Thoracic phosphaturic mesenchymal tumors causing oncogenic osteomalacia.

Oncogenic osteomalacia is a rare paraneoplastic syndrome induced by mesenchymal tumors. Just over 100 cases have been reported for this rare disorder, and only seven instances were caused by phosphaturic mesenchymal tumors of the spine. The authors present an illustrative case of a 61-year-old woman with oncogenic osteomalacia induced by a tumor of the spine, and review the literature describing the clinical presentation, surgical treatment, and follow-up of this syndrome.

Diagnosis of phosphaturic mesenchymal tumor (mixed connective tissue type) by cytopathology.

Oncogenic osteomalacia (OO) is a rare paraneoplastic condition in which a bone or soft tissue tumor induces biochemical and clinical signs and symptoms of osteomalacia (or rickets) most often by the production of the phosphaturic protein, fibroblast growth factor-23. Phosphaturic mesenchymal tumor, mixed connective tissue type (PMTMCT) is a rare, histologically distinct tumor that represents the most common cause of OO. As the clinical diagnosis of OO is typically suspected on the basis of clinical and biochemical features and the presence of a bone or soft tissue tumor, cytologic examination might potentially provide the necessary pathologic confirmation of OO. In this case of a 46-year-old female with clinical stigmata of OO and a right distal humeral mass, we report that the fine-needle aspiration findings of short, cytologically bland spindled cells embedded in a fine, fibrillary stromal-rich matrix and the presence of osteoclast-type giant cells associated with the stromal matrix provide strong pathological evidence for PMTMCT and assist in pathologically confirming the clinical impression of OO, thus alleviating the need for a more invasive diagnostic surgical procedure.

Selective venous catheterization for the localization of phosphaturic mesenchymal tumors.

Tumor-induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D(3) metabolism and is caused by fibroblast growth factor 23 (FGF-23)-producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF-23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF-23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47-0.99] and a specificity of 0.71 (95% CI 0.29-0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies.

[Oncogenic osteomalacia due to phosphaturic mesenchymal tumour in infratemporal fossa]. / Osteomalacia oncogénica por tumor mesenquimal fosfatúrico en fosa infratemporal.

Oncogenic osteomalacia is an uncommon syndrome characterized by phosphaturic tumours that produce mineral metabolism abnormalities. Head and neck is the second most frequent location of these tumours. We describe a case of a phosphaturic mesenchymal tumour in the infratemporal fossa that caused oncogenic osteomalacia, resolved by means of surgical excision.

Clinical manifestations and etiology of renal stones in children less than 14 years age.

Urolithiasis is one of the commonest problems in pediatric nephrology. Prevalence of urolithiasis in pediatric patients is increasing. The purpose was to properly diagnose and treat with the special attention to the risk factors. This study is case-series and was performed on 100 pediatric patients for evaluation of clinical manifestation and etiology of renal stone in Qom. Hundred Children, fewer than 14 years old with mean age of 3.32 years, were included (54% male). Etiology of urolithiasis in 5% was unclear. Metabolic disorders found in patients were mainly: Hypocitraturia in 54, hyperoxaluria in 14, hyperuricosuria in 25, cystinuria in 6, hypercalciuria in 28 and phosphaturia in 8 patients. The main clinical presentation was fever, pain, irritability, dysuria and hematuria. Family history of urolithiasis was found in 23% of patients and 54% presented with urinary tract infection (UTI). We conclude that majority of patients were symptomatic and hypocitraturia was the commenest risk factor among others.

Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.

An autosomal recessive form of hypophosphatemia (ARHP) was recently shown to be caused by homozygous mutations in DMP1, the gene encoding dentin matrix protein-1 (DMP-1), a non-collagenous bone matrix protein with an important role in the development and mineralization of bone and teeth. Here, we describe a previously not reported consanguineous ARHP kindred in which the three affected individuals carry a novel homozygous DMP-1 mutation. The index case presented at the age of 3 years with bowing of his legs and showed hypophosphatemia due to insufficient renal phosphate retention. Serum alkaline phosphatase activity was elevated, with initially normal PTH. FGF23 was inappropriately normal at an older age while being treated with oral phosphate and 1,25(OH)(2)D. Similar clinical and biochemical findings, except for elevated FGF23 levels, were present in his 16-month-old brother and his 12.5-year-old female cousin; the parents of the three affected children are first-degree cousins. Nucleotide sequence analysis was performed on PCR-amplified exons encoding DMP-1 and flanking intronic regions. A novel homozygous frame-shift mutation (c.485Tdel; p.Glu163ArgfsX53) in exon 6 resulting in a premature stop codon was identified in all effected individuals. The parents and available unaffected siblings were heterozygous for c.485Tdel. Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent and deciduous teeth displayed enlarged pulp chambers. The identified genetic mutation underscores the importance of DMP-1 mutations in the pathogenesis of ARHP. Furthermore, DMP-1 mutations appear to contribute, through yet unknown mechanisms, to tooth development.

Oncogenous osteomalacia.

Oncogenous osteomalacia is a rare paraneoplastic renal phosphaturic condition, often associated with highly vascular benign mesenchymal tumors. We report a case of a 48-year-old male who presented with debilitating osteomalacia unresponsive to standard therapy. Two years later, sinonasal hemangiopericytoma was diagnosed; the patient underwent complete surgical excision with rapid symptomatic improvement.

Defective O-glycosylation due to a novel homozygous S129P mutation is associated with lack of fibroblast growth factor 23 secretion and tumoral calcinosis.

BACKGROUND: Homozygous mutations in fibroblast growth factor (FGF23) have recently been described as the genetic cause of one form of hyperphosphatemic tumoral calcinosis (HFTC). However, it remained unclear to date how these mutations lead to loss of biologically active FGF23 in the circulation. METHODS: We here report a novel homozygous mutation, c.385T>C in FGF23 exon 2, which changes codon 129 from serine to proline (S129P) in a previously described individual affected by HFTC. The S129P mutation as well as two known FGF23 mutations, S71G and S129F, were introduced into an expression vector encoding wild-type (wt) human (h) FGF23 to yield [P129]hFGF23, [F129]hFGF23, and [G71]hFGF23; whole lysates, glycoprotein fractions, and conditioned media from HEK293 and COS-7 cells expressing these constructs were subjected to Western blot analysis using affinity-purified goat anti-hFGF23(51-69) and anti-hFGF23(206-222) antibodies. RESULTS: We detected 25- and 32-kDa protein species in total lysates of HEK293 cells expressing wt-hFGF23. The 32-kDa band, representing O-glycosylated hFGF23, was not detectable in the glycoprotein fraction of lysates from HEK293 cells expressing [P129]hFGF23, and in comparison with wt-FGF23 only small amounts of [P129]hFGF23 were secreted into the medium. Similar results were obtained for cells expressing [G71]hFGF23 and [F129]hFGF23. CONCLUSION: Our data for the first time directly show that FGF23 mutations associated with HFTC impair O-glycosylation in vitro resulting in poor secretion of the mutant hormone thereby explaining the characteristic hyperphosphatemic phenotype of homozygous carriers in vivo.

A familial disorder with low bone density and renal phosphate wasting.

Hereditary forms of renal phosphate wasting have been studied thoroughly in the past years. X-linked Hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and autosomal recessive hypophosphatemic rickets (ARHR) are known genetic disorders in which a disturbance of phosphatonins is a causative factor in the pathogenesis. We describe a comparable but yet undescribed disorder in a family in which a 53 year old man presented with a spontaneous fracture after suffering for years with severe fatigue and musculoskeletal pains. A low serum phosphate was discovered. The two subsequent generations of this family developed the same symptoms but at an earlier age. Almost all family members have been investigated and the majority appears to have low bone density and/or renal phosphate wasting and/or low serum phosphate. Remarkably no rickets was found. No elevation of FGF23 or mutations in the gene encoding FGF23 were found. We believe this is a new familial disorder of bone metabolism and phosphate homeostasis in which a disturbance of bone modulators may play a central role.

Clinical and metabolic features of urolithiasis and microlithiasis in children.

We evaluated the clinical, radiological and metabolic features of 162 children with urolithiasis or microlithiasis who had been referred to our pediatric nephrology clinics between 1998 and 2008 with suspected urolithiasis. The medical histories of these children (78 girls, 84 boys), who ranged in age from 2 months to 16 years (mean age 5.59 +/- 0.35 years), were reviewed retrospectively for clinical and metabolic features of urinary tract calculi. Urinary tract infections (UTI) were present in 45.9% of the cases. The most common presenting symptoms were flank pain or restlessness (25.3%) and hematuria (21.6%), followed by UTI (16%), whereas 23.5% of the cases were detected incidentally during evaluation for other medical conditions. Other symptoms at presentation included dysuria, passing stones, penile edema, enuresis, vomiting and anorexia. Urine analysis revealed metabolic abnormalities in 87% of the cases, including hypercalciuria (33.8%), hypocitraturia (33.1%), hyperoxaluria (26.5%), hyperuricosuria (25.4%), hypocitraturia + hypercalciuria (21.1%), hyperphosphaturia (20.8%) and cystinuria (5.7%). Almost 50% of the patients had a positive family history for urolithiasis. The most frequently involved site was in the kidneys (86%). Ureters and bladder were involved in 12 and 2% of the cases, respectively. A family history of urolithiasis, presenting symptoms and underlying metabolic abnormalities were similar for microlithiasis and the patients with larger stones. However, in our study population, microlithiasis was mainly a disease of young infants, with a greater chance for remission and often not associated with structural changes. The presenting symptoms of urolithiasis show a wide spectrum, so that a high index of suspicion is important for early detection. A metabolic abnormality can be identified in 87% of cases of urolithiasis. Detection of microlithiasis may explain a number of symptoms, thus reducing invasive diagnostic procedures and allowing early recognition of metabolic abnormalities. These results draw attention to the importance of screening for UTIs in patients with urolithiasis.

Oncogenic osteomalacia, a rare paraneoplastic syndrome due to phosphate wasting--a case report and review of the literature.

An appropriate phosphate homeostasis is absolutely required for correct bone mineralization and remodeling, for diverse signaling pathways as well as cell membrane formation. Its disequilibrium results in serious complications like hypophosphatemia and excessively reduced fractional tubule phosphate reabsorption (TRP). A rare cause of such a disturbed phosphate balance is tumor-induced osteomalacia (TIO)--a phosphate wasting disorder sometimes associated with certain mesenchymal tumors. These primitive tumors secrete so-called phosphatonins--recently identified factors involved in the regulation of phosphate homeostasis such as the secreted frizzled related protein 4 (sFRP-4), the fibroblast growth factors 7 and 23 (FGF-7/-23), or the matrix extracellular phosphoglycoprotein (MEPE). Progressive muscular weakness and spontaneous bone fractures caused by inadequate osteoid mineralization are the characteristic clinical symptoms, which completely resolve after tumor resection. Here we report a new case of TIO caused by tumor secreted FGF-23 and review the literature to facilitate the correct diagnosis of this rare disorder.

Adverse renal and metabolic effects associated with oral sodium phosphate bowel preparation.

Colorectal cancer can be prevented by the removal of adenomatous polyps during screening colonoscopy, but adequate bowel preparation is required. Oral sodium phosphate (OSP), an effective bowel purgative, is available over the counter and requires a substantially lower volume than polyethylene glycol-based preparative agents. Accumulating reports implicate OSP in electrolyte disturbances as well as acute kidney injury (AKI) in a syndrome termed phosphate nephropathy (a form of nephrocalcinosis). Despite published case reports and case series, the actual incidence, risk factors, and natural history of phosphate nephropathy remain largely undefined. Several recent observational studies have provided new information on these important issues while supporting a link between OSP and acute phosphate nephropathy as well as the development of chronic kidney disease in elderly patients, many of whom had a normal serum creatinine at the time of OSP ingestion. This review summarizes current knowledge about the renal complications of OSP, risk factors for its development, and the pathophysiology of acute and chronic kidney damage in nephrocalcinosis.

Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.

BACKGROUND: Generalized arterial calcification of infancy has been reported to be frequently lethal, and the efficiency of any therapy, including bisphosphonates, is unknown. A phosphate-poor diet markedly increases survival of NPP1 null mice, a model of generalized arterial calcification of infancy. METHODS AND RESULTS: We performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients survived the critical period of infancy. In all 8 surviving patients tested, hypophosphatemia due to reduced renal tubular phosphate reabsorption developed during childhood. Eleven of 17 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients survived beyond infancy. Forty different homozygous or compound heterozygous mutations, including 16 novel mutations in ENPP1, were found in 41 (75%) of the 55 patients. Twenty-nine (71%) of these 41 patients died in infancy (median, 30 days). Seven of the 14 (50%) patients without ENPP1 mutations died in infancy (median, 9 days). When present on both alleles, the mutation p.P305T was associated with death in infancy in all 5 cases; otherwise, no clear genotype-phenotype correlation was seen. CONCLUSION: ENPP1 coding region mutations are associated with generalized arterial calcification of infancy in approximately 75% of subjects. Except for the p.P305T mutation, which was universally lethal when present on both alleles, the identified ENPP1 mutations per se have no discernable effect on survival. However, survival seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment.

[The diagnosis of familial hypomagnesemia with hypercalciuria and nephrocalcinosis in a girl with acute lymphoblastic leukemia--case report]. / Rozpoznanie rodzinnej hipomagnezemii z hiperkalciuria i nefrokalcynoza u dziewczynki chorej na ostra bialaczke limfoblastyczna--opis przypadku.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubulopathy resulting from mutation in the gene encoding paracelin 1. The main symptoms of FHHNC include excessive urinary calcium and magnesium excretion, nephrocalcinosis, and chronic renal failure. We present 16-year old girl in whom symptoms of FHHNC were accidentally recognized during therapy of acute lymphoblastic leukemia. In our patient, some symptoms of FHHNC were initially taken for the adverse effects of cytostatic therapy that delayed an adequate diagnosis. To the best of our knowledge, this is the first report of FHHNC associated with acute lymphoblastic leukemia. However, in our opinion this association is accidental.

Deformity correction by external fixation and/or intramedullary nailing in hypophosphatemic rickets.

BACKGROUND: There are many modalities of treatment for complex lower extremity deformity in hypophosphatemic rickets. We evaluated the outcomes of deformity correction using an external fixation and/or intramedullary nailing in hypophosphatemic rickets. PATIENTS AND METHODS: 55 segmental deformities (20 femora, 35 tibiae) from 20 patients were examined retrospectively. There were 9 children and 11 adults. Distraction osteogenesis was used in 28 segments and acute deformity correction in 27. External fixation was applied in 24 segments, intramedullary nailing in 6, and external fixation and intramedullary nailing in 25. RESULTS: There were 18 major and 13 minor complications in 26 of 28 segments with distraction osteogenesis, and 13 major and 10 minor complications in 19 of 27 segments with acute correction. Recurrent deformity or refracture occurred in 10 of 21 segments with distraction osteogenesis by external fixation only, 4 of 6 with acute correction by intramedullary nailing, and 1 of 25 with distraction osteogenesis or acute correction by external fixation and intramedullary nailing. Nail-related complications occurred in 3 of 6 with intramedullary nailing and 2 of 25 with external fixation and intramedullary nailing. INTERPRETATION: External fixation and intramedullary nailing can be recommended to prevent complications during or after deformity correction in hypophosphatemic rickets.