BackgroundPhenylketonuria (PKU) is a rare inborn error of metabolism often complicated by a progressive bone impairment of uncertain etiology, as documented by both ionizing and non- ionizing techniques.MethodologyPeripheral blood mononuclear cell (PBMC) cultures were performed to study osteoclastogenesis, in the presence or absence of recombinant human monocyte-colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). Flow cytometry was utilized to analyze osteoclast precursors (OCPs) and T cell phenotype. Tumour necrosis factor α (TNF-α), RANKL and osteoprotegerin (OPG) were quantified in cell culture supernatants by ELISA. The effects of RANKFc and anti-TNF-α antibodies were also investigated to determine their ability to inhibit osteoclastogenesis. In addition, bone conditions and phenylalanine levels in PKU patients were clinically evaluated.Principal FindingsSeveral in vitro studies in PKU patients' cells identified a potential mechanism of bone formation inhibition commonly associated with this disorder. First, PKU patients disclosed an increased osteoclastogenesis compared to healthy controls, both in unstimulated and M-CSF/RANKL stimulated PBMC cultures. OCPs and the measured RANKL/OPG ratio were higher in PKU patients compared to healthy controls. The addition of specific antagonist RANKFc caused osteoclastogenesis inhibition, whereas anti-TNF-α failed to have this effect. Among PBMCs isolated from PKU patients, activated T cells, expressing CD69, CD25 and RANKL were identified. Confirmatory in vivo studies support this proposed model. These in vivo studies included the analysis of osteoclastogenesis in PKU patients, which demonstrated an inverse relation to bone condition assessed by phalangeal Quantitative Ultrasound (QUS). This was also directly related to non-compliance to therapeutic diet reflected by hyperphenylalaninemia.ConclusionsOur results indicate that PKU spontaneous osteoclastogenesis depends on the circulating OCP increase and the activation of T cells. Osteoclastogenesis correlates with clinical parameters, suggesting its value as a diagnostic tool for an early assessment of an increased bone resorption in PKU patients.
In children with syndromic hypoparathyroidism, substitutive treatment with rhPTH (1-34) maintains adequate blood calcium levels and allows prompt normalization of urinary calcium excretion, through direct action on the kidney and through calcium and vitamin D therapy layoff.
Hyponatremia and hypernatremia, common electrolyte abnormalities in children hospitalized for intracranial diseases, are life-threatening events. Diagnosis and adequate treatment of hypo- and hypernatremia are mandatory to prevent neurological sequelae. We report ante-and post-hypophyseal dysfunctions, disabilities and acute sodium metabolism derangements in 16 children affected by hypothalamic-hypophyseal tumors treated by neurosurgery and/or chemotherapy during a long-lasting follow-up. We compare acute hypo- and hypernatremic episodes during surgery between these patients, treated with a specific hormonal and infusive protocol (protocol A), and a previous cohort of patients, affected by similar tumors, treated with a previously published protocol (protocol B). All patients showed multiple or isolated pituitary dysfunctions and disabilities before chemotherapy and/or surgical treatment that worsened during the follow-up period. We found a statistical significant decrease of hyponatremic intra-operative acute events in children treated with protocol A. Sodium metabolism derangements complicating the course of hypothalamic-hypophyseal tumors can be partially prevented with specific per-operative protocols. Aim of this study is to present a new sodium metabolism derangements management in children treated for hypothalamic-hypophyseal tumors and to compare this with a previous one.
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