Thyroid function, sensitivity to thyroid hormones, and metabolic syndrome in euthyroid children and adolescents with Down syndrome.

PURPOSE: Patients with Down Syndrome (DS) showed multiple comorbidities, including thyroid disorders, obesity, and metabolic derangement. Different thyroid hormone (THs) patterns and sensitivity to thyroid hormone indices (STHI) seem to be associated with metabolic disorders. The study's aim was to evaluate the prevalence of metabolic syndrome (MS) in pediatric patients affected by DS, taking into consideration the relationship between the metabolic parameters, THs and STHI. METHODS: We enlisted 50 euthyroid patients with DS (9.03 ± 4.46). Clinical parameters, TSH, FT3, FT4 and the presence of MS were recorded. Indexes of peripheral sensitivity (FT3/FT4 ratio) and central sensitivity (TSH index, TSHI; TSH T4 resistance index, TT4RI; TSH T3 resistance index, TT3RI) were also detected. Thirty healthy subjects were included as a control group. RESULTS: MS was detected in 12% of the subjects with DS. FT3, FT4, and TSH levels were higher in DS than in the control group (p < 0.01); higher levels of FT3/FT4 ratio, TSHI and TT3RI and lower TT4RI values (p < 0.01) were also detected. A significant correlation was detected between FT3 and fasting blood glucose (FBG) (R = 0.46), triglyceride (TG) (r = 0.37), total (r = 0.55) and high density lipoprotein-cholesterol (HDL-C) (r = - 0.38), diastolic blood pressure (DBP) (r = - 0.4); FT3/FT4 ratio and waist circumference (WC) (r = 0.36); TSHI and total (r = 0.30) and HDL cholesterol (r = - 0.31); TT4RI and HDL cholesterol (r = - 0.31); TT3RI and total (r = 0.39) and HDL cholesterol (r = - 032). CONCLUSION: We confirmed a higher MS prevalence in children with DS compared to the control group. A significant association between THs, STHI, and the glucose and lipid metabolism parameters was detected supporting their role in metabolic alterations related to the DS.

Non-thyroidal illness syndrome and SARS-CoV-2-associated multisystem inflammatory syndrome in children.

PURPOSE: COVID-19 disease may result in a severe multisystem inflammatory syndrome in children (MIS-C), which in turn may alter thyroid function (TF). We assessed TF in MIS-C, evaluating its impact on disease severity. METHODS: We retrospectively considered children admitted with MIS-C to a single pediatric hospital in Milan (November 2019-January 2021). Non-thyroidal illness syndrome (NTIS) was defined as any abnormality in TF tests (FT3, FT4, TSH) in the presence of critical illness and absence of a pre-existing hormonal abnormality. We devised a disease severity score by combining severity scores for each organ involved. Glucose and lipid profiles were also considered. A principal component analysis (PCA) was performed, to characterize the mutual association patterns between TF and disease severity. RESULTS: Of 26 (19 M/7F) patients, median age 10.7 (IQR 5.8-13.3) years, 23 (88.4%) presented with NTIS. A low FT3 level was noted in 15/23 (65.3%), while the other subjects had varying combinations of hormone abnormalities (8/23, 34.7%). Mutually correlated variables related to organ damage and inflammation were represented in the first dimension (PC1) of the PCA. FT3, FT4 and total cholesterol were positively correlated and characterized the second axis (PC2). The third axis (PC3) was characterized by the association of triglycerides, TyG index and HDL cholesterol. TF appeared to be related to lipemic and peripheral insulin resistance profiles. A possible association between catabolic components and severity score was also noted. CONCLUSIONS: A low FT3 level is common among MIS-C. TF may be useful to define the impact of MIS-C on children's health and help delineate long term follow-up management and prognosis.

Phenotypes of prediabetes and metabolic risk in Caucasian youths with overweight or obesity.

PURPOSE: To assess the prevalence of pre-diabetes phenotypes, i.e., impaired fasting glucose (IFG), impaired glucose tolerance (IGT), increased HbA1c (IA1c), and their association with metabolic profile and atherogenic lipid profile in youths with overweight/obesity (OW/OB). METHODS: This cross-sectional study analyzed data of 1549 youths (5-18 years) with OW/OB followed in nine Italian centers between 2016 and 2020. Fasting and post-load measurements of glucose, insulin, and HbA1c were available. Insulin resistance (IR) was estimated by HOMA-IR and insulin sensitivity (IS) by reciprocal of fasting insulin. The atherogenic lipid profile was assessed by triglycerides-to-HDL ratio or cholesterol-to-HDL ratio. Insulinogenic index was available in 939 youths, in whom the disposition index was calculated. RESULTS: The prevalence of overall pre-diabetes, IFG, IGT and IA1c was 27.6%, 10.2%, 8% and 16.3%, respectively. Analyzing each isolated phenotype, IGT exhibited two- to three-fold higher odds ratio of family history of diabetes, and worse metabolic and atherogenic lipid profile vs normoglycemic youths; IFG was associated only with IR, while IA1c showed a metabolic and atherogenic lipid profile intermediate between IGT and IFG. CONCLUSION: Prevalence of pre-diabetes was high and IA1c was the most prevalent phenotype in Italian youths with OW/OB. The IGT phenotype showed the worst metabolic and atherogenic lipid profile, followed by IA1c. More studies are needed to assess whether HbA1c may help improving the prediction of diabetes.

Anti-gastric parietal cell antibodies for autoimmune gastritis screening in juvenile autoimmune thyroid disease.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Deep breathing acutely improves arterial dysfunction in obese children: evidence of functional impairment?

BACKGROUND AND AIMS: Similarly to diabetes type 2, patients with obesity show insulin resistance and autonomic and vascular abnormalities associated with increased morbidity and mortality. We tested whether arterial dysfunction in obese children may have a functional nature, reversible with appropriate interventions (e.g., by reduction of sympathetic activity), or else results from anatomic arterial modifications (likely irreversible). For this purpose, we tested whether deep breathing (an intervention known to transiently reduce sympathetic activity) could acutely improve arterial function, hence showing a functional abnormality. METHODS AND RESULTS: A total of 130 obese children and 67 age-matched healthy normal-weight control children were recruited. Arterial function was measured by augmentation index (AIx), by direct analysis of blood pressure contour, and by pulse wave velocity (PWV), during spontaneous and controlled breathing. The markers of metabolic syndrome were evaluated at baseline. AIx showed increased values in obese male participants as compared with the control group. Slow breathing acutely reduced Aix in obese children, to a greater extent than in normal-weight control children. Similarly, the blood pressure contour showed higher values in obese children that were significantly attenuated by slow breathing. Baseline PWV was not altered in obese participants. The markers of metabolic syndrome correlated with AIx and PWV. CONCLUSIONS: Obese subjects showed impaired arterial function. The acute improvement in vascular abnormalities with reduction in sympathetic activity indicates that this alteration was largely functional, likely related to initial autonomic dysfunction and to metabolic abnormalities. As a consequence, this study provides a rationale for strategies aiming at preventing arterial function deterioration in the early ages.

Diagnosis of growth hormone deficiency is affected by calibrators used in GH immunoassays.

Growth hormone (GH) values vary among immunoassays depending on different factors, such as the assay method used, specificity of antibodies, matrix difference between standards and samples, and interference with endogenous GH binding proteins (GHBPs). We evaluated whether the use of different calibrators for GH measurement may affect GH values and, consequently, the formulation of GH deficiency (GHD) diagnosis in children. Twenty-three short children (5 F, 18 M; age 11.4±3.1 years), with the clinical characteristics of GHD (height: -2.3±0.5 SDS; height velocity -2.3±1.5 SDS; IGF-I -1.2±0.9 SDS), underwent GH stimulation tests to confirm the clinical diagnosis of GHD. Serum GH values were measured with Immulite 2000, using 2 different calibrators, IS 98/574, a recombinant 22 kDa molecule of more than 95% purity, and IS 80/505, of pituitary origin and resembling a variety of GH isoforms. We found blunted GH secretion in 20 subjects with the Immulite assay using the IS 98/574 GH as a calibrator, confirming the diagnosis of GHD. Subsequently, using IS 80/505 GH as a calibrator, in the same samples only 14 children showed reduced GH levels. The total cost for the first year of GH therapy of patients diagnosed with IS 98/574 as a calibrator was higher than that for patients diagnosed with IS 80/505 as a calibrator. These data confirm that GH values may depend on different calibrators used in the GH assay, affecting the formulation of GHD diagnosis and the consequent decision to start GH treatment.

HHV6 meningoencephalitis sequelae in previously healthy children.

INTRODUCTION: Human herpes virus 6 (HHV6) infection is a self-limiting illness occurring in early childhood. As with other herpes viruses, the encephalopathy associated with HHV6 is often attributable to the reactivation of a virus previously latent in human brain tissue. Previous reports on HHV6 encephalopathy dealt mainly with virus reactivation in immune-depressed older children and, above all, refer to encephalitis and not to meningoencephalitis. Complications are rare in healthy children. Encephalopathy has rarely been associated with HHV6 infection in children not affected by chronic disease. PURPOSE: The aim of this study was to evaluate sequelae of HHV6 meningoencephalitis in previously healthy children. RESULTS: We report three cases of HHV6 meningoencephalitis in previously healthy children followed for a 10-year period. Two of the patients presented invalidating sequelae. In detail, one patient developed speech disturbance and the other persistent hemiplegia and bilateral visual deficit. To our knowledge, this is the first case in which an ocular complication developed in the course of HHV6 meningoencephalitis. CONCLUSION: HHV6 meningoencephalitis can be associated with a wide range of clinical outcomes, from long-term neurological sequelae to a benign post-infectious clinical course.

Neurological manifestations of Kawasaki disease and multisystem inflammatory syndrome in children associated with COVID-19: A comparison of two different clinical entities.

Kawasaki disease (KD) is one of the most frequent idiopathic vasculitis in children, affecting medium- and small-sized vessels. Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 has recently emerged as a new systemic hyperinflammatory condition affecting children some weeks after an acute COVID-19 infection. KD and MIS-C share different aspects and differ in many others: patients affected by MIS-C are usually older, with prominent gastrointestinal manifestations, diffuse adenopathy, extensive conjunctivitis, myocardial damage, leukopenia, and thrombocytopenia at the laboratory exams. Both conditions can present neurological complications. The aim of this manuscript is to provide a narrative review of neurological involvement in KD and MIS-C. A comprehensive review literature has been performed, and the main clinical features have been analyzed, contributing to neurological differential diagnosis.

Reduced sebum production in Turner syndrome: a study of twenty-two patients.

Turner's syndrome (TS) is a genetic disorder caused by numeric and/or structural abnormalities of the X chromosome. In a previous study it was observed that acne is less frequent in TS than in the general population. Since the onset of acne in pre-pubertal or pubertal age is related to sebum production, this study evaluates sebum secretion in TS patients, comparing the results with those of a control group of age-matched healthy female subjects. A total of 22 patients affected by TS (mean age 26.56±7.89 years) and a control group of 23 age-matched healthy females were studied. Sebum production was measured using a Sebumeter SM810. Mean sebum secretion in TS subjects was significantly lower than in the control group (81.35±66.44 UA vs 147.09±33.62 UA, p<0.001) and this significant difference was found in every facial zone. The reduction of sebum secretion may explain, using a simple and non-invasive method, the absence or the low incidence of acne in TS patients.

Thrombophilic screening in Turner syndrome.

AIM: The aim of this study was to determine, in patients with Turner syndrome (TS), the prevalence of thrombophilic disorders correlating with a higher risk of venous thromboembolism (VTE), to evaluate if thrombophilia is associated with the genetic features of these patients and whether screening before hormone replacement therapy (HRT) is advisable. PATIENTS AND METHODS: We examined 82 TS patients. In all patients we analyzed activated factor VIII:C, fibrinogen, antithrombin (AT), protein C (PC), protein S (PS), activated PC resistance, and homocysteine. For every patient, an investigation for mutations in prothrombin G20210A, factor V R506Q, methylenetetrahydropholate reductase (MTHFR) C 677T and A1298C was conducted. RESULTS: Low values of PC in 3 patients (3.70%), low values of PS in 12 (14.81%), and hyperhomocysteinemia in 4 (4.87%) were found; 52 girls (64.2%) presented hyperfibrinogenemia. Three patients were heterozygous for the prothrombin G20210A allele mutation (3.66%) and the factor V mutation was present in 4 patients (4.88%). No TS patient had a homozygous mutation. Mutations in the MTHFR gene were present in 62 girls, in 17 patients (20.7%) they were homozygous and in 45 patients (54.88%) heterozygous. CONCLUSIONS: Considering the increased risks with the association between VTE and the higher prevalence of PC and PS deficiencies, TT genotype mutations and high level of fibrinogen, it is advisable to perform a complete thrombophilia screening in TS patients before starting HRT.

Thyroid ultrasound in patients with Turner syndrome: influence of clinical and auxological parameters.

OBJECTIVES: To determine thyroid volume and structure by ultrasound (US) in patients with Turner syndrome (TS) compared to healthy controls; to evaluate the frequency and characteristics of autoimmune thyroid disease (ATD) and its association with clinical and auxological parameters. PATIENTS: 73 patients and 93 height-matched healthy female controls in the same age range were included in the study. RESULTS: Thirty-two TS patients (43.8%) presented ATD. They had a larger body mass index (BMI) and presented the 45,X karyotype more frequently than those without. They were older, with a higher prevalence of lymphoedema at birth and pterygium colli without statistical significance. Thyroid volume was 20% larger in the presence of ATD (p=0.037). A dyshomogeneous thyroid structure was observed in all patients with ATD and less frequently in those without (p=0.016). Dyshomogeneity in TS without ATD was also associated with older age (p<0.001), larger BMI (p=0.003) and larger thyroid volume (p=0.006). Six TS patients presented solitary thyroid nodules (5 benign nodules). We observed a significant interaction between diagnosis and height (p=0.035) and age (p=0.047), indicating that both age and height conditioned the observed differences in thyroid volume. CONCLUSIONS: Most TS patients presented ATD with a normal thyroid function or subclinical hypothyroidism, without goiter. Dyshomogeneous thyroid structure was also observed in TS patients without ATD. In TS, the evaluation of thyroid volume according to chronological age does not seem to be efficient because of a link between height and thyroid volume. The prevalence of nodular thyroid disease is similar to that observed in the general population.

Early-onset metabolic syndrome in prepubertal obese children and the possible role of alanine aminotransferase as marker of metabolic syndrome.

INTRODUCTION: Obesity is often associated with increased serum alanine aminotransferase (ALT), and elevation of ALT is a marker of non-alcoholic fatty liver disease which is caused in part by insulin resistance, the essential characteristic of metabolic syndrome (MS). We evaluated the prevalence of MS in prepubertal obese children and the usefulness of ALT as an MS marker. PATIENTS: 120 obese children (6.3 ± 1.6 years old) and 50 normal-weight controls (5.3 ± 2.0 years old) were included. Patients were classified as having MS if they met ≥ 3 of the following criteria: body mass index >97th percentile, triglycerides >95th percentile, high-density lipoprotein cholesterol <5th percentile, systolic (SBP) and/or diastolic (DBP) blood pressure >95th percentile, fasting blood glucose 100 mg/dl and/or impaired insulin sensitivity with homeostasis model assessment for insulin resistance >97.5th percentile. ALT levels were also evaluated. RESULTS: MS occurred in 16.6% of obese patients. Significant differences were present in body mass index (p < 0.001), SBP (p = 0.002) and DBP (p < 0.001) between non-MS and MS obese patients; laboratory data, except total cholesterol, were significantly different in the two groups. The strongest association with MS (as evaluated by the c-statistic) was found for insulin and homeostasis model assessment for insulin resistance (c = 0.92 and 0.91, respectively); also, DBP and SBP showed good discrimination ability (c = 0.73 and 0.72, respectively). ALT levels in the MS group were higher than in the non-MS group (p = 0.02) and associated with MS (p = 0.001; c = 0.69). CONCLUSION: MS is a consequence of obesity already in very young children. Also, pathological serum ALT levels were significantly correlated with MS and might be considered a marker for defining MS, though confirmation in a longitudinal study is called for.

The osteopontin gene +1239A/C single nucleotide polymorphism is associated with type 1 diabetes mellitus in the Italian population.

Secreted phosphoprotein 1, also known as Osteopontin (Opn), is a proinflammatory cytokine involved in the TH1 response and is highly expressed in the islets and pancreatic lymph nodes of non-obese diabetic mice before the onset of diabetes. In humans, typing of the +1239A/C single nucleotide polymorphism (SNP) in the 3UTR of the Opn gene (SPP1) showed that +1239C carriers displayed higher Opn serum levels than +1239A homozygotes and a higher risk of developing autoimmune/lymphoproliferative syndrome, multiple sclerosis, and systemic lupus erythematosus. The aim of this work is to evaluate whether +1239A/C is also associated with type 1 diabetes mellitus (T1DM). We typed +1239A/C in an initial cohort of 184 T1DM patients and 361 controls, and confirmed our data in a second cohort of 513 patients and 857 controls. In both cohorts, +1239C carriers displayed a significantly higher risk of T1DM than +1239A homozygotes (combined cohorts: OR=1.63, 95 percent CI: 1.34-1.97). Clinical analysis did not detect any differences between patients carrying or not +1239C in terms of gender distribution and age at T1DM diagnosis. These data suggest that SPP1 variants marked by +1239C are associated with T1DM development in the Italian population. The predisposing effect may depend on its effect on Opn levels.

Utility of breast ultrasonography in the diagnostic work-up of precocious puberty and proposal of a prognostic index for identifying girls with rapidly progressive central precocious puberty.

OBJECTIVE: To determine the utility of breast ultrasono- graphy in the diagnostic work-up of precocious puberty and to create a prognostic index for early differentiation between non/slowly progressive or transient forms of precocious puberty and rapidly progressive central precocious puberty. METHODS: We recruited consecutively 60 girls with precocious pubertal development. In all the girls we evaluated Tanner stage, basal and gonadotropin-releasing hormone (GnRH)-stimulated follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, estradiol (E2) levels, and bone age, and performed pelvis and breast ultrasound examinations. Logistic regression models were fitted to identify possible diagnostic factors for rapidly progressive central precocious puberty and non/slowly progressive or transient forms. RESULTS: Ultrasound breast volume>or=0.85 cm3 was associated with rapidly progressive central precocious puberty (P=0.01). Uterine volume>or=5 cm3, LH peak>or=7 IU/L, presence of an endometrial echo, E2 levels>or=50 pmol/L and bone age>2 SD above expected were significantly associated with rapidly progressive central precocious puberty. A multivariate model including uterine volume, E2 level, bone age, presence of an endometrial echo and ultrasound breast volume revealed a strong ability to classify rapidly progressive forms. From this multivariate analysis a prognostic index for rapidly progressive central precocious puberty was defined. CONCLUSIONS: Ultrasound imaging allows better definition of the breast and the maturation stage than does use of Tanner's stages. Ultrasound breast volume>or=0.85 cm3 is an independent predicting factor of rapidly progressive central precocious puberty. A prognostic index that was created from a multivariate model including uterine volume, E2 level, presence of an endometrial echo, bone age and ultrasonographically determined breast volume, may help in the early differentiation between rapidly progressive central precocious puberty and non/slowly progressive or transient forms.

Recurrence of giant juvenile breast fibroadenoma in a girl with Turner's syndrome.

Pathological breast conditions are rare in childhood and adolescence. The spectrum of breast disease in pediatric patients is different from that in adults and most lesions are benign. Fibroadenomas are the most common type of breast tumor in adolescent girls and young women. These lesions occasionally develop into very large masses, particularly in adolescent girls. Such masses are called solitary giant juvenile fibroadenomas, and local recurrence is unusual. We report here a case of recurrent juvenile giant breast fibroadenoma in a girl with Turner's syndrome.

Prevalence of metabolic syndrome (MS) in children and adolescents with varying degrees of obesity.

OBJECTIVE: Childhood obesity is increasingly common and is associated with health problems; in particular, obesity plays a central role in the metabolic syndrome (MS). We estimated the prevalence of MS in Caucasian children and adolescents with varying degrees of obesity. PATIENTS AND METHODS: We studied 191 obese [body mass index (BMI) > 97th percentile] children and adolescents. Obesity was stratified on the basis of a threshold BMI z-score and subjects were classified as moderately (z-score 2-2.5) or severely obese (z-score > 2.5). Seventy-six, nonobese subjects were recruited into a comparison group. Thirty-one of them were of normal weight (BMI < 75th percentile) and 45 overweight (BMI 75th-97th percentile). Patients were classified as having MS if they met three or more of the following criteria for age and sex: BMI > 97th percentile, triglyceride levels > 95th percentile, high density lipoprotein (HDL) cholesterol level < 5th percentile, systolic or diastolic blood pressure > 95th percentile and impaired glucose tolerance (blood glucose level: 7.8-11.1 mmol/l at 2 h). Insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMA-IR) and impaired insulin sensitivity was defined as a HOMA-IR > or = 2.5 in prepubertal patients and HOMA-IR > 4 in pubertal subjects. RESULTS: The overall prevalence of MS was 13.9% and was present in 12.0% of moderately obese and 31.1% of severely obese subjects; no overweight or normal weight subjects met the criteria for MS. The rate of the MS increased progressively with increasing BMI categories (P < 0.001). Severely obese patients had a threefold increased risk with respect to moderately obese patients. CONCLUSIONS: The prevalence of the MS is higher in obese as opposed to nonobese subjects and increases with severity of obesity.

Major childhood infectious diseases and other determinants associated with type 1 diabetes: a case-control study.

The objective of the study was to evaluate the association between infectious diseases and other events pertaining to childhood medical history and type 1 diabetes. A case-control study was carried out, taking as cases 159 type 1 diabetic patients (0-29 years) recorded from 1988 to 2000 within the population registry of the Pavia province (North Italy). As controls 318 non-diabetic subjects were matched by age and sex. A questionnaire was administered by standardised interviewers. Data were analysed by conditional logistic regression. Viral childhood diseases (OR 4.29; 95%CI 1.57-11.74) and bottle feeding (OR 1.83; 95%CI 1.08-3.09) were directly correlated to type 1 diabetes; an inverse correlation was found for vitamin D administration during lactation (0-14 years) (OR 0.31; 95%CI 0.11-0.86) and for history of scarlet fever in both sexes and age groups (OR 0.19; 95%CI 0.08-0.46). Most associations of the studied variables confirm already known findings. The significant inverse correlation of type 1 diabetes with scarlet fever history is a peculiar finding, the meaning of which is still obscure, although it has been recently described that streptococcal A infections are regulated by HLA class II alleles.