RESUMO
OBJECTIVE: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. STUDY DESIGN: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record. RESULTS: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor. CONCLUSIONS: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.
Assuntos
Hemorragia Gastrointestinal/etiologia , Telômero/genética , Adolescente , Adulto , Ataxia/complicações , Ataxia/genética , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/genética , Medula Óssea/anormalidades , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Calcinose/complicações , Calcinose/genética , Cistos do Sistema Nervoso Central/complicações , Cistos do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Disceratose Congênita/complicações , Disceratose Congênita/genética , Feminino , Retardo do Crescimento Fetal/genética , Hemorragia Gastrointestinal/genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Leucoencefalopatias/complicações , Leucoencefalopatias/genética , Masculino , Microcefalia/complicações , Microcefalia/genética , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Mutação , Retina , Doenças Retinianas/complicações , Doenças Retinianas/genética , Convulsões/complicações , Convulsões/genética , Telômero/metabolismo , Telômero/patologia , Adulto JovemRESUMO
AIMS: Osteoporosis (OP) remains a major public health problem worldwide. The most serious complications of this disease are fragility fractures, which increase morbidity and mortality. Management of OP represents an economic burden for health systems. Therefore, it is necessary to develop new screening strategies to identify the population at risk and implement preventive measures. We previously identified the SNPs rs3801387 in WNT16, rs7108738 in SOX6, rs10036727 in SLIT3 and rs7584262 in PKDCC as associated with bone mineral density in postmenopausal women through a genome-wide association study. The aim of this study was to validate those SNPs in two independent cohorts of non-related postmenopausal women. MATERIALS AND METHODS: We included 1160 women classifying them as normal, osteopenic or osteoporotic and a group with hip fragility fracture. Genotyping was performed using predesigned TaqMan assays. RESULTS: The variants rs10036727 and rs7108738 showed a significant association with BMD at the femoral neck. SLIT3 has been previously proposed as a potential biomarker and therapeutic resource. CONCLUSIONS: Our results provide new evidence regarding a possible involvement of SLIT3 in bone metabolisms and encourage the development of more studies in different populations to support these observations.
Assuntos
Densidade Óssea/genética , Proteínas de Membrana/genética , Osteoporose Pós-Menopausa/genética , Fatores de Transcrição SOXD/genética , Absorciometria de Fóton , Idoso , Doenças Ósseas Metabólicas/genética , Feminino , Colo do Fêmur/diagnóstico por imagem , Fraturas do Quadril/genética , Humanos , Vértebras Lombares/diagnóstico por imagem , México , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/diagnóstico por imagem , Fraturas por Osteoporose/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Proteínas Tirosina Quinases/genética , Proteínas Wnt/genéticaRESUMO
Turner syndrome (TS) is a common genetic disorder. TS-phenotype includes short stature, gonadal dysgenesis, cardiac and kidney malformations, low bone mineral density (low-BMD) and thyroiditis. TS-phenotype varies from patient to patient and the cause is not clear, the genomic background may be an important contributor for this variability. Our aim was to identify the association of specific single nucleotide variants in the PTPN22, VDR, KL, and CYP27B1 genes and vitamin D-metabolism, heart malformation, renal malformation, thyroiditis, and low-BMD in 61 Mexican TS-patients. DNA samples were genotyped for SNVs: rs7975232 (VDR), rs9536282 (KL), rs4646536 (CYP27B1), and rs1599971 (PTPN22) using the KASP assay. Chi-square test under a recessive model and multifactorial dimensionality reduction method were used for analysis. We found a significant association between renal malformation and the rs9536282 (KL) variant and between rs4646536 (CYP27B1) and low-BMD, these variants may have modest effects on these characteristics but contribute to the variability of the TS phenotype. In addition, we identified gene-gene interactions between variants in genes KL, CYP27B1 and VDR related to vitamin D-metabolism and low-BMD in TS-patients. Our results support the idea that the genetic background of TS-patients contributes to the clinical variability seen in them.
Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Doenças Ósseas Metabólicas/genética , Glucuronidase/genética , Receptores de Calcitriol/genética , Síndrome de Turner/genética , Anormalidades Urogenitais/genética , Adolescente , Adulto , Densidade Óssea/genética , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Epistasia Genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Lactente , Rim/anormalidades , Proteínas Klotho , Redes e Vias Metabólicas/genética , México/epidemiologia , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Receptores de Calcitriol/metabolismo , Síndrome de Turner/complicações , Síndrome de Turner/epidemiologia , Anormalidades Urogenitais/complicações , Anormalidades Urogenitais/epidemiologia , Vitamina D/metabolismo , Adulto JovemRESUMO
BACKGROUND: Aromatase deficiency is a rare autosomal recessive disorder. 46,XY-affected patients often remain undiagnosed until late puberty. Only 2 pediatric cases have been reported. Data on pubertal development in affected males are scarce. AIM: To report the clinical phenotype and hormonal studies of an aromatase-deficient boy during the prepubertal and early pubertal period. RESULTS: The patient was the older brother of a 46,XX girl with aromatase deficiency. Molecular analysis revealed a previously reported homozygous mutation (Arg192Cys) in the CYP19A1 gene. Pubertal onset was at 9.8 years. At 11.3 years of age, signs of rapidly progressive puberty were seen. Laboratory tests revealed normal pubertal basal and GnRH-stimulated gonadotropin levels, normal Sertoli cell markers, and increased testosterone. The prepubertal lumbar spine bone mineral density (BMD) was normal but pubertal bone mineral accrual was incomplete, leading to osteopenia. CONCLUSION: Estrogen restraint on gonadotropin secretion has been demonstrated in animal and human models. Interestingly, our patient presented with accelerated puberty and apparently normal pituitary gonadal function. These findings suggest that aromatase activity may be required to define pubertal progression in boys. Estrogen deficiency due to aromatase deficiency is responsible for insufficient bone mineral accrual during puberty.
Assuntos
Aromatase/deficiência , Transtornos Cromossômicos , Estrogênios/deficiência , Homozigoto , Puberdade , Densidade Óssea/genética , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Criança , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/metabolismo , Transtornos Cromossômicos/patologia , Feminino , Humanos , Masculino , Coluna Vertebral/metabolismo , Coluna Vertebral/patologiaRESUMO
Chronic kidney disease mineral bone disorder (CKD-MBD) is common in end-stage renal disease and is associated with an increased risk of cardiovascular morbidity and mortality. Mainstays of treatment include decreasing serum phosphorus level toward the normal range with dietary interventions and phosphate binders and treating increased parathyroid hormone levels with activated vitamin D and/or calcimimetics. There is significant variation in serum levels of mineral metabolism markers, intestinal absorption of phosphorus, and therapeutic response among individual patients and subgroups of patients with end-stage renal disease. This variation may be partly explained by polymorphisms in genes associated with calcium and phosphorus homeostasis such as the calcium-sensing receptor gene, the vitamin D-binding receptor gene, and genes associated with vascular calcification. In this review, we discuss how personalized medicine may be used for the management of CKD-MBD and how it ultimately may lead to improved clinical outcomes. Although genetic variants may seem attractive targets to tailor CKD-MBD therapy, complete understanding of how these polymorphisms function and their clinical utility and applicability to personalized medicine need to be determined.
Assuntos
Doenças Ósseas Metabólicas/terapia , Cálcio/metabolismo , Hiperparatireoidismo Secundário/terapia , Falência Renal Crônica/terapia , Fósforo/metabolismo , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/metabolismo , Doenças Cardiovasculares , Humanos , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/metabolismo , Absorção Intestinal , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Hormônio Paratireóideo/metabolismo , Polimorfismo Genético , Medicina de Precisão , Receptores de Detecção de Cálcio/genética , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Vitamina D/metabolismo , Proteína de Ligação a Vitamina D/genéticaRESUMO
Osteoporosis is one of the major diseases that affects mostly postmenopausal women. Despite being a multifactorial disease, some genes have been shown to play an important role in osteoporosis. Bone mineral density (BMD) is still largely used to diagnose it, although many other biomarkers are used to better follow the disease onset. It has been shown that the apolipoprotein E (APOE) gene could be a biomarker for risk of fractures as well as to predict lower BMD in patients with osteoporosis. The human APOE gene encodes 3 protein isoforms called ApoE2, ApoE3, and ApoE4, resulting in 4 possible genotypes, because they are a product of a single nucleotide polymorphism found in this gene. So far, the APOE4 allele has been associated with low BMD in postmenopausal women and to incidence of bone breaking in older women. This study aimed to investigate the role of ApoE isoforms in a cohort of 413 postmenopausal Brazilian women. These patients were randomly recruited, clinically examined, and subjected to dual-energy X-ray absorptiometry to measure their BMD. Patients were further grouped as normal BMD (T-score < 0.5) or low BMD (T-score > 1.0, osteopenic or osteoporotic). Patients with osteopenia or osteoporosis were further genotyped for APOE alleles as well as tested for many serum bone turnover biomarkers. Our data showed that presence of the APOE3 allele was associated with both higher BMDs and higher serum concentrations of osteocalcin and alkaline phosphatase, biomarkers for bone formation. On the other hand, the APOE2 and APOE4 alleles were associated with lower BMD as well as higher levels of serum C-terminus collagen peptide and urinary deoxipyridinolines, biomarkers for bone resorption. However, these effects on lower BMD and bone resorption biomarkers observed in either APOE2 or APOE4 alleles were eliminated when patients' genotype carried the APOE3 allele. Codominance of the APOE3 allele was also associated with lesser cases of bone fractures in these patients within a 5-year follow-up. In conclusion, our data show that APOE4 may be associated with lower bone formation as well as increased risk of osteoporosis and bone fractures, whereas APOE3 seems to decrease lowering BMD in postmenopausal women, and its presence seemed to lower the incidence of bone breaking in patients with osteoporosis.
Assuntos
Apolipoproteínas E/genética , Densidade Óssea/genética , Osteoporose Pós-Menopausa/genética , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/genética , Absorciometria de Fóton , Idoso , Alelos , Biomarcadores/sangue , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/genética , Brasil/epidemiologia , Calcificação Fisiológica , Feminino , Genótipo , Humanos , Incidência , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/diagnóstico por imagem , Fraturas por Osteoporose/diagnóstico por imagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: Osteoporosis is a complex disease characterized principally by low bone mineral density (BMD), which is determined by an interaction of genetic, metabolic, and environmental factors. The aim of this study was to analyze the possible association among one polymorphism of LRP5 and three polymorphisms of TNFRSF11B as well as their haplotypes with BMD variations in Maya-Mestizo postmenopausal women. METHODS: We studied 583 postmenopausal women of Maya-Mestizo ethnic origin. A structured questionnaire for risk factors was applied and BMD was measured in lumbar spine (LS), total hip (TH), and femoral neck (FN) by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. One single-nucleotide polymorphism of LRP5 (rs3736228, p.A1330V) and three of TNFRSF11B (rs4355801, rs2073618, and rs6993813) were studied using real-time PCR allelic discrimination for genotyping. Differences between the means of the BMDs according to the genotype were analyzed with covariance. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r(2), and haplotype analysis of TNFRSF11B was conducted. RESULTS: The Val genotype of the rs3736228 (p.A1330V) of LRP5 was significantly associated with BMD variations at the LS, TH, and FN. None of the three polymorphisms of TNFRSF11B was associated with BMD variations. CONCLUSIONS: Our results show that p.A1330V was significantly associated with BMD variations at all three skeletal sites analyzed; the Val allele and the Val/Val genotype were those most frequently found in our population.
Assuntos
Densidade Óssea , Doenças Ósseas Metabólicas/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Osteoprotegerina/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Absorciometria de Fóton , Idoso , Alelos , Doenças Ósseas Metabólicas/epidemiologia , Feminino , Fêmur/fisiologia , Haplótipos , Humanos , Indígenas Norte-Americanos , Desequilíbrio de Ligação , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/sangue , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Vértebras Lombares/fisiologia , México/epidemiologia , Pessoa de Meia-Idade , Osteoporose/epidemiologia , Osteoporose/genética , Osteoprotegerina/sangue , Osteoprotegerina/metabolismo , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Osteoporosis is a complex health disease characterized by low bone mineral density (BMD), which is determined by an interaction of genetics with metabolic and environmental factors. The tumor necrosis factor receptor superfamily, member 11b (TNFRSF11B) gene, has been investigated in relation to BMD. Three polymorphisms in/nearby TNFRSF11B have been associated with BMD variations in some populations. The aim of this study was to investigate the possible association among three SNPs of TNFRSF11B and their haplotypes with the presence of BMD variations in postmenopausal Mexican Mestizo women. SUBJECTS AND METHODS: One thousand unrelated postmenopausal women of Mexican-Mestizo ethnic origin, who attended the outpatient clinic for routine, general medical evaluation, were invited and 750 women accepted to participate in the study. A structured questionnaire for risk factors was applied and BMD was measured in total hip and lumbar spine by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Three single-nucleotide polymorphisms in TNFRSF11B gene were studied: rs4355801, rs2073618, and rs6993813. Real-time PCR allelic discrimination was used for genotyping. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r(2), and haplotype analysis was conducted. RESULTS: Of the subjects, 31% had osteoporosis, 45.1% had osteopenia, and 23.9% had normal BMD. Genotype and allele distributions showed no significant differences; however, A-G-T haplotype was associated with variations in femoral neck BMD (P=0.022). CONCLUSIONS: In our study population, analysis of the haplotypes of TNFRSF11B is a better genetic marker for variations in BMD.
Assuntos
Densidade Óssea/genética , Doenças Ósseas Metabólicas/genética , Fêmur/metabolismo , Haplótipos , Osteoporose Pós-Menopausa/genética , Osteoprotegerina/genética , Polimorfismo de Nucleotídeo Único , Absorciometria de Fóton , Idoso , Alelos , Doenças Ósseas Metabólicas/epidemiologia , Feminino , Marcadores Genéticos , Humanos , Leucócitos , Desequilíbrio de Ligação , México/epidemiologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/epidemiologia , Pós-Menopausa , Prevalência , Valores de Referência , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
Clinical, biochemical and genetic analysis related to bone mineral density (BMD) were carried out in children born small for gestational age (SGA) that failed to achieve postnatal catch-up growth (CUG), SGA children that completed CUG and adequate for gestational age (AGA) children. Serum IGF-I, IGF-II, IGF binding protein-3 and acid-labile subunit were lower in the SGA-CUG children as compared with the other groups. Frequencies of polymorphic variants of vitamin D receptor, estrogen receptor and collagen genes were similar among groups. The genotype 194-192 of the IGF-I gene was higher in the SGA-CUG and 196-192 was higher in the SGA+CUG group. In the SGA-CUG group, the genotype SS of the COLIA1 gene was associated with lower BMD. Therefore, IGF system and COLIA1 polymorphism distinguish prepubertal SGA-CUG children from the SGA+CUG children of the same age. Furthermore, COLIA1 polymorphism could be useful to predict osteopenia in SGA-CUG children.
Assuntos
Densidade Óssea , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/genética , Desenvolvimento Infantil , Transtornos do Crescimento/sangue , Transtornos do Crescimento/genética , Recém-Nascido Pequeno para a Idade Gestacional , Polimorfismo Genético , Doenças Ósseas Metabólicas/etiologia , Proteínas de Transporte/sangue , Criança , Pré-Escolar , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Diagnóstico Precoce , Feminino , Estudos de Associação Genética , Glicoproteínas/sangue , Transtornos do Crescimento/fisiopatologia , Humanos , Recém-Nascido , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like II/análise , MasculinoRESUMO
BACKGROUND: Turner syndrome (TS) patients present low bone mineral density (BMD) and increased fracture risk, probably due to a genetic defect aggravated by hormonal deficiency. AIM: To study the relationship between vitamin D receptor (VDR) gene polymorphisms and BMD and bone parameters in TS patients. METHODS: DNA from 65 TS patients and 110 controls was amplified by PCR and digested with FokI, BsmI and ApaI restrictases. Lumbar and femoral BMD were determined by DEXA and serum intact parathyroid hormone, osteocalcin and beta-CrossLaps by electrochemiluminescence. RESULTS: Genotype distribution within the ApaI site was different in both groups: genotype Aa was more abundant in TS (63.8% vs. 41.3%; p<0.01), whereas AA predominated in controls (33.9% vs. 15.5%; p<0.01). Patients carrying genotype bb (BsmI) or ff (FokI) had lower BMD than those with other genotypes (p<0.01 and p<0.05, respectively). CONCLUSION: BsmI and FokI polymorphic sites of VDR could be genetic determinants of BMD in TS patients.