RESUMEN
PIGQ (OMIM *605754) encodes phosphatidylinositol glycan biosynthesis class Q (PIGQ) and is required for proper functioning of an N-acetylglucosamine transferase complex in a similar manner to the more established PIGA, PIGC, and PIGH. There are two previous patients reported with homozygous and apparently deleterious PIGQ mutations. Here, we provide the first detailed clinical report of a patient with heterozygous deleterious mutations associated with glycosylphosphatidylinositol-anchored protein (GPI-AP) biosynthesis deficiency. Our patient died at 10 months of age. The rare skeletal findings in this disorder expand the differential diagnosis of long bone radiolucent lesions and sphenoid wing dysplasia. This clinical report describes a new and rare disorder-PIGQ GPI-AP biosynthesis deficiency syndrome.
Asunto(s)
Anomalías Múltiples/genética , Enfermedades del Desarrollo Óseo/genética , Glicosilfosfatidilinositoles/deficiencia , Proteínas de la Membrana/genética , Hipotonía Muscular/genética , Mutación , Convulsiones/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/metabolismo , Anomalías Múltiples/patología , Enfermedades del Desarrollo Óseo/diagnóstico , Enfermedades del Desarrollo Óseo/metabolismo , Enfermedades del Desarrollo Óseo/patología , Resultado Fatal , Expresión Génica , Glicosilfosfatidilinositoles/genética , Glicosilfosfatidilinositoles/metabolismo , Heterocigoto , Humanos , Lactante , Masculino , Proteínas de la Membrana/deficiencia , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/metabolismo , Hipotonía Muscular/patología , Fenotipo , Convulsiones/diagnóstico , Convulsiones/metabolismo , Convulsiones/patología , Hueso Esfenoides/metabolismo , Hueso Esfenoides/patología , Síndrome , Secuenciación del ExomaRESUMEN
Hypercortisolism in humans suppresses osteoblastogenesis and osteoblast function through the upregulation of Wnt-signaling antagonists (sclerostin, Dkk1) and changes in microRNAs levels (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) which are associated with mesenchymal stem-cell commitment to adipocytes or cartilage cells over the osteoblasts. INTRODUCTION: The purpose of this study was to evaluate the responses of bone to chronic glucocorticoid (GC) excess by measuring the levels of selected mRNA and microRNA (miR) in bone samples of patients with Cushing's disease (CD). METHODS: Bone samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 16 patients with clinically and biochemically evident CD and 10 patients with clinically non-functioning pituitary adenomas (NFPA) matched by sex, age, and body mass index. Quantitative polymerase chain reactions (qPCR) were used to examine the expression of genes (mRNA and miRs) known to be involved in bone remodeling regulation based on studies in animals and cell culture. RESULTS: Hypercortisolism was associated with the downregulation of genes involved in osteoblast function and maturation (ACP5, ALPL, BGLAP, COL1A1, COL1A2, BMP2, RUNX2, TWIST1). An excess of GC caused increased expression of Wnt-signaling antagonists (Dkk1, SOST) and changes in the levels of miRs that are known to suppress osteoblastogenesis (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) p < 0.05, q < 0.1. Interestingly, compensatory mechanisms were found in long-term hypercortisolism: upregulation of Wnt10b, LRP5, and LRP6; downregulation of SFRP4; changes in miRs involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p); and downregulation of genes associated with osteoclastogenesis. None of these changes prevented the suppression of bone formation. CONCLUSIONS: An excess of endogenous GC in humans suppresses bone formation through the upregulation of Wnt-signaling antagonists and dysregulation of miRs involved in mesenchymal stem-cell commitment. Both Wnt-signaling antagonists and miRs seem to be promising targets for further research in therapeutic intervention in glucocorticoid-induced osteoporosis.
Asunto(s)
Remodelación Ósea/genética , Regulación de la Expresión Génica/fisiología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Hueso Esfenoides/metabolismo , Adulto , Densidad Ósea/genética , Densidad Ósea/fisiología , Remodelación Ósea/fisiología , Diferenciación Celular/genética , Femenino , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Osteoblastos/patología , Osteoclastos/fisiología , Osteoporosis/etiología , Osteoporosis/genética , Osteoporosis/patología , Osteoporosis/fisiopatología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/complicaciones , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , ARN Mensajero/genética , Hueso Esfenoides/patología , Vía de Señalización Wnt/genética , Vía de Señalización Wnt/fisiologíaRESUMEN
The aim of this study was to assess the effect of the flavonoid naringin on the growth of the spheno-occipital synchondrosis by quantifying the levels of expression of Sox9 and PTHrP in an in vitro mouse model. Fifty 1-day-old BALB/c mice were randomly assigned to experimental or control groups, and each group equally divided into five time frames (6, 24, 48, 72 and 168 hours). The mice were sacrificed with phenobarbitone sodium, and the spheno-occipital synchondroses dissected and cultured in control or experimental medium, with the experimental medium supplemented with 0.1 µm naringin. Sections of the specimens underwent immunohistochemical staining for Sox9 and PTHrP, and the amount of expression was quantified using true-colour RGB (red-green-blue) computer-assisted image-analysing system with digital imaging. Data analysis showed there was a significant increase of expression of Sox9 at 6 and 24 hours (P < 0.001) between experimental and control groups, however, there was no significant difference between the levels of expression of PTHrP between experimental and control groups at any of the time frames. There was a very weak correlation found in this study between the expression of PTHrP and Sox9. In conclusion, naringin enhances the growth of the spheno-occipital synchondrosis through over expression of Sox9. This is a successful in vitro model to study factors regulating the growth of the spheno-occipital synchondrosis.
Asunto(s)
Flavanonas/farmacología , Hueso Occipital/efectos de los fármacos , Proteína Relacionada con la Hormona Paratiroidea/metabolismo , Factor de Transcripción SOX9/metabolismo , Hueso Esfenoides/efectos de los fármacos , Animales , Ratones , Ratones Endogámicos BALB C , Hueso Occipital/crecimiento & desarrollo , Hueso Occipital/metabolismo , Hueso Esfenoides/crecimiento & desarrollo , Hueso Esfenoides/metabolismoRESUMEN
OBJECTIVE: This study aimed to determine the effect of C-type natriuretic peptide (CNP) overexpression on craniofacial growth during the pubertal growth period in mice. DESIGN: Six-week-old C57BL/6 mice were injected with pLIVE-Empty vectors (Control mice) and pLIVE-NPPC vectors (CNP mice) using the hydrodynamic method. Morphological analyses were performed at the age of 12 weeks. RESULTS: Micro-computed tomography (µCT) images showed significant (p < 0.05) hyperplasia in the maxilla along the sagittal plane (CNP mice: 13.754 mm, Control mice: 13.215 mm). Further, the images revealed significant bone overgrowth in the sagittal direction in the sphenoid (CNP mice: 6.936 mm, Control mice: 6.411 mm) and occipital (CNP mice: 4.051 mm, Control mice: 3.784 mm) bones in the CNP mice compared with that in the Control mice. Compared with SAP-Nppc-Tg mice in previous studies, although there was no effect on nose length and nasal bone length, the effect was sufficient to improve craniofacial hypogrowth. Furthermore, CNP promoted sagittal cranial growth by increasing the thickness of the spheno-occipital synchondrosis in organ cultures and nasal septal cartilage in micromass cultures, which were derived from 6-week-old mice. CONCLUSIONS: We have previously shown that the elevated blood levels of CNP from the neonatal period affect midfacial skeletogenesis by promoting endochondral ossification using mice (SAP-Nppc-Tg mice). The overexpression of CNP, even in 6-weeks-old mice, promoted growth in the sagittal direction within the maxillary region. These findings indicate the therapeutic potential of CNP for the treatment of midfacial hypoplasia during the pubertal growth spurt.
Asunto(s)
Péptido Natriurético Tipo-C , Hueso Esfenoides , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Péptido Natriurético Tipo-C/administración & dosificación , Péptido Natriurético Tipo-C/biosíntesis , Pubertad/metabolismo , Hueso Esfenoides/crecimiento & desarrollo , Hueso Esfenoides/metabolismo , Microtomografía por Rayos XRESUMEN
OBJECTIVE: To evaluate the response of bone to chronic long-term growth hormone (GH) and insulin-like growth factor-1 (IGF1) excess by measuring the expression of selected mRNA and microRNA (miR) in bone tissue samples of patients with active acromegaly. DESIGN: Case-control study. METHODS: Bone tissue samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 14 patients with clinically and biochemically confirmed acromegaly and 10 patients with clinically non-functioning pituitary adenoma (NFPA) matched by sex and age. Expression of genes involved in the regulation of bone remodeling was studied using quantitative polymerase chain reaction (qPCR). RESULTS: Of the genes involved in osteoblast and osteoclast activity, only alkaline phosphatase (ALP) mRNA was 50% downregulated in patients with acromegaly. GH excess caused increased expression of the Wnt signaling antagonists (DKK1) and agonists (WNT10B) and changes in the levels of miR involved in mesenchymal stem cell commitment to chondrocytes (miR-199a-5p) or adipocytes (miR-27-5p, miR-125b-5p, miR-34a-5p, miR-188-3p) P < 0.05; q < 0.1. Relevant compensatory mechanisms were found through the changes in miR involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p), but the expression of TWIST1 was 50% downregulated and RUNX2 was unchanged. CONCLUSIONS: Acromegaly had minimal effects on tested mRNAs specific to osteoblast or osteoclast function except for downregulated ALP expression. The expressions of miR known to be involved in mesenchymal stem cell commitment and downregulated TWIST1 expression suggest acromegaly has a negative effect on osteoblastogenesis.
Asunto(s)
Acromegalia/metabolismo , Hormona de Crecimiento Humana/biosíntesis , MicroARNs/biosíntesis , ARN Mensajero/biosíntesis , Hueso Esfenoides/metabolismo , Acromegalia/diagnóstico , Acromegalia/genética , Adulto , Estudios de Casos y Controles , Estudios Transversales , Femenino , Expresión Génica , Hormona de Crecimiento Humana/genética , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , ARN Mensajero/genética , Hueso Esfenoides/patologíaRESUMEN
Fibrous dysplasia commonly involves the skull in both its monostotic and polyostotic variants. We present two cases of fibrous dysplasia involving the sphenoid wing, which were strikingly similar in their bone scan appearance. Both patients demonstrated intense increased uptake of Tc-99m MDP in a pattern reminding us of a "pirate wearing an eyepatch." We propose that this characteristic appearance of fibrous dysplasia of the sphenoid wing be called the "pirate sign." A review of the literature revealed several other pathologic conditions that have been reported to involve the sphenoid bone and should be considered in the differential diagnosis of abnormal bone tracer uptake in this region.
Asunto(s)
Displasia Fibrosa Poliostótica/diagnóstico por imagen , Hueso Esfenoides/anomalías , Hueso Esfenoides/diagnóstico por imagen , Medronato de Tecnecio Tc 99m , Adulto , Femenino , Displasia Fibrosa Poliostótica/metabolismo , Humanos , Masculino , Cintigrafía , Radiofármacos/farmacocinética , Hueso Esfenoides/metabolismo , Medronato de Tecnecio Tc 99m/farmacocinética , Distribución TisularRESUMEN
Bone bridges linking the epiphysis and metaphysis termed "tethers" have been found in the femoral growth plates of C57Bl/6 mice and are disrupted when the vitamin D receptor (VDR) is ablated. It is unknown if tethers are found in other growth centers, if they are regulated in a comparable manner, or if they have a functional role in skeletal development or stability. To address this, distal femoral growth plates (GPs) and spheno-occipital synchondroses (SOSs) of wild-type C57Bl/6 mice from 2 to 15 weeks of age were analyzed using µCT scans. The GPs and SOSs of VDR+/+ and VDR-/- mice fed regular or rescue diets to restore mineral homeostasis until 10 weeks of age were also scanned. Tethers in GPs and SOSs both thickened and accumulated in number as these growth centers decreased in size. Ablating the VDR made GPs and SOSs rachitic and nearly eliminated tether formation. Rescue diets restored the volume of both growth centers but only partially restored growth center thickness and tether formation, suggesting that lα,25-dihydroxy vitamin D(3) partially regulates tether formation in these growth centers via its receptor. In VDR+/+ mice 2-15 weeks in age, growth center thickness was inversely correlated to animal weight whereas tether phenotype (tether volume/growth center volume, tether number/mm, tether width, tether spacing) was significantly related to animal weight. In both 2-15 week old VDR+/+ and 10 week old VDR+/+ and VDR-/- mice on normal and rescue diets, tether phenotype (tether number/mm, tether spacing) had strikingly similar relationships to growth center thickness. These results show that tethers are present in growth centers in different anatomic and undergo developmental changes in a comparable manner; in both sites, VDR-regulated tether formation is strongly linked to growth center morphology; and tether formation is associated with body weight, suggesting a role in maintaining growth plate stability during growth.
Asunto(s)
Fémur , Placa de Crecimiento , Hueso Occipital , Receptores de Calcitriol/metabolismo , Hueso Esfenoides , Animales , Dieta , Fémur/anatomía & histología , Fémur/crecimiento & desarrollo , Fémur/metabolismo , Placa de Crecimiento/anatomía & histología , Placa de Crecimiento/crecimiento & desarrollo , Placa de Crecimiento/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Minerales/metabolismo , Hueso Occipital/anatomía & histología , Hueso Occipital/crecimiento & desarrollo , Hueso Occipital/metabolismo , Fenotipo , Receptores de Calcitriol/genética , Hueso Esfenoides/anatomía & histología , Hueso Esfenoides/crecimiento & desarrollo , Hueso Esfenoides/metabolismo , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Microtomografía por Rayos XRESUMEN
The prognosis of pediatric chordomas is difficult to predict based on histology. The objective of this study was to assess the expression of a proliferation marker and adhesion molecules in pediatric chordomas and relate the expressions to outcome. In 8 pediatric chordomas, we calculated the MIB-1 labeling index (LI) by counting the number of MIB-1-positive tumor cells in 100 tumor cells. The grade of expression of E-cadherin and CD44 was calculated by estimating the percentage of tumor cells expressing these markers. MIB-1 LI correlated with tumor recurrence (P = 0.007) and low survival rate (P = 0.007). The expression of E-cadherin correlated with disease-free survival (P = 0.009), tumor recurrence (P > 0.0007), and low survival rate (P > 0.0007). CD44 expression did not correlate with recurrence (P = 0.056) or survival rate (P = 0.056). Our results suggest that MIB-1 LI and expression of E-cadherin are helpful to predict outcome in pediatric chordomas.