RESUMO
Tumor-induced osteomalacia (TIO), also known as "oncogenic osteomalacia", is a rare cause of osteomalacia. TIO often has an insidious onset characterized clinically by progressive muscle weakness and bone pain with fractures. The hallmark biochemical finding is a persistent low serum phosphorus concentration due to renal phosphate wasting. The vast majority of cases of TIO result from production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) by a histologically distinctive mesenchymal tumor, termed "phosphaturic mesenchymal tumor" (PMT). Circulating FGF23 induces internalization of renal sodium/phosphate co-transporters resulting in reduced proximal tubular phosphate reabsorption. FGF23 also inhibits production of 1α,25-dihydroxyvitamin D which is inappropriately low or normal in the context of hypophosphatemia. Diagnosis is often delayed owing to the rarity of the condition and an underappreciation for the role of phosphorus as a cause for the constellation of symptoms. Primary treatment for TIO is identification of the offending tumor and surgical removal. However, these tumors are notoriously difficult to find, precluding the opportunity for a curative surgery in many. In such cases, phosphate and calcitriol therapy is used to improve symptoms and heal the osteomalacia. Recently, molecular genetic studies have shown recurrent genetic events in PMT, including the novel fusions FN1-FGFR1 and less commonly FN1-FGF1. These fusion events are hypothesized to result in autocrine/paracrine signaling loops within the tumor, spurring tumorigenesis. This review will cover the clinical features, imaging characteristics, pathologic features, molecular genetic aspects, and therapy of PMT, with a brief discussion of other neoplasms that may cause TIO.
Assuntos
Endocrinologistas , Neoplasias de Tecido Conjuntivo/sangue , Neoplasias de Tecido Conjuntivo/diagnóstico por imagem , Fósforo/sangue , Papel do Médico , Calcitriol/uso terapêutico , Endocrinologistas/normas , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Neoplasias de Tecido Conjuntivo/tratamento farmacológico , Osteomalacia , Síndromes Paraneoplásicas , Fosfatos/uso terapêuticoRESUMO
UNLABELLED: Mutations of the CYP24A1 gene can result in hypercalcemia, hyerpercalciuria, and nephrolithiasis, but disease severity is variable. Clinical and biochemical phenotypes were correlated with gene sequence information in a family with two CYP24A1 mutations. A gene dose effect was apparent with monoallelic mutations demonstrating milder disease manifestations than biallelic mutations. INTRODUCTION: The objective was to examine the spectrum of clinical and biochemical phenotypes in a family with monoallelic and biallelic mutations of CYP24A1 after identification of the proband with two mutations of the CYP24A1 gene: (A) p.R396W and (B) E143del-Het. METHODS: Clinical and biochemical phenotypes were correlated with CYP24A1 sequence information in the proband and four siblings, a daughter, and two nieces of the proband. The subjects' medical histories were evaluated, and measurement of serum minerals, vitamin D metabolites, PTH, bone turnover markers, and urinary calcium and sequencing of the CYP24A1 gene were performed. RESULTS: The proband had nephrolithiasis, osteopenia, hypercalcemia, hypercalciuria, elevated serum 1,25(OH)2D, undetectable 24,25(OH)2D, and inappropriately low PTH concentrations. Two subjects with biallelic (A/B) mutations had nephrolithiasis, marked hypercalciuria (583 ± 127 mg/24 h, mean ± SD), compared with five subjects with monoallelic mutations (A or B) with a urine calcium of 265 ± 85 mg/24 h. Two subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia. Five subjects had high 1,25(OH)2D measurements, including three with monoallelic mutations. The 25OHD/24,25(OH)2D ratio, in subjects with biallelic mutations was 291 versus 19.8 in the subjects with monoallelic mutations. CONCLUSIONS: In this family, adults with CYP24A1 mutations a gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations which are not easily characterized through biochemical assessment.
Assuntos
Dosagem de Genes , Fenótipo , Vitamina D3 24-Hidroxilase/genética , Adulto , Idoso , Alelos , Doenças Ósseas Metabólicas/genética , Cálcio/urina , Saúde da Família , Feminino , Humanos , Hipercalcemia/genética , Hipercalciúria/genética , Masculino , Pessoa de Meia-Idade , Mutação , Nefrolitíase/genética , Linhagem , Vitamina D/sangueRESUMO
INTRODUCTION: Zoledronic acid is an intravenous bisphosphonate used to increase bone mineral density and reduce the risk of fractures. Its safety profile compares well with pamidronate in pediatric patients. We describe an acute, severe, life-threatening, inflammatory reaction in a child. METHODS: A 7-year-old boy with complex medical problems and chronic ventilator requirements was admitted to the pediatric intensive care unit (due to ventilator needs) for zoledronic acid infusion and subsequent monitoring. His history was significant for osteoporosis secondary to immobilization with multiple fractures since 2 years of age, hypoxic-ischemic encephalopathy, quadriplegic cerebral palsy, seizure disorder, ventilator dependence, and pulmonary hypertension. He had previously been treated with four cycles of pamidronate without adverse events. He received 0.013 mg/kg of zoledronic acid infused over 30 minutes. Beginning 3 hours after completion of the infusion, he developed progressive tachycardia, fever, hypotension requiring vasopressor infusion, and increasing oxygen requirements. Laboratory studies revealed leukopenia, thrombocytopenia, elevated C-reactive protein, abnormal coagulation profile, metabolic acidosis, and negative cultures. The following day, he developed moderate acute respiratory distress syndrome and pulmonary hemorrhage requiring higher ventilatory settings, and subsequently diarrhea and abdominal distension. Initial clinical resolution was noted from the third day onward, and he was discharged on the sixth day after zoledronate administration. RESULTS: Our pediatric patient demonstrated an acute, severe, life-threatening reaction to zoledronic acid requiring intensive cardiorespiratory support without an underlying pre-existing inflammatory disorder. CONCLUSION: Our case highlights the importance of careful monitoring of children following zoledronic acid therapy. We recommend inpatient observation after an initial infusion of zoledronic acid in medically complex children. Children and their parents should be thoroughly counseled on the potential risks of bisphosphonate treatment, which can sometimes be severe and life threatening.
Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Imidazóis/efeitos adversos , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Criança , Humanos , Masculino , Osteoporose/tratamento farmacológico , Ácido ZoledrônicoRESUMO
RATIONALE AND OBJECTIVES: The authors have addressed the ability of magnetic resonance (MR) imaging to resolve incremental thinning of articular cartilage by assessment of three-dimensional (3-D) and two-dimensional (2-D) representations. METHODS: Using a porcine knee model, sequential cartilage shavings were characterized using a 3-D fat suppressed spoiled gradient-echo (SPGR) MR imaging protocol that provided good contrast between high-signal articular cartilage and lower signal surrounding tissues. Lesion dimensional measurements were made on both MR images and 3-D computerized reconstructions. Volumes of cartilage removed were approximately 0.06 mL. RESULTS: Incremental articular cartilage thinning typically was apparent on 3-D reconstructed images. Three-dimensional articular cartilage reconstructions were effective in depicting location and orientation of shaved cartilage regions. Average percent error associated with length and with measurements based on 2-D MR images was approximately 19% for observer 1 and 33% for observer 2 when compared with direct measurements of the shaved cartilage. Average percent error of thickness measurements based on 2-D MR was approximately 21% for observer 1 and 37% for observer 2. Overall average errors associated with length, width, and thickness measurements were approximately 25%. CONCLUSIONS: Incremental thinning of articular cartilage can be tracked qualitatively and quantitatively using 3-D computerized reconstructions and 2-D MR images. Errors associated with the quantitative measurements can be attributed to limitations of measurement methods and intrinsic limitation of MR resolution.
Assuntos
Cartilagem Articular/patologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Animais , Modelos Animais de Doenças , Articulação do Joelho/patologia , Variações Dependentes do Observador , Osteoartrite/diagnóstico , Sensibilidade e Especificidade , SuínosRESUMO
CONTEXT: Surgically managed endocrinopathies are rare in children. Most surgeons have limited experience in this field. Herein we report our operative experience with pediatric patients, performed over two decades by high-volume endocrine surgeons. SETTING: The study was conducted at the Mayo Clinic (a tertiary referral center). PATIENTS: Patients were <19 years old and underwent an endocrine operation (1993-2012). MAIN OUTCOME MEASURES: Demographics, surgical procedure, diagnoses, morbidity, and mortality were retrospectively reviewed. RESULTS: A total of 241 primary cases included 177 thyroid procedures, 13 neck dissections, 24 parathyroidectomies, 14 adrenalectomies, 7 paragangliomas, and 6 pancreatic procedures. Average age of patients was 14.2 years. There were 133 total thyroidectomies and 40 hemithyroidectomies. Fifty-three cases underwent a central or lateral neck dissection. Six-month follow-up was available for 98 total thyroidectomy patients. There were four cases of permanent hypoparathyroidism (4%) and no permanent recurrent laryngeal nerve (RLN) paralyses. Sequelae of neck dissections included temporary RLN neurapraxia and Horner's syndrome. Parathyroidectomy was performed on 24 patients: 20 with primary hyperparathyroidism (HPT), three with tertiary HPT, and one with familial hypocalciuric hypocalcemia. Three patients (16%) had recurrent HPT, all with multiglandular disease. One patient had temporary RLN neurapraxia. We performed seven bilateral and seven unilateral adrenalectomies; eight were laparoscopic. Indications included pheochromocytoma, Cushing's syndrome, adrenocortical carcinoma, congenital adrenal hyperplasia, and ganglioneuroma. One death was due to adrenocortical carcinoma. Five paraganglioma patients had succinate dehydrogenase subunit B mutations, and one recurred. Six patients with insulinoma underwent enucleation (n = 5) or distal pancreatectomy (n = 1). A single postoperative abscess was managed nonoperatively. CONCLUSION: Pediatric endocrine procedures are uncommon but can be safely performed with complication rates comparable to those of the adult population. It is imperative that these operations be performed by high-volume surgeons.