RESUMO
BACKGROUND: X-linked hypophosphatemic rickets (XLHR) is a rare genetic disease, often delayed in diagnosis due to the low degree of suspicion and limited access to sophisticated diagnostic tools that confirm the diagnosis, such as genetic testing. METHODS: Through a cross-sectional and observational study, 26 patients with a previously presumptive diagnosis of X-linked hypophosphatemic rickets (based on clinical history, laboratory findings, and physical examination), were followed for approximately 12 months. During 12 months of follow-up, only 16 patients underwent genetic testing and enrolled in the study. Previous data were analyzed, such as clinical history (e.g., gender, current age, age of clinical diagnosis, age of admission to hospital, family history, and previous orthopedic surgery), physical exam, imaging tests (e.g., radiological changes) and laboratory tests (e.g., tubular maximum reabsorption rate of phosphate to glomerular filtration rate, alkaline phosphatase, and phosphate levels) at the time of the patient's admission to IEDE and UFRJ, to corroborate and substantiate our research. These data were extracted from the medical records of the patients. RESULTS: Among the 16 patients analyzed by molecular biology techniques, the new generation sequencing (NGS), using DNA samples from oral swabs, we obtained seven variants never previously described, which were verified by Sanger sequencing. Among the seven variants never previously described, the most common coding impact was the nonsense mutation. We found two frameshift, one intronic splicing variant, three nonsense, and one deletion splice junction loss. Among patients with new mutations who presented data in the medical record, 100% showed a reduction in TmP/GFR (average of 1.98 mg/dl), the most sensitive laboratory parameter at the time of diagnosis, as well as serum phosphorus (100% had hypophosphatemia on arrival at the referral hospitals--average of 2.4 mg/dl and median 2.3 mg/dl). We also performed NGS on three mothers of the patients with identified mutations. Among these mothers, only one tested negative for the mutation and no family history was reported as well. This mother had serum phosphate of 3.5 mg/dl (normal range: 2.5-4.5 mg/dl) at the time of genetic test collection. The others had a positive test, low serum phosphorus at the time of the molecular test, in addition to a positive family history. CONCLUSION: This study describes seven new variants in the PHEX gene and aims to increase the knowledge of the scientific community about the types of mutations involving this gene, increasing information on the genetic basis of this condition, enabling future considerations about genotype-phenotype correlation, in addition to diagnosis accurate and early.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Brasil , Estudos Transversais , Raquitismo Hipofosfatêmico Familiar/genética , Hospitais , Humanos , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fosfatos , FósforoRESUMO
BACKGROUND: Craniosynostosis is an underdiagnosed complication associated with hypophosphatemic rickets. The study aims to describe the clinical and auxological characteristic of children with hypophosphatemic rickets and craniosynostosis, describe the usual treatment, and compare the characteristics with those of children without craniosynostosis. METHODS AND PATIENTS: An observational and retrospective cohort study was conducted. Clinical notes and cranial images were reviewed. Out of 96 children, only the 50 patients who had skull images were included. RESULTS: Out of 50 patients, 26 (15 males) had craniosynostosis (52%). No differences were observed in birth size, age, height, body proportions, alkaline phosphatase, serum phosphate, or percent tubular reabsorption of phosphate at first appointment among children with or without craniosynostosis. Among patients with craniosynostosis, dolichocephaly was prevalent. The sagittal suture was affected in all patients with craniosynostosis, with 19 of 26 children (73%) affected with isolated scaphocephaly. Pan-sutural craniosynostosis was present in 7 children (27%). None of the children had microcephaly, 7 of them presented macrocephaly and, in the remaining subjects, head circumference was normal. Five patients had undergone at least 1 cranial remodeling surgery. One patient with craniosynostosis was diagnosed with a Chiari I malformation. Molecular characterization of PHEX gene was performed in 14 cases. CONCLUSIONS: Craniosynostosis is an underdiagnosed complication of hypophosphatemic rickets. Many patients with normal head size and growth may go undiagnosed, thus it is important to consider this association for early diagnosis and possible surgical treatment. A multidisciplinary approach is necessary for a correct long-term follow-up.
Assuntos
Craniossinostoses/patologia , Raquitismo Hipofosfatêmico Familiar/complicações , Predisposição Genética para Doença , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Criança , Pré-Escolar , Craniossinostoses/etiologia , Craniossinostoses/metabolismo , Craniossinostoses/cirurgia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
Abstract Background and objective: Magnesium ammonium phosphate stones (MAP), also known as struvite stones, are associated with urinary infection and impairment of renal unit. The aim of this study is to evaluate the urinary metabolic risk factors for recurrence of renal calculi in patients submitted to nephrectomy due to MAP stones. Methods: We retrospectively reviewed the charts of patients > 18 years old submitted to total nephrectomy due to pure MAP stones and pure calcium oxalate (CaOx) stones from July 2006 to July 2016. Urinary metabolic parameters were assessed through 24-hour urine exams ≥ 3 months after nephrectomy. Urinary metabolic parameters and new event related to lithiasis were compared. Results: Twenty-eight and 39 patients were included in MAP and CaOx group, respectively. Abnormalities in 24-hour urine samples were similar between groups. Hypercalciuria occurred in 7.1 and 10.3% of patients in MAP and CaOx group, respectively (p = 0.66), whereas hypocitraturia was present in 65.2 and 59.0% of patients with MAP and CaOx group, respectively (p = 0.41). No significant difference in new events was found between MAP and CaOx groups (17.9 vs. 23.1%, respectively; p = 0.60). Conclusion: A 24-hour urine evaluation should be offered to patients submitted to nephrectomy due to pure MAP stones in order to detect metabolic risk, improve treatment, and prevent stone recurrence.
Resumo Contexto e objetivo: Cálculos de fosfato de amônio e magnésio (FAM), também conhecidos como cálculos de estruvita, estão associados à infecção urinária e ao comprometimento da unidade renal. O objetivo deste estudo é avaliar os fatores de risco metabólico-urinários para recorrência de cálculos renais em pacientes submetidos à nefrectomia devido a cálculo de FAM. Métodos: Revisamos retrospectivamente os prontuários de pacientes > 18 anos submetidos à nefrectomia total devido a cálculos de FAM puro e cálculos de oxalato de cálcio puro (OxCa) de julho de 2006 a julho de 2016. Os parâmetros metabólicos urinários foram avaliados através de exames de urina de 24 horas ≥ 3 meses após a nefrectomia. Os parâmetros metabólicos urinários e um novo evento relacionado à litíase foram comparados. Resultados: Vinte e oito e 39 pacientes foram incluídos nos grupos FAM e OxCa, respectivamente. As anormalidades em amostras de urina de 24 horas foram similares entre os grupos. A hipercalciúria ocorreu em 7,1 e 10,3% dos pacientes nos grupos FAM e OxCa, respectivamente (p = 0,66), enquanto a hipocitratúria esteve presente em 65,2 e 59,0% dos pacientes nos grupos FAM e OxCa, respectivamente (p = 0,41). Nenhuma diferença significativa em novos eventos foi encontrada entre os grupos FAM e OxCa (17,9 vs. 23,1%, respectivamente; p = 0,60). Conclusão: Uma avaliação de urina de 24 horas deve ser oferecida aos pacientes submetidos à nefrectomia devido a cálculos de FAM puro, a fim de detectar risco metabólico, melhorar o tratamento e prevenir a recorrência de cálculos.
Assuntos
Humanos , Feminino , Pré-Escolar , Doenças Ósseas , Hipofosfatemia , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/genética , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , MutaçãoRESUMO
Abstract Phosphopenic rickets may be caused by mutations in the PHEX gene (phosphate regulating endopeptidase homolog X-linked). Presently, more than 500 mutations in the PHEX gene have been found to cause hypophosphatemic rickets. The authors report a clinical case of a 4-year-old girl with unremarkable family history, who presented with failure to thrive and bowing of the legs. Laboratory tests showed hypophosphatemia, elevated alkaline phosphatase, normal calcium, mildly elevated PTH and normal levels of 25(OH)D and 1.25(OH)D. The radiological study showed bone deformities of the radius and femur. Clinical diagnosis of phosphopenic rickets was made and the genetic study detected a heterozygous likely pathogenic variant of the PHEX gene: c.767_768del (p.Thr256Serfs*7). This variant was not previously described in the literature or databases. Knowledge about new mutations can improve patient's outcome. Genetic analysis can help to establish a genotype-phenotype correlation.
Resumo O raquitismo fosfopênico pode ser causado por mutações no gene PHEX (ligado ao X do homólogo da endopeptidase que regula o fosfato). Atualmente, mais de 500 mutações no gene PHEX causam raquitismo hipofosfatêmico. Os autores relatam um caso clínico de uma menina de 4 anos com histórico familiar sem relevância, que apresentou falha no crescimento e arqueamento das pernas. Os exames laboratoriais mostraram hipofosfatemia, fosfatase alcalina elevada, cálcio normal, PTH levemente elevado e níveis normais de 25(OH)D e 1,25(OH)D. O estudo radiológico mostrou deformidades ósseas no rádio e no fêmur. O diagnóstico clínico do raquitismo fosfopênico foi realizado e o estudo genético detectou uma provável variante patogênica heterozigótica do gene PHEX: c.767_768del (p.Thr256Serfs*7). Esta variante não foi descrita anteriormente na literatura ou nas bases de dados. O conhecimento sobre novas mutações pode melhorar o desfecho de pacientes. A análise genética pode ajudar a estabelecer uma correlação genótipo-fenótipo.
Assuntos
Humanos , Feminino , Pré-Escolar , Doenças Ósseas , Hipofosfatemia , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/genética , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , MutaçãoRESUMO
X-Linked Hypophosphatemia (XLH) is the most common cause of inherited hypophosphatemic rickets. Dental involvement, including spontaneous abscesses and/or fistulae, is an important part of the disease and has not been completely defined, especially in cohorts from developing countries. To describe oral health status in a cohort of Chilean patients with XLH and explore its correlation with biochemical presentation and treatment, we conducted a cross-sectional observational study of patients with PHEX mutation-confirmed XLH. All patients had an oral clinical exam, radiographic evaluation; clinical and biochemical data were obtained to determine their association with oral features. Twenty-six patients were included, 77% adults and 23% children. Most adults (89%) had past or current dental pulp pathology (abscesses and/or fistulae). Pulpal chamber enlargement and radiolucent apical lesions were common radiological features (94 and 74%, respectively). In children, abscess and/or fistulae were also common (33%). Caries index, which was determined by dmft/DMFT, was higher than the Chilean national average. Early and long-term therapy with phosphate and activated vitamin D was associated with lower carious index and attachment loss. XLH patients frequently present with high pulpal involvement and carious index. Conventional therapy was associated with lower carious index and attachment loss. These data highlight the importance of early and periodical dental care in order to prevent dental damage and assure a good quality of oral health for XLH patients.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Adulto , Criança , Estudos Transversais , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/epidemiologia , Raquitismo Hipofosfatêmico Familiar/genética , Fator de Crescimento de Fibroblastos 23 , Humanos , Mutação , Saúde Bucal , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , FosfatosRESUMO
Phosphopenic rickets may be caused by mutations in the PHEX gene (phosphate regulating endopeptidase homolog X-linked). Presently, more than 500 mutations in the PHEX gene have been found to cause hypophosphatemic rickets. The authors report a clinical case of a 4-year-old girl with unremarkable family history, who presented with failure to thrive and bowing of the legs. Laboratory tests showed hypophosphatemia, elevated alkaline phosphatase, normal calcium, mildly elevated PTH and normal levels of 25(OH)D and 1.25(OH)D. The radiological study showed bone deformities of the radius and femur. Clinical diagnosis of phosphopenic rickets was made and the genetic study detected a heterozygous likely pathogenic variant of the PHEX gene: c.767_768del (p.Thr256Serfs*7). This variant was not previously described in the literature or databases. Knowledge about new mutations can improve patient's outcome. Genetic analysis can help to establish a genotype-phenotype correlation.
Assuntos
Doenças Ósseas , Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Humanos , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genéticaRESUMO
OBJECTIVE: The aim of this cross-sectional study was to estimate the prevalence of XLH in Paraná, a state in southern Brazil, and report the clinical features and complications of the disease. METHODS: We invited all endocrinologists (n = 205), nephrologists (n = 221), orthopedic surgeons (n = 1020), and pediatricians (n = 1000) in Paraná to fill out an electronic survey with information on patients with X-linked hypophosphatemia (XLH), and searched the records of the state's health department for all calcitriol prescriptions in 2018. RESULTS: In all, 244 (10%) specialists responded to the email, of whom 18 (7.4%) reported to be taking care of patients with XLH and answered the online survey. A total of 57 patients with XLH were identified (prevalence 5 per million inhabitants). The median age at diagnosis was 22 years, and 42.2% were children and adolescents. Fifteen patients had genetic testing showing a PHEX mutation. Overall, 91.2% had bone deformities, 30.8% had a history of fragility fractures, and 22.4% had renal complications. CONCLUSION: This study demonstrated a prevalence of XLH of 5 cases per million inhabitants in the state of Paraná, a rate lower than the one reported in other countries. Manifestations of renal calcification and bone fragility were frequent among the patients. This is the first epidemiological study evaluating the prevalence and clinical presentation of XLH in Latin America.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Doenças Genéticas Ligadas ao Cromossomo X , Adolescente , Brasil/epidemiologia , Criança , Estudos Transversais , Raquitismo Hipofosfatêmico Familiar/epidemiologia , Raquitismo Hipofosfatêmico Familiar/genética , Humanos , Endopeptidase Neutra Reguladora de Fosfato PHEX , PrevalênciaRESUMO
ABSTRACT Objective: The aim of this cross-sectional study was to estimate the prevalence of XLH in Paraná, a state in southern Brazil, and report the clinical features and complications of the disease. Materials and methods: We invited all endocrinologists (n = 205), nephrologists (n = 221), orthopedic surgeons (n = 1020), and pediatricians (n = 1000) in Paraná to fill out an electronic survey with information on patients with X-linked hypophosphatemia (XLH), and searched the records of the state's health department for all calcitriol prescriptions in 2018. Results: In all, 244 (10%) specialists responded to the email, of whom 18 (7.4%) reported to be taking care of patients with XLH and answered the online survey. A total of 57 patients with XLH were identified (prevalence 5 per million inhabitants). The median age at diagnosis was 22 years, and 42.2% were children and adolescents. Fifteen patients had genetic testing showing a PHEX mutation. Overall, 91.2% had bone deformities, 30.8% had a history of fragility fractures, and 22.4% had renal complications. Conclusion: This study demonstrated a prevalence of XLH of 5 cases per million inhabitants in the state of Paraná, a rate lower than the one reported in other countries. Manifestations of renal calcification and bone fragility were frequent among the patients. This is the first epidemiological study evaluating the prevalence and clinical presentation of XLH in Latin America.
Assuntos
Humanos , Criança , Adolescente , Doenças Genéticas Ligadas ao Cromossomo X , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/epidemiologia , Brasil/epidemiologia , Prevalência , Estudos Transversais , Endopeptidase Neutra Reguladora de Fosfato PHEXRESUMO
This study was designed to determine the in vivo performance of three different materials as scaffolds for dental pulp stem cells (DPSC) undergoing induced odontogenic differentiation. An odontogenic medium modified by the addition of recombinant human bone morphogenetic protein 2 was used in the experimental groups to induce differentiation. Mesenchymal stem cell medium was used in the control groups. DPSC were transplanted onto the backs of mice via three scaffolds: copolymer of L-lactide and DL-lactide (PLDL), copolymer of DL-lactide (PDL) and hydroxyapatite tricalcium phosphate (HA/TCP). The expression levels of dentin sialo-phosphoprotein (DSPP), dentin matrix protein-1 (DMP1), enamelysin/matrix metalloproteinase 20 (MMP20) and phosphate-regulating gene with homologies to endopeptidases on X chromosome (PHEX) were analysed using RT-PCR. The expressions in the experimental groups were compared to those in the control groups. The transcript expressions at 6 and 12 weeks were significantly different for all scaffolds (p < 0.05), except for the expression of DSPP in the PLDL group with regard to the time variable. Although there was a decrease in the expression of enamelysin/MMP20 in PLDL and HA/TCP at 12 weeks, all other expressions increased and reached their highest level at 12 weeks. The highest DSPP expression was in the PDL group (p < 0.05). The highest expression of DMP1 was detected in the HA/TCP group (p < 0.05). The highest expression of PHEX was in the PLDL group (p < 0.05). Consequently, PLDL and PDL seemed to be promising scaffold candidates for odontogenic regeneration at least as HA-TCP, when they were applied with the DPSC induced for odontogenic differentiation.