Assuntos
Humanos , Feminino , Lactente , Deficiência de Vitamina D , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/etiologia , Raquitismo Hipofosfatêmico/complicações , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/diagnóstico por imagem , Doenças Ósseas Metabólicas/diagnóstico , Radiografia , Diagnóstico DiferencialRESUMO
OBJECTIVES: Vitamin D dependent rickets type 1A (VDDR1A) is a rare autosomal recessive condition due to inactivating mutation of CYP27B1. It mimics clinically, biochemically and rediologically to nutritional and hypophosphatemic rickets. In developing countries like Pakistan, VDDR1A is often misdiagnosed as nutritional rickets or hypophosphatemic rickets due lack of free access to 1,25 (OH) 2 D level and genetic testing. This study was aimed to determine the clinical spectrum and diagnostic challenges of VDDR1A due to CYP27B1 mutation in developing countries. METHODS: Retrospective review of all cases of VDDR1A due to CYP27B1 mutation over a period of two years presenting in the Pediatric Endocrine clinic of Hameed Latif Hospital, Lahore, Pakistan. RESULTS: Six cases of VDDR1A (4 males) were identified. Mean age of clinical manifestation was 14 (9-24) months. Mean age of presentation to endocrine department was 5.5 (1.5-11.8) years. Growth failure and bony deformities were the most common presentation (n=6), followed by repeated diarrheas and abdominal distension (n=3) and recurrent fractures (n=1). All cases shared same biochemical profile of low/normal calcium, hypophosphatemia, raised alkaline phosphatase, raised PTH, normal/high 25(OH)D and tubular reabsorption of phosphate (TRP) <85%. Patients treated with calcitriol showed rapid healing as compared to those treated with 1-alfacalcidol. CONCLUSIONS: We should have a high index of suspicion of VDDR1A in rickets not responding to cholecalciferol therapy.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Raquitismo Hipofosfatêmico , Raquitismo , Criança , Pré-Escolar , Humanos , Lactente , Masculino , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Calcitriol/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Mutação , Raquitismo/diagnóstico , Raquitismo/tratamento farmacológico , Raquitismo/genética , Raquitismo Hipofosfatêmico/tratamento farmacológico , Vitamina D/uso terapêutico , FemininoRESUMO
CONTEXT: Autosomal recessive hypophosphatemic rickets (ARHR) are rare, heritable renal phosphate-wasting disorders that arise from overexpression of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) leading to impaired bone mineralization (rickets and osteomalacia). Inactivating mutations of Dentin matrix protein 1 (DMP1) give rise to ARHR type 1 (ARHR1). Short stature, prominent bowing of the legs, fractures/pseudofractures, and severe enthesopathy are prominent in this patient population. Traditionally, treatment consists of oral phosphate replacement and the addition of calcitriol but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects. OBJECTIVE: The advent of burosumab (Crysvita), a fully humanized monoclonal antibody to FGF23 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, offers a unique opportunity to evaluate its safety and efficacy in patients with ARHR1. RESULTS: Monthly administration of burosumab to 2 brothers afflicted with the disorder resulted in normalization of serum phosphate, healing of pseudofracture, diminished fatigue, less bone pain, and reduced incapacity arising from the extensive enthesopathy and soft tissue fibrosis/calcification that characterizes this disorder. No adverse effects were reported following burosumab administration. CONCLUSION: The present report highlights the beneficial biochemical and clinical outcomes associated with the use of burosumab in patients with ARHR1.
Assuntos
Doenças Ósseas Metabólicas , Entesopatia , Raquitismo Hipofosfatêmico Familiar , Osteomalacia , Raquitismo Hipofosfatêmico , Anticorpos Monoclonais Humanizados/uso terapêutico , Calcitriol/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Hormônios/uso terapêutico , Humanos , Masculino , Osteomalacia/metabolismo , Fosfatos/metabolismo , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/genéticaRESUMO
Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormone, 25-hydroxyvitamin D3, and calciuria. An adequate calcium intake and normal 25-hydroxyvitamin D3 levels should be assured in all patients. Children with calcipenic rickets require the supplementation or pharmacological treatment with native or active vitamin D depending on the underlying pathophysiology. Treatment of phosphopenic rickets depends on the underlying pathophysiology. Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible. Burosumab, a fully humanized FGF23-antibody, was recently approved for treatment of X-linked hypophosphatemia (XLH) and TIO and shown to be superior for treatment of XLH compared to conventional treatment. Forms of hypophosphatemic rickets independent of FGF23 due to genetic defects of renal tubular phosphate reabsorption are treated with oral phosphate only, since they are associated with excessive 1,25-dihydroxyvitamin D production. Finally, forms of hypophosphatemic rickets caused by Fanconi syndrome, such as nephropathic cystinosis and Dent disease require disease-specific treatment in addition to phosphate supplements and active vitamin D. Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Síndrome de Fanconi , Raquitismo Hipofosfatêmico , Raquitismo , Cálcio/uso terapêutico , Criança , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Fatores de Crescimento de Fibroblastos , Humanos , Osteomalacia , Síndromes Paraneoplásicas , Fosfatos , Raquitismo/tratamento farmacológico , Raquitismo/etiologia , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/etiologia , Vitamina D/uso terapêuticoRESUMO
Hypophosphatemic rickets is one of the major causes of refractory rickets exhibiting genetic heterogeneity. Most cases are X-linked due to PHEX gene mutations. However recently, autosomal dominant (AD) forms have been described, due to mutations in FGF23. The authors present a 13-year-old girl who had hypophosphatemic rickets due to R179W mutation in FGF23 gene, being the first case in India with this mutation. She presented with bone pains, short stature and osteopenic bones, symptoms appearing after onset of menarche. This presentation is different from that seen in younger children with rickets. Burosumab, an anti-FGF23 antibody is an effective novel therapy for FGF23-related rickets but it is not available in India. High doses of calcitriol and phosphate were required to alleviate the symptoms and signs. The authors aim to alert pediatricians to keep in mind this treatable disorder to prevent diagnostic delays and improve treatment outcome.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Fatores de Crescimento de Fibroblastos/genética , Raquitismo Hipofosfatêmico , Adolescente , Análise Mutacional de DNA , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Índia , Mutação , Fosfatos , Raquitismo Hipofosfatêmico/diagnóstico , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/genéticaRESUMO
The three members of the endocrine-fibroblast growth factor (FGF) family, FGF19, 21, and 23 are circulating hormones that regulate critical metabolic processes. FGF23 stimulates the assembly of a signaling complex composed of α-Klotho (KLA) and FGF receptor (FGFR) resulting in kinase activation, regulation of phosphate homeostasis, and vitamin D levels. Here we report that the C-terminal tail of FGF23, a region responsible for KLA binding, contains two tandem repeats, repeat 1 (R1) and repeat 2 (R2) that function as two distinct ligands for KLA. FGF23 variants with a single KLA binding site, FGF23-R1, FGF23-R2, or FGF23-wild type (WT) with both R1 and R2, bind to KLA with similar binding affinity and stimulate FGFR1 activation and MAPK response. R2 is flanked by two cysteines that form a disulfide bridge in FGF23-WT; disulfide bridge formation in FGF23-WT is dispensable for KLA binding and for cell signaling via FGFRs. We show that FGF23-WT stimulates dimerization and activation of a chimeric receptor molecule composed of the extracellular domain of KLA fused to the cytoplasmic domain of FGFR and employ total internal reflection fluorescence microscopy to visualize individual KLA molecules on the cell surface. These experiments demonstrate that FGF23-WT can act as a bivalent ligand of KLA in the cell membrane. Finally, an engineered Fc-R2 protein acts as an FGF23 antagonist offering new pharmacological intervention for treating diseases caused by excessive FGF23 abundance or activity.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Multimerização Proteica/fisiologia , Sítios de Ligação , Calcinose/tratamento farmacológico , Calcinose/genética , Membrana Celular/metabolismo , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/uso terapêutico , Células HEK293 , Humanos , Hiperostose Cortical Congênita/tratamento farmacológico , Hiperostose Cortical Congênita/genética , Hiperfosfatemia/tratamento farmacológico , Hiperfosfatemia/genética , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Klotho , Mutação , Osteomalacia/tratamento farmacológico , Osteomalacia/genética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Domínios Proteicos , Multimerização Proteica/efeitos dos fármacos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/genéticaRESUMO
Objective: Hypophosphatemic rickets (HR) is a rare renal phosphate-wasting disorder, which is usually X-linked and is commonly caused by PHEX mutations. The treatment and follow-up of HR is challenging due to imperfect treatment options. Methods: Here we present nationwide initial and follow-up data on HR. Results: From 24 centers, 166 patients were included in the study. Genetic analysis (n=75) showed PHEX mutation in 80% of patients. The mean follow-up period was 6.7±2.4 years. During the first 3-years of treatment (n=91), mild increase in phosphate, decrease in alkaline phosphatase and elevation in parathyroid hormone (PTH) levels were detected. The height standard deviation scores were -2.38, -2.77, -2.72, -2.47 at initial, 1st, 2nd and 3rd year of treatment, respectively (p>0.05). On follow-up 36% of the patients showed complete or significant improvement in leg deformities and these patients had similar phosphate levels at presentation with better levels in 1st and 2nd years of treatment; even the treatment doses of phosphate were similar. Furthermore, 27 patients developed nephrocalcinosis (NC), the patients showed no difference in biochemical differences at presentation and follow-up, but 3rd year PTH was higher. However, higher treatment doses of phosphate and calcitriol were found in the NC group. Conclusion: HR treatment and follow-up is challenging and our results showed higher treatment doses were associated with NC without any change in serum phosphate levels, suggesting that giving higher doses led to increased phosphaturia, probably through stimulation of fibroblast growth factor 23. However, higher calcitriol doses could improve bone deformities. Safer and more efficacious therapies are needed.
Assuntos
Calcitriol/administração & dosagem , Hormônios e Agentes Reguladores de Cálcio/administração & dosagem , Fosfatos/administração & dosagem , Fosfatos/sangue , Raquitismo Hipofosfatêmico/sangue , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Masculino , Avaliação de Resultados em Cuidados de Saúde , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , TurquiaRESUMO
Hypophosphatemic rickets, mostly of the X-linked dominant form caused by pathogenic variants of the PHEX gene, poses therapeutic challenges with consequences for growth and bone development and portends a high risk of fractions and poor bone healing, dental problems and nephrolithiasis/nephrocalcinosis. Conventional treatment consists of PO4 supplements and calcitriol requiring monitoring for treatment-emergent adverse effects. FGF23 measurement, where available, has implications for the differential diagnosis of hypophosphatemia syndromes and, potentially, treatment monitoring. Newer therapeutic modalities include calcium sensing receptor modulation (cinacalcet) and biological molecules targeting FGF23 or its receptors. Their long-term effects must be compared with those of conventional treatments.
Assuntos
Raquitismo Hipofosfatêmico/diagnóstico , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/genética , Calcimiméticos/uso terapêutico , Criança , Diagnóstico Diferencial , Fator de Crescimento de Fibroblastos 23 , Hormônio do Crescimento/uso terapêutico , Humanos , Mutação , Fosfatos/uso terapêutico , Vitamina D/uso terapêuticoAssuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Suplementos Nutricionais , Fraturas Ósseas/induzido quimicamente , Hipofosfatemia/induzido quimicamente , Fosfatos/efeitos adversos , Fosfatos/uso terapêutico , Raquitismo Hipofosfatêmico/tratamento farmacológico , Feminino , Humanos , Lactente , Recém-Nascido , Resultado do TratamentoRESUMO
The bone tendon attachment site known as the enthesis comprises a transitional zone between bone and tendon, and plays an important role in enabling movement at this site. X-linked hypophosphatemia (XLH) is characterized by impaired activation of vitamin D, elevated serum FGF23 levels and low serum phosphate levels, which impair bone mineralization. Paradoxically, an important complication of XLH is mineralization of the enthesis (enthesopathy). Studies were undertaken to identify the cellular and molecular pathways important for normal post-natal enthesis maturation and to examine their role during the development of enthesopathy in mice with XLH (Hyp). The Achilles tendon entheses of Hyp mice demonstrate an expansion of hypertrophic-appearing chondrogenic cells by P14. Post-natally, cells in wild-type and Hyp entheses similarly descend from scleraxis- and Sox9-expressing progenitors; however, Hyp entheses exhibit an expansion of Sox9-expressing cells, and enhanced BMP and IHH signaling. These results support a role for enhanced BMP and IHH signaling in the development of enthesopathy in XLH.
Assuntos
Entesopatia/complicações , Entesopatia/genética , Raquitismo Hipofosfatêmico/complicações , Raquitismo Hipofosfatêmico/genética , Fosfatase Alcalina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Proliferação de Células/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Modelos Animais de Doenças , Entesopatia/tratamento farmacológico , Entesopatia/patologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/farmacologia , Fatores de Crescimento de Fibroblastos/uso terapêutico , Proteínas Hedgehog/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/patologia , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Vitamina D/análogos & derivados , Vitamina D/farmacologia , Vitamina D/uso terapêuticoAssuntos
Alopecia/etiologia , Raquitismo Hipofosfatêmico/complicações , Alopecia/tratamento farmacológico , Alopecia/patologia , Biópsia , Criança , Dermoscopia , Sobrancelhas , Feminino , Humanos , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/patologia , Couro CabeludoAssuntos
Humanos , Feminino , Criança , Alopecia/etiologia , Raquitismo Hipofosfatêmico/complicações , Couro Cabeludo , Biópsia , Dermoscopia , Alopecia/patologia , Alopecia/tratamento farmacológico , Sobrancelhas , Raquitismo Hipofosfatêmico/patologia , Raquitismo Hipofosfatêmico/tratamento farmacológicoRESUMO
BACKGROUND: We recently demonstrated multilineage somatic mosaicism in cutaneous skeletal hypophosphatemia syndrome (CSHS), which features epidermal or melanocytic nevi, elevated fibroblast growth factor (FGF)-23, and hypophosphatemia, finding identical RAS mutations in affected skin and bone. OBJECTIVE: We sought to: (1) provide an updated overview of CSHS; (2) review its pathobiology; (3) present a new patient with CSHS; and (4) discuss treatment modalities. METHODS: We searched PubMed for "nevus AND rickets," and "nevus AND hypophosphatemia," identifying cases of nevi with hypophosphatemic rickets or elevated serum FGF-23. For our additional patient with CSHS, we performed histopathologic and radiographic surveys of skin and skeletal lesions, respectively. Sequencing was performed for HRAS, KRAS, and NRAS to determine causative mutations. RESULTS: Our new case harbored somatic activating HRAS p.G13 R mutation in affected tissue, consistent with previous findings. Although the mechanism of FGF-23 dysregulation is unknown in CSHS, interaction between FGF and MAPK pathways may provide insight into pathobiology. Anti-FGF-23 antibody KRN-23 may be useful in managing CSHS. LIMITATIONS: Multilineage RAS mutation in CSHS was recently identified; further studies on mechanism are unavailable. CONCLUSION: Patients with nevi in association with skeletal disease should be evaluated for serum phosphate and FGF-23. Further studies investigating the role of RAS in FGF-23 regulation are needed.
Assuntos
Genes ras/genética , Mosaicismo , Nevo Pigmentado/genética , Osteomalacia/genética , Raquitismo Hipofosfatêmico/genética , Neoplasias Cutâneas/genética , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Nevo Pigmentado/tratamento farmacológico , Osteomalacia/tratamento farmacológico , Raquitismo Hipofosfatêmico/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , SíndromeRESUMO
Patients with generalized arterial calcification of infancy (GACI) develop vascular calcifications early in life. About half of them die within the first 6 months despite optimal medical care. A subset of those who survive eventually develop hypophosphatemic rickets. Since hypophosphatemia and hyperphosphaturia have been previously associated with increased survival in GACI patients, physicians often avoid phosphate repletion as treatment for rickets. As a consequence, GACI patients develop severe rachitic complications such as short stature and skeletal deformities. It appears that the recognition of hypophosphatemia later in life in some GACI patients is a consequence of having survived the first few months of life, and not the cause of their survival per se. Here, we report the long-term follow-up of a GACI patient who was phosphate-repleted for his rickets for more than 7 years without worsening of vascular calcification.
Assuntos
Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Raquitismo Hipofosfatêmico/tratamento farmacológico , Calcificação Vascular/tratamento farmacológico , Adolescente , Adulto , Criança , Seguimentos , Humanos , Masculino , Mutação , Fosfatos/administração & dosagem , Raquitismo Hipofosfatêmico/genética , Raquitismo Hipofosfatêmico/fisiopatologia , Calcificação Vascular/genética , Calcificação Vascular/fisiopatologiaRESUMO
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone and works by binding to Klotho-FGF receptor complex. Excessive and deficient actions of FGF23 result in hypophosphatemic and hyperphosphatemic diseases, respectively. Therefore, it is reasonable to think that modulating FGF23 activities may be a novel therapeutic measure for these diseases. Several preclinical reports indicate that the inhibition of FGF23 activities ameliorates hypophosphatemic rickets/osteomalacia caused by excessive actions of FGF23. In addition, phase I-II clinical trials of anti-FGF23 antibody in adult patients with X-linked hypophosphatemia rickets, the most prevalent cause of genetic FGF23-related hypophosphatemic rickets, indicated that the antibody enhances renal tubular phosphate reabsorption and increases serum phosphate. However, it is not known whether the inhibition of FGF23 activities actually brings clinical improvement of rickets and osteomalacia. Available data indicate that FGF23-FGF receptor/Klotho pathway can be a new drug target for disorders of phosphate and bone metabolism.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Osteomalacia/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Raquitismo Hipofosfatêmico/metabolismo , Osso e Ossos/metabolismo , Descoberta de Drogas , Fator de Crescimento de Fibroblastos 23 , Humanos , Proteínas Klotho , Osteomalacia/tratamento farmacológico , Raquitismo Hipofosfatêmico/tratamento farmacológicoRESUMO
The aim of the present study was to analyse the effects of combined treatment with calcitriol and phosphate, to find out the incidence of the nephrocalcinosis, and to elucidate the risk factor of nephrocalcinosis in patients with hypophosphatemic rickets. We followed six patients. The median age at diagnosis was 3.25 (0.75-10.5) years. The median follow-up duration was 8.25 (3.5-12.5) years. The mean dose of calcitriol and phosphate treatments was 39.1±8 ng/kg/day, 90.5±57.1 mg/kg/day, respectively. Nephrocalcinosis was detected in three patients (50%). The mean dose of phosphate taken by the patients found to have nephrocalcinosis was detected to be high with a statistically significant difference (p=0.041). No significant relationship was found the mean dose of calcitriol. We found no relationship between the development of nephrocalcinosis and the incidence of hypercalciuria or hypercalcemia episodes. We found the increased phosphate dose administered for treatment to play a role in nephrocalcinosis development.
Assuntos
Nefrocalcinose/etiologia , Raquitismo Hipofosfatêmico/complicações , Adolescente , Calcitriol/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Nefrocalcinose/epidemiologia , Fosfatos/uso terapêutico , Raquitismo Hipofosfatêmico/tratamento farmacológico , Fatores de Risco , Adulto JovemRESUMO
We report on a boy who presented with hypophosphatemic rickets with elevated serum fibroblast growth factor 23 (FGF23) and polyostotic osteolytic lesions at age 2 years. Tumor-induced hypophosphatemic rickets was suspected; however, bone biopsy for osteolytic changes revealed no tumorous change, except for irregularly dilated vessels associated with osteoclasts and fibrous proliferation. Venous sampling failed to point to FGF23-producing foci. After alfacalcidol and phosphate supplementation, the rachitic skeletal changes improved, but FGF23 increased and new osteolytic lesions developed. Serum levels of neopterin and a few cytokines, including plasma transforming growth factor-ß and soluble tumor necrosis factor receptor type II, were elevated. At age 4 years, high doses of phosphate resulted in increased serum phosphate levels, decreased neopterin and cytokines, decreased FGF23, and stabilization of osteolysis. We excluded germline mutations in PHEX, FGF23, DMP1, and ENPP1 (genes for hereditary hypophosphatemic rickets) and somatic mutations in the GNAS and HRAS/KRAS (the disease-causing genes for McCune-Albright syndrome and linear nevus sebaceous syndrome, respectively). We could not perform octreotide scintigraphy or fluorodeoxyglucose-positron emission tomography, and thus could not completely exclude occult FGF23-producing tumors. However, considering the course of the disease, it is intriguing to assume that dysregulation of osteoclast-macrophage lineage may have induced increased neopterin levels, increased cytokine levels, osteolytic process, and possibly FGF23 overproduction.
Assuntos
Fatores de Crescimento de Fibroblastos/genética , Displasia Fibrosa Poliostótica/genética , Osteólise/genética , Raquitismo Hipofosfatêmico/genética , Proliferação de Células , Pré-Escolar , Citocinas/sangue , Citocinas/genética , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Displasia Fibrosa Poliostótica/sangue , Displasia Fibrosa Poliostótica/tratamento farmacológico , Displasia Fibrosa Poliostótica/patologia , Regulação da Expressão Gênica , Humanos , Hidroxicolecalciferóis/uso terapêutico , Masculino , Neopterina/sangue , Neopterina/genética , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteólise/sangue , Osteólise/tratamento farmacológico , Osteólise/patologia , Fosfatos/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/genética , Raquitismo Hipofosfatêmico/sangue , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/patologia , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/genéticaRESUMO
Hypophosphataemic rickets is a rare, genetic disorder resulting in defect bone mineralisation and rickets. The current medical treatment consists of phosphate supplementation and alfacalcidol, but side effects such as secondary hyperparat-hyroidism and nephrocalcinosis are common. This treatment regimen often fails to prevent bone deformity and reduced final height. The rarity and complexity of these diseases call for centralised specialist care and international collaboration. Future medical treatment may be improved by addition of new promising experimental treatments.
Assuntos
Raquitismo Hipofosfatêmico/tratamento farmacológico , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Criança , Cinacalcete/administração & dosagem , Cinacalcete/efeitos adversos , Cinacalcete/uso terapêutico , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Hidroxicolecalciferóis/administração & dosagem , Hidroxicolecalciferóis/efeitos adversos , Hidroxicolecalciferóis/uso terapêutico , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Oligopeptídeos/uso terapêutico , Fosfatos/administração & dosagem , Fosfatos/efeitos adversos , Fosfatos/sangue , Fosfatos/uso terapêutico , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/uso terapêutico , Radiografia , Raquitismo Hipofosfatêmico/complicações , Raquitismo Hipofosfatêmico/diagnóstico por imagem , Raquitismo Hipofosfatêmico/fisiopatologiaRESUMO
Osteomalacia is a rare disorder of bone metabolism leading to reduced bone mineralization. Underlying vitamin D deficiency and a disturbed phosphate metabolism (so-called hypophosphatemic osteomalacia) can cause the disease. Leading symptoms are dull localized or generalized bone pain, muscle weakness and cramps as well as increased incidence of falls. Rheumatic diseases, such as polymyalgia rheumatica, rheumatoid arthritis, myositis and fibromyalgia must be considered in the differential diagnosis. Alkaline phosphatase (AP) is typically elevated in osteomalacia while serum phosphate and/or 25-OH vitamin D3 levels are reduced. The diagnosis of osteomalacia can be confirmed by an iliac crest bone biopsy. Histological correlate is reduced or deficient mineralization of the newly synthesized extracellular matrix. Treatment strategies comprise supplementation of vitamin D and calcium and for patients with intestinal malabsorption syndromes vitamin D and calcium are also given parenterally. In renal phosphate wasting syndromes substitution of phosphate is the treatment of choice, except for tumor-induced osteomalacia when removal of the tumor leads to a cure in most cases.
Assuntos
Densidade Óssea/fisiologia , Osso e Ossos/fisiopatologia , Osteoartrite/fisiopatologia , Fosfatase Alcalina/fisiologia , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Cálcio/uso terapêutico , Humanos , Osteoartrite/diagnóstico , Osteoartrite/tratamento farmacológico , Osteomalacia/diagnóstico , Osteomalacia/tratamento farmacológico , Osteomalacia/fisiopatologia , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/tratamento farmacológico , Síndromes Paraneoplásicas/fisiopatologia , Raquitismo Hipofosfatêmico/diagnóstico , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/fisiopatologia , Vitamina D/uso terapêutico , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/fisiopatologiaRESUMO
Fanconi syndrome is a complex of multiple tubular dysfunctions of proximal tubular cells, occurring alone or in association with a variety of inherited (primary) or acquired (secondary) disorders. It is characterized by aminoaciduria, normoglycemic glycosuria, tubular proteinuria without hematuria, metabolic acidosis without anion gap and excessive urinary excretion of phosphorous, calcium, uric acid, bicarbonate, sodium, potassium and magnesium. Diabetes insipidus is a disease of collecting tubules and children mainly present with dehydration and hypernatremia. We are reporting the first case of idiopathic Fanconi's syndrome along with nephrogenic diabetes insipidus in a child who presented to us with vitamin D resistant rickets. Medline search did not reveal any case of nephrogenic diabetes insipidus (NDI) associated with idiopathic Fanconi syndrome. We hypothesized that the NDI may be due to to severe hypokalemia induced tubular dysfunction.