Assuntos
Calcinose/diagnóstico , Hiperostose Cortical Congênita/diagnóstico , Hiperfosfatemia/diagnóstico , Músculo Esquelético/diagnóstico por imagem , Adulto , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Calcinose/sangue , Calcinose/genética , DNA/genética , Análise Mutacional de DNA , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Testes Genéticos , Humanos , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/genética , Hiperfosfatemia/sangue , Hiperfosfatemia/genética , Mutação , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Fosfatos/sangue , Doenças Raras , Tomografia Computadorizada por Raios X , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
High bone mass (HBM) is usually caused by gene mutations, and its mechanism remains unclear. In the present study, we identified a novel mutation in the long noncoding RNA Reg1cp that is associated with HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous Reg1cp individuals had higher bone density compared with subjects with WT Reg1cp Mutant Reg1cp increased the formation of the CD31hiEmcnhi endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant Reg1cp directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted of Klf3 in endothelial cells showed a high abundance of CD31hiEmcnhi vessels and increased bone mass. Notably, we identified a natural compound, Ophiopogonin D, which functions as a KLF3 inhibitor. Administration of Ophiopogonin D increased the abundance of CD31hiEmcnhi vessels and bone formation. Our findings revealed a specific mutation in lncRNA Reg1cp that is involved in the pathogenesis of HBM and provides a new target to treat osteoporosis.
Assuntos
Hiperostose Cortical Congênita/genética , Hiperostose Cortical Congênita/metabolismo , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Mutação , Osteopetrose/genética , Osteopetrose/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Densidade Óssea/genética , China , Estudos de Coortes , Células Progenitoras Endoteliais/metabolismo , Feminino , Heterozigoto , Humanos , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/patologia , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neovascularização Fisiológica/genética , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteopetrose/sangue , Osteopetrose/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Saponinas/administração & dosagem , Saponinas/farmacologia , Sialoglicoproteínas/metabolismo , Espirostanos/administração & dosagem , Espirostanos/farmacologia , Adulto JovemRESUMO
Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder of ectopic calcification due to deficiency of or resistance to intact fibroblast growth factor 23 (iFGF23). Inactivating mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO (KL) have been reported as causing HFTC/HHS. We present what we believe is the first identified case of autoimmune hyperphosphatemic tumoral calcinosis in an 8-year-old boy. In addition to the classical clinical and biochemical features of hyperphosphatemic tumoral calcinosis, the patient exhibited markedly elevated intact and C-terminal FGF23 levels, suggestive of FGF23 resistance. However, no mutations in FGF23, KL, or FGF receptor 1 (FGFR1) were identified. He subsequently developed type 1 diabetes mellitus, which raised the possibility of an autoimmune cause for hyperphosphatemic tumoral calcinosis. Luciferase immunoprecipitation systems revealed markedly elevated FGF23 autoantibodies without detectable FGFR1 or Klotho autoantibodies. Using an in vitro FGF23 functional assay, we found that the FGF23 autoantibodies in the patient's plasma blocked downstream signaling via the MAPK/ERK signaling pathway in a dose-dependent manner. Thus, this report describes the first case, to our knowledge, of autoimmune hyperphosphatemic tumoral calcinosis with pathogenic autoantibodies targeting FGF23. Identification of this pathophysiology extends the etiologic spectrum of hyperphosphatemic tumoral calcinosis and suggests that immunomodulatory therapy may be an effective treatment.
Assuntos
Autoanticorpos , Doenças Autoimunes , Calcinose , Fatores de Crescimento de Fibroblastos , Hiperostose Cortical Congênita , Hiperfosfatemia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Calcinose/sangue , Calcinose/imunologia , Calcinose/patologia , Criança , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/imunologia , Hiperostose Cortical Congênita/patologia , Hiperfosfatemia/sangue , Hiperfosfatemia/imunologia , Hiperfosfatemia/patologia , Sistema de Sinalização das MAP Quinases/imunologia , MasculinoRESUMO
BACKGROUND: Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disease caused by mutations in genes encoding FGF23 or its regulators, and leading to functional deficiency or resistance to fibroblast growth factor 23 (FGF23). Subsequent biochemical features include hyperphosphatemia due to increased renal phosphate reabsorption, and increased or inappropriately normal 1,25-dihydroxyvitamin D (1,25-D) levels. CASE-DIAGNOSIS/TREATMENT: A 15-year-old girl was referred for a 1.2-kg-calcified mass of the thigh, with hyperphosphatemia (2.8 mmol/L); vascular impairment and soft tissue calcifications were already present. DNA sequencing identified compound heterozygous mutations in the FGF23 gene. Management with phosphate dietary restriction, phosphate binders (sevelamer, aluminum, nicotinamide), and acetazolamide moderately decreased serum phosphate levels; oral ketoconazole was secondary administered, leading to significantly decreased 1,25-D levels albeit only moderate additionally decreased phosphate levels. However, therapeutic compliance was questionable. Serum phosphate levels always remained far above the upper normal limit for age. The patient presented with two relapses of the thigh mass, requiring further surgery. CONCLUSIONS: We suggest that control of phosphate metabolism is crucial to prevent recurrences and vascular complications in HFTC; however, the medical management remains challenging.
Assuntos
Calcinose/terapia , Quelantes/uso terapêutico , Diuréticos/uso terapêutico , Fatores de Crescimento de Fibroblastos/genética , Hiperostose Cortical Congênita/terapia , Hiperfosfatemia/terapia , Fosfatos/metabolismo , Adolescente , Nádegas/diagnóstico por imagem , Nádegas/cirurgia , Calcinose/sangue , Calcinose/diagnóstico , Calcinose/genética , Terapia Combinada/métodos , Análise Mutacional de DNA , Feminino , Fator de Crescimento de Fibroblastos 23 , Heterozigoto , Humanos , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/diagnóstico , Hiperostose Cortical Congênita/genética , Hiperfosfatemia/sangue , Hiperfosfatemia/diagnóstico , Hiperfosfatemia/genética , Imageamento por Ressonância Magnética , Fosfatos/sangue , Resultado do TratamentoRESUMO
Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research.
Assuntos
Calcinose , Fatores de Crescimento de Fibroblastos/genética , Glucuronidase/genética , Hiperostose Cortical Congênita , Hiperostose , Hiperfosfatemia , N-Acetilgalactosaminiltransferases/genética , Adolescente , Adulto , Calcinose/sangue , Calcinose/genética , Calcinose/patologia , Calcinose/terapia , Criança , Estudos de Coortes , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Hiperostose/sangue , Hiperostose/genética , Hiperostose/patologia , Hiperostose/terapia , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/genética , Hiperostose Cortical Congênita/patologia , Hiperostose Cortical Congênita/terapia , Hiperfosfatemia/sangue , Hiperfosfatemia/genética , Hiperfosfatemia/patologia , Hiperfosfatemia/terapia , Proteínas Klotho , Masculino , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
FGF23 is essential for the homeostasis of phosphate, and vitamin D. Loss-of-function mutations in this hormone cause hyperphosphatemic familial tumoral calcinosis (HFTC). Earlier reports suggested that intact FGF23 from loss of function mutants such as FGF23/S129F (iFGF23/S129F) is retained intracellularly while the carboxy-terminal fragment is secreted. We sought to investigate the fate of iFGF23/S129F mutant hormone in vivo and in vitro. Five patients clinically diagnosed with HFTC and confirmed by DNA sequencing to carry the c.386 C>T; p.S129F mutation in the homozygous state were studied. Healthy and heterozygous individuals were used as controls in the study. Using ELISA assays, we showed that iFGF23/S129F was 2-5 folds higher in patients' plasma, compared to heterozygous or healthy controls. Importantly, the mutant hormone could not be detected in the patients' sera. However, using proteinase inhibition profiling, we found that a serum metalloproteinase degraded the iFGF23/S129F explaining our failure to detect it in sera. The serum metalloproteinase degrades the WT and the mutant at different rates. Also, confocal microscopy imaging using wild-type (WT) FGF23 or FGF23/S129F mutant in transiently transfected HEK293 and HeLa cells showed weak staining of the Golgi complex with some vesicular staining resembling the ER. Additionally, FGF23 variants (FGF23/WT, FGF23/S129F, FGF23/S71G, and FGF23/R176Q) from stably transfected HEK293 cells secreted high levels into a serum-free medium that can be detected by ELISA and Western blot. Our results suggest that iFGF23/S129F mutant bypasses the ER/Golgi quality control system to the circulation of HFTC patients by an unknown pathway. Finally, we hypothesize that either the mutant hormone is unable to bind α-Klotho-FGFR1c, or it binds the dyad receptor with low affinity and, therefore, incapable of initiating maximal intracellular signaling. Our findings raise the potential use of the WT hormone in therapies of some HFTC patients.
Assuntos
Calcinose/genética , Retículo Endoplasmático/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Complexo de Golgi/metabolismo , Hiperostose Cortical Congênita/genética , Hiperfosfatemia/genética , Mutação/genética , Calcinose/sangue , Sistema Livre de Células , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/química , Células HEK293 , Células HeLa , Homozigoto , Humanos , Hiperostose Cortical Congênita/sangue , Hiperfosfatemia/sangue , Inibidores de Metaloproteinases de Matriz/farmacologia , Modelos Biológicos , Proteínas Mutantes/sangue , Transporte Proteico/efeitos dos fármacos , TransfecçãoRESUMO
BACKGROUND: Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. METHODS: We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. RESULTS: We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. CONCLUSIONS: This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families.
Assuntos
Calcinose/genética , DNA/genética , Fatores de Crescimento de Fibroblastos/genética , Hiperostose Cortical Congênita/genética , Hiperfosfatemia/genética , Mutação , Fosfatos/sangue , Calcificação Vascular/genética , Adulto , Alelos , Calcinose/sangue , Calcinose/complicações , Análise Mutacional de DNA , Ensaio de Imunoadsorção Enzimática , Exoma , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Genótipo , Humanos , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/complicações , Hiperfosfatemia/sangue , Hiperfosfatemia/complicações , Imuno-Histoquímica , Masculino , Calcificação Vascular/sangue , Calcificação Vascular/etiologiaRESUMO
BACKGROUND: In some neonates suffering from ductus arteriosus dependent congenital heart defect, a Prostaglandin E(1) (PGE1) therapy longer than 2 weeks may be needed. However, PGE1 analogue compounds may produce several adverse effects. METHODS: The authors retrospectively analyzed the data of nine patients who underwent a PGE1 treatment lasting longer than 14 days. RESULTS: The leukocyte count of the patients remained high throughout the treatment period, and the proportion of neutrophils was over 50%. Transient feeding difficulty and abdominal distension, and possible signs of gastric-outlet obstruction, were observed in two cases. In the case of three patients, cortical hyperostosis developed after different cumulative doses (1584, 3384 and 4320 microg). Significant correlations were found between the doses of PGE1 and serum K(+) levels (r=-0.770, P < 0.05) and between the blood standard bicarbonate levels and PGE1 doses (r= 0.889, P < 0.01). Bartter syndrome-like condition developed in those three patients who received the largest cumulative doses. CONCLUSIONS: Fluid-electrolyte parameters must be controlled frequently in the case of each patient treated with PGE1 for longer than 2 weeks. Although the dose, the length of the therapy and individual susceptibility may be equally important, fluid-electrolyte disturbances and the development of pseudo-Bartter syndrome seem to be more dose-dependent than cortical hyperostosis.
Assuntos
Alprostadil/efeitos adversos , Síndrome de Bartter/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Obstrução da Saída Gástrica/tratamento farmacológico , Cardiopatias Congênitas/tratamento farmacológico , Hiperostose Cortical Congênita/tratamento farmacológico , Leucocitose/induzido quimicamente , Equilíbrio Ácido-Base , Fosfatase Alcalina/sangue , Alprostadil/administração & dosagem , Síndrome de Bartter/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fibrinolíticos/administração & dosagem , Seguimentos , Obstrução da Saída Gástrica/sangue , Cardiopatias Congênitas/sangue , Humanos , Hiperostose Cortical Congênita/sangue , Recém-Nascido , Infusões Intravenosas , Contagem de Leucócitos , Leucocitose/sangue , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de TempoRESUMO
An early case of prenatal Caffey disease is reported. Ultrasound examination performed at 20 weeks showed major angulations of long bones, but both ultrasound scan and X-rays failed to make the differential diagnosis between Caffey disease and lethal osteogenesis imperfecta. A cordocentesis allowed us to find important biological abnormalities. The pregnancy was terminated after the rapid development of hydrops fetalis. The definitive diagnosis of Caffey disease was obtained by special X-ray and pathological study.
Assuntos
Hiperostose Cortical Congênita/diagnóstico , Diagnóstico Pré-Natal , 5'-Nucleotidase/sangue , Aborto Terapêutico , Adulto , Contagem de Células Sanguíneas , Proteína C-Reativa/metabolismo , Cordocentese , Erros de Diagnóstico , Feminino , Humanos , Hidropisia Fetal/complicações , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/complicações , Hiperostose Cortical Congênita/diagnóstico por imagem , Imunoglobulina M/análise , Osteogênese Imperfeita/diagnóstico , Gravidez , Radiografia , gama-Glutamiltransferase/sangueRESUMO
This is a report of a 6-year-old girl with the rare syndrome of hyperostosis with hyperphosphatemia. Only eight cases have been previously reported. The main features of this syndrome are repeated attacks of bone pain and swelling, the radiologic finding of periosteal reaction with cortical hyperostosis, and the laboratory finding of increased serum phosphorus level with normal serum calcium and parathyroid hormone levels. The purpose of this article is to review the clinical picture, laboratory and radiological findings, and the differential diagnosis.
Assuntos
Hiperostose Cortical Congênita/sangue , Fosfatos/sangue , Tíbia , Biópsia , Criança , Diagnóstico Diferencial , Feminino , Humanos , Hiperostose Cortical Congênita/diagnóstico por imagem , Hiperostose Cortical Congênita/epidemiologia , Hiperostose Cortical Congênita/patologia , Osteomielite/diagnóstico , Radiografia , Cintilografia , Recidiva , Síndrome , TecnécioRESUMO
An unusual case of Caffey-Silverman's disease with thrombocythemia and increased type M immunoglobulins and C-reactive protein levels is reported. These particularities were rarely reported in the literature. These conditions suggest that control should be exercised before steroid treatment in view of the known thrombocythemic effect of the drug. These hematologic abnormalities suggest that this syndrome is infectious in origin and emphasize the risk of steroid treatment.
Assuntos
Proteína C-Reativa/análise , Hiperostose Cortical Congênita/sangue , Imunoglobulina M/análise , Trombocitose/sangue , Humanos , Recém-Nascido , MasculinoRESUMO
A 2-year-old black boy with the Kenny-Caffey syndrome was first evaluated because of growth retardation and hypocalcemia. Hypothalamic-pituitary function was normal. Basal serum somatomedin C levels were normal for age, but did not increase during short-term administration of human growth hormone. Serum immunoreactive parathyroid hormone levels remained inappropriately low during spontaneous and induced hypocalcemia, indicating that hypocalcemia was the consequence of hypoparathyroidism. The manifestations of 15 patients with this syndrome are tabulated.
Assuntos
Transtornos do Crescimento/etiologia , Hiperostose Cortical Congênita/etiologia , Hipocalcemia/etiologia , Pré-Escolar , Humanos , Hiperostose Cortical Congênita/sangue , Hipoparatireoidismo/sangue , Magnésio/sangue , Masculino , Hormônio Paratireóideo/sangueAssuntos
Plaquetas , Hiperostose Cortical Congênita/sangue , Difosfato de Adenosina/farmacologia , Corticosteroides/farmacologia , Contagem de Células Sanguíneas , Transtornos Plaquetários/etiologia , Epinefrina/farmacologia , Humanos , Hiperostose Cortical Congênita/complicações , Estudos Longitudinais , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Trombose/etiologiaAssuntos
Fosfatase Alcalina/sangue , Hiperostose Cortical Congênita/sangue , Distúrbios do Metabolismo do Fósforo/etiologia , Fósforo/sangue , Adulto , Osso e Ossos/patologia , Calcitonina/sangue , Diagnóstico Diferencial , Humanos , Hiperostose Cortical Congênita/diagnóstico por imagem , Masculino , Radiografia , SíndromeRESUMO
Twenty-nine cases of infantile cortical hyperostosis with a wide range of bone involvement are reviewed. Soft tissue painful swellings began before roentgenographic changes appeared in the underlying bone. In 17 babies gradual involvement of different bones was noted. In seven cases lesions previously healed became reactivated. The disease is self-limiting and appears in a narrow age group. Mandibular involvement is most common. The clinical picture and laboratory data are reported. Differential diagnosis and possible etiological factors are discussed. The similarity of infantile cortical hyperostosis to extreme periosteal new bone formation in response to trauma in sensorily deprived children is suggested as a possible etiological factor.