Luiz Claudio Castro

Hypophosphatemic rickets and osteomalacia

The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases, all of them sharing the same pathophysiologic mechanism: reduction in the phosphate reabsorption by the renal tubuli. This process leads to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of calcitriol, causing osteomalacia or rickets in children and osteomalacia in adults. X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic rickets, and tumor-induced osteomalacia are the main syndromes involved in the hypophosphatemic rickets. Although these conditions exhibit different etiologies, there is a common link among them: increased activity of a phosphaturic factor, being the fibroblast growth factor 23 (FGF-23) the most studied one and to which is attributed a central role in the pathophysiology of the hyperphosphaturic disturbances. Activating mutations of FGF-23 and inactivating mutations in the PHEX gene (a gene on the X chromosome that codes for a Zn-metaloendopeptidase proteolytic enzyme which regulates the phosphate) involved in the regulation of FGF-23 have been identified and have been implicated in the pathogenesis of these disturbances. Genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo-renal metabolic axis, whose mechanisms of interaction have been poorly understood so far. This paper reviews the current knowledge status concerning the pathophysiology of phosphate metabolism regulation and the pathophysiologic basis of hypophosphatemic rickets. It also analyzes the clinical picture and the therapeutic aspects of these conditions as well.

O sistema endocrinológico vitamina D

The vitamin D endocrine system comprises a group of 7-dehydrocholesterol-derived secosteroid molecules, including its active metabolite 1,25-dihydroxy-vitamin D (1,25(OH)(2)D), its precursors and other metabolites, its binding protein (DBP) and nuclear receptor (VDR), as well as cytochrome P450 complex enzymes participating in activation and inactivation pathways of those molecules. The biologic effects of 1,25(OH)(2)D are mediated by VDR, a ligand-activated transcription factor which is a member of the nuclear receptors family, spread in almost all human cells. In addition to its classic role in the regulation of calcium metabolism and bone health, evidence suggests that 1,25(OH)(2)D directly or indirectly modulates about 3% of the human genome, participating in the regulation of chief functions of systemic homeostasis, such as cell growth, differentiation and apoptosis, regulation of immune, cardiovascular and musculoskeletal systems, and insulin metabolism. Given the critical influence of the vitamin D endocrine system in many processes of systemic metabolic equilibrium, the laboratory assays available for the evaluation of this system have to present high accuracy and reproducibility, enabling the establishment of cutoff points that, beyond being consensually accepted, reliably express the vitamin D status of the organism, and the respective clinical-metabolic impacts on the global health of the individual.

25-Hydroxy-vitamin D levels among Callithrix penicillata primate species raised in captivity

Background  Animals in captivity should receive adequate sunlight exposure for sufficient generation of vitamin D [25(OH)D]. In the present study, 25(OH)D serum levels of 84 Callithrix penicillata primates were evaluated.

Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations

Background Amelogenesis imperfecta (AI) is a group of genetic diseases characterised by tooth enamel defects. AI was recently described in patients with familial hypercalciuria and hypomagnesaemia with nephrocalcinosis (FHHNC) caused by CLDN16 mutations. In the kidney, claudin-16 interacts with claudin-19 to control the paracellular passage of calcium and magnesium. FHHNC can be linked to mutations in both genes. Claudin-16 was shown to be expressed during amelogenesis; however, no data are available on claudin-19. Moreover, the enamel phenotype of patients with CLDN19 mutations has never been described. In this study, we describe the clinical and genetic features of nine patients with FHHNC carrying CLDN19 mutations and the claudin-19 expression profile in rat ameloblasts. Methods Six FHHNC Brazilian patients were subjected to mutational analysis. Three additional French patients were recruited for orodental characterisation. The expression profile of claudin-19 was evaluated by RT-qPCR and immunofluorescence using enamel epithelium from rat incisors. Results All patients presented AI at different degrees of severity. Two new likely pathogenic variations in CLDN19 were found: p.Arg200Gln and p.Leu90Arg. RT-qPCR revealed low Cldn19 expression in ameloblasts. Confocal analysis indicated that claudin-19 was immunolocalised at the distal poles of secretory and maturing ameloblasts. Conclusions For the first time, it was demonstrated that AI is associated with FHHNC in patients carrying CLDN19 mutations. The data suggest claudin-19 as an additional determinant in enamel formation. Indeed, the coexistence of hypoplastic and hypomineralised AI in the patients was consistent with claudin-19 expression in both secretory and maturation stages. Additional indirect systemic effects cannot be excluded.

Screening for celiac disease among patients with Turner syndrome in Brasília, DF, midwest region of Brazil

CONTEXT Several studies have demonstrated a higher prevalence of celiac disease (CD) among females with Turner syndrome when compared to the general population. Nevertheless, there is no record in literature concerning this investigation among Brazilian patients. OBJECTIVE To assess the prevalence of CD among a group of Brazilian patients with Turner syndrome. METHODS Fifty-six females with Turner syndrome and on gluten-containing diet were screened for CD utilizing immunoglobulin A antiendomysium (IgA-EMA) and immunoglobulin A anti-tissue transglutaminase (IgA-tTG) antibody assays. Additionally, they were genotyped for CD human leukocyte antigen (CD-HLA) predisposing alleles. Patients showing positivity in serological testing were offered to perform small intestine biopsy for histological confirmation. RESULTS Mean age at diagnosis of Turner syndrome was 5.5 ± 4.4 years; mean age at screening for CD was 17.0 ± 9.3 years (from 10 months of age to 52 years). Two girls were positive for IgA-EMA and IgA-tTG, presented predisposing HLA-DQ2 alleles and both had the diagnosis of CD confirmed by jejunal biopsy. CONCLUSION The 3.6% prevalence of biopsy-proven CD among this group of females with Turner syndrome is 10 times higher than the one among females from the general population of the same geographical area. This result provides additional support to an association between these two disorders and restates that girls and women with Turner syndrome represent a high risk population for developing CD.

Serologic screening and genetic testing among brazilian patients with celiac disease and their first degree relatives

CONTEXT Celiac disease susceptibility has been shown to be associated with the HLA alleles DQA1*0501 and DQB1*0201 (together encoding the DQ2 heterodimer) that are present in practically all celiac disease patients. The DQ8 heterodimer (coded by DQA1*03-DQB1*0302), which is carried on a DRB1*04 (DR4) haplotype, is commonly encoded for by the few celiacs who do not carry the DQ2 heterodimer. Only a few celiac disease patients have been reported without these known risk alleles. OBJECTIVE To assess the prevalence of celiac disease in a group of first degree relatives of celiac patients, and the frequency of HLA predisposing alleles both in the group of celiac patients and in their first degree relatives, identifying those first degree relatives who would need further screening for celiac disease. METHODS Ninety celiac disease patients and 207 first degree relatives underwent serologic screening for celiac disease (endomysial and transglutaminase antibodies) followed by intestinal biopsy in positive patients. The HLA-DQA1*0501, DQB1*0201 and DRB1*04 frequencies of celiac patients and their first degree relatives were determined utilizing the PCR method. RESULTS All the celiac disease patients (n = 90) with the exception of one (1.1%) carried at least one of the alleles investigated. Altogether 11 (5.3%) of the investigated first degree relatives did not carry any of the alleles studied. Fourteen (6.7%) new cases of celiac disease were found among the 207 celiac disease patients first degree relatives. CONCLUSIONS Considering the cost-benefit of the HLA typing of all the first degree relatives of celiac patients, their HLA status should be decided on an individual basis, taking account of their profile and preferences, and the existence of other medical conditions.

Dental panoramic indices and fractal dimension measurements in osteogenesis imperfecta children under pamidronate treatment.

OBJECTIVES To verify radiomorphometric indices and fractal dimension (FD) in dental panoramic radiographs (DPRs) of children with different types of osteogenesis imperfecta (OI) and also to verify the effect of pamidronate (PAM) treatment in such panoramic analyses. METHODS In this retrospective study, 197 DPRs of 62 children with OI Types I, III and IV who were in treatment with a comparable dosage of intravenous PAM were selected. The mandibular cortical width (MCW), mandibular cortical index, visual estimation of the cortical width and FD of three standardized trabecular and cortical mandibular regions of interest were obtained from the radiographs. Factorial analysis of variance and Fisher test were used to compare FD and MCW measurements in children with different types of OI for different PAM cycles. RESULTS Children with all types of OI have thinner and more porous mandibular cortices at the beginning of treatment. There were significant differences between MCW and FD of the cortical bone, regarding different types of OI and number of PAM cycles (p = 0.037 and p = 0.044, respectively). FD measurements of the trabecular bone were not statistically different among OI types nor were PAM cycles (p > 0.05). CONCLUSIONS Children with OI presented cortical bone alterations after PAM treatment. Both MCW and the FD of the cortical bone were higher in children with OI after PAM treatment. It is argued that cortical bone should be considered for analyzing patients with OI, as well as to monitor the progress of PAM treatment.

Maternal celiac disease: improbable risk factor for neural tube defect

Objectives To verify the existence of possible relation between maternal celiac disease (CD) and the appearance of neural tube defects (NTD) in the newborn serological testing in 208 mothers with NTD-affected pregnancy were performed. Methods All sera were tested for total serum immunoglobulin A (IgA) levels and for IgA class endomysial antibody using indirect immunofluorescence technique. Participant age ranged from 19 to 43 years (mean: 33 years). None had been previously investigated for or had a family history of CD. Results Immunoglobulin levels were normal and results of the IgA-endomysial antibody tests were negative in all women tested. Conclusion This study, although nonconclusive, did not corroborate earlier findings described in the literature of increased frequency of CD in mothers with a history of NTD-affected pregnancy. At this moment we feel that a routine screening for CD in pregnant women to avoid a possible pregnancy aggravated by NTD would not be justifiable.

Evaluation of 25-hydroxy-vitamin D and parathyroid hormone in Callithrix penicillata primates living in their natural habitat in Brazil

Vitamin D is a secosteroid hormone with important roles in the control of bone and mineral metabolism of vertebrates and in the maintenance of systemic homeostasis. This study aimed (i) to evaluate the serum concentrations of 25‐hydroxy‐vitamin D levels [25(OH)D], parathyroid hormone (PTH) and ionized calcium (iCa) of wild Callithrix penicillata (black‐tufted marmosets) and (ii) to propose reference ranges for those analytes for free‐living marmosets.

NPHS1 gene mutations confirm congenital nephrotic syndrome in four Brazilian cases: A novel mutation is described

Autosomal recessive mutations in NPHS1 gene are a common cause of congenital nephrotic syndrome (CNS). The disorder is characterized by massive proteinuria that manifests in utero or in the neonatal period during the first 3 months of life. NPHS1 encodes nephrin, a member of the immunoglobulin family of cell adhesion molecules and the main protein expressed at the renal slit diaphragm. Currently, there are approximately 250 mutations described in the NPHS1 gene distributed among all nephrin domains. The main objective of this study was to perform the analysis of the NPHS1 gene in patients with congenital nephrotic syndrome in order to determine the molecular cause of the disease.