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1.
Bone Rep ; 14: 100744, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33490314

RESUMO

Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.

2.
Bone ; 142: 115664, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32987199

RESUMO

BACKGROUND: Hypophosphatasia (HPP) is the rare, inherited, metabolic bone disease characterized by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) leading to excess extracellular inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP). Asfotase alfa is the human recombinant enzyme-replacement therapy that replaces deficient TNSALP. However, there is limited information concerning the appropriate dose of asfotase alfa for adult patients with pediatric-onset HPP. Thus, we evaluated the pharmacodynamics and safety/tolerability of different doses of asfotase alfa in such patients. METHODS: This 13-week, Phase 2a, open-label study enrolled adults (aged ≥18 years) with pediatric-onset HPP. They were randomized 1:1:1 to receive a single subcutaneous dose of asfotase alfa (0.5, 2.0, or 3.0 mg/kg) at Week 1, then 3 times per week (ie, 1.5, 6.0, or 9.0 mg/kg/wk) starting at Week 3 for 7 weeks. Key outcome measures included change from Baseline to before the third dose during Week 9 (trough) in plasma PPi (primary outcome measure) and PLP (secondary outcome measure). RESULTS: Twenty-seven adults received asfotase alfa 0.5 (n = 8), 2.0 (n = 10), and 3.0 (n = 9) mg/kg; all completed the study. Median (range) age was 45 (18-77) years; most patients were white (96%) and female (59%). Median plasma PPi and PLP concentrations decreased from Baseline to Week 9 in all 3 cohorts. Differences in least squares mean (LSM) changes in PPi were significant with 2.0 mg/kg (p = 0.0008) and 3.0 mg/kg (p < 0.0001) vs. 0.5 mg/kg. Differences in LSM changes in PLP were also significant for 2.0 mg/kg (p = 0.0239) and 3.0 mg/kg (p = 0.0128) vs. 0.5 mg/kg. Injection site reactions were the most frequent treatment-emergent adverse event (78%), showing increasing frequency with increasing dose. CONCLUSIONS: Adults with pediatric-onset HPP receiving asfotase alfa at 6.0 mg/kg/wk (the recommended dose) or 9.0 mg/kg/wk had greater reductions in circulating PPi and PLP concentrations compared with a lower dose of 1.5 mg/kg/wk. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02797821.


Assuntos
Fosfatase Alcalina , Hipofosfatasia , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão
3.
Mol Genet Metab Rep ; 25: 100661, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33101980

RESUMO

Hypophosphatasia (HPP) is an inherited metabolic condition caused by pathogenic mutations in the ALPL gene. This leads to deficiency of tissue non-specific alkaline phosphatase (TNSALP), resulting in decreased mineralization of the bones and/or teeth and multi-systemic complications. Inheritance may be autosomal dominant or recessive, and the phenotypic spectrum, including age of onset, varies widely. We present four families demonstrating both modes of inheritance of HPP and phenotypic variability and discuss the resultant challenges in disease management, genetic counseling, and risk assessment. Failure to consider different modes of inheritance in a family with HPP may lead to an inaccurate risk assessment upon which medical and reproductive decisions may be made. We highlight the essential role of high-quality genetic counseling and meaningful biochemical and molecular testing strategies in the evaluation and management of families with HPP.

4.
Case Rep Endocrinol ; 2020: 1047327, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32695531

RESUMO

We describe a case of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) in a 32-year-old female with short stature, chronic pathologic genu valgum deformity, and knee pain who was referred to endocrinology clinic after previous inconclusive workups. We present imaging spanning 10 years of untreated disease. Biochemical studies showed hypophosphatemia with undetectable fibroblast growth factor 23 (FGF23.) Renal ultrasound revealed bilateral medullary nephrocalcinosis despite no apparent hypercalciuria. Due to concern for HHRH, genetic testing was performed that determined this patient to be homozygous in the SLC34A3 gene for a previously described missense variant (c.1402C > T, p.Arg468Trp). There was no known family history of rickets. A bone biopsy with metabolic studies was performed for diagnostic and prognostic reasons. The histopathological findings along with tetracycline uptake studies were consistent with a diagnosis of HHRH. Treatment with phosphorous supplementation and surgical correction of her valgum deformity resulted in resolution of pain, but no change in bone histomorphometry.

5.
Radiol Case Rep ; 15(5): 492-497, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32140194

RESUMO

Tumor-induced osteomalacia (TIO) is a rare disease in which patients suffer from fractures and progressive disabling bone pain and muscle weakness. TIO is caused by the hypersecretion of Fibroblast Growth Factor 23 (FGF23) from rare neoplasms of mesenchymal origin. This case report describes a 29-year-old male with 2 years of low back/hip pain, gait changes, proximal muscle weakness, and multiple stress fractures. Bone densitometry was remarkable for severe osteoporosis, hypophosphatemia was seen on routine labs, and advanced labs demonstrated an "inappropriately normal" FGF23 level. A 68Ga-DOTATATE scan and MRI showed a 1.3 × 1.1 × 1.0 cm intracranial mass. The patient underwent tumor resection by Neurosurgery. Shortly after, laboratory levels normalized, and the patient's symptoms improved drastically. This case exemplifies the notion that TIO can be caused by FGF23 levels within normal limits, the role of 68-Ga DOTATATE imaging for establishing a diagnosis, and that these tumors can arise anywhere-even intracranially. We also review current surgical and nonsurgical treatment options, as well as emerging novel therapeutics.

6.
Radiol Case Rep ; 15(4): 344-348, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32153690

RESUMO

Chronic osteomyelitis can be difficult to diagnose given its similar radiographic appearance to other lesions. This case report describes a 48-year-old woman, who presented with left thigh pain and on radiography a large disorganized sclerotic lesion involving nearly the entire femoral diaphysis, concerning for Paget disease or malignancy. Biopsy suggested chronic osteomyelitis but did not identify a causative organism. Treatment with antibiotics led to resolution of pain and improvement of biochemical markers. This case exemplifies the role of radiographic imaging in the diagnosis of chronic osteomyelitis and the possible utility of antibiotics for culture-negative chronic osteomyelitis. We review imaging modalities for the diagnosis of chronic osteomyelitis and Paget disease.

7.
Appl Clin Inform ; 11(1): 160-165, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32102108

RESUMO

BACKGROUND: Despite guideline recommendations, vitamin D testing has increased substantially. Clinical decision support (CDS) presents an opportunity to reduce inappropriate laboratory testing. OBJECTIVES AND METHODS: To reduce inappropriate testing of vitamin D at the Vanderbilt University Medical Center, a CDS assigned providers to receive or not receive an electronic alert each time a 25-hydroxyvitamin D assay was ordered for an adult patient unless the order was associated with a diagnosis in the patient's chart for which vitamin D testing is recommended. The CDS ran for 80 days, collecting data on number of tests, provider information, and basic patient demographics. RESULTS: During the 80 days, providers placed 12,368 orders for 25-hydroxyvitamin D. The intervention group ordered a vitamin D assay and received the alert for potentially inappropriate testing 2,181 times and completed the 25-hydroxyvitamin D order in 89.9% of encounters, while the control group ordered a vitamin D assay (without receiving an alert) 2,032 times and completed the order in 98.1% of encounters, for an absolute reduction of testing of 8% (p < 0.001). CONCLUSION: This CDS reduced vitamin D ordering by utilizing a soft-stop approach. At a charge of $179.00 per test and a cost to the laboratory of $4.20 per test, each display of the alert led to an average reduction of $14.70 in charges and of $0.34 in spending by the laboratory (the savings/alert ratio). By describing the effectiveness of an electronic alert in terms of the savings/alert ratio, the impact of this intervention can be better appreciated and compared with other interventions.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Vitamina D/análogos & derivados , Humanos , Guias de Prática Clínica como Assunto , Vitamina D/sangue
8.
Clin Spine Surg ; 32(5): E252-E257, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30730424

RESUMO

STUDY DESIGN: Retrospective Cohort. OBJECTIVE: Establish 1-year patient-reported outcomes after spine surgery for symptomatic pseudarthrosis compared with other indications. In the subgroup of pseudarthrosis patients, describe preexisting metabolic and endocrine-related disorders, and identify any new diagnoses or treatments initiated by an endocrine specialist. SUMMARY OF BACKGROUND: Despite surgical advances in recent decades, pseudarthrosis remains among the most common complications and indications for revision after fusion spine surgery. A better understanding of the outcomes after revision surgery for pseudarthrosis and risk factors for pseudarthrosis are needed. METHODS: Using data from our institutional spine registry, we retrospectively reviewed patients undergoing elective spine surgery between October 2010 and November 2016. Patients were stratified by surgical indication (pseudarthrosis vs. not pseudarthrosis), and 1-year outcomes for satisfaction, disability, quality of life, and pain were compared. In a descriptive subgroup analysis of pseudarthrosis patients, we identified preexisting endocrine-related disorders, frequency of endocrinology referral, and any new diagnoses and treatments initiated through the referral. RESULTS: Of 2721 patients included, 169 patients underwent surgery for pseudarthrosis. No significant difference was found in 1-year satisfaction between pseudarthrosis and nonpseudarthrosis groups (77.5% vs. 83.6%, respectively). A preexisting endocrine-related disorder was identified in 82% of pseudarthrosis patients. Endocrinology referral resulted in a new diagnosis or treatment modification in 58 of 59 patients referred. The most common diagnoses identified included osteoporosis, vitamin D deficiency, diabetes, hyperlipidemia, sex-hormone deficiency, and hypothyroidism. The most common treatments initiated through endocrinology were anabolic agents (teriparatide and abaloparatide), calcium, and vitamin D supplementation. CONCLUSIONS: Patients undergoing revision spine surgery for pseudarthrosis had similar 1-year satisfaction rates to other surgical indications. In conjunction with a bone metabolic specialist, our descriptive analysis of endocrine-related disorders among patients with a pseudarthrosis can guide protocols for workup, indications for endocrine referral, and guide prospective studies in this field.


Assuntos
Doenças do Sistema Endócrino/complicações , Doenças Metabólicas/complicações , Pseudoartrose/complicações , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Pseudoartrose/cirurgia
9.
J Clin Endocrinol Metab ; 103(6): 2234-2243, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659871

RESUMO

Context: Mutations in alkaline phosphatase (AlkP), liver/bone/kidney (ALPL), which encodes tissue-nonspecific isozyme AlkP, cause hypophosphatasia (HPP). HPP is suspected by a low-serum AlkP. We hypothesized that some patients with bone or dental disease have undiagnosed HPP, caused by ALPL variants. Objective: Our objective was to discover the prevalence of these gene variants in the Vanderbilt University DNA Biobank (BioVU) and to assess phenotypic associations. Design: We identified subjects in BioVU, a repository of DNA, that had at least one of three known, rare HPP disease-causing variants in ALPL: rs199669988, rs121918007, and/or rs121918002. To evaluate for phenotypic associations, we conducted a sequential phenome-wide association study of ALPL variants and then performed a de-identified manual record review to refine the phenotype. Results: Out of 25,822 genotyped individuals, we identified 52 women and 53 men with HPP disease-causing variants in ALPL, 7/1000. None had a clinical diagnosis of HPP. For patients with ALPL variants, the average serum AlkP levels were in the lower range of normal or lower. Forty percent of men and 62% of women had documented bone and/or dental disease, compatible with the diagnosis of HPP. Forty percent of the female patients had ovarian pathology or other gynecological abnormalities compared with 15% seen in controls. Conclusions: Variants in the ALPL gene cause bone and dental disease in patients with and without the standard biomarker, low plasma AlkP. ALPL gene variants are more prevalent than currently reported and underdiagnosed. Gynecologic disease appears to be associated with HPP-causing variants in ALPL.


Assuntos
Fosfatase Alcalina/genética , Hipofosfatasia/genética , Doenças Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Doenças Uterinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo
10.
J Dermatol ; 40(8): 649-52, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23663061

RESUMO

Calciphylaxis is a metastatic calcification-induced vasculopathy that results in the occlusion of small blood vessels. Although calciphylaxis is normally associated with end-stage renal disease, calciphylaxis from non-uremic origin occurs as well. While the number of reports continues to increase, a standard treatment for non-uremic calciphylaxis has yet to be established. Sodium thiosulfate (STS), which has been proven to be effective in the treatment of uremic calciphylaxis, shows promise; however, reports of its use in non-uremic cases are limited. We describe a case of non-uremic calciphylaxis in a patient with normal renal and parathyroid function who had complete resolution of disease after treatment with STS, and we review similar cases in the published work. Based on the successful outcomes detailed in this case series, STS appears to be an effective therapy for non-uremic calciphylaxis.


Assuntos
Antídotos/uso terapêutico , Calciofilaxia/tratamento farmacológico , Tiossulfatos/uso terapêutico , Adulto , Feminino , Humanos
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