Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

The differential effect of modern intravenous iron on fibroblast growth factor 23 and phosphate in non-dialysis dependent CKD - the exploratory randomized controlled double-blind ExplorIRON-CKD study.

BACKGROUND: Intravenous iron is commonly used in patients with non-dialysis-dependent chronic kidney disease (CKD). Modern intravenous iron compounds (e.g. ferric derisomaltose (FDI), ferric carboxymaltose (FCM)) are increasingly utilized with similar efficacy. A differential effect in terms of hypophosphatemia has been noted following administration of FCM, which may be related to fibroblast growth factor 23 (FGF23). This study was designed to examine the comparative effects of FDI and FCM on FGF23, phosphate and other markers of bone turnover. METHODS: The single-center double-blind randomized controlled trial "Iron and Phosphaturia - ExplorIRON-CKD" primarily assessed the effects of FCM and FDI on intact FGF23 and phosphate, whilst also studying the impact on vitamin D, parathyroid hormone and phosphaturia. Bone markers including alkaline phosphatase, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide and carboxy-terminal collagen cross-linked telopeptide were monitored. Non-dialysis-dependent CKD patients (stage 3a-5) with iron deficiency with/without anemia (serum ferritin < 200 µg/L or transferrin saturation = 20% and serum ferritin 200-299 µg/L) were randomized to receive FDI or FCM in a 1:1 ratio. At baseline 1000 mg of intravenous iron was administered followed by 500-1000 mg at 1 month to achieve replenishment. Measurements were performed at baseline, 1-2 days following iron administration, 2 weeks, 1 month (second iron administration), 1-2 days following second administration, 2 months and 3 months following initial infusion. RESULTS: Twenty-six patients participated in the trial; 14 randomized to FDI and 12 to FCM. Intact FGF23 increased following administration of iron, and the increase was significantly higher with FCM compared to FDI (Baseline to 1-2 days following 1st administration: FDI: 3.0 (IQR: - 15.1 - 13.8) % vs. FCM: 146.1 (IQR: 108.1-203.1) %; p < 0.001 and Baseline to 1-2 days following 2nd administration: FDI: 3.2 (IQR: - 3.5 - 25.4) % vs. FCM: 235.1 (138.5-434.6) %; p = 0.001). Phosphate levels decreased in the FCM group, causing a significant difference versus FDI 2 weeks following administration of the first dose. A significantly greater decrease in 1,25 (OH)2 Vitamin D was noted with FCM. Several markers of bone turnover significantly changed following administration of FCM but not FDI. CONCLUSIONS: The study suggests a differential effect on FGF23 following administration of FCM compared to FDI in non-dialysis-dependent CKD patients, similar to other patient groups. This may lead to changes consistent with hypovitaminosis D and alterations in bone turnover with potential clinical consequences. Further definitive studies are required to understand these differences of intravenous iron compounds. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) number: 2019-004370-26 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004370-26/GB ) (First date of trial registration: 03/12/2019).

Use of Teriparatide in Hyperphosphatemic Familial Tumor Calcinosis: Evaluating the Interaction Between FGF23 and PTH on the Phosphaturic Effect.

Hyperphosphatemic familial tumor calcinosis (HFTC) is a rare disease characterized by hyperphosphatemia and calcium and phosphorus crystal deposition. It occurs due to the loss of function of FGF23. Herein, we report a case of a 50-year-old woman diagnosed with HFTC (homozygous variant in the GALNT3 gene, c.803_804 C insertion) with a history of ectopic calcifications in the past 30 years. Laboratory tests on admission were as follows: phosphate (P) 7.1 mg/dL (Normal range (NR) 2.5-4.5 mg/dL), FGF23 c-terminal 2050 RU/mL (NR < 150 RU/mL), and intact FGF23 (iFGF23) 18.93 pg/mL (NR 12.0-69.0 pg/mL). Treatment with acetazolamide, sevelamer, and a phosphorus-restricted diet was started, but phosphatemia remained high and calcifications continued to progress. In an attempt to further decrease P, a 36-day cycle of teriparatide (TPTD) 20 mcg twice daily was added, decreasing P from 6.2 to 5.2 mg/dL and increasing the 1.25(OH)2 vitamin D by 34.2%. As urinalysis was not feasible at the end of the 36-day cycle, a second cycle was performed for another 28 days, producing a similar decrease in P (from 6.4 to 5.5 mg/mL) and an evident decrease in the rate of tubular reabsorption of P (from 97.2 to 85.3%), however, accompanied by a worrying increase in calciuria. The use of TPTD 20 mcg twice daily in a patient with genetic resistance to FGF23 (HFTC) was associated with consistent increase in phosphaturia and reduction in phosphatemia, in addition to an increase in calcitriol. The resulting hypercalciuria precludes the therapeutic use of TPTD in HFTC and suggests an important role of FGF23, not only in phosphate homeostasis but also in avoiding any excess of calcitriol.

All-trans retinoic acid reduces the transcriptional regulation of intestinal sodium-dependent phosphate co-transporter gene (Npt2b).

Inorganic phosphate (Pi) homeostasis is regulated by intestinal absorption via type II sodium-dependent co-transporter (Npt2b) and by renal reabsorption via Npt2a and Npt2c. Although we previously reported that vitamin A-deficient (VAD) rats had increased urine Pi excretion through the decreased renal expression of Npt2a and Npt2c, the effect of vitamin A on the intestinal Npt2b expression remains unclear. In this study, we investigated the effects of treatment with all-trans retinoic acid (ATRA), a metabolite of vitamin A, on the Pi absorption and the Npt2b expression in the intestine of VAD rats, as well as and the underlying molecular mechanisms. In VAD rats, the intestinal Pi uptake activity and the expression of Npt2b were increased, but were reduced by the administration of ATRA. The transcriptional activity of reporter plasmid containing the promoter region of the rat Npt2b gene was reduced by ATRA in NIH3T3 cells overexpressing retinoic acid receptor (RAR) and retinoid X receptor (RXR). On the other hand, CCAAT/enhancer-binding proteins (C/EBP) induced transcriptional activity of the Npt2b gene. Knockdown of the C/EBP gene and a mutation analysis of the C/EBP responsible element in the Npt2b gene promoter indicated that C/EBP plays a pivotal role in the regulation of Npt2b gene transcriptional activity by ATRA. EMSA revealed that the RAR/RXR complex inhibits binding of C/EBP to Npt2b gene promoter. Together, these results suggest that ATRA may reduce the intestinal Pi uptake by preventing C/EBP activation of the intestinal Npt2b gene.

Mutational landscape and genetic signatures of cell-free DNA in tumour-induced osteomalacia.

Tumour-induced osteomalacia (TIO) is a very rare paraneoplastic syndrome with bone pain, fractures and muscle weakness, which is mostly caused by phosphaturic mesenchymal tumours (PMTs). Cell-free DNA (cfDNA) has been regarded as a non-invasive liquid biopsy for many malignant tumours. However, it has not been studied in benign tumours, which prompted us to adopt the targeted next-generation sequencing approach to compare cfDNAs of 4 TIO patients, four patients with bone metastasis (BM) and 10 healthy controls. The mutational landscapes of cfDNA in TIO and BM groups were similar in the spectrum of allele frequencies and mutation types. Markedly, deleterious missense mutations in FGFR1 and loss-of-function mutations in MED12 were found in 3/4 TIO patients but none of BM patients. The gene ontology analysis strongly supported that these mutated genes found in TIOs would play a potential role in PMTs' process. The genetic signatures and corresponding change in expression of FGFR1 and FGF23 were further validated in PMT tissues from a test cohort of another three TIO patients. In summary, we reported the first study of the mutational landscape and genetic signatures of cfDNA in TIO/PMTs.

A paternally inherited non-sense variant c.424G>T (p.G142*) in the first exon of XLαs in an adult patient with hypophosphatemia and osteopetrosis.

XLαs, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gsα), is paternally expressed. The significance of XLαs in humans remains largely unknown. Here, we report a patient who presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone (PTH) levels. His serum calcium was in the lower limit of the normal range. Whole exome sequencing of this subject found a novel non-sense variant c.424G>T (p. G142*) in the first exon of XLαs, which was inherited from his father and transmitted to his daughter. This variant was predicted to exclusively influence the expression of XLαs, while possibly having no significant effects on other gene products of this locus. Ellsworth-Howard test revealed normal renal response to PTH in proband. Human SaOS2 cells transfected with mutant XLαs failed to generate cyclic adenosine monophosphate under PTH stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating sclerostin, dickkopf1, and osteoprotegerin (OPG) levels, while lower receptor activator of nuclear factor kappa-B ligand/OPG ratio, leading to reduced bone resorption. Our findings indicate that XLαs plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.

Pharmacological Npt2a Inhibition Causes Phosphaturia and Reduces Plasma Phosphate in Mice with Normal and Reduced Kidney Function.

BACKGROUND: The kidneys play an important role in phosphate homeostasis. Patients with CKD develop hyperphosphatemia in the later stages of the disease. Currently, treatment options are limited to dietary phosphate restriction and oral phosphate binders. The sodium-phosphate cotransporter Npt2a, which mediates a large proportion of phosphate reabsorption in the kidney, might be a good therapeutic target for new medications for hyperphosphatemia. METHODS: The authors assessed the effects of the first orally bioavailable Npt2a inhibitor (Npt2a-I) PF-06869206 in normal mice and mice that had undergone subtotal nephrectomy (5/6 Nx), a mouse model of CKD. Dose-response relationships of sodium, chloride, potassium, phosphate, and calcium excretion were assessed in response to the Npt2a inhibitor in both groups of mice. Expression and localization of Npt2a/c and levels of plasma phosphate, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) were studied up to 24-hours after Npt2a-I treatment. RESULTS: In normal mice, Npt2a inhibition caused a dose-dependent increase in urinary phosphate (ED50 approximately 21 mg/kg), calcium, sodium and chloride excretion. In contrast, urinary potassium excretion, flow rate and urinary pH were not affected dose dependently. Plasma phosphate and PTH significantly decreased after 3 hours, with both returning to near baseline levels after 24 hours. Similar effects were observed in the mouse model of CKD but were reduced in magnitude. CONCLUSIONS: Npt2a inhibition causes a dose-dependent increase in phosphate, sodium and chloride excretion associated with reductions in plasma phosphate and PTH levels in normal mice and in a CKD mouse model.

FGF23 and inflammation-a vicious coalition in CKD.

High serum concentrations of the phosphaturic hormone, fibroblast growth factor 23 (FGF23), contribute to various tissue injuries. In chronic kidney disease, the sources of FGF23 and the stimuli that control FGF23 production differ from those in the physiologic scenario. Mediators of inflammation are intensively studied as potential factors that contribute to FGF23 elevations and thereby might function as drug targets to lower FGF23 levels. The present study focuses on tumor necrosis factor.

Distinct phenotype of kidney stone formers with renal phosphate leak.

Background: Hypercalciuria is the most frequent metabolic disorder encountered in kidney stone formers (SF). Reduced renal phosphate reabsorption (i.e. renal phosphate leak) was proposed to be a driver of hypercalciuria in calcium SF. However, the phenotype of SF with renal phosphate leak remains poorly defined and the association of renal phosphate leak with stone history, stone composition and bone mineral density (BMD) has not been studied. Methods: To fill these knowledge gaps, we conducted a cross-sectional analysis in a cohort of 555 idiopathic calcareous SF. The ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was used to evaluate renal phosphate transport. Results: Multivariable regression analyses revealed a negative association of parathyroid hormone (PTH), a positive association of 25-hydroxy vitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH)2D) but no association of fibroblast growth factor 23 (FGF23) with TmP/GFR. SF with low TmP/GFR had their first stone event at a younger age and were more likely to have a positive family history of kidney stones. In addition, urinary calcium excretion and prevalence of brushite stones were significantly higher in SF with low TmP/GFR. However, BMD, measured by dual-energy X-ray absorptiometry, was not associated with TmP/GFR in SF. Conclusions: Renal phosphate handling has a strong heritable component in SF and correlates with PTH, 25(OH)D and 1,25(OH)2D, but not with FGF23 levels. Furthermore, a low TmP/GFR (i.e. a renal phosphate leak) is associated with higher urinary calcium excretion and an increased prevalence of brushite stones.

Congenital hypophosphataemia in adults: determinants of bone turnover markers and amelioration of renal phosphate wasting following total parathyroidectomy.

Congenital hypophosphataemia (CH) is a collection of disorders that cause defective bone mineralisation manifesting with rickets in childhood and osteomalacia in adulthood. Bone turnover markers (BTMs) are surrogate measures of metabolic bone disease severity. We explored the utility of BTMs in 27 adults with CH: 23 had X-linked hypophosphataemia (XLH), of whom 2 were hypoparathyroid post-total parathyroidectomy (PTx); 2 had autosomal dominant hypophosphataemic rickets (ADHR), and 2 had none of the known mutations. We measured the renal tubular maximum reabsorption rate of phosphate (TmP/GFR), C-terminal fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), ionised calcium, 1,25-dihydroxyvitamin D [1,25(OH)2D], and a panel of BTMs: serum bone-specific alkaline phosphatase (bone ALP), osteocalcin (Oc), total procollagen type I amino-terminal propeptide (PINP), and carboxy-terminal telopeptide of type I collagen (CTX); and urine amino-terminal telopeptides of type I collagen (uNTX). After excluding 2 patients with XLH and PTx, the frequency of abnormal elevation in BTMs was: bone ALP (96%); CTX (72%); PINP (52%); uNTX (48%); Oc (28%). The strongest association with bone ALP was TmP/GFR. Those patients receiving phosphate supplements and alfacalcidol had significant elevation in CTX. The 2 patients with XLH and PTx had normalisation of TmP/GFR and near normalisation of BTMs post-operatively, despite marked elevation in both C-terminal and intact FGF23. In conclusion, BTMs in our CH patients indicated that most have abnormalities consistent with osteomalacia and many have mild secondary hyperparathyroidism; and the normalisation of TmP/GFR after total PTx in 2 cases of XLH remains unexplained, but possible causes are speculated.

Ubiquitin COOH-terminal hydrolase L1 deletion is associated with urinary α-klotho deficiency and perturbed phosphate homeostasis.

Loss of ubiquitin COOH-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme required for neuronal function, led to hyperphosphatemia accompanied by phosphaturia in mice, while calcium homeostasis remained intact. We therefore investigated the mechanisms underlying the phosphate imbalance in Uchl1-/- mice. Interestingly, phosphaturia was not a result of lower renal brush border membrane sodium-phosphate cotransporter expression as sodium-phosphate cotransporter 2a and 2c expression levels was similar to wild-type levels. Plasma parathyroid hormone and fibroblast growth factor 23 levels were not different; however, fibroblast growth factor 23 mRNA levels were significantly increased in femur homogenates from Uchl1-/- mice. Full-length and soluble α-klotho levels were comparable in kidneys from wild-type and Uchl1-/- mice; however, soluble α-klotho was reduced in Uchl1-/- mice urine. Consistent with unchanged components of 1,25(OH)2D3 metabolism (i.e., CYP27B1 and CYP24A1), sodium-phosphate cotransporter 2b protein levels were not different in ileum brush borders from Uchl1-/- mice, suggesting that the intestine is not the source of hyperphosphatemia. Nonetheless, when Uchl1-/- mice were fed a low-phosphate diet, plasma phosphate, urinary phosphate, and fractional excretion of phosphate were significantly attenuated and comparable to levels of low-phosphate diet-fed wild-type mice. Our findings demonstrate that Uchl1-deleted mice exhibit perturbed phosphate homeostasis, likely consequent to decreased urinary soluble α-klotho, which can be rescued with a low-phosphate diet. Uchl1-/- mice may provide a useful mouse model to study mild perturbations in phosphate homeostasis.

Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone.

Phosphate (Pi) homeostasis is regulated by renal, intestinal, and endocrine mechanisms through which Pi intake stimulates parathyroid hormone (PTH) and fibroblast growth factor-23 secretion, increasing phosphaturia. Mechanisms underlying the early adaptive phase and the role of the intestine, however, remain ill defined. We investigated mineral, endocrine, and renal responses during the first 4 hours after intravenous and intragastric Pi loading in rats. Intravenous Pi loading (0.5 mmol) caused a transient rise in plasma Pi levels and creatinine clearance and an increase in phosphaturia within 10 minutes. Plasma calcium levels fell and PTH levels increased within 10 minutes and remained low or high, respectively. Fibroblast growth factor-23, 1,25-(OH)2-vitamin D3, and insulin concentrations did not respond, but plasma dopamine levels increased by 4 hours. In comparison, gastric Pi loading elicited similar but delayed phosphaturia and endocrine responses but did not affect plasma mineral levels. Either intravenous or gastric loading led to decreased expression and activity of renal Pi transporters after 4 hours. In parathyroidectomized rats, however, only intravenous Pi loading caused phosphaturia, which was blunted and transient compared with that in intact rats. Intravenous but not gastric Pi loading in parathyroidectomized rats also led to higher creatinine clearance and lower plasma calcium levels but did not reduce the expression or activity of Pi transporters. This evidence suggests that an intravenous or intestinal Pi bolus causes rapid phosphaturia through mechanisms requiring PTH and downregulation of renal Pi transporters but does not support a role of the intestine in stimulating renal clearance of Pi.

Bone mineral density reductions after tenofovir disoproxil fumarate initiation and changes in phosphaturia: a secondary analysis of ACTG A5224s.

Background: It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia. Methods: We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir ( n = 134) versus abacavir ( n = 135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24. Results: Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P ≥ 0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 ( r = -0.22, P = 0.028) and week 48 ( r = -0.26, P = 0.010), but not at week 96 ( r = -0.14, P = 0.18). Conclusions: Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48.

Hyperparathyroidism and increased fractional excretion of phosphate predict allograft loss in long-term kidney transplant recipients.

BACKGROUND: After kidney transplantation, fibroblast growth factor-23 (FGF-23) normally returns to baseline within 1 year whereas hyperparathyroidism persists in most kidney transplant (KT) recipients. As a result, serum phosphate remains relatively low in association with increased serum calcium and urinary phosphate excretion when compared to chronic kidney disease patients. The relationship between mineral metabolism and outcomes in long-term KT recipients has not been extensively studied. This study investigated whether the alteration in mineral metabolism influenced graft survival in long-term KT recipients. METHODS: This study included 273 KT recipients after 1 year of transplantation. Mineral parameters were obtained at the time of enrolment and patients were followed prospectively for an average of 71 months. RESULTS: Graft loss (death-censored) occurred in 41 (15%) patients. In univariate analysis, deceased donor transplantation, decreased serum albumin and estimated glomerular filtration rate, increased serum phosphate, parathyroid hormone (PTH), FGF-23 and fractional excretion of phosphate (FePi) predicted future allograft loss. After adjustments for cardiovascular disease risk factors, donor type, dialysis vintage, serum albumin and allograft function, only increased PTH and FePi remained associated with the outcome. Relationships between increased serum phosphate and FGF-23 with graft survival were lost after adjustments. Adjusted survival curves revealed the association between PTH > 90 pg/mL and FePi > 20% with worse graft survival. CONCLUSIONS: Hyperparathyroidism and increased FePi predicted allograft loss in long-term KT recipients.

Treatment of ear and bone disease in the Phex mouse mutant with dietary supplementation.

HYPOTHESIS: Phosphorus and vitamin D (calcitriol) supplementation in the Phex mouse, a murine model for endolymphatic hydrops (ELH), will improve otic capsule mineralization and secondarily ameliorate the postnatal development of ELH and sensorineural hearing loss (SNHL). BACKGROUND: Male Phex mice have X-linked hypophosphatemic rickets (XLH), which includes osteomalacia of the otic capsule. The treatment for XLH is supplementation with phosphorus and calcitriol. The effect of this treatment has never been studied on otic capsule bone and it is unclear if improving the otic capsule bone could impact the mice's postnatal development of ELH and SNHL. METHODS: Four cohorts were studied: 1) wild-type control, 2) Phex control, 3) Phex prevention, and 4) Phex rescue. The control groups were not given any dietary supplementation. The Phex prevention group was supplemented with phosphorus added to its drinking water and intraperitoneal calcitriol from postnatal day (P) 7-P40. The Phex rescue group was also supplemented with phosphorus and calcium but only from P20 to P40. At P40, all mice underwent auditory brainstem response (ABR) testing, serum analysis, and temporal bone histologic analysis. Primary outcome was otic capsule mineralization. Secondary outcomes were degree of SNHL and presence ELH. RESULTS: Both treatment groups had markedly improved otic capsule mineralization with less osteoid deposition. The improved otic capsule mineralized did not prevent the development of ELH or SNHL. CONCLUSION: Supplementation with phosphorus and calcitriol improves otic capsule bone morphology in the Phex male mouse but does not alter development of ELH or SNHL.

Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour.

Phosphaturic mesenchymal tumours (PMTs) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour-induced osteomalacia (TIO) through secretion of phosphatonins including fibroblast growth factor 23 (FGF23). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1-FGFR1 fusion gene in three out of four PMTs by next-generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT-PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1-FGFR1 fusion out of an additional 11 PMTs. Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded protein's oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia-inducing FGFR1 fusion genes, which are ligand-independent, the FN1-FGFR1 chimeric protein was predicted to preserve its ligand-binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis.

ERG and FLI1 are useful immunohistochemical markers in phosphaturic mesenchymal tumors.

Phosphaturic mesenchymal tumors (PMT) are the most common cause of tumor-induced osteomalacia (TIO) related to mesenchymal neoplasms. The lineage of differentiation of PMTs has not been elucidated in existing literature. Fourteen cases of PMT were analyzed for this study to elucidate its lineage. We used vascular and/or lymphatic endothelial markers for the immunohistochemical analysis, which included CD31, CD34, factor VIII-related antigen, podoplanin, Freund's leukemia integration site 1 (FLI1), and avian v-ets erythroblastosis virus E26 oncogene homolog (ERG). FLI1 and ERG were stained in all cases with proportion of immunopositive tumor cells largely more than 50 %; staining intensity was moderate or strong for both FLI1 and ERG. The tumor cells were stained with CD31 and/or CD34, with significantly less staining than observed for FLI1 and ERG. The tumor cells were completely immunonegative for factor VIII-related antigen and podoplanin. FLI1 and ERG are known to have considerable specificity to endothelial cells; ERG is more widely equipped in surgical pathology laboratories than FLI1. We concluded that ERG (or FLI1 if available) is useful marker for the diagnosis of PMT, and that PMTs may have an endothelial cell lineage.

A case of phosphaturic mesenchymal tumor.

Phosphaturic mesenchymal tumors (PMTs) are rare and found to be commonly associated with phosphaturia and oncogenic osteomalacia. They commonly affect middle-aged adults and are located mostly in the extremities. Most of them are benign with only a few metastatic cases described in the literature. PMT-mixed connective tissue (PMTMCT) type is the most common PMT. Though most cases of PMTMCT have been associated with oncogenic osteomalacia and phosphaturia, there have been many reports of nonphosphaturic variants of this tumor with no clinical or laboratory evidence of tumor-induced osteomalacia. However, most of these nonphosphaturic variants previously described were not metastatic. We describe an unusual case of PMTMCT with widespread osseous metastases and without evidence of tumor-induced osteomalacia or phosphaturia.