gestational age (SGA) children without spontaneous catch-up. There are few reports on preterm SGA children. Prematurity is an additional risk factor for adult short stature. AIM: To describe GH efficacy in preterm SGA patients. METHODS: Twenty-five preterm SGA patients, 2-4 years old, treated with GH 0.066 mg/kg/day, were compared with 14 age-matched preterm SGA historical controls. Height, weight, IGF-I, IGFBP-3, fasting glucose and insulin were measured every 6 months. RESULTS: At start of GH treatment, mean height and weight were -2.4 and -2.4 SDS, respectively. There was a significant increment in height SDS of 1.3 and 2.1 during the 1st and the 2nd year of GH therapy, respectively. There was no significant difference between the progression of chronological and bone ages. A significant increase in IGF-I, IGFBP-3 and molar ratio was observed during GH therapy. There was no difference in glucose, insulin or HOMA-IR index. CONCLUSION: We showed for the first time that the height increment of preterm SGA with GH treatment is similar to that described in other studies with term SGA patients. Therefore, short-term GH treatment in a subset of preterm SGA patients between 2-4 years of age was able to promote adequate growth recovery with no excessive bone age acceleration or adverse effects on carbohydrate metabolism.

Size of the exon 1-CAG repeats of the androgen receptor gene employed as a molecular marker in the diagnosis of Turner syndrome in girls with short stature.

Turner syndrome (TS) is one of the most common chromosomal abnormalities among girls. Complete monosomy of X chromosome is responsible for almost 50% of all cases of TS, and mosaicism and X anomaly are detected in the other half. It has already been demonstrated that early diagnosis of these children allows appropriate growth hormone treatment with better final height prognosis and introduction of estrogen at an ideal chronological age. Sixty-four short-stature girls were selected and the clinical data obtained were birth weight and height, weight and height at the first medical visit and target height. Other clinical data including cardiac and renal abnormalities, otitis, Hashimoto thyroiditis, cubitus valgus, short neck, widely separated nipples, and pigmented nevi were obtained from the patients' medical records. The aim of the present study was to evaluate the screening of a group of short-stature girls for TS based on the number of CAG repeats of the androgen receptor gene analyzed by GeneScan software. Patient samples with two alleles (heterozygous) were 49/64 (76.5%) and with one allele (homozygous) were 15/64 (23.5%). A karyotype was determined in 30 patients, 9 homozygous and 21 heterozygous. In the homozygous group, 6/9 were 45,X and 3/9 were 46,XX. In the heterozygous group, 17/21 were 46,XX, and 4/21 were TS patients with mosaicism (45,X/46,XX; 45,X/46XiXq; 46XdelXp). The pattern obtained by GeneScan in two patients with mosaicism in the karyotype was an imbalance between the peak heights of the two alleles, suggesting that this imbalance could be present when there is a mosaicism. The frequency of TS abnormalities (18.7%) did not differ between TS and 46,XX girls. Thus, it is important to accurately assess the incidence of TS in growth-retarded girls, even in the absence of other dysmorphisms. In this study, we diagnosed 6 cases of TS 45,X (9.4%) by molecular analysis, with a 100% sensitivity and 85% specificity. This molecular analysis was able to detect all cases of TS 45,X and the majority of mosaicisms, without the need for more X chromosome markers. In conclusion, determining the number of CAG repeats of the androgen receptor gene analyzed by GeneScan was a fast method with high sensitivity for the detection of TS 45,X, suggesting that it could be interesting as a method for screening a population of growth-retarded girls.

Size of the exon 1-CAG repeats of the androgen receptor gene employed as a molecular marker in the diagnosis of Turner syndrome in girls with short stature

Turner syndrome (TS) is one of the most common chromosomal abnormalities among girls. Complete monosomy of X chromosome is responsible for almost 50% of all cases of TS, and mosaicism and X anomaly are detected in the other half. It has already been demonstrated that early diagnosis of these children allows appropriate growth hormone treatment with better final height prognosis and introduction of estrogen at an ideal chronological age. Sixty-four short-stature girls were selected and the clinical data obtained were birth weight and height, weight and height at the first medical visit and target height. Other clinical data including cardiac and renal abnormalities, otitis, Hashimoto thyroiditis, cubitus valgus, short neck, widely separated nipples, and pigmented nevi were obtained from the patients’ medical records. The aim of the present study was to evaluate the screening of a group of short-stature girls for TS based on the number of CAG repeats of the androgen receptor gene analyzed by GeneScan software. Patient samples with two alleles (heterozygous) were 49/64 (76.5%) and with one allele (homozygous) were 15/64 (23.5%). A karyotype was determined in 30 patients, 9 homozygous and 21 heterozygous. In the homozygous group, 6/9 were 45,X and 3/9 were 46,XX. In the heterozygous group, 17/21 were 46,XX, and 4/21 were TS patients with mosaicism (45,X/46,XX; 45,X/46XiXq; 46XdelXp). The pattern obtained by GeneScan in two patients with mosaicism in the karyotype was an imbalance between the peak heights of the two alleles, suggesting that this imbalance could be present when there is a mosaicism. The frequency of TS abnormalities (18.7%) did not differ between TS and 46,XX girls. Thus, it is important to accurately assess the incidence of TS in growth-retarded girls, even in the absence of other dysmorphisms. In this study, we diagnosed 6 cases of TS 45,X (9.4%) by molecular analysis, with a 100% sensitivity and 85% specificity. This molecular analysis was...

A novel mutation in DAX1 gene causing different phenotypes in three siblings with adrenal hypoplasia congenita.

Adrenal hypoplasia congenita (AHC) is a rare disease that can be caused by many abnormalities, including an X-linked form. Mutations in the DAX1 gene have been assigned as the genetic cause of AHC. We describe here three siblings with AHC, clinically presented at different ages, two in the neonatal period and one oligosymptomatic during infancy. Molecular analysis was able to detect a novel mutation in exon 1 of the DAX1 gene, consisting of a transition of C to T at position 359, determining a stop codon at position 359 (Q359X). The mutated gene encodes a truncated protein missing a large portion of the ligand-binding domain (C-terminal domain). The recognition of the disease in the index case suggested the diagnosis in the other siblings. Interestingly, the same mutation is presented with different phenotypes, suggesting that first-degree family members of patients with DAX1 mutations should be carefully evaluated routinely.

The influence of parental origin of X chromosome genes on the stature of patients with 45 X Turner syndrome.

Thirty-seven 45 X Turner syndrome patients with confirmed peripheral blood lymphocyte karyotype were initially selected to determine the origin of the retained X chromosome and to correlate it with their parents' stature. Blood samples were available in 25 families. The parental origin of the X chromosome was determined in 24 informative families through the analysis of the exon 1-CAG repeat variation of the androgen receptor gene. In 70.8% of the cases, the retained X chromosome was maternal in origin and 29.2% was paternal. When we classified the patients according to maternal (Xm) or paternal (Xp) X chromosome, there was a positive correlation between patients' and maternal heights only in the Xm group. There was no correlation with paternal height in either group, and a significant correlation with target height was only observed in the Xm group. In conclusion, maternal height is the best variable correlating with the height of 45 X Turner syndrome patients who retain the maternal X chromosome, suggesting a strong influence of genes located on the maternal X chromosome on stature.

Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus.

BACKGROUND: Oxidative stress plays an important role in the pathophysiology of diabetes mellitus. The aim of this study was to evaluate the formation of cholesterol oxides (ChOx) as biomarkers of oxidative stress in subjects with impaired glucose tolerance (IGT) and diabetes. METHODS: Blood plasma levels of cholesterol oxidation products were determined in the following groups: type 1 diabetes mellitus (DM1), type 2 diabetes (DM2), impaired glucose tolerance (IGT), children without diabetes (C1) and adults without diabetes (C2). The serum levels of cholest-5-ene-3alpha,7alpha-diol (7alpha-hydroxycholesterol, 7alpha-OH), cholest-5-ene-3beta,7beta-diol (7beta-hydroxycholesterol, 7beta-OH), 3beta-hydroxycholest-5-7-one (7-ketocholesterol, 7-K), 5alpha-cholestane-3beta,5,6beta-triol (cholestanetriol), 5,6alpha-epoxy-5alpha-cholestan-3alpha-ol (cholesterol-5alpha,6alpha-epoxide,), 5,6beta-epoxy-5beta-cholestan-3beta-ol (cholesterol-5beta,6beta-epoxide) and cholest-5-eno-3beta,25-diol (25-hydroxycholesterol, 25-OH) (trivial name and abbreviations indicated in parentheses) were quantified by gas chromatography using flame ionization detection. RESULTS: The levels of total ChOx were elevated in the DM1 and DM2 groups compared to age-matched subjects without diabetes (p < 0.05). The concentrations of 7beta-hydroxycholesterol, cholesterol-alpha-epoxide and cholesterol-beta-epoxide were higher in the blood plasma of subjects in the DM2 group than in the blood plasma of subjects in the C2 and IGT groups (p < 0.05). Treatment of type 2 diabetic patients with oral hypoglycemic drugs associated with insulin resulted in lower concentrations of nitrotyrosine in the blood plasma without significant changes in the concentrations of glucose and glycated hemoglobin. Moreover, combination with statins in both treatments decreased the concentrations of ChOx. CONCLUSIONS: ChOx are suitable biomarkers of oxidative stress and may be useful in clinical studies to follow drug effects on lipid oxidative modifications in diabetic patients.

The influence of parental origin of X chromosome genes on the stature of patients with 45 X Turner syndrome

Thirty-seven 45 X Turner syndrome patients with confirmed peripheral blood lymphocyte karyotype were initially selected to determine the origin of the retained X chromosome and to correlate it with their parents’ stature. Blood samples were available in 25 families. The parental origin of the X chromosome was determined in 24 informativefamilies through the analysis of the exon 1 - CAG repeat variation of the androgen receptor gene. In 70.8% of the cases, the retained X chromosome was maternal in origin and 29.2% was paternal. When we classified the patients according to maternal (Xm) or paternal (Xp) X chromosome, there was a positive correlation between patients’ and maternal heights only in the Xm group. There was no correlation with paternal height in either group, and a significant correlation with target height was only observed in the Xm group. In conclusion, maternal height is the best variable correlating with the height of 45 X Turner syndrome patients who retain the maternal X chromosome, suggesting a strong influence of genes located on the maternal X chromosome on stature.

A novel mutation in DAX1 gene causing different phenotypes in three siblings with adrenal hypoplasia congenita

Adrenal hypoplasia congenita (AHC) is a rare disease that can be caused by many abnormalities, including an X-linked form. Mutations in the DAX1 gene have been assigned as the genetic cause of AHC. We describe here three siblings with AHC, clinically presented at different ages, two in the neonatal period and one oligosymptomatic during infancy. Molecular analysis was able to detect a novel mutation in exon 1 of the DAX1 gene, consisting of a transition of C to T at position 359, determining a stop codon at position 359 (Q359X). The mutated gene encodes a truncated protein missing a large portion of the ligand-binding domain (C-terminal domain). The recognition of the disease in the index case suggested the diagnosis in the other siblings. Interestingly, the same mutation is presented with different phenotypes, suggesting that first-degree family members of patients with DAX1 mutations should be carefully evaluated routinely.

Transdermal estradiol priming during clonidine stimulation test in non-growth hormone deficient children with short stature: a pilot study.

The diagnosis of growth hormone (GH) deficiency is strongly influenced by age, body mass index and presence of gonadal steroids. Priming with oral estradiol (E2) is one possible way to overcome the impact of variable levels of sex steroids. We describe the effects of transdermal estradiol (E2-t) priming on GH response after clonidine stimulation in prepubertal children with familial short stature (group 1, n = 12) or constitutional growth delay (group 2, n = 22). All patients underwent a clonidine test (0.1 mg/m2, p.o.) followed by a clonidine plus E2-t test (50 microg/day) with a 7-day interval. Before E2-t, basal GH and insulin-like growth factor-I (IGF-I) values were similar in the two groups. After E2-t priming, basal GH was significantly higher only in group 2. When compared with group 1, patients from group 2 had a significant increase of GH peak response when submitted to E2-t. The number of patients in both groups with adequate GH peak response was higher after E2-t priming. We conclude that E2-t priming is able to increase GH peak response after clonidine stimulation and also improves the accuracy of the clonidine test in the diagnosis of GH deficiency. Compared to oral administration, E2-t delivery can prevent liver toxicity, providing a more physiological mechanism of GH secretion.

Inhibin alpha-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers.

The R337H TP53 mutation is a low-penetrance molecular defect that predisposes to adrenocortical tumour (ACT) formation in Brazilian and possibly other populations. Additional genetic defects may be responsible for the variable expression of ACTs in these cases. The inhibin alpha-subunit gene (INHA) on 2q33-qter has been implicated in mouse adrenocortical tumourigenesis. We studied 46 pediatric patients with ACTs from Brazil for INHA genetic alterations; 39 of these patients were heterozygous carriers of the R337H TP53 mutation. We first mapped the INHA gene by radiation hybrid analysis and determined 10 linked microsatellite markers in an area flanked by D2S1371 and D2S206 on 2q33-qter. These markers were then used for loss of heterozygozity (LOH) studies in nine paired germline and tumour DNA samples. Mapping placed the INHA gene in close proximity to D2S2848 (SHGC11864) with a log of odds (LOD) score of 5.84. LOH for at least one marker in the region was identified in 8/9 tumours (89%). Six patients were heterozygous for three INHA mutations: one in exon 1, 127C>G, and two in exon 2, 3998G>A and 4088G>A, all leading to amino acid substitutions (P43A, G227R, and A257T, respectively). A257T is located in a conserved INHA region, highly homologous to transforming growth factor-beta; both G227R and A257T change polarity, and, in addition, G227R changes the pH. We conclude that these sequence alterations and the detected 2q allelic changes suggest that INHA may be one of the contributing factors needed for ACT formation in pediatric patient carriers of the R337H TP53 mutation.

[Cryptorchism: basic concepts and hormonal therapy]. / Criptorquismo: conceitos básicos e tratamento hormonal.

The authors analyze the clinical results of 368 cryptorchid testis that received intramuscular human chorionic gonadotropin (HCG), at the dose of 50 U/kg once a week for 6 weeks. The patients with inguinal anatomical abnormalities or only with subtle retractility were excluded. There was a correlation among the testicle position, the cryptorchism side, the patient's age at the time of the therapy and the results obtained. We observed (i) a delay on child referral; (ii) concurrence of cryptorchism and systemic diseases, most of them with genetical origin; (iii) better results was obtained in children with retractile testis, older than 4 years old and with bilateral cryptorchism. The efficacy of second hormonal treatment was only present in retractile testis that showed partial response to the first hormonal therapy. It is argued that, although the treatment of children under 2 is less effective, the possible prevention of testicular lesions for this early intervention justify the hormonal therapy between 6 and 9 months of life.

Aspectos da fase näo-insulinodependente do diabetes mellitus do tipo I / Aspects of non-insulin-dependent phase of type I diabetes mellitus

Trata-se de um caso de diabetes mellitus do tipo I(DMI) no qual tivemos a oportunidade de diagnosticá-lo 23 meses antes das suas manifestaçöes clínicas mais freqüentes. Durante esse período foram observadas alteraçöes como o retorno de enurese, diminuiçäo na velocidade de crescimento e episódios de hiperglicemia e/ou glicosúria transitórios, apresentadas pela paciente, que podem näo ser devidamente valorizadas, na rotina clínica. Como, também, o aparecimento de marcadores imunológicos (ICA) e alteraçöes precoces na secreçäo de insulina (diminuiçäo na sua primeira fase de liberaçäo) vários meses antes do DMI manifesto. Esses marcadores imunológicos e essas alteraçöes endócrinas deveriam, se possível, ser pesquisados em pacientes com o quadro clínico inicial aqui apresentado, e em parentes jovens de DMI, no sentido de se detectar indivíduos com elevado risco de evoluírem para a fase manifesta dessa moléstia. O seguimento desses pacientes possibilitaria o diagnóstico precoce do DMI e a aplicaçäo de medidas no sentido de impedir a deteriorizaçäo total das células beta-pancreáticas e a evoluçäo para distúrbios metabólicos mais graves, como a cetoacidose diabética, com morbidade e mortalidade reconhecida

[The non-insulin-dependent phase of type I diabetes mellitus]. / Aspectos da fase não-insulinodependent do diabetes mellitus do tipo I.

Case report on a child whose type I diabetes mellitus was diagnosed 23 months before the appearance of overt glucose intolerance. In this pre-IDDM stage of DMI were observed secondary enuresis, decreased growth speed, transient hyperglycemia and asymptomatic glycosuria. These alterations may represent the earliest clinical manifestation of impaired beta cell function. Immunologic markers (ICA and/or AAI) of DMI and abnormalities of the first-phase insulin secretion in response to intravenous glucose also may precede by several months the most common clinical picture of type I diabetes as they were detected in this child. If possible, markers and alterations should be tested in such patients and their young relatives with DMI in order to detect high risk individuals who may develop DMI. Such and accurate predictive ability should be a prerequisite to institution of appropriate therapy to preventing further beta cell destruction and severe metabolic decompensation, thus having the potential to reduce morbidity and mortality from new onset DMI.