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Bisphosphonates are the first-choice treatment of osteoporosis and Paget’s disease of bone. Among the bisphosphonates, the non-amino-bisphosphonates, such as clodronic acid, are intracellular converted into toxic analogues of ATP and induce cellular apoptosis whereas the amino-bisphosphonates, such as zoledronic acid, inhibit the farnesyl-diphosphate-synthase, an enzyme of the mevalonate pathway. This pathway regulates cholesterol and glucose homeostasis and is a target for statins. In this retrospective cohort study, we evaluated the effects of an intravenous infusion of zoledronic acid (5 mg) or clodronic acid (1500 mg) on blood lipid (i.e. total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides) and glucose levels in patients with osteoporosis and Paget’s disease of bone. All patients were evaluated before, 1 and 6 months after bisphosphonate treatment. Pagetic and osteoporotic patients treated with zoledronic acid showed a significant reduction in glucose and atherogenic lipids during follow-up whereas these phenomena were not observed after clodronic treatment. The effect on circulating lipid levels was similar in naïve and re-treated Pagetic patients. Zoledronic acid treatment was associated with a reduction in blood glucose and atherogenic lipids in patients with metabolic bone disorders. The extent of change was similar to that obtained with the regular assumption of a low-intensity statin. Further studies are warranted to better evaluate the clinical implications of these observations. Supplementary Information The online version of this article (10.1007/s00223-021-00811-w) contains supplementary material, which is available to authorized users.

STUDY QUESTION Are GnRH tests and serum inhibin B levels sufficiently discriminating to distinguish transient constitutional delay of growth and puberty (CDGP) from congenital hypogonadotropic hypogonadism (CHH) that affects reproductive health for life? SUMMARY ANSWER Both parameters lack the specificity to discriminate CDGP from CHH. WHAT IS KNOWN ALREADY GnRH tests and inhibin B levels have been proposed to differentiate CDGP from CHH. However, their diagnostic accuracies have been hampered by the small numbers of CHH included and enrichment of CHH patients with more severe forms. STUDY DESIGN, SIZE, DURATION The aim of this study was to assess the diagnostic performance of GnRH tests and inhibin B measurements in a large cohort of CHH male patients with the whole reproductive spectrum. From 2008 to 2018, 232 males were assessed: 127 with CHH, 74 with CDGP and 31 healthy controls. PARTICIPANTS/MATERIALS, SETTING, METHODS The participants were enrolled in two French academic referral centres. The following measurements were taken: testicular volume (TV), serum testosterone, inhibin B, LH and FSH, both at baseline and following the GnRH test. MAIN RESULTS AND THE ROLE OF CHANCE Among CHH patients, the LH response to the GnRH test was very variable and correlated with TV. Among CDGP patients, the LH peak was also variable and 47% of CHH patients had peak LH levels overlapping with the CDGP group. However, no patients with CDGP had an LH peak below 4.0 IU/l, while 53% CHH patients had LH peak below this threshold. Among CHH patients, inhibin B levels were also variable and correlated with TV and peak LH. Inhibin B was significantly lower in CHH patients than in CDGP patients but 50% of CHH values overlapped with CDGP values. Interestingly, all patients with CDGP had inhibin B levels above 35 pg/ml but 50% of CHH patients also had levels above this threshold. LIMITATIONS, REASONS FOR CAUTION As CHH is very rare, an international study would be necessary to recruit a larger CHH cohort and consolidate the conclusion reached here. WIDER IMPLICATIONS OF THE FINDINGS Peak LH and basal inhibin B levels are variable in both CHH and CDGP with significant overlap. Both parameters lack specificity and sensitivity to efficiently discriminate CHH from CDGP. This reflects the varying degree of gonadotropin deficiency inherent to CHH. These two diagnostic procedures may misdiagnose partial forms of isolated (non-syndromic) CHH, allowing them to be erroneously considered as CDGP. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Agence Française de Lutte contre le Dopage: Grant Hypoproteo AFLD-10 (to J.Y.); Agence Nationale de la Recherche (ANR): Grant ANR-09-GENO-017-01 (to J.Y.); European Cooperation in Science and Technology, COST Action BM1105; Programme Hospitalier de Recherche Clinique (PHRC), French Ministry of Health: PHRC-2009 HYPO-PROTEO (to J.Y.); and Programme Hospitalier de Recherche Clinique (PHRC) “Variété”, French Ministry of Health, N° P081216/IDRCB 2009-A00892-55 (to P.C.). There are no competing interests. TRIAL REGISTRATION NUMBER N/A

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.

Context Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, usually caused by small, benign, and slow-growing phosphaturic mesenchymal tumors. Clinically, TIO is characterized by renal phosphate leak, causing hypophosphatemia and osteomalacia. This review was performed to assess the clinical characteristics of TIO patients described worldwide so far. Evidence Acquisition On June 26, 2021, a systematic search was performed in Medline, Google Scholar, Google book, and Cochrane Library using the terms: “tumor induced osteomalacia,” “oncogenic osteomalacia,” “hypophosphatemia.” There were no language restrictions. This review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria. Evidence Results Overall, 1725 TIO cases were collected. TIO was more frequent in adult men, who showed a higher incidence of fractures compared with TIO women. The TIO-causing neoplasms were identified in 1493 patients. The somatostatin receptor-based imaging modalities have the highest sensitivity for the identification of TIO-causing neoplasms. TIO-causing neoplasms were equally located in bone and soft tissues; the latter showed a higher prevalence of fractures and deformities. The surgery is the preferred TIO definitive treatment (successful in > 90% of patients). Promising nonsurgical therapies are treatments with burosumab in TIO patients with elevated fibroblast growth factor-23 levels, and with radiolabeled somatostatin analogs in patients with TIO-causing neoplasm identified by somatostatin receptor-based imaging techniques. Conclusion TIO occurs preferentially in adult men. The TIO clinical expressiveness is more severe in men as well as in patients with TIO-causing neoplasms located in soft tissues. Treatments with burosumab and with radiolabeled somatostatin analogs are the most promising nonsurgical therapies.

Background Constitutional delay of growth and puberty (CDGP) is classified as the most frequent cause of delayed puberty (DP). Finding out the etiology of DP during first evaluation may be a challenge. In details, pediatricians often cannot differentiate CDGP from permanent hypogonadotropic hypogonadism (PHH), with definitive diagnosis of PHH awaiting lack of puberty by age 18 yr. Neverthless, the ability in providing a precise and tempestive diagnosis has important clinical consequences. Main text A growth failure in adolescents with CDGP may occur until the onset of puberty; after that the growth rate increases with rapidity. Bone age is typically delayed. CDGP is generally a diagnosis of exclusion. Nevertheless, other causes of DP must be evaluated. A family history including timing of puberty in the mother and in the father as well as physical examination may givee information on the cause of DP. Patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions, such as celiac disease, inflammatory bowel diseases, kidney insufficiency and anorexia nervosa, may experience a functional hypogonadotropic hypogonadism. PHH revealing testosterone or estradiol low serum values and reduced FSH and LH levels may be connected to abnormalities in the central nervous system. So, magnetic resonance imaging is required in order to exclude either morphological alterations or neoplasia. If the adolescent with CDGP meets psychological difficulties, treatment is recommended. Conclusion Even if CDGP is considered a variant of normal growth rather than a disease, short stature and retarded sexual development may led to psychological problems, sometimes associated to a poor academic performance. A prompt and precise diagnosis has an important clinical outcome. Aim of this mini-review is throwing light on management of patients with CDGP, emphasizing the adolescent diagnosis and trying to answer all questions from paediatricians.

The prevalence of primary hypertension in pediatric patients is increasing, especially as a result of the increased prevalence of obesity in children. New diagnostic guidelines for blood pressure were published by the American Academy of Pediatrics (AAP) in 2017 to better define classes of hypertension in children. The aim of our study is to evaluate the impact of new guidelines on diagnosis of hypertension in pediatrics and their capacity to identify the presence of cardiovascular and metabolic risk. Methods: Retrospective clinical and laboratory data from 489 overweight and obese children and adolescents were reviewed. Children were classified according to the 2004 and 2017 AAP guidelines for systolic and diastolic blood pressure. Lipid profile and glucose metabolism data were recorded, triglyceride/HDL ratio (TG/HDL) was calculated as an index of endothelial dysfunction. Hepatic steatosis was detected using the ultrasonographic steatosis score. Results: Children with elevated blood pressure increased from 12.5% with the 2004 AAP to 23.1% with the 2017 AAP criteria (p &lt, 0.001). There was a statistically significant increase in children with high blood pressure in all age groups according to the new cut-off values. Notably, the diagnosis of hypertension according to 2017 AAP criteria had a greater positive association with Hepatic Steatosis (rho 0.2, p &lt, 0.001) and TG/HDL ratio (rho 0.125, p = 0.025). Conclusions: The 2017 AAP tables offer the opportunity to better identify overweight and obese children at risk for organ damage, allowing an earlier and more impactful prevention strategy to be designed.

ObjectiveTo study the link between a high body mass index (BMI) in childhood and the occurrence of pediatric-onset multiple sclerosis (POMS) and to compare, within the MS population, the clinical-radiologic-biological characteristics, according to BMI.MethodsA case-control study comparing BMI data of 60 patients with POMS (39 girls and 21 boys) at Bicêtre Hospital with that of 113 non-neurologic controls NNCs (68 girls and 45 boys) and 18,614 healthy controls HCs (9,271 girls and 9,343 boys) was performed. Crude BMI (cBMI), residual BMI (rBMI = measured BMI − expected BMI for age), z-score (rBMI/SD), and adult equivalent categories (International Obesity Task Force ≥25 = overweight, ≥30 = obese) were assessed.ResultsIn boys, cBMI and rBMI were significantly higher in patients with POMS compared with NNCs (cBMI: +2.9; rBMI: +2.95, p < 0.01) and HCs (cBMI: +2.04, p < 0.01). In girls, cBMI or rBMI did not differ between POMS and NNCs patients (cBMI p = 0.4; rBMI p = 0.44) but with HCs (cBMI +0.99, p < 0.01). CSF inflammatory markers increased with BMI in prepubertal patients (p < 0.01), whereas vitamin D level at diagnosis was lower in boys with higher BMI (p = 0.016). Increased BMI was not associated with clinical and radiologic disease characteristics.ConclusionsOverweight and obesity are more frequently observed at diagnosis, particularly in boys with POMS compared with non-neurologic controls and French HCs. Moreover, BMI is related to initial inflammation in the CSF in prepubertal patients with POMS suggesting an interaction between excess body fat, sexual hormones, and POMS occurrence.

Context Unlike homozygous variants, the implication of heterozygous variants on the leptin–melanocortin pathway in severe obesity has not been established. Objective To describe the frequency, the phenotype, and the genotype–phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. Methods In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. Results The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI. Conclusion Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.

Over the last decades the diagnosis and management of pediatric endocrine disorders has substantially improved. However, clinicians still face some key challenges, without straightforward solutions, during their daily clinical practice. This Research Topic includes a collection of papers on relevant topics in Pediatric Endocrinology and Diabetes, which can support clinicians in better understanding endocrine conditions and their management. The global obesity epidemic has brought to light that metabolic complications, previously thought to affect only obese adults, can manifest at a younger age. The true incidence of pediatric type 2 diabetes (T2D) is still debated (1), and North American and European studies show contrasting results. Indeed, the exponential increase in the incidence of T2D reported among North American obese children and adolescents is not confirmed among European youth. Data from different populations and Countries are essential to better understand the epidemiology of T2D. In this issue, Al-Kandari et al. report the incidence of T2D in Kuwait, providing some Country-specific unique epidemiological data. The prevalence of glucokinase (GKC) deficit in pregnant women with diabetes is the focus of Bitterman et al.’s paper. Although maturity onset diabetes of the young (MODY) due to GCK deficit is a benign condition, a prompt diagnosis is essential for the optimal course of pregnancy and planning of appropriate newborn care. Available data indicate that the prevalence of GKC deficit varies between 0-80% among pregnant women, dependent on the screening criteria and the populations’ characteristics (2, 3). In this retrospective study, the authors show that even the recent “new-pregnancy-specific criteria,” based on BMI 99 mg/dl, do not reach optimal sensitivity and specificity thresholds. Therefore, better criteria applicable to different populations, are required for a tailored selection of pregnant women eligible for genetic tests. This issue also includes a systematic review and meta-analysis addressing the potential association between type 1 diabetes (T1D) and periodontal disease in children (4). Previous studies reported a three- to four-fold increased risk of periodontal disease in adults with T2D and suggested a bidirectional relationship between these two conditions. Rapone et al. highlight lack of strong evidence for similar associations in children with T1D. Current evidence is primarily based on cross-sectional studies, which show a higher prevalence of periodontal disease in children with diabetes. However, pediatric studies do not support a role of periodontal disease in the pathogenesis of T1D and its complications and exclude an effect on glycemic control. The hypothalamic-pituitary-gonadal axis is discussed in two comprehensive reviews. Bizzarri and Cappa offer an interesting description of the transient sex-specific activation of hypothalamic-pituitary-gonadal axis during the first 6 months of life in boys, and the first 2 years in girls. This phenomenon, known as “mini-puberty,” is fascinating and provides insights into the understanding of the mechanisms of pubertal development later in life. Festa et al. review genetic causes of pubertal delay and propose a diagnostic algorithm to distinguish between self-limited delayed puberty and other forms of hypogonadotropic hypogonadism. Self-limited delayed puberty is a frequent condition in endocrine clinical practice, whereas congenital hypogonadotropic hypogonadism accounts for 4% and 5.7% cases of delayed puberty in boys and girls, respectively. The authors offer an in-depth discussion of the benefits and limitations of genetic testing in the clinical setting, underling its potential role for a better classification and management of delayed puberty. Assessment of bone maturation (BM) in children and adolescents is relevant in medical and non-medical fields (5). Despite a few issues related to the use of different methods, bone age is a unique tool to assess the maturational changes during childhood and adolescence, and to aid the diagnostic workout of growth disorders. In this Research Topic, Cavallo et al. provide an overview of the main methods to assess bone age and discuss their advantages and disadvantages. In a second paper, Pepe et al. report the results of a prospective study assessing the link between BM and postnatal growth during the first year of life in a population of children born small for gestational age (SGA). Although most SGA children show spontaneous catch-up growth during the first two years of life, a percentage of them remains short during childhood (6). In the present study, SGA newborns with delayed BM showed greater growth velocities and height gains at 12 months of age compared to those with adequate BM at birth. Besides, the study shows that ultrasonographic evaluation of the Beclard’s nucleus could be a useful noninvasive technique to identify intrauterine BM delay. Another key topic discussed in this issue is the reason for and appropriateness of pediatric endocrinology referrals. A clear understanding of referral pathways is essential to optimize resource use and plan continuous medical education and public health interventions. Bellotto et al. report data on endocrine referrals to a single Italian tertiary center for pediatric endocrinology. The study highlights that growth and puberty represent nearly half of all reasons for endocrine referrals, and that timing for referral (i.e. urgent vs deferrable priority) is often inappropriate. The authors suggest that medical education of primary care can be better tailored to improve the timing of referral and the ability to recognize subclinical and para-physiological conditions. These steps are paramount to better define windows of intervention and optimize clinical outcomes. We hope that this Research Topic will provide a valuable resource for the management of clinical endocrine issues in daily practice and we encourage the readers to submit their General Commentary articles on these articles.

Obesity may affect bone health, but literature reports are contradictory about the correlation of body mass index (BMI) and bone markers. LIGHT, one of the immunostimulatory cytokines regulating the homeostasis of bone and adipose tissue, could be involved in obesity. The study involved 111 obese subjects (12.21 &plusmn, 3.71 years) and 45 controls. Patients underwent the evaluation of bone status by quantitative ultrasonography (QUS). LIGHT amounts were evaluated in sera by ELISA, whereas its expression on peripheral blood cells was evaluated by flow cytometry. Osteoclastogenesis was performed by culturing peripheral blood mononuclear cells (PBMCs) with or without anti-LIGHT antibodies. Obese patients showed significant high BMI-standard deviation score (SDS), weight-SDS, and Homeostatic model assessment for insulin resistance (HOMA-IR) that negatively correlated with the reduced Amplitude Dependent Speed of Sound (AD-SoS)-Z-score and Bone Transmission Time (BTT-Z)-score. They displayed significantly higher serum levels of LIGHT compared with controls (497.30 &plusmn, 363.45 pg/mL vs. 186.06 &plusmn, 101.41 pg/mL, p &lt, 0.001). LIGHT expression on monocytes, CD3+-T-cells, and neutrophils was also higher in obese patients than in the controls. Finally, in PBMC cultures, the addition of anti-LIGHT antibodies induced a significant osteoclastogenesis inhibition. Our study highlighted the high serum levels of LIGHT in obese children and adolescents, and its relationship with both the grade of obesity and bone impairment.

Osteoporosis and nephrolithiasis are common multifactorial disorders with high incidence and prevalence in the adult population worldwide. Both are associated with high morbidity and mortality if not correctly diagnosed and accurately treated. Nephrolithiasis is considered a risk factor for reduced bone mineral density. Aim of this retrospective longitudinal study was to evaluate if osteoporosis is a predictive factor for the nephrolithiasis occurrence. Free-living subjects referring to “COMEGEN” general practitioners cooperative operating in Naples, Southern Italy. Twelve thousand seven hundred ninety-four Caucasian subjects (12,165 female) who performed bone mineral density by dual-energy X-ray absorptiometry and have a negative personal history for nephrolithiasis. Subjects aged less than 40 years or with signs or symptoms suggestive of secondary osteoporosis were excluded from the study. In a mean lapse of time of 19.5 months, 516 subjects had an incident episode of nephrolithiasis. Subjects with osteoporosis had an increased risk of nephrolithiasis than subjects without osteoporosis (Hazard Ratio = 1.33, 95% Confidence Interval 1.01–1.74, p = 0.04). Free-living adult subjects over the age of 40 with idiopathic osteoporosis have an increased risk of incident nephrolithiasis, suggesting the advisability of appropriate investigation and treatment of the metabolic alterations predisposing to nephrolithiasis in patients with osteoporosis. The study protocol was approved by the ASL Napoli 1 Ethical Committee, protocol number 0018508/2018

Context Nephrolithiasis (NL) and primary hyperparathyroidism (HPTH) are metabolic complications of Paget disease of bone (PDB), but recent data regarding their prevalence in PDB patients are lacking. Objectives Study 1: To compare the prevalence of primary HPTH and NL in 708 patients with PDB and in 1803 controls. Study 2: To evaluate the prevalence of NL-metabolic risk factors in 97 patients with PDB and NL, 219 PDB patients without NL, 364 NL patients without PDB, and 219 controls, all of them without HPTH. Design Cross-sectional multicentric study. Setting Italian referral centers for metabolic bone disorders. Participants Patients with PDB from the Associazione Italiana malati di osteodistrofia di Paget registry. Participants in the Olivetti Heart and the Siena Osteoporosis studies. Main Outcome Measures HPTH; NL; NL-metabolic risk factors. Results Patients with PDB showed higher prevalence of primary HPTH and NL compared with controls (P < 0.01). The NL recurrence occurs more frequently in patients with polyostotic PDB. About one-half of patients with PDB but without NL showed 1 or more NL-related metabolic risk factors. The hyperoxaluria (HyperOx) prevalence was higher in patients with PDB and NL compared with patients with NL but without PDB and in patients with PDB without NL compared with controls (P = 0.01). Patients with PDB and HyperOx showed a longer lapse of time from the last aminobisphosphonate treatment. Conclusions NL and HPTH are frequent metabolic complication of PDB. The NL occurrence should be evaluated in patients with PDB, particularly in those with polyostotic disease and/or after aminobisphosphonate treatment to apply an adequate prevention strategy.

Context Intravenous aminobisphosphonates (N-BPs) can induce an acute phase reaction (APR) in up to 40% to 70% of first infusions, causing discomfort and often requiring intervention with analgesics or antipyretics. Objective Our aim was to explore the risk factors of APR in a large sample of patients with Paget’s disease of bone (PDB) and to assess the possible preventive effects of vitamin D administration. Methods An observational analysis was performed in 330 patients with PDB at the time of N-BP infusion. Then, an interventional study was performed in 66 patients with active, untreated PDB to evaluate if vitamin D administration (oral cholecalciferol 50 000 IU/weekly for 8 weeks before infusion) may prevent APR. Results In a retrospective study, APR occurred in 47.6% and 18.3% of naive or previously treated patients, respectively. Its prevalence progressively increased in relation to the severity of vitamin D deficiency, reaching 80.0% in patients with 25-hydroxyvitamin D (25OHD) levels below 10 ng/mL (relative risk (RR) = 3.7; 95% confidence interval (CI) 2.8–4.7, P < .0001), even in cases previously treated with N-BPs. Moreover, APR occurred more frequently in patients who experienced a previous APR (RR = 2.8; 95% CI 1.5–5.2; P < .001) or in carriers of SQSTM1 mutation (RR = 2.3; 95% CI 1.3–4.2; P = .005). In the interventional study, vitamin D supplementation prevented APR in most cases, equivalent to a RR of 0.31 (95% CI 0.14–0.67; P < .005) with respect to prevalence rates of the observational cohort. A similar trend was observed concerning the occurrence of hypocalcemia. Conclusions The achievement of adequate 25OHD levels is recommended before N-BP infusion in order to minimize the risk of APR or hypocalcemia in PDB.

BACKGROUND Iodine is an essential micronutrient for intellectual development in children. Information on iodine intakes based on 24-h urinary iodine excretion (UIE) is scant, because iodine status is only assessed by the measurement of urinary iodine concentration (UIC) in spot urine samples. OBJECTIVES The aim of our study was to evaluate the iodine intake of school-age children and adolescents, using UIE measurement in 24-h urine collections. METHODS The study population included 1270 healthy subjects (677 boys, 593 girls) aged 6-18 y (mean age ± SD: 10.3 ± 2.9) from 10 Italian regions. Daily iodine intake was estimated as UIE/0.92, based on the notion that $\sim$92% of the dietary iodine intake is absorbed. The adequacy of intakes was assessed according to the Dietary Reference Values for iodine of the European Food Safety Authority (EFSA). Body mass index (BMI) and UIC were also measured for each subject. RESULTS Based on the scientific opinion of EFSA, 600 of 1270 subjects (47.2%) had a lower than adequate iodine intake, with a higher prevalence among girls (54.6%) compared with boys (40.2%) (P

Context and objectiveIdiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic–pituitary–gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations.DesignAn observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients.ResultsMKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4–6.0) vs 7.0 years (6.0–7.0), P=0.01).ConclusionsMKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders, This Consensus Statement and the series of consensus meetings were supported by funds from the European Cooperation in Science and Technology (COST) action BM1208 on imprinting disorders (www.imprinting- disorders.eu), the European Society for Paediatric Endocrinology (ESPE) and the European Society for Endocrinology (ESE). Travel costs and housing of the representatives of the Asian Pacific Paediatric Endocrine Society (APPES) and of the Pediatric Endocrine Society (PES) were supported by their societies. The authors received no funding from pharmaceutical companies

The interleukin (IL)-6 biological system plays a key role in the pathogenesis of Paget disease (PD) of bone and pathological bone pain. Bone pain, particularly in the lower back region, is the most frequent symptom in patients with PD. This case-control study aimed to evaluate the relationship between the IL-6 system and low back pain (LBP) in patients with PD. We evaluated 85 patients with PD, with the disease localized in the lumbar spine, pelvis, and/or sacrum, and classified them based on the presence or absence of LBP, before and after aminobisphosphonate treatment. We also examined 32 healthy controls without LBP. Before treatment, IL-6 levels in patients with PD were higher than those in the controls, without difference between patients with or without LBP. Patients with PD with LBP (35/85) showed higher IL-6-soluble receptor (sIL-6R) and lower soluble glycoprotein (sgp) 130 levels compared with both patients with PD without LBP and controls (sIL-6R: 46.9 ± 7.4 vs 35.4 ± 8.6 vs 29.9 ± 4.2 ng/mL; sgp130: 307.2 ± 35.4 vs 341.4 ± 41.4 vs 417.1 ± 58.5 ng/mL, respectively). Paget disease remission, 6 months after treatment, is associated with LBP improvement. This phenomenon is associated with reduced sIL-6R levels and increased sgp130 levels in patients with PD with LBP at the baseline. Considering the biological properties of IL-6, sIL-6R, and sgp130, the results of the study suggest that the perception of LBP in patients with PD could be linked to an enhanced transmission of IL-6 signal in the specialized neural system activated by nociceptors.

International audience; Obesity is a heterogeneous disease with many different subtypes. Epigenetics could contribute to these differences. The aim of this study was to investigate genome-wide DNA methylation searching for methylation marks associated with obesity in children and adolescents. We studied DNA methylation profiles in whole blood cells from 40 obese children and controls using Illumina Infinium HumanMethylation450 BeadChips. After correction for cell heterogeneity and multiple tests, we found that compared to lean controls, 31 CpGs are differentially methylated in obese patients. A greatest proportion of these CpGs is hypermethylated in obesity and located in CpG shores regions. We next focused on severely obese children and identified 151 differentially methylated CpGs among which 10 with a difference in methylation greater than 10%. The top pathways enriched among the identified CpGs included the " IRS1 target genes " and several pathways in cancer diseases. This study represents the first effort to search for differences in methylation in obesity and severe obesity, which may help understanding these different forms of obesity and their complications.

Even though SQSTM1 gene mutations have been identified in a consistent number of patients, the etiology of Paget's disease of bone (PDB) remains in part unknown. In this study we analyzed SQSTM1 mutations in 533 of 608 consecutive PDB patients from several regions, including the high-prevalence area of Campania (also characterized by increased severity of PDB, higher number of familial cases, and peculiar phenotypic characteristics as giant cell tumor). Eleven different mutations (Y383X, P387L, P392L, E396X, M401V, M404V, G411S, D423X, G425E, G425R, and A427D) were observed in 34 of 92 (37%) and 43 of 441 (10%) of familial and sporadic PDB patients, respectively. All five patients with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations were observed in southern Italy (showing 9 of the 11 mutations) than in central and northern Italy. Genotype-phenotype analysis showed only a modest reduction in age at diagnosis in patients with truncating versus missense mutations, whereas the number of affected skeletal sites did not differ significantly. Patients from Campania had the highest prevalence of animal contacts (i.e., working or living on a farm or pet ownership) without any difference between patients with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutations. Interestingly, a progressive age-related decrease in the prevalence of animal contacts, as well as a parallel increase in the prevalence of SQSTM1 mutations, was observed in most regions except in the subgroup of patients from Campania. Moreover, patients reporting animal contacts showed an increased number of affected sites (2.54 ± 2.0 versus 2.19 ± 1.9, p

Patients with Paget's bone disease (PDB) have an increased risk of developing giant cell tumor (GCT). This study was performed to evaluate the clinical characteristics and evolution of GCT complicating PDB and to compare these clinical characteristics to those observed in two large PDB cohorts, the PDB Italian Registry and the United Kingdom's Multi-Centre Randomised Controlled Trial of Symptomatic Versus Intensive Bisphosphonate Therapy for Paget's Disease (PRISM) study. A systematic literature review identified 117 cases of PDB complicated by GCT (PDB-GCT), which involved the skeletal sites affected by PDB (110 patients) or the extraskeletal tissues adjacent to affected bones (7 patients). In contrast to what previously reported for GCT patients without GCT patients (83.2%) were white and one-fourth of them (24.8%) had multifocal GCTs. Compared to PDB patients without GCT, PDB-GCT patients showed a higher male/female ratio (2.1 versus 1.2) and more severe disease (age at PDB onset 52.1 +/- 12.1 versus 63.3 +/- 10.6 years; number of affected sites 6.1 +/- 2.9 versus 2.34 +/- 1.6; prevalence of polyostotic PDB 93.3% versus 60.6%). The mortality rate of PDB-GCT patients was higher than those occurring in GCT patients without PDB (about 50% versus 0% to 5% at 5 years) or in PDB patients without GCT (log rank=29.002). Moreover, up to 98% of PDB-GCT cases had elevated total alkaline phosphatase levels at neoplasm diagnosis, suggestive of active PDB. Importantly, PDB-GCT patients from Southern Italy (45.6% of all GCT patients) showed a higher prevalence of multifocal GCT (51.7%) and of positive familial history for PDB (70.8%) and GCT (65.0%). Finally, indirect evidence suggests a decline in the incidence of GCT in PDB patients. The occurrence of GCT in PDB patients is associated with severe disease and reduced life expectancy of affected patients. The increased prevalence of familial diseases in PDB-GCT patients from Southern Italy suggests a founder effect. The observed changes over time in the incidence of GCT in PDB patients could be related to improved clinical management and/or living conditions of patients. (c) 2014 American Society for Bone and Mineral Research.

Context: Nephrolithiasis affects about 10% of the population in industrialized countries, with calcium salts composing more than 80% of renal stones. A significant percentage of patients with calcium nephrolithiasis and normal parathyroid function show hypophosphatemia and reduced renal phosphate reabsorption (i.e. a renal phosphate leak). Objectives: The objective of the study was to compare serum levels of fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, in 110 recurrent stone formers with or without renal phosphate leak, six patients affected by X-linked hypophosphatemic rickets, five patients affected by oncogenic osteomalacia, and 60 unrelated healthy controls. Design: This was a prospective interventional study. Methods: Renal phosphate leak was identified based on the occurrence of idiopathic hypophosphatemia [serum phosphate concentration < 2.50 mg/dl ( Results: In 22 stone formers with renal phosphate leak, serum FGF23 concentration was significantly higher as compared with 88 stone formers without renal phosphate leak and with controls [83.3 (65.6–101.1) vs. 32.1 (26.8–37.4) and 24.5 (19.8–29.1) reference units (RU)/ml, respectively]. Stone formers with renal phosphate leak showed lower FGF23, compared with patients with oncogenic osteomalacia and X-linked hypophosphatemic rickets [572.3 (235.9–908.7) RU/ml]. Among stone formers and controls, serum FGF23 concentration displayed a strong inverse association with serum phosphate (r = −0.784, P = 0.009) and the rate of tubular phosphate reabsorption (r = −0.791, P = 0.008). Conclusions: In our study population, renal phosphate leak affected 20% of stone formers and was strongly associated with increased serum FGF23 concentration.

Imerslund-Gräsbeck syndrome is a rare autosomal recessive disorder, characterized by vitamin B12 deficiency due to selective malabsorption of the vitamin and usually results in megaloblastic anemia appearing in childhood. It is responsive to parenteral vitamin B12 therapy. The estimated prevalence (calculated based on Scandinavian data) is less than 6:1,000,000. However, many cases may be misdiagnosed. When there is reasonable evidence to suspect that a patient suffers from IGS, a new and straightforward approach to diagnosis is mutational analysis of the appropriate genes. We report for the first time the case of a girl of Italian ancestry with IGS genetically confirmed by the detection of a homozygous missense mutation in the AMN gene (c.208-2 A > G).

Background. Epidemiological data indicate an increasing incidence and prevalence of nephrolithiasis (NL) worldwide in the last few decades. Methods. The aim of this study was to compare the clinical and biochemical profiles of recurrent stone formers referred to a Kidney Stone Centre from March 1983 to June 1986 with the one featured by patients seen 25 years later in the same geographical area, Campania, southern Italy. Results. Idiopathic calcium stone formers made up the large majority of the patient population in both series. Those examined in 2008–11 showed higher age at the onset of NL, higher prevalence of overweight/obesity and higher urinary excretion of oxalate and phosphate compared with those seen in 1983–86. The differences in the urinary biochemical variables remained significant upon accounting for age, gender, creatinine clearance and body mass index (BMI), and were not observed in patients with primary hyperparathyroidism enrolled in the same periods. A greater prevalence of uric acid stone formers was also observed in the 2008–11 population. Conclusions. The massive epidemics of overweight/obesity and the substantial modifications of dietary habits over the last few decades in most Western countries may be the factors underlying the changing clinical and biochemical profiles of patients with recurrent NL.

Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome-wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree. © 2013 American Society for Bone and Mineral Research.

Background. Metabolic syndrome is a risk factor for nephrolithiasis. This study was performed to evaluate the clinical and biochemical profile of calcium-oxalate nephrolithiasis in stone formers with metabolic syndrome. Methods. A total of 526 recurrent stone formers, 184 of them with metabolic syndrome, and 214 controls were examined on a free diet and after a sodium-restricted diet (sodium intake 0.05]. After the test diet, this index was lower in diet-compliant stone formers with metabolic syndrome compared to diet-compliant stone formers without metabolic syndrome [1.15 (1.10–1.21) vs 1.39 (1.31–1.45); P < 0.01]. Conclusions. The biochemical profiles and responses to the sodium-restricted diet were significantly different between stone formers with metabolic syndrome and those without. Dietary habits play a central role in the pathogenesis of nephrolithiasis in stone formers with metabolic syndrome.

BACKGROUND: A significant percentage of patients with calcium nephrolithiasis and normal parathyroid function have renal phosphate leak. This disorder is characterized by idiopathic hypophosphatemia and reduced renal phosphate threshold normalized for the glomerular filtration rate (TmPi/GFR). The majority of these patients harbor high or inappropriately normal circulating levels of fibroblast growth factor 23 (FGF23), a hormone regulating phosphate homeostasis. AIM: The aim of this study was to define the role of FGF23 allelic variants in the pathogenesis of hypophosphatemic nephrolithiasis. SUBJECTS AND METHODS: We sequenced the regulative and coding regions of the FGF23 gene in 106 stone formers, 17 of which had renal phosphate leak, and in 87 healthy controls. We subsequently performed in vitro studies. RESULTS: A C716T nonsynonymous change (T239M, rs7955866) in the FGF23 gene was detected in seven of the 17 stone formers with renal phosphate leak. The prevalence of the T allele and of the CT genotype in stone formers with renal phosphate leak was significantly higher compared to that observed in stone formers without renal phosphate leak and in controls (P < 0.03 in all cases). In the whole study population, FGF23(716T) subjects showed levels of serum phosphate and TmPi/GFR significantly lower compared to FGF23(716C) subjects. In vitro studies showed that the T239M change increases FGF23 secretion and that the FGF23(239M) variant induces a higher activation of the FGF receptor/ERK pathway compared to FGF23(239T). CONCLUSION: Our results highlight a novel significant association between the C716T missense variation in the FGF23 gene and calcium nephrolithiasis with renal phosphate leak

BACKGROUND: Metabolic syndrome is a risk factor for nephrolithiasis. This study was performed to evaluate the clinical and biochemical profile of calcium-oxalate nephrolithiasis in stone formers with metabolic syndrome. METHODS: A total of 526 recurrent stone formers, 184 of them with metabolic syndrome, and 214 controls were examined on a free diet and after a sodium-restricted diet (sodium intake < 100 mmol/24 h). RESULTS: On free diet, stone formers with metabolic syndrome showed higher sodium excretion [mean (95% confidence interval), 196 (176-218) vs 160 (150-168) mmol/24 h; P < 0.01] and lower citrate excretion [2.23 (1.99-2.58) vs 2.84 (2.51-3.17) mmol/24 h; P < 0.01] compared to controls, whereas stone formers without metabolic syndrome showed higher calcium and oxalate excretion [5.43 (5.01-5.82) vs 3.58 (2.84-4.19) and 0.34 (0.32-0.36) vs 0.26 (0.20-0.31)m mmol/24 h for calcium and oxalate, respectively; P < 0.01] and lower citrate excretion [2.18 (1.98-2.38) vs 2.84 (2.51-3.17) mmol/24 h; P < 0.01] compared to controls. The ion activity product of urinary calcium-oxalate salts was similar between stone formers with and without metabolic syndrome [1.41 (1.31-1.59) vs 1.40 (1.35-1.45); P > 0.05]. After the test diet, this index was lower in diet-compliant stone formers with metabolic syndrome compared to diet-compliant stone formers without metabolic syndrome [1.15 (1.10-1.21) vs 1.39 (1.31-1.45); P < 0.01]. CONCLUSIONS: The biochemical profiles and responses to the sodium-restricted diet were significantly different between stone formers with metabolic syndrome and those without. Dietary habits play a central role in the pathogenesis of nephrolithiasis in stone formers with metabolic syndrome.

Aminobisphosphonates actually represent the most common treatment for Paget disease of bone (PDB). In a previous study we demonstrated that either zoledronic acid (4 mg) or neridronate (200 mg) given as a single intravenous infusion showed a similar short-term efficacy in achieving biochemical remission in up to 90% of patient nonresponders to pamidronate. In this study we compared the long-term (36 months) effects of a same neridronate dose (200 mg) given as an intravenous (100-mg infusion for 2 consecutive days) or intramuscular (25-mg injection weekly for 2 months) regimen in 56 patients with active PDB. All patients were advised to receive calcium plus vitamin D supplementation throughout the study period. At 6 months, 92.6% and 96.5% of patients receiving intravenous and intramuscular neridronate, respectively, achieved a therapeutic response [defined as normalization of alkaline phosphatase (ALP) levels or a reduction of at least 75% in total ALP excess]. The response to treatment was significantly correlated with baseline ALP and 25-hydroxyvitamin D [25(OH)D] levels at 6 months. The decrease in ALP levels was highest in patients with higher baseline total or bone-specific ALP levels and with higher 25(OH)D levels at 6 months. Response rates were maintained at 12 months but decreased progressively at 24 and 36 months without significant differences between the two neridronate regimens. Both regimens were well tolerated. The only relevant side effect was an acute-phase response occurring in 14% of the patients. In conclusion, these results indicate that a 200-mg intramuscular neridronate course has a similar efficacy as an intravenous infusion of the same dose for the treatment of PDB and might be of particular value for patients intolerant to oral bisphosphonates and unwilling or unable to undergo intravenous infusions.