RESUMEN
XLαs, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gsα), is paternally expressed. The significance of XLαs in humans remains largely unknown. Here, we report a patient who presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone (PTH) levels. His serum calcium was in the lower limit of the normal range. Whole exome sequencing of this subject found a novel non-sense variant c.424G>T (p. G142*) in the first exon of XLαs, which was inherited from his father and transmitted to his daughter. This variant was predicted to exclusively influence the expression of XLαs, while possibly having no significant effects on other gene products of this locus. Ellsworth-Howard test revealed normal renal response to PTH in proband. Human SaOS2 cells transfected with mutant XLαs failed to generate cyclic adenosine monophosphate under PTH stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating sclerostin, dickkopf1, and osteoprotegerin (OPG) levels, while lower receptor activator of nuclear factor kappa-B ligand/OPG ratio, leading to reduced bone resorption. Our findings indicate that XLαs plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Predisposición Genética a la Enfermedad , Hipofosfatemia Familiar/genética , Osteopetrosis/genética , Adulto , Línea Celular , Codón sin Sentido/genética , Exones/genética , Humanos , Hipofosfatemia Familiar/patología , Masculino , Osteopetrosis/patología , Hormona Paratiroidea/farmacología , Herencia Paterna/genética , Seudohipoparatiroidismo/genética , Seudohipoparatiroidismo/patologíaRESUMEN
Inorganic phosphate (Pi) homeostasis is regulated by intestinal absorption via type II sodium-dependent co-transporter (Npt2b) and by renal reabsorption via Npt2a and Npt2c. Although we previously reported that vitamin A-deficient (VAD) rats had increased urine Pi excretion through the decreased renal expression of Npt2a and Npt2c, the effect of vitamin A on the intestinal Npt2b expression remains unclear. In this study, we investigated the effects of treatment with all-trans retinoic acid (ATRA), a metabolite of vitamin A, on the Pi absorption and the Npt2b expression in the intestine of VAD rats, as well as and the underlying molecular mechanisms. In VAD rats, the intestinal Pi uptake activity and the expression of Npt2b were increased, but were reduced by the administration of ATRA. The transcriptional activity of reporter plasmid containing the promoter region of the rat Npt2b gene was reduced by ATRA in NIH3T3 cells overexpressing retinoic acid receptor (RAR) and retinoid X receptor (RXR). On the other hand, CCAAT/enhancer-binding proteins (C/EBP) induced transcriptional activity of the Npt2b gene. Knockdown of the C/EBP gene and a mutation analysis of the C/EBP responsible element in the Npt2b gene promoter indicated that C/EBP plays a pivotal role in the regulation of Npt2b gene transcriptional activity by ATRA. EMSA revealed that the RAR/RXR complex inhibits binding of C/EBP to Npt2b gene promoter. Together, these results suggest that ATRA may reduce the intestinal Pi uptake by preventing C/EBP activation of the intestinal Npt2b gene.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Intestino Delgado/metabolismo , Riñón/metabolismo , Regiones Promotoras Genéticas , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/genética , Transcripción Genética/efectos de los fármacos , Tretinoina/farmacología , Animales , Antineoplásicos/farmacología , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patología , Hipofosfatemia Familiar/prevención & control , Intestino Delgado/efectos de los fármacos , Riñón/efectos de los fármacos , Masculino , Ratones , Células 3T3 NIH , Ratas , Ratas Wistar , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/metabolismoRESUMEN
Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and salt wasting in pendrin/NCC dKO mice. Both high salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe salt wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and phosphate in the proximal tubule via processes that are mediated by PGE-2.
Asunto(s)
Calcio/metabolismo , Dinoprostona/metabolismo , Nefronas/metabolismo , Fosfatos/metabolismo , Animales , Proteínas de Transporte de Anión/deficiencia , Dieta , Modelos Animales de Enfermedad , Hipercalciuria/etiología , Hipercalciuria/metabolismo , Hipercalciuria/patología , Hipofosfatemia Familiar/etiología , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patología , Pruebas de Función Renal , Masculino , Ratones , Ratones Noqueados , Nefronas/patología , Fenotipo , Miembro 1 de la Familia de Transportadores de Soluto 12/deficiencia , Transportadores de SulfatoRESUMEN
The transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ("f")-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ("Δ") had undetectable serum intact FGF23, elevated serum phosphate (p < 0.05), and increased kidney Cyp27b1 mRNA (p < 0.05), similar to global Fgf23-KO mice. To isolate cellular FGF23 responses during phosphate challenge, Fgf23(Δ/f) mice were mated with early osteoblast type Iα1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23(Δ/f) /Col2.3-cre(+) and Fgf23(Δ/f) /Dmp1-cre(+) exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre(-) mice had 2.1-fold to 2.5-fold increased serum FGF23 (p < 0.01), but Col2.3-cre(+) mice had no significant increase, and Dmp1-cre(+) mice had only a 37% increase (p < 0.01) despite prevailing hyperphosphatemia in both models. The Fgf23(Δ/f) /Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23(Δ/f) /Col2.3-cre(+) mice had serum FGF23 <4% of Hyp (p < 0.01), and this targeted restriction normalized serum phosphorus and ricketic bone disease. In summary, deleting FGF23 within early osteoblasts and osteocytes demonstrated that both cell types contribute to baseline circulating FGF23 concentrations, and that targeting osteoblasts/osteocytes for FGF23 production can modify systemic responses to changes in serum phosphate concentrations and rescue the Hyp genetic syndrome. © 2016 American Society for Bone and Mineral Research.
Asunto(s)
Huesos/metabolismo , Factores de Crecimiento de Fibroblastos/deficiencia , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/metabolismo , Osteocitos/metabolismo , Fosfatos/metabolismo , Animales , Huesos/patología , Factor-23 de Crecimiento de Fibroblastos , Eliminación de Gen , Hipofosfatemia Familiar/patología , Ratones , Ratones Noqueados , Osteocitos/patologíaRESUMEN
Phosphaturic mesenchymal tumors (PMT) are the most common cause of tumor-induced osteomalacia (TIO) related to mesenchymal neoplasms. The lineage of differentiation of PMTs has not been elucidated in existing literature. Fourteen cases of PMT were analyzed for this study to elucidate its lineage. We used vascular and/or lymphatic endothelial markers for the immunohistochemical analysis, which included CD31, CD34, factor VIII-related antigen, podoplanin, Freund's leukemia integration site 1 (FLI1), and avian v-ets erythroblastosis virus E26 oncogene homolog (ERG). FLI1 and ERG were stained in all cases with proportion of immunopositive tumor cells largely more than 50 %; staining intensity was moderate or strong for both FLI1 and ERG. The tumor cells were stained with CD31 and/or CD34, with significantly less staining than observed for FLI1 and ERG. The tumor cells were completely immunonegative for factor VIII-related antigen and podoplanin. FLI1 and ERG are known to have considerable specificity to endothelial cells; ERG is more widely equipped in surgical pathology laboratories than FLI1. We concluded that ERG (or FLI1 if available) is useful marker for the diagnosis of PMT, and that PMTs may have an endothelial cell lineage.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Hipofosfatemia Familiar/patología , Mesodermo/patología , Neoplasias/metabolismo , Neoplasias/patología , Proteína Proto-Oncogénica c-fli-1/metabolismo , Adulto , Anciano , Femenino , Humanos , Hipofosfatemia Familiar/metabolismo , Inmunohistoquímica , Masculino , Mesodermo/metabolismo , Persona de Mediana Edad , Regulador Transcripcional ERG/metabolismoRESUMEN
Phosphaturic mesenchymal tumors (PMTs) are rare and found to be commonly associated with phosphaturia and oncogenic osteomalacia. They commonly affect middle-aged adults and are located mostly in the extremities. Most of them are benign with only a few metastatic cases described in the literature. PMT-mixed connective tissue (PMTMCT) type is the most common PMT. Though most cases of PMTMCT have been associated with oncogenic osteomalacia and phosphaturia, there have been many reports of nonphosphaturic variants of this tumor with no clinical or laboratory evidence of tumor-induced osteomalacia. However, most of these nonphosphaturic variants previously described were not metastatic. We describe an unusual case of PMTMCT with widespread osseous metastases and without evidence of tumor-induced osteomalacia or phosphaturia.
Asunto(s)
Neoplasias Óseas/patología , Hipofosfatemia Familiar/patología , Mesenquimoma/patología , Neoplasias Óseas/secundario , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome associated with tumors that secrete phosphaturic hormones, most notably fibroblast growth factor 23 (FGF23). The majority of tumors associated with this syndrome show stereotypical histological features and are now known as phosphaturic mesenchymal tumors (PMTs). We postulated that immunohistochemistry for somatostatin receptor 2A (SSTR2A) could be used to definitively identify PMTs or other tumors that cause TIO. Immunohistochemistry for FGF23 and SSTR2A was performed on 15 tumors from 14 patients with a definite diagnosis of TIO. All showed positive staining for both markers. While FGF23 staining was quite focal in some tumors, SSTR2A showed diffuse strong expression. In 40 control tumors not known to be associated with the clinical or biochemical features of TIO, FGF23 expression was found in 2 cases (one aneurysmal bone cyst and one osteosarcoma). SSTR2A expression was found in 9 control tumors (4 synovial sarcomas, 2 hemangiomas, 2 aneurysmal bone cysts and one osteosarcoma). Only one tumor (an aneurysmal bone cyst) showed positive staining for both FGF23 and SSTR2A. SSTR2A also commonly stained neoplastic and non-neoplastic endothelial cells. We conclude that neither FGF23 nor SSTR2A expression are specific for the diagnosis of PMT. However both stains are highly sensitive. Because of its diffuse strong expression and widespread availability, immunohistochemistry for SSTR2A is useful to confirm the diagnosis of PMT in an appropriate setting particularly if material is limited. Negative staining can serve as an excellent rule out test for this diagnosis.
Asunto(s)
Hipofosfatemia Familiar/diagnóstico , Mesenquimoma/diagnóstico , Neoplasias de Tejido Conjuntivo/diagnóstico , Osteomalacia/diagnóstico , Síndromes Paraneoplásicos/diagnóstico , Receptores de Somatostatina/metabolismo , Adulto , Medicamentos Herbarios Chinos , Eleutherococcus , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patología , Masculino , Mesenquimoma/metabolismo , Mesenquimoma/patología , Persona de Mediana Edad , Neoplasias de Tejido Conjuntivo/metabolismo , Neoplasias de Tejido Conjuntivo/patología , Osteomalacia/metabolismo , Osteomalacia/patología , Síndromes Paraneoplásicos/metabolismo , Síndromes Paraneoplásicos/patologíaRESUMEN
Fibroblast growth factor 23 (FGF23) plays a crucial role in renal phosphate regulation, exemplified by the causal role of PHEX and DMP1 mutations in X-linked hypophosphatemic rickets and autosomal recessive rickets type 1, respectively. Using whole exome sequencing we identified compound heterozygous mutations in family with sequence similarity 20, member C (FAM20C) in two siblings referred for hypophosphatemia and severe dental demineralization disease. FAM20C mutations were not found in other undiagnosed probands of a national Norwegian population of familial hypophosphatemia. Our results demonstrate that mutations in FAM20C provide a putative new mechanism in human subjects leading to dysregulated FGF23 levels, hypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis of the long bones in the absence of rickets.
Asunto(s)
Calcinosis , Exoma , Proteínas de la Matriz Extracelular , Factores de Crecimiento de Fibroblastos/metabolismo , Hipofosfatemia Familiar , Anomalías Dentarias , Adolescente , Adulto , Calcinosis/genética , Calcinosis/metabolismo , Calcinosis/patología , Quinasa de la Caseína I , Análisis Mutacional de ADN , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Humanos , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patología , Masculino , Mutación , Noruega , Osteosclerosis/genética , Osteosclerosis/metabolismo , Osteosclerosis/patología , Anomalías Dentarias/genética , Anomalías Dentarias/metabolismo , Anomalías Dentarias/patologíaRESUMEN
Oncogenic osteomalacia (OO) is a rare paraneoplastic condition in which a bone or soft tissue tumor induces biochemical and clinical signs and symptoms of osteomalacia (or rickets) most often by the production of the phosphaturic protein, fibroblast growth factor-23. Phosphaturic mesenchymal tumor, mixed connective tissue type (PMTMCT) is a rare, histologically distinct tumor that represents the most common cause of OO. As the clinical diagnosis of OO is typically suspected on the basis of clinical and biochemical features and the presence of a bone or soft tissue tumor, cytologic examination might potentially provide the necessary pathologic confirmation of OO. In this case of a 46-year-old female with clinical stigmata of OO and a right distal humeral mass, we report that the fine-needle aspiration findings of short, cytologically bland spindled cells embedded in a fine, fibrillary stromal-rich matrix and the presence of osteoclast-type giant cells associated with the stromal matrix provide strong pathological evidence for PMTMCT and assist in pathologically confirming the clinical impression of OO, thus alleviating the need for a more invasive diagnostic surgical procedure.
Asunto(s)
Hipofosfatemia Familiar/complicaciones , Hipofosfatemia Familiar/patología , Mesenquimoma/diagnóstico , Mesenquimoma/patología , Biopsia con Aguja Fina , Femenino , Estudios de Seguimiento , Humanos , Húmero/diagnóstico por imagen , Húmero/patología , Hipofosfatemia Familiar/diagnóstico por imagen , Mesenquimoma/complicaciones , Mesenquimoma/diagnóstico por imagen , Persona de Mediana Edad , RadiografíaRESUMEN
Fibroblast growth factor-23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis which inhibits renal tubular phosphate reabsorption. Binding of circulating FGF23 to FGF receptors in the cell membrane requires the concurrent presence of the co-receptor αKlotho. It is still controversial whether αKlotho is expressed in the kidney proximal tubule, the principal site of phosphate reabsorption. Hence, it has remained an enigma as to how FGF23 downregulates renal phosphate reabsorption. Here, we show that renal proximal tubular cells do express the co-receptor αKlotho together with cognate FGF receptors, and that FGF23 directly downregulates membrane expression of the sodium-phosphate cotransporter NaPi-2a by serine phosphorylation of the scaffolding protein Na(+)/H(+) exchange regulatory cofactor (NHERF)-1 through ERK1/2 and serum/glucocorticoid-regulated kinase-1 signaling.
Asunto(s)
Factores de Crecimiento de Fibroblastos/farmacología , Hipofosfatemia Familiar/enzimología , Hipofosfatemia Familiar/patología , Proteínas Inmediatas-Precoces/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/enzimología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Activación Enzimática/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/enzimología , Células Epiteliales/patología , Factor-23 de Crecimiento de Fibroblastos , Regulación de la Expresión Génica/efectos de los fármacos , Glucuronidasa/genética , Glucuronidasa/metabolismo , Humanos , Proteínas Inmediatas-Precoces/genética , Túbulos Renales Proximales/patología , Proteínas Klotho , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Intercambiadores de Sodio-Hidrógeno/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismoRESUMEN
BACKGROUND: The etiology of nephrocalcinosis is variable. In this study, we wanted to elucidate whether the histopathological appearance of calcium phosphate deposits provides information about possible etiology. METHODS: Autopsy cases from the years 1988 to 2007 and native kidney biopsies from a 50-year period (1959-2008) with nephrocalcinosis were identified. The biopsy cases were re-evaluated by light microscopy. The autopsy cases were analysed according to the underlying disease. The biopsy cases were grouped with respect to the likely etiology of nephrocalcinosis. Total number, density, localization, size and pattern of all calcification foci were documented and correlated with clinical and laboratory data. RESULTS: About 223 of 12,960 autopsy cases (1.7%) had nephrocalcinosis, 111 of which (49.8%) suffered from advanced malignant tumours. Nephrocalcinosis was the main diagnosis in 48 of 12,480 native kidney biopsies (0.4%). Clinicopathological correlation revealed a specific pattern of calcification associated with hyperphosphataemia and/or hyperphosphaturia: these cases showed predominant globular or shell-like calcifications (phosphate type). In contrast, the biopsies of the hypercalcaemic/hypercalciuric group had a different predominant pattern with clumpy or finely granular calcifications (calcium type). CONCLUSIONS: Our results indicate that hyperphosphaturia-associated cases of nephrocalcinosis can be distinguished from hypercalciuria-associated cases histopathologically.
Asunto(s)
Calcio/metabolismo , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patología , Nefrocalcinosis/metabolismo , Nefrocalcinosis/patología , Fosfatos/metabolismo , Adolescente , Adulto , Anciano , Autopsia , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neoplasias/etiología , Neoplasias/metabolismo , Neoplasias/patología , Nefrocalcinosis/complicaciones , Pronóstico , Adulto JovenRESUMEN
Parathyroid hormone (PTH) is widely recognized as a key regulator of mineral ion homeostasis. Daily intermittent administration of PTH is the only currently available anabolic therapy for bone disorders such as osteoporosis. Recent studies have shown that PTH increases transcription and secretion of fibroblast growth factor 23 (FGF-23), another important regulator of phosphate homeostasis and skeletal metabolism. However, the full relationship between PTH and FGF-23 is largely unknown. This study evaluated the effect of FGF-23/Klotho signaling on the phosphaturic and anabolic functions of PTH. Eight-day-old wild-type (WT) Fgf23(-/-) and Kl(-/-) mice were injected with 100 µg/kg PTH(1-34) or vehicle daily for a 2-week-period and then euthanized. Intermittent injection of PTH successfully reduced the serum phosphate levels and reversed the hyperphosphatemia of Fgf23(-/-) and Kl(-/-) mice. Bone changes were analyzed in the distal femur metaphysis by peripheral quantitative computed tomography (pQCT), micro-computed tomography (µCT), and histomorphometry. PTH treatment induced substantial increases in bone mineral density (BMD) and trabecular bone volume in each mouse genotype. Expression of osteoblastic marker genes, including Runx2, Col1, Alp, Ocn, and Sost, was similarly altered. In addition, primary osteoblasts were isolated and treated with 100 nM PTH in vitro. PTH treatment similarly induced cAMP accumulation and phosphorylation of ERK1/2 and CREB in the osteoblasts from each genotype. Taken together, our results demonstrate that FGF-23/Klotho signaling is not essential for the phosphaturic and anabolic functions of PTH, suggesting that PTH can function as a therapeutic agent to improve the skeletal quality of patients even in the presence of abnormal serum FGF-23 levels.
Asunto(s)
Anabolizantes/farmacología , Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/metabolismo , Hipofosfatemia Familiar/metabolismo , Hormona Paratiroidea/farmacología , Transducción de Señal/efectos de los fármacos , Anabolizantes/administración & dosificación , Animales , Densidad Ósea/efectos de los fármacos , Huesos/efectos de los fármacos , Huesos/patología , Calcitriol/sangre , Calcio/sangre , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/deficiencia , Regulación de la Expresión Génica/efectos de los fármacos , Glucuronidasa/deficiencia , Humanos , Hipofosfatemia Familiar/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Proteínas Klotho , Ratones , Tamaño de los Órganos/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoblastos/enzimología , Osteoblastos/patología , Hormona Paratiroidea/administración & dosificación , Fenotipo , Fosfatos/sangreRESUMEN
Oncogenic osteomalacia is a rare paraneoplastic syndrome that occurs secondary to tumor development in a variety of locations. Only about 140 cases have been reported in the literature. The most common causal tumor is phosphaturic mesenchymal tumor (PMT), a histologically benign lesion. The two most common sites of PMT are the lower extremities and the head/neck. We report the case of a 33-year-old woman with oncogenic osteomalacia who was diagnosed with two PMTs; the first arose in the tibia, and the second occurred 2 years later in the maxillary sinus. To the best of our knowledge, this is the first reported case of multiple PMTs. Despite resection of both tumors, the patient's signs and symptoms did not resolve, suggesting either incomplete tumor removal or the presence of another undetected tumor. We discuss the diagnosis of oncogenic osteomalacia, its associated biochemical abnormalities, and its histopathology.
Asunto(s)
Neoplasias Óseas/etiología , Hipofosfatemia Familiar/patología , Mesenquimoma/etiología , Osteomalacia/complicaciones , Tibia/patología , Adulto , Biomarcadores de Tumor/análisis , Neoplasias Óseas/patología , Neoplasias Óseas/cirugía , Femenino , Humanos , Mesenquimoma/patología , Mesenquimoma/cirugía , Neoplasias de los Tejidos Conjuntivo y Blando/patología , Osteomalacia/patología , Osteomalacia/cirugía , Tibia/cirugíaAsunto(s)
Fracturas Óseas/patología , Hipofosfatemia Familiar/patología , Neoplasias Hepáticas/patología , Mesenquimoma/patología , Osteomalacia/patología , Neoplasias de la Médula Espinal/patología , Nervios Espinales/patología , Femenino , Fracturas Óseas/complicaciones , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Osteomalacia/complicaciones , Médula Espinal/patología , Tomografía Computarizada por Rayos XRESUMEN
Oncogenous osteomalacia is a rare paraneoplastic renal phosphaturic condition, often associated with highly vascular benign mesenchymal tumors. We report a case of a 48-year-old male who presented with debilitating osteomalacia unresponsive to standard therapy. Two years later, sinonasal hemangiopericytoma was diagnosed; the patient underwent complete surgical excision with rapid symptomatic improvement.
Asunto(s)
Osteomalacia/patología , Osteomalacia/cirugía , Hemangiopericitoma/complicaciones , Hemangiopericitoma/patología , Humanos , Hipofosfatemia Familiar/complicaciones , Hipofosfatemia Familiar/patología , Masculino , Persona de Mediana Edad , Síndromes Paraneoplásicos/complicaciones , Síndromes Paraneoplásicos/patología , Neoplasias de los Tejidos Blandos/complicaciones , Neoplasias de los Tejidos Blandos/patología , Resultado del TratamientoRESUMEN
A one year eight month old male child and his nine month old female sibling were presented with Growth retardation, abdominal distension, doll-like faces, hepatomegaly, phosphaturia, proximal renal tubular dysfunction. The elder sibling also presented with glucosuria, hyperglycemia, hypoinsulinemia. The younger one later presented with galactosemia. Biopsy of liver on these two patients revealed the accumulation of glycogen in hepatocytes.
Asunto(s)
Trastornos del Crecimiento/diagnóstico , Hepatomegalia/diagnóstico , Hipofosfatemia Familiar/diagnóstico , Biopsia , Femenino , Glucógeno/metabolismo , Trastornos del Crecimiento/metabolismo , Trastornos del Crecimiento/patología , Hepatocitos/metabolismo , Hepatocitos/patología , Hepatomegalia/metabolismo , Hepatomegalia/patología , Humanos , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patología , Lactante , Hígado/metabolismo , Hígado/patología , Masculino , SíndromeAsunto(s)
Médula Ósea/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Hipofosfatemia Familiar/patología , Nevo/patología , Neoplasias Cutáneas/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico por imagen , Femenino , Humanos , Hipofosfatemia Familiar/diagnóstico por imagen , Nevo/diagnóstico por imagen , Radiografía , Neoplasias Cutáneas/diagnóstico por imagen , Síndrome , Adulto JovenRESUMEN
Although increased circulating levels of PTH with mild hypocalcemia has been reported in Hyp mice, hyperparathyroidism in X-linked hypophosphatemic rickets is postulated to arise from the standard use of phosphate salts, which induce chronic stimulation of PTH secretion. In this study, we sought to examine the role of PTH in the metabolic derangements associated with Hyp by generating hemizygous hypophosphatemic (Hyp/Y) mice homozygous for the Pth-null allele (Pth(-/-);Hyp/Y). Early postnatal lethality was observed in the Pth(-/-);Hyp/Y mice. Within the first 6 h, postpartum serum phosphorus increased to levels comparable to those in the Pth(-/-) mice, whereas in Hyp mice, it decreased during the first 48 h after birth. Serum calcium concentration started low after birth and remained reduced in both Pth(-/-);Hyp/Y and Pth(-/-) mice although more profoundly so in the former group, whereas in Hyp/Y mice, the levels were initially lower than but reached wild-type levels by 24 h. Circulating PTH levels in Hyp/Y mice were higher than wild-type levels throughout the first 48 h after birth and continued to be so well into adulthood. Twice-daily administration of PTH 1-34 to Pth(-/-);Hyp/Y newborn mice increased serum calcium levels and prevented their early demise. The findings here indicate that the cause of death in the Pth(-/-);Hyp/Y mice is severe hypocalcemia. A potential role for fibroblast growth factor 23 in promoting secondary hyperparathyroidism by suppressing renal 25-hydroxyvitamin D(3)-1alpha-hydroxylase (Cyp27b1) activity while increasing that of renal 25-hydroxyvitamin D(3) 24-hydroxylase (Cyp24) is proposed. Hyperparathyroidism, therefore, is an integral component in the pathophysiology of Hyp, and likely X-linked hypophosphatemic rickets and serves to prevent severe hypocalcemia in mice and perhaps in patients afflicted with the disorder.
Asunto(s)
Eliminación de Gen , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/mortalidad , Hormona Paratiroidea/genética , Animales , Animales Recién Nacidos , Femenino , Hipocalcemia/genética , Hipocalcemia/mortalidad , Hipocalcemia/fisiopatología , Hipofosfatemia Familiar/tratamiento farmacológico , Hipofosfatemia Familiar/patología , Masculino , Ratones , Ratones Noqueados , Hormona Paratiroidea/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Fenotipo , Terapia Recuperativa , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
Hyperphosphatemic familial tumoral calcinosis (HFTC) is an autosomal recessive metabolic disorder characterized by extensive phenotypic and genetic heterogeneity. HFTC was shown recently to result from mutations in two genes: GALNT3, coding for a glycosyltransferase responsible for initiating O-glycosylation, and FGF23, coding for a potent phosphaturic protein. All GALNT3 mutations reported so far have been identified in patients of either Middle Eastern or African-American extraction, corroborating numerous historical reports of the disorder in Africa and in the Middle East. In the present study, we describe a patient of Northern European origin displaying typical features of HFTC. Mutation analysis revealed that this patient carries a homozygous novel nonsense mutation in GALNT3 predicted to result in the synthesis of a significantly truncated protein. The present results expand the spectrum of known mutations in GALNT3 and demonstrate the existence of HFTC-causing mutations in this gene outside the Middle Eastern and African-American populations.