Caso clinicoUna lattante di 6 mesi, con anamnesi negativa, è giunta presso il pronto soccorso pediatrico per la comparsa, nell'arco di poche ore, di ittero isolato.Nella settimana precedente aveva effettuato la vaccinazione antimeningococcica, seguita da lieve puntata febbrile isolata.All'esame fisico la bambina era in discrete condizioni generali, con parametri vitali stabili, senza segni di disidratazione.Gli esami ematici mostravano anemia, trombocitopenia, iperbilirubinemia indiretta, incremento dell'LDH e modico rialzo della PCR [Tabella 1].Nell'ipotesi di anemia emolitica, veniva eseguito lo striscio venoso periferico, con conferma di aniso-poichilocitosi e rari schistociti; test di Coombs diretto/indiretto negativo e aptoglobina indosabile.Nel sospetto di una microangiopatia trombotica, è stato dosato il fattore ADAMTS13, risultato >30%; negatività della ricerca di anticorpi anti-ADAMTS13.Esclusa l'ipotesi di sindrome di Moschcowitz, si è posta diagnosi di sindrome uremico-emolitica; nel frattempo si è evidenziata una iniziale alterazione della funzionalità renale, con creatinina ai limiti superiori del range per età [Tabella 2] e riscontro di ridotta differenziazione cortico-midollare all'ecografia renale, segnale di iniziale danno corticale renale.

Background: To assess whether previously identified obesity-susceptibility loci were associated with overweight/obesity risk in a homogeneous population of Caucasian schoolchildren and whether these associations varied with age. Methods: Seven hundred and forty-five schoolchildren (353 boys, mean age: 8.3 ± 1.4 years) underwent anthropometric assessments. A saliva sample was collected for DNA extraction and assessment of 19 single-nucleotide polymorphisms previously associated with obesity. Results: Only the rs12970134 in the MC4R gene was significantly associated with overweight/obesity risk, with a higher frequency of the AA risk genotype in children with a BMI >85th (8.3%) than in those with a BMI <85th percentile (3.0%), p = 0.001; odds ratio (95% CI) of 1.544 (1.192-1.998), p = 0.001, after adjusting for age, sex and pubertal stage. BMI standard deviation scores (SDS) and waist-to-height ratio (W/Hr) progressively increased across the rs12970134 genotypes (GG vs. AG vs. AA): BMI SDS, p = 0.004; W/Hr, p = 0.009. When dividing the study population into two groups based on the median age of participants (8.3 years), the differences in BMI SDS and W/Hr across the MC4R genotypes persisted only in children older than 8.3 years. Conclusions: In a population of Caucasian schoolchildren, the rs12970134 MC4R variant was significantly associated with excess body weight, particularly in children older than 8 years of age.

OBJECTIVEGNRH analog (GNRHa) therapy has not been supported by beneficial effects on adult stature in girls with early puberty. Furthermore, an increased prevalence of polycystic ovary syndrome (PCOS) has been described in girls treated for central precocious puberty. Women with PCOS are at increased risk of cardiometabolic dysfunctions and infertility. Our aim was to assess GNRHa effectiveness on reaching adult stature and the risk of PCOS in girls with early puberty.DESIGNLongitudinal study of GNRHa-treated and GNRHa-untreated girls at baseline and at final height.METHODSTwenty-five GNRHa-treated girls and 55 controls were compared. Insulin resistance (IR; homeostasis model assessment of IR (HOMA-IR) and glucose-to-insulin ratio (G/I)), the effect of GNRHa on final height, and the prevalence of PCOS were assessed.RESULTSIn GNRHa-treated girls, no significant difference was found between predicted final height and final height, whereas a significant difference was detected in untreated girls (P=0.0001). At final height, GNRHa-treated girls showed higher HOMA-IR and lower G/I (P=0.03 for both) as well as higher DHEAS and androstenedione levels (P=0.02 and P=0.01 respectively) than untreated girls. The prevalence of PCOS and hyperandrogenemia was significantly higher in GNRHa-treated adolescents than in untreated adolescents (36 and 14.5% respectively, P=0.04; 56 and 23.6% respectively, P=0.01). Finally, gonadotropin-suppressive therapy was significantly related to PCOS during adolescence (P=0.03).CONCLUSIONSIn girls with early puberty, GNRHa therapy is associated with the achievement of predicted final height; nevertheless, this treatment seems to act as an independent risk factor for the development of PCOS already during adolescence.

Insulin resistance is a key component of the metabolic syndrome (MS) and is strongly associated with liver steatosis. Our aim was to evaluate whether MS should be diagnosed already in obese prepubertal children and whether its prevalence is influenced by the inclusion of hepatic steatosis as a diagnostic criterion. Eighty-nine obese children (43 boys; age median [range], 8.5 [6-10] years) were enrolled. Metabolic syndrome was diagnosed according to a classic definition: presence of 3 or more of the following criteria—body mass index greater than 2 standard deviation score, triglycerides greater than the 95th percentile, high-density lipoprotein cholesterol less than the fifth percentile, blood pressure greater than the 95th percentile, and impaired glucose tolerance. Afterward, liver steatosis was included as an additional criterion to this definition. Metabolic syndrome was diagnosed in 12 children (13.5%) according to the first definition and in 18 children (20.2%) when liver steatosis was included. The prevalence of MS increased across homeostasis model assessment of insulin resistance tertiles (P for trend = .01). The prevalence of the single components of the MS was as follows: obesity, 100%; hypertriglyceridemia, 27%; low high-density lipoprotein cholesterol, 2.2%; hypertension, 34.8%; impaired glucose tolerance, 4.5%; and nonalcoholic fatty liver disease, 21.3%. In conclusion, MS is common already among prepubertal obese children, particularly when liver steatosis is included among the diagnostic criteria. Therefore, screening for the MS should be performed in this age group; and hepatic steatosis should be considered as an additional diagnostic criterion.

Episodic spontaneous hypothermia is an infrequent disorder, the pathogenic mechanisms of which have not been completely clarified, although alterations in the serotoninergic system have been suggested. We report the history of a girl with episodes of dizziness and shivering associated with a body temperature lower than 35°C since the age of 10 months. At the age of 11 years, she was admitted to a local hospital and an oral glucose tolerance test showed high total insulin levels. Hypoglycemia secondary to hyperinsulinemia was suspected, and a low-carbohydrate (simple) diet was proposed without results. Due to the recurrence of the episodes, episodic spontaneous hypothermia triggered by hyperinsulinemia was suspected, and treatment with flunarizine, a drug considered the first line in the treatment of migraine-related disorders, was started with a resulting reduction in the episodes. A new endocrinological evaluation showed decreased insulin secretion. In our patient, the success of the therapy might be due to the well-known effect of calcium antagonists in inhibiting serotonin uptake and thereby regulating serotonin levels after hyperinsulinism. This case suggests hyperinsulinemia as a potential mechanism for episodic spontaneous hypothermia, probably mediated by an interaction between insulin and the serotoninergic system.

The AGE-RAGE pathway has been considered as an important mediator of early glomerular changes in diabetic patients. Several growth factors and vasoactive molecules involved in early nephropathy have been shown to be directly produced as a consequence of RAGE activation. Furthermore, the C-truncated form of the endogenous secretory RAGE (esRAGE) has been shown to reveale the system function. Therefore, we tested whether impaired esRAGE concentrations are associated with early signs of diabetic nephropathy (DN), defined as changes in kidney volume and renal resistive indexes (RIs). A group of 56 prepubertal and pubertal normoalbuminuric patients with type diabetes (T D) with at least 4 years diabetes duration, were recruited and compared with 54 age, sex and pubertal stage matched controls. In all subjects, anthropometric measurements (height, BMI) were evaluated and esRAGE was measured in fasting blood samples. Kidney ultrasonography was performed and renal volume was calculated using the ellipsoid formula and adjusted for body surface. In addition, doppler ultrasonographic registration of intrarenal RI was performed. esRAGE was significantly lower in prepuberal (0.45±0.18 vs 0.9±0.8 ng/ml, p= 0.013) and postpubertal (0.4±0.17 vs 0.75±0.48 ng/ml, p=0.02) patients with T1D compared with controls. In both prepubertal and pubertal subjects, mean-kidney volume (p=0.03 and p=0.01) and mean doppler RI values (p=0.013 and p=0.002) were significantly increased in T D patients when compared with controls. In a multiple regression analysis, an inverse relationship between esRAGE and adjusted kidney mean volume (p=0.042, beta=-0.367) was documented in diabetic patients. This study demonstrated decreased levels of esRAGE which appeared to be strongly related to increased kidney volume and RI in normoalbuminuric prepubertal children and adolescents with T D, suggesting a potential role of esRAGE in the development of kidney disease. However, further longitudinal studies are required in order to define a causal-effect relationship between esRAGE and the risk of DN later in life.

OBJECTIVE:To determine whether in obese prepubertal children insulin resistance (IR) is associated with the development of liver steatosis.METHODS AND PROCEDURES:Cross-sectional study evaluating the prevalence of liver steatosis in 100 severely obese prepubertal children and comparing IR indexes between children with (group 1) and without steatosis (group 2). Furthermore, IR indexes were compared to values of 50 normal weight children. Fasting blood samples were collected for the evaluation of liver function tests, lipid profile, plasma glucose, and insulin levels. All children underwent an oral glucose tolerance test and anthropometric measurements. Hepatic ultrasound was performed according to international criteria and by one single operator. Analysis was performed by Mann-Whitney U-test, Pearson correlation, and logistic regression.RESULTS:Liver steatosis was found in 52% obese children and was equally distributed between the two sexes. Obese children were more insulin resistant when compared to controls (homeostasis model assessment of IR (HOMA-IR): P = 0.0001; whole body insulin sensitivity index (WBISI): P = 0.0005; fasting glucose/fasting insulin ratio (G/I): P = 0.0001), and group 1 presented an even higher degree of IR when compared to group 2 (HOMA-IR P = 0.0001; WBISI P = 0.0004; G/I P = 0.0001). The area under the curve (AUC) for insulin was significantly higher in group 1 when compared to group 2, while no difference was found in the AUC for glucose. There was no association between IR and adiposity indexes (P >0.05). The role of IR as a predictor for the development of steatosis was analyzed by multiple logistic regression, which documented that IR indexes were significantly related to steatosis independently of BMI-SDS.DISCUSSION:Liver steatosis is an emerging problem in prepubertal severely obese children, and it appears to be an association between liver steatosis and IR in these subjects.

The AGE-RAGE pathway has been considered as an important mediator of early glomerular changes in diabetic patients. Several growth factors and vasoactive molecules involved in early nephropathy have been shown to be directly produced as a consequence of RAGE activation. Furthermore, the C-truncated form of the endogenous secretory RAGE (esRAGE) has been shown to reveale the system function. Therefore, we tested whether impaired esRAGE concentrations are associated with early signs of diabetic nephropathy (DN), defined as changes in kidney volume and renal resistive indexes (RIs). A group of 56 prepubertal and pubertal normoalbuminuric patients with type diabetes (T D) with at least 4 years diabetes duration, were recruited and compared with 54 age, sex and pubertal stage matched controls. In all subjects, anthropometric measurements (height, BMI) were evaluated and esRAGE was measured in fasting blood samples. Kidney ultrasonography was performed and renal volume was calculated using the ellipsoid formula and adjusted for body surface. In addition, doppler ultrasonographic registration of intrarenal RI was performed. esRAGE was significantly lower in prepuberal (0.45±0.18 vs 0.9±0.8 ng/ml, p= 0.013) and postpubertal (0.4±0.17 vs 0.75±0.48 ng/ml, p=0.02) patients with T1D compared with controls. In both prepubertal and pubertal subjects, mean-kidney volume (p=0.03 and p=0.01) and mean doppler RI values (p=0.013 and p=0.002) were significantly increased in T D patients when compared with controls. In a multiple regression analysis, an inverse relationship between esRAGE and adjusted kidney mean volume (p=0.042, beta=-0.367) was documented in diabetic patients. This study demonstrated decreased levels of esRAGE which appeared to be strongly related to increased kidney volume and RI in normoalbuminuric prepubertal children and adolescents with T D, suggesting a potential role of esRAGE in the development of kidney disease. However, further longitudinal studies are required in order to define a causal-effect relationship between esRAGE and the risk of DN later in life.

OBJECTIVES:To investigate the relationship between ambulatory blood pressure (ABPM) parameters and insulin resistance in obese children. METHODS:A population of 56 obese prepubertal children was recruited for the study. They underwent ABPM, an oral glucose tolerance test and complete physical examination, including adiposity indexes such as body mass index (BMI), skinfolds, waist-to-hip ratio (WHR) and fat mass. RESULTS:The standard deviation score for BMI was significantly correlated with 24-h systolic blood pressure (SBP) (r = 0.30; P = 0.02) and diastolic blood pressure (DBP) (r = 0.29; P = 0.03), daytime SBP and DBP (r = 0.28; P = 0.04 and r = 0.32; P = 0.02), night-time SBP and DBP (r = 0.32; P = 0.01 and r = 0.27; P = 0.04). Fat mass was correlated with 24-h SBP (r = 0.46; P = 0.005), daytime SBP (r = 0.40; P = 0.01) and night-time SBP (r = 0.49; P = 0.03). No correlations were found between ABPM parameters and WHR. Furthermore, significant correlations were found between insulin resistance indexes, such as the homeostasis model assessment of insulin resistance and quantitative insulin-sensitivity check index, and 24-h DBP (r = 0.34; P = 0.01 and r = -0.29; P = 0.03), daytime DBP (r = 0.35; P = 0.009 and r = -0.34; P = 0.01) and daytime SBP (r = 0.32; P = 0.02 and r = -0.27; P = 0.04). Only 24-h and daytime DBP remained correlated with insulin resistance after adjustment for obesity. The analysis of the circadian rhythm of blood pressure revealed that 24 out the 56 children were non-dippers. CONCLUSIONS:The results of the present study indicate that adiposity and insulin resistance have an important role in influencing blood pressure in obese children, and also show a high prevalence of non-dipping phenomenon. This is of particular relevance because blood pressure tracks from childhood into adulthood and an already early-life high blood pressure is associated with an increased cardiovascular risk.

We studied the evolution of beta-cell function in 32 children treated for acute lymphoblastic leukemia (ALL) through a long-term follow-up after completion of therapy. Our results show that although alterations of the glucose metabolism persists after stop-therapy they are reversible with time.

Responses to GH vary among etiologies and among patients within an etiology. The relationship between GH dose and response remains one of the challenges of Rx. Frasier et al. ( ) published a dose-response curve for exogenous human GH at doses of 30, 60, 80 and 00 mIU/kg TIW 25 yrs ago. Given that 3 IU = mg and converting from TIW to total dose per week, the Frasier doses were 0.03, 0.06, 0.08, and 0. 0 mg/kg/wk. The data were described by the equation 14.28 + 5.80 * log10 (dose in mg/kg/wk) which is a rather flat response. First yr growth data from GH deficient (GHD) patients with characteristics similar to Frasier’s were selected from Genentech’s (GNE) National Cooperative Growth Study (NCGS) and GNE trials with TIW dosing to provide an update based on larger numbers. The new equation is .88 + 3.89 * log10 (dose in mg/kg/wk), even “flatter” than the Frasier equation. The figure below illustrates the new equation. Ranke et al. (2) presented a multiple regression equation for st yr growth velocity in GHD with a coefficient of 1.62 for the natural logarithm for the dose in IU/kg/wk. Translated to log10 and mg/kg/wk, the coefficient for Ranke’s equation is 3.73, which is not notably different from that obtained from the combined GNE and Frasier data for GHD. Results for TIW and daily (QD) treatment for GHD and TIW and QD for Idiopathic Short Stature (ISS) from NCGS and GNE trials are also in the figure but not used to compute the new equation. While QD gives a better response than TIW, and GHD patients respond better than ISS patients, their positions on the curve confirm the flatness of dose response. Conclusion: A new dose response equation for st yr GH treatment is presented and demonstrates clearly that the curve is rather flat. For the physician choosing to individualize the dose to achieve a specific therapeutic goal, characteristics of this response curve need to be considered. Ref: ) Frasier SD et al. J Clin Endocrinol Metab 53:1213, 1981. 2) Ranke M et al: J Clin Endo Metab 84:1174, 1999.

Oxidant-antioxidant status was investigated in a group of severely obese prepubertal children in comparison with healthy subjects and in relation to a dietary restriction-weight loss program. All subjects underwent anthropometric measurements and determination of lipid profile, lag phase, malondialdehyde (MDA), and vitamin E. Compared with controls, obese children had a significantly higher body mass index (BMI) (28.97 +/- 2.42 vs. 16.03 +/- 1.88 kg/m2; P = 0.0002) and waist-to-hip ratio (WHR) (0.89 +/- 0.03 vs. 0.80 +/- 0.01; P = 0.0004); lag phase and vitamin E levels were significantly decreased [24.05 +/- 16.21 vs. 43.16 +/- 10 min (P = 0.004) and 21.12 +/- 14.96 vs. 35.54 +/- 13.62 micromol/liter (P = 0.02), respectively], whereas MDA was significantly increased (0.90 +/- 0.31 vs. 0.45 +/- 0.24 nmol/mg; P = 0.001). Both lag phase and MDA significantly correlated with BMI [respectively, r = -0.34 (P = 0.004) and r = 0.57 (P = 0.002)] and WHR [respectively, r = -0.63 (P = 0.0001) and r = 0.38 (P = 0.04)]. Oxidant status normalized after 6 months of dietary restriction [lag phase, 59.11 +/- 14.74 min (P = 0.002); MDA, 0.47 +/- 0.09 nmol/mg (P = 0.003)], which was associated with a reduction of BMI (27.34 +/- 1.87 kg/m2; P = 0.003), WHR (0.87 +/- 0.02; P = 0.001), and fat mass (34.49 +/- 2.68%; P = 0.008), but returned to baseline levels together with fatness indexes after another 6 months of free diet. Altered oxidant-antioxidant status is already present in prepubertal severely obese children and is reversible with a dietary restriction-weight loss program, which should be highly encouraged and maintained over time in this age group.

An 8-year-old girl was referred in October, 2004, for evaluation of persistent hyperferritinaemia. She was otherwise healthy and had an unremarkable past medical and family history. High serum ferritin concentrations; 1103·7 μg/L; (NR: 10–120) were incidentally diagnosed at the age of 5 years when she underwent routine blood testing, and ferritin remained high over the next 3 years. Blood tests on admission showed hyperferritinaemia (1100 μg/L), with normal levels of serum iron (15 μmol/L; range 6·6–30), total iron binding capacity (41 μmol/L; 36–65), soluble transferrin receptor (19 mg/L; 8·3–17), haptoglobin (0·7 g/L; 0·3–2) and reticulocytes (1·1%; range 0·5–1·5). Total number of red blood cells (6·65×1012/L), haemoglobin concentration (132 g/L), mean corpuscular volume (76·8 fl), mean corpuscular haemoglobin (27·3 pg) and mean corpuscular haemoglobin concentration (356 g/L) were normal. The erythrocyte sedimentation rate and C-reactive protein concentration were normal. Liver, kidney, pancreatic, and thyroid function tests were normal and autoantibodies were negative. Chest radiographs showed no abnormalities. Cardiac function, assessed by electrocardiogram and ultrasound, was normal. Abdominal ultrasound and liver MRI excluded the presence of iron overload and tissue damage.