Abstract Objectives Data on the predictive values of parameters included in the diagnostic work-up for precocious puberty (PP) remain limited. We detected the diagnostic value of basal sex hormone levels, pelvic ultrasound parameters and bone age assessment for activation of the hypothalamic-pituitary-gonadal axis in girls with PP, in order to help in the decision to perform GnRH testing. Patients and methods We retrospectively considered 177 girls with PP. According to puberty evolution, the girls were divided into two groups: rapid progressive central precocious puberty (RP-CPP) and non/slowly progressive/transient forms (SP-PP). In all patients we considered Tanner stage, basal luteinizing hormone (LH) and estradiol (E2) values, bone age, and pelvis examination. We assessed the diagnostic value of each variable and identified the number of pathological parameters that best identify patients with RP-CPP. Results Basal LH ≥ 0.2IU/L, E2 level ≥ 50 pmol/L, uterine longitudinal diameter ≥ 3.5 cm, transverse uterine diameter ≥ 1.5 cm, endometrial echo and ovarian volume ≥ 2 cm3 were significantly associated with RP-CPP (p ≤ 0.01). The ability to diagnose RP-CPP was enhanced with increasing number of pathological hormonal and instrumental parameters (p < 0.001). With more than three parameters detected, sensitivity and specificity reached 58% (95%CI 48–67) and 85% (95%CI 74–92), respectively, with a PPV = 86% (95%CI 76–93) and PPN = 54% (95%CI 43–54); the area under the ROC curve was 0.71 (95%CI 0.65–0.78). Conclusion Despite the availability of different tests, diagnosing RP-CPP remains difficult. A diagnosis model including at least three hormonal and/or ultrasound parameters may serve as a useful preliminary step in selecting patients who require GnRH testing for early detection of RC-PP.

Patients with autoimmune thyroid disease (ATD) have a higher prevalence of autoimmune gastritis (AIG) compared with the general population. The association between ATD and AIG is poorly characterized in the pediatric age. We reviewed the prevalence of anti-gastric parietal cell antibodies (PCA) in young patients with ATD to evaluate its usefulness as a marker for AIG screening. We evaluated 220 children and adolescents (11.28 ± 6.37 years) with ATD (186 with autoimmune thyroiditis (AT) and 34 with Graves’ disease (GD). At ATD diagnosis and annually thereafter, blood counts and PCA levels were measured. In patients positive for PCA, plasma gastrin, chromogranin A, vitamin B12, iron and ferritin levels and H. pylori antigen were measured. PCA-positive patients > 18 years were invited to undergo a gastroscopic exam. PCA positivity was detected in ten (4.5%) subjects (5F/5M; 12.6 ± 3.4 years). The prevalence of PCA positivity was not significantly different in the comparison of GD and AT patients (p = 0.9). PCA positivity was detected after 2.7 ± 2.7 years of follow-up in AT and 4.4 ± 4.0 years in GD (p = 0.4). Autoantibody positivity was more prevalent in female patients, in both AT and GD (p = 0.02 and p = 0.03, respectively). At detection of PCA positivity, five out of ten PCA-positive patients had iron deficiency, four vitamin B12 deficiency, two anemia, three hypergastrinemia and two elevated chromogranin values. Two patients had H. pylori infection. Gastroscopy was performed in the five ATD patients and in all patients, AIG was confirmed. In the juvenile population, ATD and AIG may also be associated. PCA screening is useful to detect subjects at risk for this condition. Due to the longer life expectancy of the pediatric population and considering the relatively high risk of malignant transformation, early surveillance monitoring is mandatory for children and adolescents with ATD.

Abstract Objectives Limited data on the evolution of thyroid disorders (TD) in Down syndrome (DS) are available. We characterized the timing, prevalence, and dynamics of TD in patients with DS during a long-term follow-up. Methods We retrospectively evaluated 91 children and adolescents with DS (12.5 ± 8.3; follow-up 7.5 ± 6.2). Children were monitored at birth, 6, and 12 months of age and twice a year thereafter. Thyroid status and autoimmunity were periodically investigated. Results TD were detected in 73.6% of patients, in particular congenital hypothyroidism (CH), autoimmune thyroid diseases (ATD) and subclinical hypothyroidism (SH) were recorded in 16.4, 31.8, and 25.3%, respectively. CH was diagnosed at newborn screening in 86.7% of cases and in the first 6 months of life in the remaining 13.3%; the condition was persistent in 61.5% of patients. In more than 30% of CH cases, glandular hypoplasia was also revealed. In the ATD group, 63.1% of patients with Hashimoto’s disease (HD, 82.6%) were treated with levothyroxine and subjects with Graves’ Disease (GD, 17.4%) started therapy with methimazole. DS with SH were treated in 42.1% of cases. A thyroid hypogenic echopattern, without autoantibody positivity was identified in 27.6% of SH patients. Conclusions The high prevalence and evolution of TD in SD requires frequent monitoring starting in the first months of life. CH can be misdiagnosed at screening. In DS subjects, there is a high prevalence of ATD and non-autoimmune diseases with early antibody-negative phases should not be excluded.

Background: The incidence of autoimmune thyroid diseases (ATD) may vary with the beginning of reproductive function, although few reports differentiate the incidence before and during the onset of puberty, examining gender bias. We analyzed onset of ATD in a pediatric population to assess gender differences in onset age, disease subtype, pubertal status, autoimmune co-morbidity, family history and treatment, focusing on the interaction between gender and pubertal stage. Patients and methods: We retrospectively recorded 382 children and adolescents with ATD. In each patient physical examination was considered. The presence of other associated autoimmune diseases (AAD) and familial predisposition was also recorded. Results: Predominant prevalence was noted in females compared to males (p < 0.001), both in Hashimoto's diseases (HD or HT) and Graves' disease (GD) (p < 0.001). Mean age at diagnosis showed no significant difference between sexes (p > 0.05). A higher prevalence in pubertal subjects was noted compared to prepubertal (p < 0.001, particularly HT in early and GD in late pubertal stage), without sexes difference intra-(prepubertal vs. pubertal) and inter-puberty groups (prepubertal vs. early pubertal vs. late pubertal). Both in HT and in GD, the prevalence of autoimmune associated diseases (AAD) was higher in males compared to females (p = 0.04), with similar distribution according to the pubertal maturation. The familial predisposition was similarly distributed in both genders (p > 0.05) and into pubertal stages (p > 0.05). Conclusions: Females are more prone to develop ATD during puberty, earlier in HT than in GD. The effect of puberty is not different between genders, suggesting the role of additional factors other than hormones. The screening for detection of ATD is recommended in all patients with positive family history and other autoimmune diseases, mostly in males. Considerations of gender in pediatrics could be important to define pathogenic mechanisms of ATD and to help in early diagnosis and clinical management.

Background The coexistence of celiac disease (CD) and obesity/overweight is not unusual. Objective We investigate the prevalence and clinical presentation of CD, detected by screening, among children with excessive weight gain. Methods We enrolled 200 children referred for overweight/obesity to our outpatient clinic. Medical history during pregnancy and childhood and lifestyle variables were recorded. Patients were screened for CD with total immunoglobulin A (IgA), IgA anti-transglutaminase (tTG-IgA) and IgA anti-endomysial antibodies (EMA-IgA). In subjects with positive autoantibodies, esophagogastroduodenoscopy (EGDS) was performed and genetic testing for HLA DQ2 and/or DQ8 haplotypes was tested. Results CD positive antibodies (tTg-IgA and EMA-IgA) were detected in eight patients (4%); in all subjects CD diagnosis was confirmed by HLA-DQ2 and/or DQ8 compatibility and EGDS. No association between CD and medical history during pregnancy and childhood or lifestyle variables was noted; however, a dietary difference was identified with those testing positive for CD also reporting a lower weekly consumption of fruits and vegetables (p=0.04). Headache was reported more frequently in patients with than without CD (p=0.04). Familiar positivity for autoimmune diseases was revealed in CD patients (p=0.01). Conclusion CD should be considered in children with excessive weight gain. Familial predisposition to other autoimmune diseases may represent a risk factor for development of CD. Even though the relationship between headache and CD is not well defined, the patients with headache of unknown origin should be screened for CD.

Background We depicted gender-differences in metabolic syndrome (MS) clustering before and after puberty in pediatrics, in order to develop gender specific preventive strategies for childhood obesity. Methods We considered 1079 children and adolescents (529 females and 550 males; mean age 11.5 ± 2.8 year). According to body mass index (BMI) percentiles the subjects were classified as normal weight BMI <75th, overweight BMI 75-95th and with obesity BMI >95th. MS was diagnosed when three of the following criteria for age and sex percentiles were met: BMI >95th, triglycerides (TGs) level >95th, high-density lipoprotein-cholesterol (HDL-c) level <5th, blood pressure (blood pressure) >95th percentile, fasting blood glucose (FBG) >100 mg/dL and/or homeostatic model assessment- insulin resistance (HOMA-IR) >97.5th percentile. Results The prevalence of dismetabolic factors was similar in both genders, except for pathological BP, which was higher in males (p = 0.02). MS was detected only in patients with obesity, with a higher prevalence in pubertal than late/post-pubertal subjects (p < 0.001), without any significant difference between gender. In pre-puberty, the most common MS combination was obesity (HBMI) + hypertension (HBP) + hyperglycemia/insulin resistance (HGLY/IR) followed by HBMI + low HDL-levels (LHDL) + HGLY/IR versus HBMI + HBP + HGLY/IR followed by HBMI + HBP + LHDL, respectively, in females and males. In the early and late/post-pubertal periods, the most prevalent combination remained similar to pre-puberty, additionally in both sexes other combinations, such as HBMI + HTG + HBP + HGLY/IR, HBMI + HBP + LHDL + HGLY/IR, HBMI + HTG + LHDL + HGLY/IR and HBMI + HTG + LHDL + HBP + HGLY/IR were also detected, differently distributed in males and females. Conclusions We confirm that MS is an important consequence related to obesity, particularly in the post-puberty stage. Some gender-based differences should be considered early in order to identify specific preventive and treatment strategies.

Celiac disease (CD) may be considered as a systemic immune-mediated disorder that is triggered by dietary gluten in genetically susceptible subjects.CD children and adolescents show typical intestinal symptoms such as diarrhea, loss of weight and abdominal distension, or extraintestinal signs, the so-called nonclassical CD, such as short stature and delayed puberty.An endocrinological investigation including an evaluation of growth hormone (GH) secretion should be performed in CD subjects who show no catch-up growth after at least 1 year on a strict gluten-free diet (GFD) in the presence of a seronegativity of anti-transglutaminase and/or antiendomysial antibodies.When the diagnosis of GH deficiency is formulated, a substitutive therapy with GH must be promptly started to obtain a complete catch-up growth.The long-term effects of GH therapy in CD children who follow a strict GFD are comparable to those found in children with idiopathic GHD.A widely documented association has been observed between CD and type I diabetes mellitus and/or Hashimoto thyroiditis and/ or Addison's disease.During follow-up, pediatricians should check antibody serology, thyroid and adrenal function and glucose-metabolic profile in order to verify the compliance with both diet and GH treatment.Adherence to a strict gluten-free diet promotes regular linear growth and may prevent CD complications as well as the onset of other autoimmune diseases.

Introduction: Allostatic load (AL) refers to the physiological response associated with the burden of chronic stress. Excessive weight is an important source of physiological stress that promotes a detrimental chronic low-inflammation state. In order to define a correlation between cumulative biological dysregulation and excess weight, we measured AL scores in a pediatric population. Patients and Methods: We enrolled 164 children and adolescents (11.89 ± 3.89). According to their body mass index (BMI) threshold, subjects were classified as normal in the BMI < 75th percentile, overweight in the BMI 75–95th percentile or obese in the BMI >95th percentile. Data based on 16 biomarkers were used to create the AL score. A dichotomous outcome for high AL was defined in those who had more than four dysregulated components. Results: High AL was noted in 88/164 subjects (53.65%), without significant differences between genders (p = 0.07) or pubertal status (p = 0.10). Subjects with a high AL, in addition to a higher BMI (p < 0.001), showed higher WC and WC/HtR (p < 0.001), triglycerides (p = 0.002), fasting blood glucose (p = 0.03), insulin resistance (p < 0.001), systolic (p < 0.001) and diastolic blood pressure (p = 0.001), GGT (p = 0.01), PCR (p = 0.01), and calprotectin (p < 0.01) as well as lower HDL cholesterol (p = 0.002) than subjects with a low AL. The rate of the cumulative biological dysregulation increased progressively with increases in BMI (p < 0.001). Conclusions: A high AL was associated with excess weight. AL may be considered a significant factor correlated with increased morbidity in children who are overweight/obese.

Background/Aim: The relationship between type 1 diabetes mellitus (T1DM) and autoimmune thyropathies is well known and has been described in the literature. Based on present knowledge, the relationship between thyropathies and other forms of diabetes, such as monogenic diabetes, has not been investigated. The aim of our study was to assess the prevalence of autoimmune thyroid diseases (ATD) in children and adolescents with maturity onset diabetes of the young type 2 (MODY2) in comparison with patients with T1DM and a control group. Patients and Methods: We examined 23 children and adolescents with MODY2 (11 F/12 M; 13.5 ± 5.3 years) and 166 patients with T1DM (80 F/86 M; 14.0 ± 4.7 years). The control group consisted of 62 age-matched healthy subjects (34 F/28 M). ATD diagnosis was based on the finding of one or more positive thyroid autoantibodies and characteristic thyroid ultrasound lacking homogeneity, with a hypogenic or mixed echo pattern. Results: ATD was diagnosed in 15 (10.5%; 9 F/6 M) patients with T1DM, in 4 with MODY2 (17.4%; 4 F), and in 1 (1.6%) control. A significantly higher ATD prevalence was detected in T1DM and MODY2 compared to the control subjects (p = 0.02), without differences between T1DM and MODY2 (p = 0.26). There were no gender differences noted in T1DM (p = 0.42); on the contrary, in MODY2 a higher prevalence was noted in females (p = 0.04). Celiac disease and a positive family history of ATD were not detected in subjects with MODY2. Conclusion: Our study showed an increased prevalence of ATD in patients with MODY2. Therefore, a careful follow-up of all children with MODY2 is recommended in order to assess the presence of thyroid disorders.

Objective:The triglyceride and glucose (TyG) index has been proposed as a simple surrogate of insulin resistance (IR) with high sensitivity as an IR index besides the well known homeostasis model assessment of IR (HOMA-IR). Limited data are reported in children. We investigated the sensitivity and specificity of TyG index in a pediatric Caucasian population, as a surrogate measure of IR and compared the results with HOMA-IR. Methods:We enrolled 541 children (11.7±2.71 yrs). According to body mass index (BMI) chart, the subjects were divided into three groups: normal weight BMI<75th percentile, overweight BMI 75th–95th percentile, and obese>95th percentile. TyG index was calculated as (ln[fasting triglycerides(mg/dl)×fasting plasma glucose(mg/dl)/2]) and considered pathological when exceeding 7.88. HOMA-IR was calculated as (insulin×glucose)/22.5 and defined pathological whenever exceeding 97.5th percentile for age and sex. Results:In children with overweight/obesity TyG index was higher compared to normal weight subjects (p<0.001). TyG index was correlated with BMI (p<0.001); WHtR (p<0.001), total and HDL cholesterol (p<0.001); ALT (p<0.001), blood pressure (p<0.001). A correlation between TyG index and HOMAIR (p<0.001) as well as high TyG index and pathological HOMA-IR (p<0.001) were noted. The optimal cut-off for IR was considered 7.98 (sensitivity 60%; specificity 78%; AUC 0.69). Conclusions:TyG index is a useful and cost-effective index of IR among children and adolescents. The cutoff 7.98 may be used for IR risk screening in childhood obesity, but we recommend caution when used in other populations.

In patients with autoimmune disease, gynecomastia should not be considered as 1 of the first signs of hyperthyroidism, rather it is a breast pathology that can be present even when euthyroidism restoration is achieved. It is unknown whether the autoimmune nature of thyroid disorders or simply the hyperthyroidism effects breast changes.

Introduction: dietary therapy plays an important role in keeping good blood glucose level in patients with type 1 diabetes (T1D). We evaluated the influence of carbohydrate counting (CC) on auxological parameters and metabolic management in children and adolescents with T1D. Methods and Materials: we enrolled all pediatric patients with T1DM followed up in our outpatient Pediatrics Diabetology Unit at IRCCS Policlinic San Matteo of Pavia, between June 2016 and June 2017. In all subjects the diagnosis was made or confirmed at least 6 months before this study started. All subjects were treated with a basal bolus insulin regimen by means of multiple daily injections or continuous subcutaneous insulin infusion with pump. Subjects were classified as “adherent” or “not adherent” to CC; auxological (weight, height, BMI score and BMI-z score) and metabolic parameters (glycated hemoglobin (HbA1c), insulin needs/24h, insulin to carbohydrates ratio (ICR), insulin-sensitivity factor (ISF)) were recorded Results: Of all the patients enrolled (n=134; 75M/ 59F; mean age 12.6±5.1 years) diagnosed with T1DM, 21 (15.7%) were adherent to CC (16 of them were on pump insulin therapy, 5 on multiple injection insulin therapy). HbA1c was not statistically different in the two groups (p=0.46 and p=0.6, respectively). Patients adherent to CC tended to show higher BMIs (p=0.005) as well as BMI z-score (p=0.04) and overweight (p=0.03) than the non adherent group. the non adherent group showed lower ICR (p=0.04) and ISF (p=0.04), significantly related to the BMI (p<0.001). Conclusion: CC represents a good alternative to the classic nutritional treatment in children and adolescents diagnosed with T1DM. Moreover, CC may influence weight and metabolic management, so it is necessary to be appropriately trained on the adequate dietary recommendations and the right counting method.

To evaluate the relationship between smoking and metabolic parameters in patients affected by type 1 diabetes (T1D).

OBJECTIVE:Patients with Turner syndrome (TS) have an unfavorable cardiometabolic profile. Hyperhomocysteinemia is a potential cardiovascular risk factor influenced by genetic and environmental factors, therapies, unbalanced diets and other lifestyle factors. We retrospectively studied the relationship between total plasma homocysteine (Hcy), serum vitamin B12 (B12) and folate concentration in TS patients, taking into account the genetic profile, diet, smoking habits, hormonal therapies and dietary supplements of the subjects.PATIENTS AND METHODS:We evaluated 50 TS patients (31.5 ± 12.5 years). Medication, including vitamin supplementation, was obtained. Eating habits, cigarette smoking, alcohol and coffee consumption were investigated using phone interviews. Levels of Hcy metabolism parameters were classified by using the relevant cutoff value for an adult population and compared with a reference sample drawn from the general population.RESULTS:Inadequate Hcy and B12 levels were noted, despite vitamin supplementation. Holotranscobalamin (HoloTC) was above the relevant cutoff in the population, and supplemented subjects showed mean levels lower than nonsupplemented subjects (p = 0.005). Dietary supplementation (p = 0.038), lifestyle (coffee consumption, p = 0.01) and hormonal replacement therapy (p = 0.02) are important factors for Hcy metabolism. No genetic influence on Hcy levels was noted. Multivariable regression analysis identified vitamin supplementation (p = 0.045) as the only independent predictor of increased Hcy levels.CONCLUSION:Cardiovascular risk in TS can be reduced using educational approaches to a healthy lifestyle with dietary guidelines. Besides this, we also recommend measuring HoloTC for the prompt detection of B12 deficiency and to consider hormone replacement therapy in the biochemical assessment of homocysteine in TS.

We studied by a whole genomic approach and trios genotyping, 12 de novo, nonrecurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis and associated with increased maternal age. Four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event. Maternal hetero/isodisomy was detected with a paternal origin of the sSMC in some cases, whereas in others two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. In other cases, the homologs were biparental while the sSMC had the same haplotype of the maternally inherited chromosome. These findings strongly suggest that most sSMCs are the result of a multiple-step mechanism, initiated by maternal meiotic nondisjunction followed by postzygotic anaphase lagging of the supernumerary chromosome and its subsequent chromothripsis.