[Seasonal variations in 25-hydroxy vitamin D3, parathormone and alkaline phosphatase in school-aged children]. / Variación estacional de 25-hidroxi-vitamina D3, hormona paratiroidea y fosfatasa alcalina en niños escolares.

INTRODUCTION: The main role of Vitamin D is to regulate calcium metabolism, whose main source is vitamin D3 ob tained mostly from the action of ultraviolet (UV) light on the skin. OBJECTIVE: To evaluate the seaso nal differences in the concentrations of 25-hydroxy-vitamin D3 (25OHVitD3), parathyroid hormone (PTH), alkaline phosphatase (ALP), and calcium in school-age children. SUBJECTS AND METHOD: The concentrations of 25OHVitD3, PTH, ALP, and calcium were measured in children from Santiago, Chile (latitude -33.4372), aged 5 to 8 years, without Vitamin D supplementation, in different seasons of the year. VitD status was defined as sufficient with concentrations of 25OHVitD3 >20 ng/mL (50 nmol/L), insufficient 12-20 ng/mL (30-50 nmol/L) and deficient <12 ng/mL (30 nmol/L) based on the recommendations of the expert group of the "Global Consensus for the Prevention and Mana gement of Nutritional Rickets". RESULTS: 133 children participated (89 preterms under or equal to 32 weeks), 41 during summer, 28 in fall, 35 in winter, and 29 in spring. The difference of means between summer and winter was 9.6 ng/mL for 25OHVitD3 (p <0.0001), -11.1 pg/mL for PTH (p <0.0001), and -47.5 IU/mL for ALP (p= 0.01). There were no differences in calcium concentrations. In sum mer, 97.6% of the subjects were classified with sufficiency status (> 20 ng/mL), which decreased significantly in winter to 54.3% (p <0.0001). CONCLUSIONS: In winter, 25OHVitD3 concentrations decreased in approximately half of the children, which was associated with an increase in PTH and ALP, and normal calcium concentrations. According to our results, children may need VitD supple mentation during fall and winter.

[Adult height of children with idiopathic short stature treated with growth hormone therapy]. / Estatura final en niños con talla baja idiopática tratados con hormona del crecimiento.

INTRODUCTION: Idiopathic short stature (ISS) is defined as a height of < or = 2 standard deviations (SD) from the mean for age. The use of Growth Hormone (GH) in ISS is controversial, and there are not results for adult height (AH) in Chilean patients with ISS treated with GH. The objective of the study is to compare AH in patients treated with GH with the height prediction at beginning of treatment. PATIENTS AND METHOD: AH was considered with bone age ≥ 17 in males and ≥15 in females. The height SD according to the NCHS curves at beginning and ending of treatment were used for the comparison. Height prediction (HP) was calculated by Bayley-Pinneau method. RESULTS: AH was reached by 18/47 patients with ISS treated with GH. Initial height -2.1 ± 0.85 SD (133.1±6.8 cm) and HP -1.94±0.86 SD, and were treated since 11.6 ± 1.2 years old. After one year of treatment their height was -1.64 ± 0.69 SD, and AH was -1.28 +/- 0.62 SD (163.76 +/- 7.22 cm). CONCLUSION: It is suggested that treatment with GH for ISS is effective to increase AH. Although with wide individual variability, a mean increase of 0.67±0.9 SD (+2.67 cm) was obtained in the AH. This is the first report on Adult Height in Chilean patients.

Leuprolide acetate-stimulated androgen response during female puberty.

BACKGROUND: A physiological increase in androgen levels occurs during adolescence. Measuring androgen concentrations is the best method to distinguish normal evolution processes from hyperandrogenic disorders. HYPOTHESIS: The increase in circulating androgens during puberty is inversely associated with insulin sensitivity in normal weight girls. OBJECTIVE: To assess circulating levels of ovarian androgens and anti-Müllerian hormone (AMH) at baseline and after GnRH analogue (GnRH-a) stimulation in normal pubertal girls across different Tanner stages. We also studied the association between this response and insulin sensitivity. DESIGN: Prospective study of healthy girls (6-12 years) from the local community (n = 63). METHODS: Tanner I (n = 23) subjects were assessed cross-sectionally, and Tanner II girls (n = 40) were evaluated every 6 months until they reached Tanner V. Early morning dehydroepiandrosterone sulphate (DHEA-S), AMH, sex hormone-binding globulin (SHBG), androstenedione, glucose and insulin levels were measured. A GnRH-a test (500 µg/m(2) ; sc) and oral glucose intolerance test (OGTT) were performed. Differences throughout puberty were evaluated. RESULTS: Basal and/or stimulated Testosterone DHEA-S and 17-hydroxyprogesterone (17OHP) were inversely associated with insulin sensitivity (WIBSI) from the beginning of puberty, whereas androstenedione was directly associated with gonadotrophins. AMH was inversely associated with basal and stimulated gonadotrophins and directly with insulin area under the curve (AUC) only in the early stages of puberty. 17OHP and testosterone responsiveness increased significantly during puberty in all subjects, whereas testosterone levels changed less consistently. This pattern of ovarian-steroidogenic response was most evident during mid- and late puberty. Moreover, during late puberty only, basal 17OHP, testosterone and DHEA-S were positively associated with gonadotrophins. CONCLUSION: In normal nonobese girls born appropriate for gestational age, androgen synthesis was associated with insulin sensitivity in early puberty and with LH only in late puberty.

[Diagnostic yield of fine-needle aspiration cytology for the detection of thyroid cancer in pediatric patients]. / Concordancia de la citología por punción con aguja fina para la detección de cáncer de tiroides en pediatría.

BACKGROUND: Despite the low frequency of thyroid nodules (TN) in children, one of every four is malignant. Fine-needle aspiration cytology (FNAC) has a high accuracy detecting thyroid cancer. AIM: To evaluate the performance of FNAC in TN in Chilean children to detect thyroid cancer. PATIENTS AND METHODS: The pathological reports of 77 thyroidectomies and 103 FNAC carried out in patients aged less than 18 years, between 2002 and 2013 were reviewed. In 36 patients aged 15 ± 2 years (77% women), both the reports of the thyroidectomy and FNAC were available. The cytological specimens were reclassified based on Bethesda 2010. The histology was classified as benign (nodular hyperplasia and follicular adenoma, n = 18), or malignant (papillary, follicular and medullar carcinoma, n = 18). The concordance of the cytology with the final biopsy report was calculated. RESULTS: FNAC classified 13 specimens as definitively benign and 13 as definitively malignant. Among these, these concordances with the pathological study of the biopsy was 100%. Of six cytology tests considered "suspicious for follicular neoplasm" by FNAC, four were benign (67%), and two malignant (33%). Of four cytology tests considered "suggestive of carcinoma" by FNAC, one was benign (25%), and three malignant (75%). CONCLUSIONS: Among the studied children, there was a good concordance between FNAC and surgical biopsies. Therefore a FNAC should be carried out when malignancy is suspected in pediatric patients with a TN.

Positive association between aldosterone-renin ratio and carotid intima-media thickness in hypertensive children.

INTRODUCTION: From an early age, hypertension can damage blood vessels through multiple mechanisms. The aim of this study was to evaluate the presence of vascular damage and whether it is associated with the mineralo- and glucocorticoid profiles of hypertensive children. SUBJECTS AND METHODS: We studied 64 hypertensive children. Anthropometric parameters and serum aldosterone (SA), plasma renin activity (PRA), aldosterone/renin ratio (ARR), cortisol (F) and cortisone (E) were measured. The serum F/E ratio was calculated to estimate the activity of the enzyme 11ß-HSD2. Vascular damage was determined by carotid intima-media thickness (cIMT) and flow-mediated dilation of the brachial artery (FMD) on ultrasound. RESULTS: (median; Q1-Q3) Of the patients observed, 39% were females, and the median value for age (years) was 11.2 (9.1-13.3), for BMI (SDS) was 1.36 (0.84-1.80), for body fat mass (%) was 28.3 (17.8-36.0), for SBP index was 1.17 (1.12-1.25) and for the DBP index was 1.27 (1.16-1.36). Measurements revealed an SA level higher than 491 pmol/l in 4/64 patients, a PRA value lower than 0.5 ng/ml/h in 2/64, an ARR higher than 10 in 3/64 and serum F/E ratio higher than 4.3 in 10/64. The median brachial FMD (%) was 8.41 (5.61-10.91), and the median cIMT (mm) was 0.40 (0.37-0.43). The ARR was the only variable that explained changes in cIMT (ß = 0.571, R(2 ) = 0.315, P < 0.0001). CONCLUSION: Our results showed a positive association between cIMT and the ARR, suggesting an important role of the renin-aldosterone axis in the regulation of early vascular damage in hypertensive children.

Accelerated early pubertal progression, ovarian morphology, and ovarian function in prospectively followed low birth weight (LBW) girls.

AIM: To compare pubertal development in age-matched healthy girls born with low birth weight (LBW) or appropriate birth weight for gestational age (AGA). SUBJECTS AND METHODS: Girls with breast in Tanner stage II and normal body mass index were followed for 3 years with a complete physical exam, bone age, pelvic ultrasound, and measurement of gonadal hormones using a leuprolide test. RESULTS: Forty-one girls (AGA 25/LBW 16) were followed up for 3 years. By 3 years, they had similar bone age, adjusted height, and body composition. In LBW girls, breast Tanner stage advanced faster during the first 2 years of follow-up, which was associated with higher serum androgens. Hirsutism score, ovarian volume, and number of follicles between AGA and LBW were not different nor was age of menarche. By the third year, basal and poststimulated levels of gonadotropins and androgens anti-Müllerian hormone and inhibin B were similar in both groups and did not show differences related to birth weight or degree of catch-up growth. CONCLUSION: LBW recruits showed a slightly faster breast development but no differences in androgen excess signs, internal genitalia, and gonadal hormonal patterns.

Clinical Update on Congenital Adrenal Hyperplasia: Recommendations from a Multidisciplinary Adrenal Program.

Congenital adrenal hyperplasia (CAH) is a common genetic disorder in endocrinology, especially its milder clinical presentation, often caused by a partial or total deficiency of the 21-hydroxylase enzyme located in the adrenal cortex. CAH is characterized by the overproduction of androgen, along with variable degrees of cortisol and aldosterone deficiency. The age at diagnosis can provide some information about underlying mutations, with those diagnosed at birth/early infancy more likely to have severe enzymatic defects, which may include adrenal insufficiency, sexual development disorders, short stature in adulthood, hirsutism, and a higher risk for metabolic syndrome and infertility. Non-classic CAH, a milder form of CAH, is usually manifested later in life and is a common differential diagnosis of Polycystic Ovary Syndrome and should be actively evaluated during initial studies of clinical or biochemical hyperandrogenism. The main goals of CAH treatment are hormone supplementation for severe cases, controlling adrenal androgen overproduction to minimize long-term side effects, managing fertility and genetic counseling, and optimizing patients' quality of life.

[New Insulins for Type 1 Diabetes treatment]. / Nuevas Insulinas en el tratamiento de la Diabetes Tipo 1.

Insulin therapy is complex in pediatric patients because they present greater variations in insulin requirements. Traditional insulins have limitations related to time of onset of action and duration of effect, which has led to the development of new insulins, seeking to reduce chronic complications, severe or nocturnal hypoglycemia, and to improve adherence to therapy. This review updates the information on new insulins, their mechanisms of action and the benefits they provide in the treatment of diabetes. Insulin analogues attempt to mimic the physiological secretion of the hormone, including time of action and duration of effect. The most used prandial analogs are the so-called rapid-acting insulins, including Faster Aspartic and the new basal insulins, glargine U300 and degludec, which have a prolonged action of more than 24 hours and therefore require a daily dose. New technologies under development include biosimilar insulins such as the glargine biosimilar, already available in the clinic. New formulations are being developed for the future, as well as novel ways of dispersing them, mimicking the action of pancreatic cells, which will allow a more physiological and personalized management of the disease.

Extremely and very preterm children who were born appropriate for gestational age show no differences in cortisol concentrations or diurnal rhythms compared to full-term children.

OBJECTIVES: The objective of this study was to compare the diurnal variations in cortisol and cortisone concentrations in serum and saliva among extremely preterm (EPT), very preterm (VPT), and full-term (FT) children, all born appropriate for gestational age (AGA). METHODS: EPT, VPT, and FT children, all born AGA, were recruited from two healthcare centers. Cortisol and cortisone concentrations in serum and saliva were measured by liquid chromatography-mass spectrometry (LC‒MS). Statistical analysis was performed using nonparametric tests. RESULTS: A total of 101 children (5.0-8.9 years old) were included in this study: EPT=18, VPT=43 and FT=40. All groups had similar distributions in terms of age, birth weight standard deviation score (SDS) and BMI (SDS), showing no differences in serum ACTH, cortisol, or cortisone levels. Additionally, salivary cortisol and cortisone concentrations decreased significantly throughout the day (p-values<0.0001). Salivary cortisol concentrations were below the limit of detection (0.55 nmol/L) before dinner and before bedtime in approximately one-third and two-thirds of all children, respectively. Salivary cortisone was detectable in all but one sample. CONCLUSIONS: The diurnal cortisol rhythm was preserved in all preterm children, regardless of their gestational age, and no differences in cortisol concentrations among the groups were found. This may have significant implications for the clinical management and follow-up of preterm individuals.

Birth weight is inversely associated with blood pressure and serum aldosterone and cortisol levels in children.

CONTEXT: Low birth weight has been independently associated with adult hypertension, and renin-angiotensin system (RAS) plays a role in this connection. OBJECTIVE: To characterize the associations between birth weight (BW) and serum aldosterone (SA), serum cortisol, plasma renin activity (PRA) and blood pressure (BP). DESIGN: Cross-sectional study. SUBJECTS: Children from the community born at a gestational age >32 weeks. METHODS: Systolic and diastolic BP indices (SBPi and DBPi) were calculated using the observed BP/50th percentile BP for gender, age and stature. BW was transformed to a standard deviation score (SDS) for gestational age, whereas SA, serum cortisol and PRA were transformed using the natural log. RESULTS: We selected 288 subjects between the ages of 4·9 and 15·5 years (Females, 50%). After adjusting for body mass index (BMI) SDS and Tanner, multiple regression analysis revealed that BW (SDS) was both independently and inversely associated with the natural log of SA (ß = -0·065; P = 0·039), the natural log of serum cortisol (ß = -0·064; P = 0·009), SBPi (ß = -0·012; P = 0·020) and DBPi (ß = -0·023; P = 0·002). An association was not observed with PRA (P = 0·178) and aldosterone renin ratio (ARR) (P = 0·452). Serum cortisol levels were positively associated with SA (r = 0·125; P = 0·034), while an association with PRA (P = 0·251) and ARR (P = 0·052) was not observed. CONCLUSIONS: The results of this study demonstrate an inverse association between birth weight and blood pressure and serum aldosterone and cortisol levels. This association is independent of BMI and Tanner, suggesting foetal programming of the hypothalamic-pituitary-adrenal axis.

Insulin resistance parameters in children born very preterm and adequate for gestational age.

BACKGROUND: Preterm neonates are at risk for metabolic syndrome later in life. Whether prematurity constitutes an independent risk factor for the development of cardiovascular disease and metabolic syndrome remains controversial. OBJECTIVE: To compare anthropometric measures, cardiometabolic risk factors and insulin resistance variables between children who were born very preterm (VPT, <32 gestational weeks) and at term (Term, >37 gestational weeks) and adequate for gestational age (AGA). METHODS: We designed a cross-sectional cohort study, recruiting 120 children (5.0-8.5 years old) from the preterm clinic at Red de Salud UC-Christus and Complejo Asistencial Dr. Sótero del Río, and term children from the community. We excluded children born small for gestational age, based on INTERGROWTH21. Anthropometrics data were classified using WHO reference standards. The homeostasis model assessment insulin resistance (HOMA-IR) index, quantitative insulin sensitivity check index (QUICKI), triglyceride-to-HDL-C ratio (TG/HDL-C) and Pediatric Score Index for Metabolic Syndrome (PsiMS) were calculated. RESULTS: VPT children born AGA had lower HDL cholesterol levels (p = .019) and a higher PsiMS score than those born at term (p = .043). We observed a higher percentage of children with HDL cholesterol ≤40 mg/dl (13.0% vs. 2.3%, p = .026) and BP ≥90th percentile among the VPT children than among the Term children (26.0% vs. 11.6%, p = .031). CONCLUSIONS: At school age, blood pressure was higher, and HDL-C was lower among VPT children born AGA, suggesting a potential metabolic risk; therefore, it is essential to follow this group throughout their lives.

[Prevalence of hypertension in school age children and its association with obesity]. / Prevalencia de hipertensión arterial y su asociación con la obesidad en edad pediátrica.

BACKGROUND: Hypertension in children is a frequently overlooked problem that is an important cardiovascular risk factor. AIM: To determine the prevalence of hypertension among school age children. MATERIAL AND METHODS: Cross-sectional study of 2980 children aged 10 ± 2 years (48% females) from 10 schools of middle and lower class in Metropolitan Santiago. Blood pressure (BP) was measured in the sitting position on three occasions after a rest period, using a mercury sphygmomanometer with appropriate cuff arm diameter, averaging the results of the measurements. Systolic and diastolic hypertension were defined as blood pressure values over 95 percentile for age, sex and height. RESULTS: The overall prevalence of hypertension was 12.2% in women and 15% in men (p < 0.05). According to nutritional status, the prevalence was 6.7, 8.9,13.6 and 26% in underweight, eutrophic, overweight and obese children, respectively (p < 0.01). Compared with normal weight children, the risk of being hypertensive for overweight children was 1.6 (95% confidence intervals (CI) 1.2-2.3) and for obese children was 3.6 (95% CI 2.8-4.7). CONCLUSIONS: The studied children had a high prevalence of hypertension, that was directly related to a higher body mass index.

Quality of Life in Chilean Transgender Children and Adolescents.

INTRODUCTION: Transgender (TG) children and adolescents experience problems in school as well as with family and social relationships that can adversely affect their physical and psychosocial health and impair their quality of life (QoL). This study aimed to assess health-related quality of life (HRQoL) in TG children. METHODS: We performed a cross-sectional study comparing HRQoL in gender non-conforming (Trans) and gender-conforming (CIS) children and adolescents using the Spanish version of KIDSCREEN-52 in 120 Chilean Trans and CIS children (aged 8-18 years) and their parents. All scores were standardized according to the KIDSCREEN manual. RESULTS: Among the 100 questionnaires answered, 38 corresponded to children and adolescents aged 8.4-18 years. Twenty-one of them were TG (71% trans males) and 17 were CIS (76% females). Sixty-two parents answered the questionnaires: 33 from families of TG children (PTrans) and 29 from families of CIS children (PCis). Trans children had lower HRQoL scores in all domains than CIS children. The lowest-scoring domains for TG children were "Moods and Emotions," "Psychological Well-Being" and "Social Acceptance," and the highest-scoring domain was "School Environment." The PTrans group had significantly higher scores than the Trans group for 3 of the 10 domains: "Psychological Well-Being," "Moods and Emotions," and "Parent Relations and Home Life." CONCLUSION: Our results revealed that TG children and adolescents have lower QoL than their CIS counterparts, especially regarding items related to mental health. Furthermore, their parents may underestimate their well-being, confirming the vulnerability of the TG population. This finding underlies the need to perform early assessments of QoL for early detection and intervention in aspects that could deteriorate their quality of life.

New autosomal recessive mutations in aquaporin-2 causing nephrogenic diabetes insipidus through deficient targeting display normal expression in Xenopus oocytes.

Aquaporin-2 (AQP2), located at the luminal side of the collecting duct principal cells, is a water channel responsible for the final concentration of urine. Lack of function, often occurring through mistargeting of mutated proteins, induces nephrogenic diabetes insipidus (NDI), a condition characterized by large urinary volumes. In the present study, two new mutations (K228E and V24A) identified in NDI-affected individuals from distinct families along with the already reported R187C were analysed in comparison to the wild-type protein (AQP2-wt) using Xenopus laevis oocytes and a mouse collecting duct cell-line (mIMCD-3). Initial data in oocytes showed that all mutations were adequately expressed at reduced levels when compared to AQP2-wt. K228E and V24A were found to be properly targeted at the plasma membrane and exhibited adequate functionality similar to AQP2-wt, as opposed to R187C which was retained in internal stores and was thus inactive. In coexpression studies using oocytes, R187C impeded the functionality of all other AQP2 variants while combinations with K228E, V24A and AQP2-wt only showed additive functionalities. When expressed in mIMCD-3 cells, forskolin treatment efficiently promoted the targeting of AQP2-wt at the plasma membrane (>90%) while K228E only weakly responded to the same treatment (approximately 20%) and both V24A and R187C remained completely insensitive to the treatment. We concluded that both V24A and K228E are intrinsically functional water channels that lack a proper response to vasopressin, which leads to NDI as found in both compound mutations studied (K228E + R187C and V24A + R187C). The discrepancies in plasma membrane targeting response found in both expression systems stress the need to evaluate such data using mammalian cell systems.

Primary aldosteronism and its impact on the generation of arterial hypertension, endothelial injury and oxidative stress.

Aldosterone plays an important role in blood pressure homeostasis, the regulation of circulating volume, and the maintenance of the sodium-potassium balance by binding to the mineralocorticoid receptor (MR). Primary aldosteronism (PA) states are associated with an increased cardiovascular risk, mediated not only by hypertension but also by the action of aldosterone in the modulation of vasodilation/vasoconstriction and oxidative stress. In this review, we discuss some of the cardiovascular actions of aldosterone and the most frequent causes of PA.

Urinary sodium-to-potassium ratio and plasma renin and aldosterone concentrations in normotensive children: implications for the interpretation of results.

OBJECTIVES: To identify associations among the plasma renin concentration (PRC), plasma aldosterone and urinary sodium (Na)/potassium (K) ratio, and to integrate these variables into a nomogram with the aim of estimating the expected versus observed aldosterone concentration. METHODS: We studied 40 healthy normotensive children (5-8 years old, 57.5% girls) who were born at term and were adequate for their gestational age. Following overnight fasting, the PRC and plasma aldosterone in blood samples were measured, and the Na/K ratio was calculated from a simultaneously obtained urinary spot sample. A mathematical function was defined with these three variables, and a nomogram was built that would return the expected aldosterone concentration from the obtained plasma renin and urinary Na/K ratio values. RESULTS: The PRC (B =  5.9, P < 0.001) and urinary Na/K ratio (B = -98.1, P = 0.003) were significant independent predictors of plasma aldosterone. The correlation between the observed plasma aldosterone and the expected plasma aldosterone, as obtained from the nomogram, was r = 0.88, P < 0.001. The average difference between the observed and expected plasma aldosterone was -0.89, with a standard deviation of ±30%. CONCLUSION: The strong correlation between the urinary Na/K ratio, from urine samples taken at the same as the blood samples, and plasma renin and aldosterone concentrations allowed us to build a nomogram to predict aldosterone levels. This approach may be useful for evaluating the renin-angiotensin-aldosterone system (RAAS) in pediatric patients with hypertension and RAAS dysfunction.

Mild fasting hyperglycemia in children: high rate of glucokinase mutations and some risk of developing type 1 diabetes mellitus.

BACKGROUND: Incidental hyperglycemia in children generates concern about the presence of preclinical type 1 diabetes mellitus (T1DM). OBJECTIVE: To genetically evaluate two common forms of maturity-onset diabetes of youth (MODY), the short-term prognosis in children with mild hyperglycemia, and a positive family history of diabetes mellitus. SUBJECTS: Asymptomatic children and adolescents (n = 14), younger than 15 yr, with fasting hyperglycemia, a positive family history of mild non-progressive hyperglycemia, and negative pancreatic autoantibodies were studied. PATIENTS AND METHODS: Glucokinase gene (GCK) and hepatocyte nuclear factor 1 alpha gene (HNF1A) causing two common forms of MODY were sequenced. The clinical outcome was evaluated after a follow-up period of 2.8 +/- 1.3 yr. RESULTS: GCK mutations were present in seven children. The confirmation of this diagnosis allowed discontinuation of insulin in two families and oral medications in three families. Mutations of HNF1A were not detected in any of the families. During the follow-up period, all the GCK mutation carrier children remained asymptomatic without medication and the last hemoglobin A1c levels were 6.4 +/- 0.7%. In the GCK-negative children (n = 7), one developed T1DM, corresponding to 7.2% of the total group. Mild fasting hyperglycemia persisted during follow-up in four GCK-negative children and normalized in the remaining two. CONCLUSIONS: The presence of mild persistent hyperglycemia in any patient without autoantibodies should lead to genetic analysis of GCK, particularly if there is a positive family history. Furthermore, those without GCK mutations should be followed with repeat autoantibody testing, and other genetic types of diabetes should be considered if hyperglycemia worsens.