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Background Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison’s disease (AD). Methods Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. Results The prevalence of APS-1 was 2.6 cases/million (range 0.5–17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. Conclusions In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

OBJECTIVE: To investigate the correlation between serum thyroid-stimulating hormone (TSH) concentration and nodule nature in pediatric patients with thyroid nodules, with the aim of identifying a marker able to differentiate benign and malignant nodules. STUDY DESIGN: This was a retrospective analysis of serum TSH concentrations in a multicentric case series of 125 pediatric patients with benign and malignant thyroid nodules. RESULTS: Of the 125 patients, 99 had benign thyroid nodules and 26 had differentiated thyroid cancer (24 papillary and 2 follicular). Final diagnosis was based on surgery in 57 cases and on a benign cytology plus clinical follow-up in 68 cases. Serum TSH concentration was significantly higher in patients with thyroid cancer compared with those with benign nodules (3.23 ± 1.59 mU/L vs 1.64 ± 0.99 mU/L; P < .001). Binary logistic regression analysis revealed that serum TSH was the sole predictor of malignancy (P < .001). Dividing the patient cohort into 5 groups based on serum TSH quintiles (TSH cutoffs 0.40, 1.00, 1.50, 1.80, and 2.80 mU/L), we observed that cancer prevalence increased in parallel with serum TSH (P < .001), with respective rates of 0%, 4%, 16%, 32%, and 52% in the 5 quintile groups. CONCLUSION: Because cases with malignant nodules are most likely seen in the upper normal serum TSH range (ie, >2.8 mU/L), serum TSH concentration can serve as a predictor of thyroid cancer in pediatric patients with thyroid nodules and can inform the decision of when to submit patients to further investigation by cytology.

Rationale & Objective: The objective of this study is to evaluate the effect of body mass index (BMI) on estimated glomerular filtration rate (eGFR) levels in children with congenital solitary kidney (CSK). Moreover, we evaluated if other factors could influence this relationship. Study Design: Multicenter cross-sectional study. Setting & Participants: University hospital pediatrics departments. Subjects: Two hundred eighty-one patients with CSK. Predictors: Weight, height, BMI-SDS (standard deviation score), duration of overweight/obesity, pubertal stage, systolic (SBP) and diastolic (DBP) blood pressure, eGFR, and renal ultrasound were obtained at the last follow-up visit. The population was classified on the basis of nutritional status and divided in tertiles for duration of overweight/obesity. We compared eGFR levels among these categories. A simple regression was used to correlate eGFR with BMI-SDS. To evaluate if other factors could influence the relationship between eGFR and BMI-SDS, a general linear model was performed, including gender, birth weight

Aim: This study assessed the prevalence of wrongly diagnosed non-febrile urinary tract infections in patients who had not been toilet trained and presented with poor feeding and, or, failure to thrive. The diagnostic value of these signs in predicting non-febrile UTIs was also explored. Methods: We focused on 59 outpatients (56.7% male) with these criteria, who had positive urine cultures and were referred to our Italian University hospital from January 2017 to January 2019. None were on antibiotics and all underwent urine cultures by bladder catheterisation. Wrongly diagnosed non-febrile UTIs were defined by sterile urine cultures. The predictive value was evaluated using logistic regression. Results: The mean age was 8.5±5.7months and 72.9% had wrongly diagnosed non-febrile UTIs. Poor feeding was significantly higher among the 16 patients with true non-febrile UTIs (P=.04). It was significantly predictive of non-febrile UTIs (odds ratio 4.1, 95% confidence interval 1.1-16.6), especially when leucocyturia was present (odds ratio 9.7, 95% confidence interval 2.3-40.7). Conclusion: Wrongly diagnosed non-febrile UTIs were high in children with poor feeding and, or, failure to thrive. Only poor feeding and, in particular, the combination of poor feeding and leucocyturia, significantly increased the odds of non-febrile UTI.

Background No information is currently available regarding the natural history of asymptomatic intracranial aneurysms in beta-thalassemia, raising several concerns about their proper management. Methods We performed a prospective longitudinal three-year-long MR-angiography study on nine beta-thalassemia patients (mean-age 40.3 ± 7.5, six females, 8 transfusion dependent) harboring ten asymptomatic intracranial aneurysms. In addition, we analyzed the clinical files of all adult beta-thalassemia patients (160 patients including those followed with MR-angiography, 121 transfusion dependent) referring to our Centers between 2014 and 2019 searching for history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms. Results At the end of the three-year-long follow-up, no patient showed any change in the size and shape of the aneurysms, none presented new intracranial aneurysms or artery stenoses, none showed new brain vascular-like parenchymal lesions or enlargement of the preexisting ones. Besides, in our database of all adult beta-thalassemia patients, no one had history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms. Conclusions Incidental asymptomatic intracranial aneurysms do not seem to be associated, in beta-thalassemia, with an increased risk of complications (enlargement or rupture) at least in the short term period, helping to optimize human and economic resources and patient compliance during their complex long-lasting management.

Background Long-term consequences of mild subclinical hypothyroidism (SH) in children are still unclear, and the need for levothyroxine (L-T4) supplementation remains controversial. We designed a 2-year, case-control, prospective study of a cohort of children with SH to evaluate the effects of L-T4 therapy on neurocognitive outcome. Methods Thirty-four children, age 9.1 ± 2.6 years, with long-lasting, idiopathic, and mild SH, and 34 healthy matched controls, were enrolled. Twenty SH children underwent a 2-year L-T4 treatment (group A), whereas 14 refused treatment and were reevaluated after a 2-year-follow-up (group B). IQ and specific cognitive domains were evaluated in all children at study entry and after 2 years of therapy (group A) or observation (group B) in SH individuals. Results In SH children baseline IQ scores were normal and comparable to controls (full-scale IQ [FSIQ] 100.4 ± 11.3 vs 101.8 ± 14.2, verbal IQ [VIQ] 99.7 ± 13.7 vs 98.3 ± 14.9 and performance IQ [PIQ] 101.2 ± 10.4 vs 105 ± 10.4). In group A, L-T4 treatment was associated with normalization of thyrotropin (6.3 ± 1.0 mIU/L at baseline vs 2.8 ± 1.4 mIU/L at 2 years, P Conclusions Our data suggest neurocognitive function in children is not impaired by persistent, mild, untreated SH and is not significantly modified by 2-year L-T4 supplementation.

Background: Children with nonclassical congenital adrenal hyperplasia (NCCAH) often present increased growth velocity secondary to elevation of adrenal androgens that accelerates bone maturation and might compromise adult height (AH). Objective: The aim of the study was to analyze prognostic factors affecting growth trajectory (GT) and AH in children with NCCAH. Methods: The study was a retrospective, multicentric study. The study population consisted of 192 children with a confirmed molecular diagnosis of NCCAH, followed by pediatric endocrinology centers from diagnosis up to AH. Clinical records were collected and analyzed. AH (standard deviation score; SDS), pubertal growth (PG) (cm), GT from diagnosis to AH (SDS), and AH adjusted to target height (TH) (AH-TH SDS) were evaluated as outcome indicators using stepwise linear regression models. Results: The stepwise linear regression analysis showed that AH and AH-TH were significantly related to chronological age (CA) (p = 0.008 and 0.016), bone age (BA)/CA ratio (p = 0.004 and 0.001), height (H) (p < 0.001 for both parameters) at NCCAH diagnosis, and TH (p = 0.013 and p = 0.002), as physiologically observed, and was positively related to height (p = 0.027), negatively to BMI (p = 0.001) and BA/CA ratio (p = 0.001) at NCCAH diagnosis. Gender, genotype, biochemical data, and hydrocortisone treatment did not significantly impair height outcomes of these NCCAH children. Conclusions: The results of this study suggest that AH and GT of NCCAH patients are mainly affected by the severity of phenotype (CA, BA/CA ratio, and H) at the time of diagnosis.

Background: To evaluate sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) of renal ultrasonography (US) in predicting renal uptake defects or reduced renal function at Tc-99m dimercaptosuccinic acid (DMSA) scan (primary outcome). We also evaluated which factors could be associated with Tc-99m DMSA renal scan anomalies. Methods: We retrospectively included all the patients with vesico-ureteral reflux (VUR) undergoing the first Tc-99m DMSA renal scan within 3 months from the most recent renal US between 2016 and 2018. Results: Sensitivity, specificity, PPV, and NPV of US in predicting abnormal Tc-99m DMSA scan were 38.9%, 91.5%, 71.9%, and 72.9%, respectively. Different length between the kidneys, expressed as standard deviation score (SDS), showed an area under the receiver operating characteristic curve of 0.70 (95% CI, 0.60–0.80; p < 0.0001) when evaluated as predictor of abnormal Tc-99m DMSA scan. A different length between the two kidneys >1.11 SDS had 91.5% sensitivity and 57.6% specificity. At multivariate analysis, the factors with significantly increased odds ratio of abnormal Tc-99m DMSA scan were difference in length between two kidneys >1.11 SDS and dilated VUR. Conclusions: The Tc-99m DMSA scan remains the gold standard to detect renal parenchymal anomalies. A different length between the kidneys >1.11 SDS and dilated VUR are predictors of abnormal Tc-99m DMSA renal scan.

Increasing evidence indicate that adults with Congenital Adrenal Hyperplasia (CAH) may have a cluster of cardiovascular (CV) risk factors. In addition, ongoing research have highlighted that children and adolescents with CAH are also prone to develop unfavorable metabolic changes, such as obesity, hypertension, insulin insensitivity, and increased intima-media thickness, which place them at a higher risk to develop CV disease in adulthood. Moreover, CAH adolescents may exhibit subclinical left ventricular diastolic dysfunction and impaired exercise performance, with possible negative consequences on their quality of life. The therapeutic management of patients with CAH still remains a challenge and current treatment regimens do not always allow optimal biochemical control. Indeed, overexposure to glucocorticoids and mineralcorticoids as well as to androgen excess may contribute to the development of unfavorable metabolic and CV abnormalities. Long-term prospective studies on large cohorts of patients will help to clarify the pathophysiology of metabolic alterations associated to CAH. In the meanwhile, further efforts should be made in order to optimize treatment and identify new therapeutic approaches to prevent metabolic derangement and improve long-term health outcomes of CAH patients.

Background: PNPLA3 I148M polymorphism has an effect on modulation of estimated glomerular filtration rate (eGFR) in nonobese nondiabetic adults and in children with histologically confirmed nonalcoholic fatty liver disease (NAFLD). Objectives: The objective of the study is to explore the impact of PNPLA3 I148M polymorphism on eGFR in children with obesity with and without NAFLD. Methods: We genotyped 591 patients with obesity for PNPLA3 I148M polymorphism. Anthropometrical, biochemical, and instrumental data were collected. NAFLD was defined by the presence of ultrasound-detected liver steatosis and/or ALT levels greater than 40 IU/L. Results: Patients with NAFLD showed significantly lower eGFR levels compared with subjects without NAFLD. Children with PNPLA3 MM genotype showed lower eGFR levels compared with those with either PNPLA3 IM or II genotypes both in the presence and absence of NAFLD. A general linear model for eGFR variance, including gender, duration of obesity, PNPLA3 genotypes, HOMA, BMI-SDS, LDL-C, and triglycerides as covariates, confirmed an inverse association between eGFR and PNPLA3 genotype only in the presence of NAFLD. Conclusions: Children with obesity and PNPLA3 MM genotype show lower eGFR levels compared with other genotypes, with a major effect of this polymorphism in the presence of NAFLD.

Summary Introduction The nocturnal polyuria is considered a significant predictive value for response to desmopressin. The cutoff value useful to define nocturnal polyuria is still a matter of debate. Moreover, it is current notion that maximal voided volume (MVV) could be used as a predictor for desmopressin response. Objective The objective of this study was to assess the impact of different definitions of nocturnal polyuria (and of its frequency) and MVV in predicting the response to desmopressin. Study design A total of 103 patients with frequent monosymptomatic nocturnal enuresis (≥4 wet nights/week) were enrolled. A bladder diary over a 4-day period was collected. The MVV was defined as the highest micturition volume detected at bladder diary. Nocturnal diuresis was measured in 5 wet nights. Then, patients were administered with 120 mcg of sublingual desmopressin. After 2 months, if there was no complete response, the dose was increased to 240 mcg. Nocturnal polyuria was defined as follows: 1.Definition 1: nocturnal urine production >130% of the expected bladder capacity (EBC). 2. Definition 2: >100% EBC. 3. Definition 3: > 20×(age + 9) mL. The primary outcome was ‘response to desmopressin’ after 3 months of treatment. Results Fifty-three patients responded to desmopressin. Comparing the responses to desmopressin on the basis of the three definitions of nocturnal polyuria, no significant difference was found. There was no cutoff value of nocturnal polyuria expressed as %EBC useful in providing a significant receiver-operating characteristic (ROC) curve. The area under the ROC curve for MVV expressed as %EBC was 0.67 (95% confidence interval [CI], 0.54–0.80; p = 0.01). A MVV >103.1% of EBC had 78.8% (95% CI, 61.1–91.0) sensitivity and 47.5% (95% CI, 31.5–63.9) specificity for predicting response to desmopressin. Among the patients with nocturnal polyuria according to definition 1, a higher percentage of subjects with nocturnal polyuria in 4 out of 5 or 5 out of 5 nights responded to desmopressin, compared with other patients. Patients presenting with nocturnal polyuria according to definition 3 in 5 out of 5 nights showed a 100% of response to desmopressin. At multivariate analysis, the only significant odds ratio (OR) to respond to desmopressin was that of patients with nocturnal polyuria according to definition 1 in >3 nights (OR = 7.1, 95% CI, 1.3–40.3). Discussion and conclusions The presence or absence of nocturnal polyuria—according to all three definitions—in at least one night was not effective in predicting the response to desmopressin. Predictors of desmopressin response were nocturnal polyuria in >3 out of 5 wet nights according to definition 1 and in 5 out of 5 wet nights according to definition 3. Download : Download high-res image (176KB) Download : Download full-size image Summary Figure . Response to desmopressin on the basis of the number of nights with nocturnal polyuria among the 5 wet nights in which the nocturnal diuresis had been measured.The ‘p’ showed in Summary Figure derives from the comparison between the percentages of response to desmopressin on the basis of the number of nights with nocturnal polyuria defined accordingly with the 3 definitions. Chi-squared test was used for this comparison. Definition 1: nocturnal urine production >130% of the EBC [1,6]. Definition 2: nocturnal urine production >100% of the EBC [3]. Definition 3: nocturnal urine production > than 20 × (age + 9) in mL [7]. EBC, expected bladder capacity.

Patients with Turner syndrome (TS) are frequently affected by congenital as well as acquired cardiovascular diseases. The aim of the study was to evaluate the blood pressure, the endothelial function (FMD) and the intima media thickness (IMT) at the level of the common carotid arteries in a group of girls and young women with TS in comparison to healthy controls. We evaluated 40 unselected TS patients, with a mean age of 18.6 ± 0.9 years and 103 age matched healthy subjects. Main outcome measures: blood pressure, FMD and IMT. No differences were found in systolic and diastolic blood pressure between TS patients and controls. FMD was higher in TS than in controls (14.2 ± 1.4 vs 11.4 ± 0.3 %, p = 0.005) whereas IMT was not statistically different in the two study groups (0.54 ± 0.04 vs 0.57 ± 0.01 mm). However, in TS patients an inverse correlation was found between FMD and both age (−0.03 ± 0.01, p = 0.003) and years of estrogen therapy (−0.72 ± 0.31, p

Background Chronic recurrent multifocal osteomyelitis (CRMO), also known as chronic nonbacterial osteomyelitis, is a rare, noninfectious inflammatory disorder that causes multifocal bone lesions with swelling and pain. Lytic and sclerotic bone lesions could be found on X-ray. Short tau inversion recovery magnetic resonance imaging (STIR MRI) shows bone marrow oedema, bone expansion, lytic areas and periosteal reaction. CRMO is characterized by periodic exacerbations and remissions of unclear/unknown pathogenesis. Case presentation A 10 years old girl, suffering from pain in her right shoulder since the age of 9 years presented to our Department. Thanks to clinical data, laboratoristic and radiological findings and bone biopsy CRMO was diagnosed. So patient started anti-inflammatory treatment and her conditions improved. Conclusions In a child with bone pain should be considered also rare condition as CRMO to perform a correct diagnosis and start an adequate treatment avoiding complications such as bone damage. This condition should be suspected in a child with recurrent bone pain, modest increase of inflammatory indices, lytic or sclerotic bone lesion on X Ray. Typical CRMO localizations are metaphyses of long bones, pelvis, clavicle, vertebral column, sternum, ribs, jaw, but any bone can be involved. The most common CRMO differential diagnosis is represented by infections, malignant bone tumors, Langerhans Cells Histiocytosis (LCH).

A 12-year-old boy, with intermittent abdominal pain from 3 years of age, presented with increased frequency of right lower quadrant pain (at least three episodes per week over the past six months) and pain during micturition affecting school attendance. His family history included referred urolithiasis. An abdominal ultrasound performed 1 year before our visit showed a small stone of 4 mm in the right renal pelvis for which he did not receive any therapy. The patient brought 25 hard stones with irregular outline, 2–8 mm in diameter, of deep brown/grey colour that he claimed to have found in his underwear (figure 1). On examination, he looked well with normal vital signs and unremarkable cardiorespiratory and abdominal examinations. Plasma creatinine was 0.41 mg/dL (36.1 μmol/L), urinalysis and urine tests were all normal (including 24 hour calcium, phosphorus, oxalate, citrate, uric acid and cystine). Repeat kidney and urinary tract ultrasound showed no evidence of calculi.Figure 1Twenty-five hard formations brought along by the patient from home.Question 1Which is the most likely diagnosis?Cystinuria.Dent disease.Idiopathic urolithiasis.Factitious disorder imposed on self.Familial hypomagnesemia with hypercalciuria and nephrocalcinosis.Question 2How would you confirm your diagnostic suspicion?Reassurance and clinical follow-up.Mass spectrometry of stones.CT urography.Increase oral fluid intake and administration of potassium citrate.Question 3How would you manage this condition?Administration of placebo.Psychological consultation.Observed 24 hour urine collection.All of the above.Answers can be found on page 2.

ObjectiveTo prospectively evaluate the course of subclinical hypothyroidism (SH) in children and adolescents with no underlying diseases and no risk factors, which might interfere with the progression of SH.DesignClinical status, thyroid function, and autoimmunity were prospectively evaluated at entry and after 6, 12, and 24 months in 92 young patients (mean age 8.1±3.0 years) with idiopathic SH.ResultsDuring the study, mean TSH levels showed a trend toward a progressive decrease while FT4 levels remained unchanged. Overall, 38 patients normalized their TSH (group A): 16 patients between 6 and 12 months, and 22 patients between 12 and 24 months. Among the remaining 54 patients, the majority maintained TSH within the baseline values (group B), whereas 11 exhibited a further increase in TSH above 10 mU/l (group C). Baseline TSH and FT4 levels were similar in the patients who normalized TSH, compared with those with persistent hyperthyrotropinemia. Even in the patients of group C, both TSH and FT4 at entry were not different with respect to those of groups A and B. No patients showed any symptoms of hypothyroidism during follow-up and no changes in both height and body mass index were observed throughout the observation period.Conclusions(a) The natural course of TSH values in a pediatric population with idiopathic SH is characterized by a progressive decrease over time; (b) the majority of patients (88%) normalized or maintained unchanged their TSH; and (c) TSH changes were not associated with either FT4 values or clinical status or auxological parameters.