The evolving epidemiology of acute gastroenteritis in hospitalized children in Italy.

Few data are available on the prevalence and features of acute gastroenteritis (AGE) in hospitalized children in Italy, where specific rotavirus vaccines were introduced into the national vaccination plan in 2017. To evaluate vaccination effects on AGE epidemiology, we analysed data from children aged ≤ 18 years admitted for AGE at the University Hospital of Pisa in 2019, comparing them with those recorded in 2012. Demographical, clinical, diagnostic, and treatment data were collected reviewing medical records and were therefore compared. In 2019 and 2012, 86 (median age 2.5 years [IQR 1.4-5.9]) and 85 children (median age 2.3 years [IQR 1.3-5.1]) were respectively admitted with AGE. The most common symptoms were diarrhoea and vomiting; decreased skin turgor was more frequent in 2019 (54% and 34% respectively, p = 0.01). Viral infections were more common than bacterial ones; in 2019, a decrease in rotavirus infections (67% and 22%, p = 0.003) and an increase in adenovirus infections (50% and 10%, p = 0.002) and in the number of patients with negative stool testing (58% and 39%, p = 0.04) were found.Conclusions: Viral infections are the leading cause of AGE in hospitalized children in Italy. The introduction of rotavirus vaccines did not reduce the number of hospitalizations per year. Adenovirus and other non-routinely screened viruses may be undergoing a selection process making them common causative agents for AGE. What is Known: • Rotavirus is the leading cause of acute severe gastroenteritis in children worldwide, especially < 5 years of age. • The introduction of specific vaccines may be changing its epidemiology. • Few data are available on acute gastroenteritis in hospitalized children in Italy. What is New: • Viral infections are the leading cause of acute gastroenteritis in hospitalized children in Italy. • Specific vaccines are reducing rotavirus infections, but adenovirus and other non-routinely screened viruses may be undergoing a selection process making them common causative agents for gastroenteritis.

X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management.

X-linked hypophosphatemic rickets (XLH) is the commonest inherited form of rickets. It is caused by an impaired regulation of fibroblast growth factor 23 (FGF23) due to a PHEX gene mutation, which leads to reduced tubular reabsorption of phosphate and renal 1α-hydroxylase activity and increased renal 24-hydroxylase activity. Hypophosphatemia associated with renal phosphate wasting, normal serum levels of calcium, parathyroid hormone, and 25-hydroxyvitamin D represents the main biochemical sign in affected patients. Patients with XLH show rickets and osteomalacia, severe deformities of the lower limbs, bone and muscular pain, stunted growth, and reduced quality of life. However, XLH is a multisystemic disorder requiring multidisciplinary approaches in specialized subdisciplines. Severe complications may occur in patients with XLH including craniosynostosis, hearing loss, progressive bone deformities, dental and periodontal recurrent lesions, and psychosocial distress. Moreover, long-term conventional treatment with active vitamin D metabolites and oral inorganic phosphate salts may cause endocrinological complications such as secondary or tertiary hyperparathyroidism, and adverse events in kidney as hypercalciuria, nephrocalcinosis, and nephrolithiasis. However, conventional treatment does not improve phosphate metabolism and it shows poor and slow effects in improving rickets lesions and linear growth. Recently, some trials of treatment with recombinant human IgG1 monoclonal antibody that targets FGF23 (burosumab) showed significant improvement of serum phosphate concentration and renal tubular reabsorption of phosphate that were associated with a rapid healing of radiologic signs of rickets, reduced muscular and osteoarticular pain, and improved physical function, being more effective for the treatment of patients with XLH in comparison with conventional therapy. Therefore, a global management of patients with XLH is strongly recommended and patients should be seen regularly by a multidisciplinary team of experts.

Complete Androgen Insensitivity Syndrome: From Bench to Bed.

Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.

Osteoporosis in children and adolescents: etiology and management.

Bone mass increases progressively during childhood, but mainly during adolescence when approximately 40% of total bone mass is accumulated. Peak bone mass is reached in late adolescence, and is a well recognised risk factor for osteoporosis later in life. Thus, increasing peak bone mass can prevent osteoporosis. The critical interpretation of bone mass measurements is a crucial factor for the diagnosis of osteopenia/osteoporosis in children and adolescents. To date, there are insufficient data to formally define osteopenia/osteoporosis in this patient group, and the guidelines used for adult patients are not applicable. In males and females aged <20 years the terminology 'low bone density for chronologic age' may be used if the Z-score is less than -2. For children and adolescents, this terminology is more appropriate than osteopenia/osteoporosis. Moreover, the T-score should not be used in children and adolescents. Many disorders, by various mechanisms, may affect the acquisition of bone mass during childhood and adolescence. Indeed, the number of disorders that have been identified as affecting bone mass in this age group is increasing as a consequence of the wide use of bone mass measurements. The increased survival of children and adolescents with chronic diseases or malignancies, as well as the use of some treatment regimens has resulted in an increase in the incidence of reduced bone mass in this age group. Experience in treating the various disorders associated with osteoporosis in childhood is limited at present. The first approach to osteoporosis management in children and adolescents should be aimed at treating the underlying disease. The use of bisphosphonates in children and adolescents with osteoporosis is increasing and their positive effect in improving bone mineral density is encouraging. Osteoporosis prevention is a key factor and it should begin in childhood. Pediatricians should have a fundamental role in the prevention of osteoporosis, suggesting strategies to achieve an optimal peak bone mass.

Longitudinal changes of lumbar bone mineral density (BMD) in patients with GH deficiency after discontinuation of treatment at final height; timing and peak values for lumbar BMD.

OBJECTIVE: GH treatment has an important role in the acquisition of bone mass in children and adolescents with GH deficiency (GHD). However, there is no information concerning the timing and value of peak bone mass in treated patients with GHD. In adolescents with GHD we longitudinally measured lumbar bone mineral density (BMD) after discontinuation of GH treatment at final height until they achieved lumbar peak BMD (pBMD). Moreover, the changes of lumbar BMD after the attainment of the peak were assessed for a period of 2 years. The results of patients were compared with those obtained in age- and sex-matched healthy controls. PATIENTS AND MEASUREMENTS: Lumbar BMDarea [bone mineral content (BMC) corrected by the vertebral surface area scanned] and lumbar BMDvolume (BMC corrected by vertebral volume estimated by a mathematical model), by dual energy X-ray absorptiometry, were assessed in 16 patients (nine males, seven females; aged 14.9-18.8 years) with isolated GHD and 157 healthy subjects (78 males, aged 16.2-24.9 years; 79 females, aged 14.1-22.8 years) as controls. In patients, lumbar BMDarea and lumbar BMDvolume were measured at final height and approximately every year up to 21-24 years and 19-22 years in males and females, respectively; BMD values of the patients were plotted on the reference curves for age and sex obtained in controls. RESULTS: At final height, seven male (78%) and five female (71%) patients had a value for lumbar BMDarea below 2SD of normal mean, whereas all patients had a value of lumbar BMDvolume between 0 and -2SD of normal mean. In patients, lumbar pBMDarea and lumbar pBMDvolume were achieved approximately 1-3 years after final height. The timing of lumbar pBMDarea and lumbar pBMDvolume was significantly (P < 0.0001) delayed in patients in comparison with controls (pBMDarea: males, 19.8 +/- 0.6 years and 18.4 +/- 0.6 years; females, 18.0 +/- 0.3 years and 16.7 +/- 0.6 years, respectively; pBMDvolume: males, 19.8 +/- 0.7 years and 18.6 +/- 0.6 years; females, 18.0 +/- 0.4 years and 16.7 +/- 0.6 years, respectively). In addition, mean values for lumbar pBMDarea and lumbar pBMDvolume were significantly (P < 0.01 to P < 0.0001) reduced in patients compared with controls (pBMDarea: males, 1.129 +/- 0.055 g/cm2 and 1.225 +/- 0.048 g/cm2; females, 1.122 +/- 0.053 g/cm2 and 1.227 +/- 0.060 g/cm2, respectively; pBMDvolume: males, 0.326 +/- 0.010 g/cm3 and 0.352 +/- 0.036 g/cm3; females, 0.348 +/- 0.010 g/cm3 and 0.388 +/- 0.039 g/cm3, respectively). In patients, mean values of lumbar BMDvolume declined significantly (P < 0.03 to P < 0.01) 2 years after its peak. At any rate, mean values of lumbar BMDarea and lumbar BMDvolume of patients one and two years after their peak remained significantly lower (P < 0.01 to P < 0.0001) than those of controls. CONCLUSIONS: The results show that treated adolescents with GHD have an increase of lumbar BMDarea and lumbar BMDvolume after discontinuation of GH treatment at final height, but they have delayed timing and reduced mean values of lumbar pBMDarea and lumbar pBMDvolume in comparison with controls. In patients, mean values of lumbar BMDvolume declined 2 years after its peak. Although the number of the patients was small, the results seem to indicate that GH has a role in the acquisition of lumbar BMD after final height in patients with GHD, suggesting that GH treatment should be continued up to the achievement of lumbar pBMD.

Genetic advances, biochemical and clinical features and critical approach to treatment of patients with X-linked hypophosphatemic rickets.

X-linked hypophosphatemic rickets (XLH) is an hereditary form of rickets due to isolated renal tubular phosphate wasting and impaired production of 1,25-dihydroxyvitamin D [1,25(OH)2D]. XLH is caused by mutations in the PHEX (phosphate regulating gene with homology to endopeptidases) gene, which is located on Xp22.1. The pathogenetic mechanisms by which mutations in the PHEX gene cause XLH are not completely known. Hypophosphatemia associated with disproportionate short stature and bone deformities of the lower limbs are the main findings in XLH patients. Some studies have shown that conventional treatment with vitamin D metabolites, such as 1,25(OH)2D3 or 1 alpha-hydroxyvitamin D3, combined with inorganic phosphate salts is able to improve serum phosphate concentrations and linear growth, as well as healing rickets. However, some patients may have poor beneficial effects by this therapy. On the other hand, some important treatment complications, such as hypervitaminosis D, nephrocalcinosis and secondary/tertiary hyperparathyroidism may occur during the current therapy. Despite conventional treatment, some patients may require surgical correction of bone deformities. In the light of the recent genetic advances the mechanisms that could be involved in the pathogenesis of XLH are discussed. Furthermore, the article reviews the effects of the medical treatment providing current recommendations for the management of XLH patients.

Molecular analysis of the GNAS1 gene for the correct diagnosis of Albright hereditary osteodystrophy and pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show Gsalpha protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the Gsalpha protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for Gsalpha activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia.

Lumbar bone mineral density at final height and prevalence of fractures in treated children with GH deficiency.

Lumbar bone mineral density (BMD) by dual energy x-ray absorptiometry was assessed in 46 (29 boys, 17 girls) treated patients with growth hormone deficiency (GHD) at final height, comparing the BMD results with normative data. Prevalence of fractures in patients during treatment and healthy controls (n = 100) during the corresponding time period was assessed. Lumbar BMD values at final height of fractured and fracture-free patients were compared between them. Lumbar BMD corrected for bone area was significantly (P < 0.01) reduced (boys, -0.4 +/- 0.8 Z score; girls, -0.5 +/- 0.7 Z score), but lumbar BMD corrected for bone size (BMDvolume) did not differ [P = not significant (NS); boys -0.2 +/- 1.0 Z score; girls, -0.3 +/- 1.0 Z score] from normal mean. Approximately 22% of patients had reduced lumbar BMD (Z score, -1 to -2). The fact that patients had a complete or partial GHD did not influence lumbar BMD. The prevalence of fractured patients did not differ (P = NS) from that of controls [n = 7 (15.2%) and n = 24 (24.0%), respectively; odds ratio, 1.837]. Lumbar BMDvolume of fractured patients was significantly (P < 0.02) lower than that of fracture-free (n = 39) patients (boys, 0.310 +/- 0.005 and 0.351 +/- 0.032 g/cm(3), respectively; girls, 0.326 +/- 0.027 and 0.382 +/- 0.036 g/cm(3), respectively). The percentage of the fractured patients with lumbar BMDvolume less than 1 SD of normal mean was significantly (P < 0.0001) higher than that of fracture-free patients [n = 6 (85.7%) and n = 4 (10.3%), respectively; odds ratio, 26.092). The fractured patients also showed reduced lumbar BMD corrected for bone area and BMDvolume at the time of fractures (-1.6 +/- 0.4 and -1.5 +/- 0.2 Z score, respectively). The results show that treated patients with GHD have normal mean values of lumbar BMDvolume at final height, but some patients have reduced lumbar BMD (Z score <1) with an increased susceptibility to fractures.

Puberty and bone development.

Puberty has a key role for bone development. Skeletal mass approximately doubles at the end of adolescence. The main determinants of pubertal gain of bone mass are the sex steroids, growth hormone and insulin-like growth factors (by their effects on bone and muscle mass), 1,25-dihydroxyvitamin D (by stimulating calcium absorption and retention) and muscle mass (by regulating modelling/remodelling thresholds). Calcium intake is an additional factor influencing bone formation. The interactions among these factors are undefined. The accrual of bone mass during puberty is a major determinant of peak bone mass and, thereby, of the risk of osteoporotic fractures during advanced age.