tumor-induced osteomalacia · tumor-induced osteomalacia (tio) is a rare and fascinating...

$: Tumor-induced osteomalacia · Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness$
REVIEWEndocrine-Related Cancer (2011) 18 R53–R77

Tumor-induced osteomalacia

William H Chong1, Alfredo A Molinolo2, Clara C Chen3

and Michael T Collins1

1Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, 2Oral Pharyngeal Cancer Branch, National Institute of

Dental and Craniofacial Research and 3Nuclear Medicine, Radiology and Imaging Sciences, Hatfield Clinical Research Center,

National Institutes of Health, Bethesda, Maryland 20892, USA

(Correspondence should be addressed to M T Collins; Email: [email protected])

Abstract

Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in whichpatients present with bone pain, fractures, and muscle weakness. The cause is high blood levelsof the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23(FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but aretypically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairsphosphate reabsorption and 1a-hydroxylation of 25-hydroxyvitamin D, leading to hypophos-phatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functionalimaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy)followed by anatomical imaging (computed tomography and/or magnetic resonance imaging),and, if needed, selective venous sampling with measurement of FGF23 is usually successful inlocating the tumors. For tumors that cannot be located, medical treatment with phosphatesupplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, themedical regimen can be cumbersome and associated with complications. This review summarizesthe current understanding of the pathophysiology of the disease and provides guidance inevaluating and treating these patients. Novel imaging modalities and medical treatments, whichhold promise for the future, are also reviewed.

Endocrine-Related Cancer (2011) 18 R53–R77

Introduction

Tumor-induced osteomalacia (TIO), also known as

oncogenic osteomalacia, is a rare paraneoplastic

syndrome of abnormal phosphate and vitamin D

metabolism caused by typically small endocrine

tumors that secrete the phosphaturic hormone, fibro-

blast growth factor 23 (FGF23; Drezner 2001, Folpe

et al. 2004, Jan de Beur 2005). Biochemical hallmarks

of the disorder are hypophosphatemia due to renal

phosphate wasting, inappropriately normal or low

1,25-dihydroxy vitamin D, and elevated or inappropri-

ately normal plasma FGF23. TIO is counted among the

ranks of endocrine neoplasms that have a striking

presentation and, when resected, a dramatic and

satisfying resolution. Due to a lack of knowledge of

the existence of the disease, the length of time from

onset of symptoms until diagnosis is often long. As a

result, patients frequently present with multiple

fractures, height loss, and generalized debilitated

status, reminiscent of how patients in the past would


1351–0088/11/018–R53 q 2011 Society for Endocrinology Printed in Great

present with advanced primary hyperparathyroidism

(Fig. 1). If the condition develops before growth plate

closure, rickets is also present. There is also a group

of patients with a TIO-like syndrome in which a tumor

is never found. Whether or not this is due to the

inability to find the tumor or this represents a separate

syndrome is not known. In our series of 31 patients

with TIO syndrome in which genetic causes of

hypophosphatemia have been excluded, we have

been able to find the tumor in 19 (61%) of them.

Given that most of the patients referred to our center

have already failed tumor localization at the referring

institution at least once, the percent of patients in

whom we have not been able to find the tumor is

probably higher than is seen in patients being evaluated

for the first time.

A TIO-like syndrome can also be seen in association

with other diseases such as prostate cancer, oat cell

cancer, hematologic malignancies, neurofibromatosis,

Britain

DOI: 10.1530/ERC-11-0006

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A B C D

Figure 1Clinical effects of advanced tumor-induced osteomalacia (TIO). The patient in the gown in panel A is depicted standing nextto his father. The patient was previously taller than his father, but this is no longer the case. Panel B demonstrates kyphosis andpectus carinatum, which resulted from multiple compression fractures due to osteomalacia. While these findings are the result ofadvanced osteomalacia, they are strikingly similar to those seen in advanced hyperparathyroidism, as demonstrated by the famouspatient reported by Fuller Albright, Captain Martell, shown in panels C and D, who suffered from years of untreatedhyperparathyroidism. (Photo of patient and father are reproduced with their permission. Material is reproduced with permission fromAlbright & Reifenstein (1948)).

W H Chong et al.: Tumor-induced osteomalacia

epidermal nevus syndrome, and polyostotic fibrous

dysplasia of bone (FD; Saville et al. 1955, Dent &

Gertner 1976, Taylor et al. 1984, Carey et al. 1986,

Rao et al. 1987, Konishi et al. 1991, Nakahama et al.

1995, Ivker et al. 1997, Reese & Rosen 1997, Collins

et al. 2001, Riminucci et al. 2003). In these cases, the

primary disease is usually obvious, and as such it may

be useful to refer to this as secondary TIO. In cases of

secondary TIO, the goal is treatment of the underlying

disease. However, when the underlying disease is not

amenable to cure or adequate treatment, as is the case

in FD, the medical treatment of the hypophosphatemic

syndrome is the same as in cases of primary TIO.

Robert McCance is often credited with the first

reported case of TIO. McCance (1947) reported a

patient with manifestations of what was clearly TIO.

The patient had pain, weakness, gait abnormalities, and

low phosphorus levels. She was treated with high doses

of vitamin D, but her symptoms did not completely

resolve until a tumor in her femur was resected.

Her cure, however, was attributed to the high-dose

vitamin D therapy. She was diagnosed with resistance

to vitamin D. During that period, vitamin D resistance

was believed to be the mechanism of what would

eventually come to be understood as FGF23-mediated

phosphate wasting disorders (Albright et al. 1937).

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The first person to clearly recognize that the disease

was the result of a ‘rachitogenic’ substance was Andrea

Prader. In 1959, he described an 11 1⁄2 -year-old girl

who developed severe rickets over the course of a year

(Prader et al. 1959). Evaluation showed decreased

tubular phosphate reabsorption but otherwise normal

studies of kidney function. A tumor, classified as a

giant cell granuloma, was identified in a rib and

resected with resultant healing of her rickets. Prader

highlighted the association between the resection of the

tumor and the cure of the rickets and posited that the

granuloma was secreting a rachitogenic substance.

Since this association was first made, w337 cases of

what may be referred to as primary TIO have been

reported in the literature (English) (Sharkis et al. 1997,

Yang et al. 1997, Malabanan et al. 1998, Baronofsky

et al. 1999, Drezner 1999, Fukumoto et al. 1999,

Gascon et al. 1999, Hasegawa et al. 1999, Heylen et al.

1999, Lamont et al. 1999, Nguyen & Wang 1999,

Ohashi et al. 1999, Zura et al. 1999, Clunie et al. 2000,

Nelson et al. 2001, 2003, Ogose et al. 2001, Park et al.

2001, Rhee et al. 2001, Sakamoto et al. 2001, Sato

et al. 2001, Seufert et al. 2001, Furco et al. 2002,

Garcia & Spencer 2002, Jan de Beur et al. 2002, Lui

et al. 2002, Moran & Paul 2002, Paglia et al. 2002,

Reis-Filho et al. 2002, 2004, Teasell & Shapiro 2002,

www.endocrinology-journals.org



Yamazaki et al. 2002, Casari et al. 2003, Dissanayake

et al. 2003, Fuentealba et al. 2003, Kimizuka et al.

2004, Nayak et al. 2004, Takeuchi et al. 2004,

Toyosawa et al. 2004, Ungari et al. 2004, Ward et al.

2004, Auethavekiat et al. 2005, Colt et al. 2005,

Dupond et al. 2005a, Narvaez et al. 2005, Zimering

et al. 2005, Cheung et al. 2006, Dowman & Khattak

2006, Hodgson et al. 2006, Imel et al. 2006,

Inokuchi et al. 2006, Kaylie et al. 2006, Koriyama

et al. 2006, Ladha et al. 2006, Nguyen 2006, Sahnoune

et al. 2006, Tartaglia et al. 2006, Vandergheynst et al.

2006, Yoshioka et al. 2006, Ahn et al. 2007, Beech

et al. 2007, Elston et al. 2007, Geller et al. 2007,

Gershinsky et al. 2007, Halperin et al. 2007, Hesse

et al. 2007a,b, Jacob et al. 2007, Kaul et al. 2007,

Khosravi et al. 2007, Oka et al. 2007, Roarke &

Nguyen 2007, Umphrey et al. 2007, Williams et al.

2007, van Boekel et al. 2008, Duet et al. 2008, Endo

et al. 2008, von Falck et al. 2008, Habra et al. 2008,

Hannan et al. 2008, Harish et al. 2008, Kenealy et al.

2008, Lewiecki et al. 2008, Mannstadt et al. 2008,

Nasu et al. 2008, Ogura et al. 2008, Policarpio-Nicolas

et al. 2008, Ratanasuwan et al. 2008, Vollbrecht & Rao

2008, Westerberg et al. 2008, Woznowski et al. 2008,

Bahrami et al. 2009, Gore et al. 2009, Harbeck et al.

2009, Khadgawat et al. 2009, Mussig et al. 2009,

Nawrot-Wawrzyniak et al. 2009, Pirola et al. 2009,

Radaideh et al. 2009, Rendina et al. 2009, Romualdo-

Silva et al. 2009, Savage & Zimmer 2009, Sciubba

et al. 2009, Seijas et al. 2009, Szumera-Cieckiewicz

et al. 2009, Uramoto et al. 2009, Woo et al. 2009,

Yun et al. 2009, Chouhan et al. 2010, Dehghani et al.

2010, Haeusler et al. 2010, Ishii et al. 2010, Ito et al.

2010, Jagtap et al. 2010, Jung et al. 2010, Kobayashi

et al. 2010, Kurien et al. 2010, Marshall et al. 2010,

Mori et al. 2010, Pedrazzoli et al. 2010, Peters et al.

2010, Peterson et al. 2010, Xia et al. 2010). The fact

that over 200 of these cases have been reported in the

last 10 years indicates a growing recognition of this

disease. This growing recognition has paralleled the

identification of FGF23 as the phosphaturic agent

(ADHR Consortium 2000, White et al. 2001). The

discovery of FGF23 has not only paved the way toward

a better understanding of the pathophysiology and

treatment of TIO, but has also provided a window

into areas of mineral metabolism physiology that for

years had been unexplained. Hopefully, greater

recognition of TIO as a distinct disease entity, a better

understanding of the underlying pathophysiology,

improved tumor localization strategies, and better

medical treatment will make the sort of presentation

that is shown in Fig. 1, a historical footnote, as is


now the case with the primary hyperparathyroidism

(Albright & Reifenstein 1948).

This review aims to provide insight into the

pathophysiology and mechanism of TIO as well as

guidance in evaluating and diagnosing this rare

disease. Clinical presentation, diagnostic testing and

therapeutic options are discussed with an emphasis on

recent advances. Future areas of interest for research

are also discussed.

Physiology and pathophysiology

Phosphate homeostasis

Phosphate is vital to normal physiologic functioning; it

plays a role in intracellular signaling, membrane

function, energy metabolism, and bone mineralization

(Sommer et al. 2007, Renkema et al. 2008).

Approximately, 65% of dietary phosphate is absorbed

in the duodenum and jejunum (Mount & Yu 2008).

Phosphate is predominantly stored in the skeleton with

a small amount available in the extracellular fluid.

This freely circulating phosphate is filtered by the

glomerulus, and under normal physiologic conditions,

85–95% of filtered phosphate is reabsorbed. As renal

phosphate load increases, phosphate reabsorption

increases until a threshold is reached, at which point

phosphate is excreted in the urine (Mount & Yu 2008).

Renal phosphate excretion is the primary mode of

phosphate clearance and regulation of phosphate

balance. The majority of phosphate reabsorption

takes place in the proximal renal tubule through type

2a and 2c Na-dependent phosphate cotransporters

(NaPi-2a and NaPi-2c; Mount & Yu 2008, Bergwitz

& Juppner 2010).

For years, it has been recognized that phosphate

concentrations are under the control of parathyroid

hormone (PTH), 1,25-vitamin D, and the so-called

‘phosphatonins’ (Mount & Yu 2008, Bergwitz &

Juppner 2010). While the primary role of PTH is

thought to be the maintenance of serum calcium levels,

it also plays an important role in phosphate regulation.

In the process of mobilizing calcium from bone, PTH

also mobilizes phosphate from bone. To help excrete

this increased blood phosphate, PTH acts to inhibit

renal phosphate reabsorption through endocytosis of

NaPi-2a, thus increasing renal phosphate excretion.

The overall effect is to lower blood phosphate levels

(Renkema et al. 2008). 1,25-vitamin D is thought to

play a role in phosphate regulation in both the

gastrointestinal tract and in the kidney, but the

mechanism is less understood. Increases in 1,25-

vitamin D lead to an increase in phosphate absorption

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from the gastrointestinal tract. In the kidney, the role

is more complex. With chronic administration of

vitamin D, there is reduction of NaPi-2a and sub-

sequent phosphaturia (Friedlaender et al. 2001). With

acute administration of vitamin D metabolites, there

is reduced renal phosphate excretion (Taketani et al.

1998). However, many of the effects of 1,25-vitamin D

on phosphate metabolism were posited before the

discovery of FGF23. It is now clear that FGF23 and

PTH play much more important roles in phosphate

homeostasis than 1,25-vitamin D.

Fibroblast growth factor 23

While Prader was the first to propose the idea of a

circulating factor that could cause phosphate wasting,

the first evidence that a circulating factor was

responsible for the hypophosphatemia of phosphaturic

disorders such as TIO was demonstrated in an elegant

set of experiments by Meyer et al. By performing

parabiosis experiments in hyp mice, the mouse model

for X-linked hypophosphatemic rickets, Meyer et al.

(1989) were able to demonstrate that a factor in the hyp

mouse’s circulation could induce hypophosphatemia in

wild-type (WT) mice. A similarly elegant set of

experiments by Nesbitt et al. (1992), in which the

transplantation of WT kidneys into hyp mice failed to

correct hypophosphatemia, confirmed the etiology as a

circulating factor and not a primary renal defect. The

first evidence to support this concept in humans was the

work by Miyauchi et al. (1988), in which a TIO tumor

resected from a patient and transplanted into nude mice

caused hypophosphatemia and the work that showed

that the supernatant from cultured tumor cells could

also cause hypophosphatemia in mice (Cai et al. 1994).

This phosphaturic substance was termed ‘phospha-

tonin’ by Econs & Drezner (1994) because of its ability

to lower blood phosphorus level.

The first identification of FGF23 as the putative

phosphatonin was when mutations in FGF23 were

identified by Econs and the autosomal-dominant

hypophosphatemic rickets (ADHR) consortium as the

cause of ADHR (ADHR Consortium 2000). FGF23 is a

member of the FGF ligand superfamily and functions

as an endocrine factor. It has a FGF-like amino

terminus and a unique carboxy-terminus domain

(ADHR Consortium 2000). Once identified as the

cause of ADHR, elevations in serum FGF23 were soon

found in TIO (White et al. 2001), X-linked hypopho-

sphatemia (XLH; Jonsson et al. 2003), FD (Riminucci

et al. 2003), ADHR (Imel et al. 2007) and autosomal-

recessive hypophosphatemic rickets (ARHR; Feng

et al. 2006). The first insight into the physiologic

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source of FGF23 was from the study of patients with

FD, wherein it was found that dysplastic osteogenic

cells are the source of FGF23 (Riminucci et al. 2003).

Reasoning that if dysplastic osteogenic cells are the

source of FGF23 in FD, we went on to show that

normal bone cells are the physiologic source of FGF23

(Riminucci et al. 2003). Physiologic regulation of

FGF23 secretion is still being defined, but probably

serum phosphorus (Larsson et al. 2003, Ferrari et al.

2005, Nishida et al. 2006, Ito et al. 2007) and/or serum

1,25-vitamin D (Collins et al. 2005) are important in

regulating the levels of FGF23.

FGF23 acts by binding to target cells via an FGF

receptor (probably FGFR1), but signaling requires the

co-receptor Klotho (Razzaque 2009). When FGFR is

activated, there is reduction of NaPi-2a transcription

and less NaPi-2a on the basal cell surface of proximal

tubule cells, which in turn leads to renal phosphate

excretion (Shimada et al. 2004). At this point, it is not

clear how this occurs, as Klotho expression has been

clearly reported only in distal tubule cells so far (Farrow

et al. 2009). There is a secreted form of Klotho, and it

is possible that this circulating Klotho may play a role

in FGF23 signaling (Kurosu et al. 2006).

There is evidence that the phosphaturic action of

FGF23 is to some extent PTH-dependent. Subjects

with hypoparathyroidism, who have very low or

undetectable PTH levels, have high serum phosphorus

in the setting of high serum FGF23, which is consis-

tent with the need for PTH for the full phosphaturic

effect of FGF23 (Gupta et al. 2004). This observation

is further supported by the fact that in patients with

TIO and XLH, medically induced hypoparathyroidism

by cinacalcet results in increased renal phosphate

reabsorption and an increase in serum phosphorus

(Geller et al. 2007, Alon et al. 2008).

In addition to its action on NaPi-2a and NaPi-2c,

FGF23 is also a regulatory hormone for 1,25-vitamin D

(Shimada et al. 2004). Through downregulation of

1a-hydroxylase and up-regulation of 24-hydroxylase,

it leads to a decrease in 1,25-dihydroxy vitamin.

Other compounds such as frizzled related protein-4,

matrix extracellular phosphoglycoprotein, and FGF7 have

also been suggested to be phosphatonins (De Beur et al.

2002, White et al. 2006). However, the preponderance of

data to date suggests that FGF23 is the primary, if not the

only, clinically relevant phosphatonin.

Histopathology

Tumors associated with TIO have included a wide

range of histopathological diagnoses, and despite the

description and classification scheme proposed by




Weidner (1991) and Folpe et al. (2004), many

clinicians and pathologists continue to be unaware of

these tumors as a distinct entity. The prototypical

phosphaturic mesenchymal tumor (mixed connective

tissue variant) (PMTMCT) contains neoplastic cells

that are spindled to stellate in shape, normochromatic

with small nuclei and indistinct nucleoli. A spectrum of

histopathological features is shown in Fig. 2A–F.

The nuclear grade is low, and mitotic activity is usually

absent or very low. The cells are typically embedded

A B

C D

E F

Figure 2 TIO tumor histopathology. (A) This tumor area showsimmature mesenchymal cells, with no particular differentiation.There are areas of edema and blood lacunae (arrow). (B) Thisproliferation is solid, with what seems to be abundantintercellular matrix (arrow). The nuclei are typical with somevariation in shape and size. (C) Numerous and irregularvascular structures (arrows), as well as areas of solidproliferation, are seen in this tumor area. (D) This tumor iscomposed mostly of irregular vascular structures (arrows)embedded in a relatively soft matrix. Variations in size andshapes of the nuclei are evident. (E) Lattice-like areas withossification (arrow). (F) This photomicrograph was taken from alung metastasis. The area shows numerous very largeosteoclastic-like giant cells (arrows). Note that even though theproliferation is biologically malignant, there are few or nohistological signs of malignancy.


within a myxoid or myxochondroid matrix with

‘grungy’ calcification that can resemble chondroid or

osteoid. Numerous osteoclast-like giant cells are a

frequent finding, and mature fat and even lamellar bone

may also be seen. A prominent feature of these tumors

is an elaborate intrinsic microvasculature with an

admixture of vessel size and vascular pattern (Folpe

et al. 2004). The most common diagnosis for these

tumors has been hemangiopericytoma, but it has also

included hemangioma, sarcomas, ossifying fibromas,

granulomas, giant cell tumors, and osteoblastomas

(Weidner 1991, Drezner 2001, Folpe et al. 2004).

Weidner (1991) reviewed the literature of w60

cases of TIO that had been described at that time.

They were the first to propose a classification system

based on the histological findings of their 16 cases

of TIO, and designated the tumors as phosphaturic

mesenchymal tumors. These were then subdivided into

four categories; mixed connective tissue variant

(PMTMCT), osteoblastoma-like variant, non-ossifying

fibroma-like variant, and ossifying fibroma-like variant.

The first group, PMTMCT, comprised neoplasias

containing primitive stromal cells, prominent vessel,

and osteoclast-like giant cells (Fig. 2D and F). Osseous

metaplasia and poorly formed cartilage-like areas with

dystrophic calcification were also present (Fig. 2B and

E). They noted that these tumors usually occurred in soft

tissue and were typically benign in behavior. The

remaining three groups tended to occur in bone and

were also typically benign in behavior. Folpe et al.

(2004) reviewed the clinic-pathological features of 32

new cases and re-reviewed all of the previously

published cases, and made the assertion that virtually

all of the cases fell into the category of PMTMCT.

Antigen expression was first evaluated in two

immunohistochemical studies by Weidner et al. In the

first study, the immunostainings were negative for

FVIII-related antigen, S-100, and cytokeratin (Weidner

et al. 1985). The second study revealed only vimentin

immunoreactivity in some cases within the tumor cells.

All other antibodies (desmin, S-100 protein, leu-M 1,

chromogranin, cytokeratin, neuron-specific enolase,

leukocyte common antigen, and factor VIII-related

antigen) were negative (Weidner et al. 1985). In their

series, Folpe et al. (2004) performed a series of

immunohistochemical stainings, including pan-cyto-

keratin, desmin, S-100, smooth muscle actin, CD34,

and FGF23. With the exception of smooth muscle actin,

which they found reactive in three cases, and FGF23,

which was positive in about 70% of all the cases

studied, all other markers were negative. In terms of

FGF23 staining, it is the proliferating cells within the

tumor that usually stain positive for FGF23 (Fig. 3A).

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In terms of ultrastructural features, Stone et al.

(1992) described features consistent with a neuroendo-

crine tumor in a PMTMCT from a 33-year-old woman.

Neurosecretory granules were also found in the case by

Wilkins et al. (1995). However, immunostaining for

typical markers of neurosecretory tumors, such as

S-100, neuron-specific enolase, chromogranin and

synaptophysin, were negative, as was staining for

actin, cytokeratin, epithelial membrane antigen, and

FVIII. The only positive finding was vimentin,

confirming what had been already described by

Weidner. An additional case communicated by

Shelekhova et al. (2006) also showed similar neuro-

secretory granules.

While typically benign, malignant presentation and

metastases can occur (Wyman et al. 1977, Rico et al.

Lung parenchyma

Metastasis

A

B

Figure 3 (A) FGF23 immunohistochemistry of lung metastasisof a PMTMCT. (B) The tumor shown in this slide was relativelyhomogeneous and composed mainly of spindle-shaped cells.Note the relatively benign histological appearance of theneoplasia (inset). FGF23 reactivity was present in almost 100%of the tumor cells.

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1986, Harvey et al. 1992, Ogose et al. 2001, Uramoto

et al. 2009). Two of the 19 tumors in our series went on

to metastasize (Figs 2F and 3B), a feature that is hard

to predict from the benign histological appearance.

While metastases are rare, infiltration of surrounding

connective tissue is typically present, which has

significant implications for surgical management and

emphasizes the importance for wide surgical margins

to avoid persistence or recurrence – a point that cannot

be emphasized enough in the management of TIO.

It seems to be that PMTMCT constitute a single,

albeit morphologically heterogeneous, histopatho-

logical entity. Regardless of tumor morphology, the

hallmark of the diagnosis of a PMTMCT is the

association of the tumor with the clinical syndrome

of TIO, which includes an elevation in plasma FGF23

and its disappearance after tumor resection. It is this

heterogeneity that may account for their frequent

misdiagnosis (Folpe et al. 2004).

To date, the immunohistochemical and electron

microscopy findings have not shed light on the cell of

origin of these neoplasias, but only served to confirm

their mesenchymal origin. It is also quite possible that

all of the tumors share a common origin: a primitive

mesenchymal cell that itself has the ability to secrete

the hormone and which can differentiate into several

cell lineages.

To summarize, PMTMCT are a group of tumors

with a spectrum of histopathologic findings that

include a background of spindle/stellate cells with

low nuclear and mitotic activity. This is true even

in cases of metastatic disease. Prominent vascularity

is common and includes vessels of different sizes

and patterns, consistent with the fact that they are

most commonly classified as hemangiopericytomas.

Osteoclast-like giant cells are frequently seen in these

tumors and mature fat or lamellar bone can be present

as well. FGF23 staining is positive and appears in the

cytoplasm of the tumor cells. It is important to note that

histopathologic diagnosis of malignant disease is

difficult, as even in clinically proven metastatic disease

the cellular features appear benign.

Clinical evaluation

A summary of our approach to the evaluation of these

patients can be found in Fig. 4, and a summary of

medical treatment recommendations can be found

in Box 1. Patients with TIO often present with

many years of symptoms before they are diagnosed.

The symptoms, which lead to their evaluation, are

non-specific, and often progressive. Common com-

plaints are bone pain, muscle weakness, and multiple



Diagnosis and treatment of tumor-induced osteomalacia

2. Confirm diagnosis

1. Signs and symptoms of tumor-induced osteomalacia

• ↓ Pi, ↓ %TRP, ↓ 1,25-D, ↑ FGF23• Exclude familial forms (if appropriate) Check: PHEX, FGF23, DMP-1, ENPP1

3. Tumor localization

• Functional imaging: FDG-PET/CT + Octreoscan/CT

• Anatomical imaging: MRI and/or CT

• Venous sampling and/or aspiration (if necessary)

Medical treatmentUnsuccessful

localized Repeat localization (1 year?)

4. Surgical excision(with wide margins)

Figure 4 Summary of the approach to diagnosis and treatment of patients with TIO. Pi, phosphate; %TRP, tubular reabsorption ofphosphate; 1,25-D, 1,25-dihydroxyvitamin D.


fractures (Jan de Beur 2005). Pediatric patients can

develop rickets and growth retardation (Jan de Beur

2005, Haeusler et al. 2010). These patients are often

misdiagnosed with a variety of musculoskeletal

ailments, rheumatologic diseases, and sometimes

even psychiatric disorders (Teasell & Shapiro 2002,

Lewiecki et al. 2008). Hypophosphatemia caused by

impaired renal phosphate reabsorption is the bio-

chemical hallmark of the disease. In many institutions,

phosphate is no longer part of the routine chemistry

panels, thus hypophosphatemia can often go unrecog-

nized, further delaying diagnosis (Halperin et al. 2007).

Box 1 Medical treatment of tumor-induced osteomalacia

Goal of therapy

Medication

Phosphorus

Calcitriol or alphacalcidiol

Monitoring

Baseline renal ultrasound for evaluation of nephrolithiasis/nephro

† Repeat if concerning symptoms arise or there is persistent inc

Serum calcium, phosphorus and PTH every 3 months

† If phosphorus level is below target, increase phosphorus supp

† If calcium level is below target, add/increase calcium supplem

† If PTH elevated, increase calcitriol

Urinary calcium (UCa) and creatinine (UCr) every 3 months (2nd

† If UCa/UCrR0.2, check for urinary hemoglobin. Also check 24h

calcium. Decrease calcitriol dose if positive urinary hemoglobin o

† If UCa/UCr %0.2, and serum phosphorus and PTH are at targ


Differential diagnosis

The differential diagnosis for hypophosphatemia

should first be separated into genetic versus acquired

causes. Genetic causes include XLH, ADHR, and

ARHR, which are essentially biochemical phenocopies

of TIO. In all of these genetic forms of hypopho-

sphatemia, the plasma FGF23 is either directly

elevated or inappropriately normal. XLH is almost

invariably present in early childhood, while ADHR can

present in either childhood or adulthood (Econs &

McEnery 1997). Therefore, a detailed personal history

to identify the age of onset, which can often be aided by

Low-end of normal for age-appropriate normal range

of phosphorus

Dosing

15–60 mg/kg per day (w1–3 g/day for adults)

Dose should be divided into 4–5 times/day to improve

tolerance

15–60 ng/kg per day (w0.75–3 mg/day for adults)

Start 1.5 mg/day and titrate. Dose can be divided into

BID and TID

calcinosis.

rease in urinary calcium

lements

ents

AM void)

urinary calcium and creatinine with goal of normal range urinary

r elevated 24h urinary calcium

et, continue current regimen

R59



review of the growth chart in the case of young

patients, and a detailed family history, looking for

family members with short stature and bowed legs, is

especially important in children and young adults.

Some genetic forms, especially XLH, are associated

with dental findings, including enamel hypoplasia,

dental abscesses, and caries; thus, a detailed dental

history is important (Baroncelli et al. 2006). Generally,

the younger the patient is at presentation, the more

likely is a genetic cause. Additional genetic disorders

that can present with hypophosphatemia and should

be considered in the hypophosphatemic patient are

hereditary hypophosphatemic rickets with hypercal-

ciuria (HHRH; Bergwitz et al. 2006), X-linked

recessive hypophosphatemia (XLRH)/Dent’s disease

(Scheinman 1998), and the inherited renal Fanconi

syndromes, Fanconi-Bickel syndrome (MIM ID

227810) (Santer et al. 1997) and Fanconi renal tubular

syndrome (MIM ID 134600) (Lichter-Konecki et al.

2001). HHRH and XLRH differ from the other genetic

causes of hypophosphatemia in that hypercalciuria due

to increased 1,25-vitamin D accompanied by nephro-

calcinosis and/or nephrolithiasis is a feature. Patients

with XLRH also have proteinuria. Patients with the

genetic Fanconi syndromes have a more generalized

renal tubulopathy. This can include any combination of

Table 1 Differential diagnosis of hypophosphatemia

Disease Gene FGF23 Other findings

Genetic causes

XLH PHEX Elevated Childhood onset,

ADHR FGF23 Elevated Variable age of o

remit and recur

ARHR DMP-1,

ENPP1

Elevated May have consan

HHRH SLC34A3 Low Increased 1,25-vi

calcium, low PT

XLRH/Dent’s CLCN5 Unknown Male predominan

nephrocalcinos

renal failure

Inherited Fanconi Various Low Glucosuria, amino

proximal renal t

Acquired causes

TIO NA Elevated Variable age of o

TmP/GFR

Acquired Fanconi NA Low Glucosuria, amino

tubular acidosis

heavy metals, c

etc. (see text)

XLH, X-linked hypophosphatemic rickets; ADHR, autosomal-dominhypophosphatemic rickets; XLRH, X-linked recessive hypophosphahypercalciuria; XLRH, X-linked recessive hypophosphatemic ricket

R60

aminoaciduria, low molecular weight proteinuria,

bicarbonaturia, calciuria, and others. However, the

most important fact that distinguishes these genetic

syndromes of hypophosphatemia from TIO is that

plasma FGF23 is high in TIO, but low in HHRH and

Fanconi syndrome. FGF23 levels in XLRH have not

been reported, but should be low as well. The genes

for the genetic forms of hypophosphatemia, as well as

various features, are detailed in Table 1.

In addition to the genetic causes of non-TIO hypo-

phosphatemia, there are acquired causes. Most of the

acquired forms of hypophosphatemia are the result of

direct renal tubular damage by a drug or a toxin. Tubular

damage usually results in a generalized tubulopathy,

similar to what is seen in the genetic Fanconi-type

tubulopathies mentioned above (Bonnardeaux & Bichet

2008). This type of tubulopathy can be seen as a result

of burns (Nordstrom et al. 1977), heavy metal exposure

(cadmium, lead and arsenic) (Omdahl & DeLuca

1971, Aranami et al. 2010), aminoglycoside antibiotics,

certain chemotherapeutic agents, especially cisplatin,

and the anti-retroviral drug, tenfovir, which is used in

the treatment of HIV and hepatitis B (Davis et al. 1980,

Izzedine et al. 2003, Earle et al. 2004). It can also occur

in association with multiple myeloma and other dyspro-

teinemias (Dash et al. 1997). 1,25-vitamin D levels are

References

rickets and dental caries The HYP Consortium (1995)

nset, may spontaneously White et al. (2000)

guinity in parents Feng et al. (2006)

Lorenz-Depiereux et al. (2006a)

Levy-Litan et al. (2010)

Lorenz-Depiereux et al. (2010)

tamin D, increased urinary

H, and nephrocalcinosis

Bergwitz et al. (2006)

Ichikawa et al. (2006)

Lorenz-Depiereux et al. (2006b)

ce, hypercalciuria,

is, kidney stones, and

Pook et al. (1993)

Lloyd et al. (1996)

Oudet et al. (1997)

aciduria, calciuria, and

ubular acidosis

Chadha & Alon (2009)

nset, low 1,25-D, low Drezner (2001)

Jan de Beur (2005)

aciduria, proximal renal

, history of exposure to

hemotherapeutic agents,

Izzedine et al. (2003)

ant hypophosphatemic rickets; ARHR, autosomal-recessivetemic rickets; HHRH, hereditary hypophosphatemic rickets withs; TIO, tumor-induced osteomalacia.




variable, and can be low, as seen in TIO. Unlike TIO,

Fanconi-type syndromes tend to be associated with more

severe proximal renal tubular defects and metabolic

acidosis. Again, the key factor in discriminating these

sorts of disorders from TIO is the plasma FGF23 level,

which is low in cases of tubular damage, and high in TIO.

Other disorders which can be associated with hypopho-

sphatemia are hematologic malignancies, total parenteral

nutrition, organ transplant, refeeding syndrome, correc-

tion of diabetic ketoacidosis, and dietary deficiency.

Approach to the diagnosis of TIO

Diagnosis confirmation

TIO should be suspected in patients who present with

consistent symptoms and with hypophosphatemia.

If hypophosphatemia is present, the presence of renal

phosphate wasting should be confirmed.

Two ways to evaluate urinary phosphate wasting are

the calculation of percent tubular reabsorption of

phosphate (%TRP) and tubular maximum for phos-

phate corrected for glomerular filtration rate (GFR)

(TmP/GFR). Open access programs that calculate

%TRP and/or TmP/GFR can be found on the Internet

(by searching under these terms), but caution should be

exercised to enter the proper units (traditional versus

SI), as indicated by the site. TmP/GFR can be

calculated only in the fasting state, but %TRP can be

calculated at any time using the following formula:

100!ð1Kððurine phosphate=urine creatinineÞ

!ðserum creatinine=serum phosphateÞÞÞ:

When phosphate is normal, the normal range is

between 85 and 95%.

The TmP/GFR is another measure of renal phos-

phate handling and is independent of plasma phosphate

and renal function. TmP/GFR can be determined using

a nomogram or algorithm (Kenny & Glen 1973,

Walton & Bijvoet 1975). Use of the algorithm is less

cumbersome and there is no clinically significant

difference between the values obtained, making it the

preferred method (Barth et al. 2000). The formula used

to calculate TmP/GFR is dependent on the value of

TRP and can be calculated using the formulas below:

If TRP is %0:86 ð86%Þ; then TmP=GFR

ZTRP!phosphate:

If TRP is O0:86 ð86%Þ; then TmP=GFR

Z 0:3!TRP=ð1K0:8!TRPÞ!phosphate:


In using these algorithms, it is important that units

for urine creatinine, urine phosphate, serum creatinine,

and serum phosphate are consistent.

The normal reference ranges for TmP/GFR are age-

and gender-dependent, but have not been well defined

in large patient populations. Reasonable age- and

gender-dependent values are listed in Table 2, and are

derived from data compiled by Stark et al. (1986),

Alon & Hellerstein (1994) and Payne (1998).

TmP/GFR should be calculated from testing done in

the fasting state, typically from second morning-void

urine and blood samples taken at the same time. In the

non-disease state, the values for TRP and TmP/GFR

will be high when there is hypophosphatemia. In TIO,

these values are abnormally low. It is important to note

that the calculations of %TRP and TmP/GFR in

patients with suspected TIO need to be done off of

phosphate supplementation. Phosphate supple-

mentation will elevate urinary phosphate in both

subjects with and without TIO and can lead to falsely

low determinations of %TRP and TmP/GFR in patients

without the disease.

After confirming renal phosphate wasting as the

etiology for hypophosphatemia, additional lab tests

can be helpful in making the diagnosis of TIO. 1,25-

vitamin D can be low or inappropriately normal.

Calcium and PTH are usually normal, but PTH can

be high reflecting secondary hyperparathyroidism,

which is the normal response to low 1,25-vitamin D

caused by elevated FGF23. Measurement of blood

FGF23 is now commercially available and is essential

for the diagnosis. Currently, only the less-sensitive

C-terminus assay is widely available for commercial

testing (Imel et al. 2006). It is important to note that

this is only valid for plasma, not serum, samples. The

most sensitive and specific assay for use in the

diagnosis of TIO is the intact assay manufactured by

Kainos (Imel et al. 2006), which at present is typically

only used in research laboratories.

Once the diagnosis of an FGF23-dependent, phos-

phate wasting disorder is made, a thorough history can

aid in excluding the genetic causes, such as XLH,

ADHR, and ARHR. Genetic testing can also be done.

Having narrowed the diagnosis to TIO, a careful

physical examination should be performed, as the

tumors that cause TIO can sometimes be found in the

subcutaneous tissue (Fig. 5; Colt et al. 2005, Dewitt

et al. 2007, Ogura et al. 2008). It is also prudent to ask

the patient if she/he has noticed any new ‘lumps’ or

‘bumps’ as well as to examine the oral cavity, as

tumors have been reports in the jaws (Yun et al. 2009).

R61


Table 2 Normal ranges for tubular maximum for phosphate

corrected for GFRa

Age Male mg/dl (mmol/l) Female mg/dl (mmol/l)

Newborn 5.7–8.1 (1.27–2.59) 5.7–8.1 (1.27–2.59)

1 month–2 years 3.6–5.4 (1.15–1.73) 3.6–5.4 (1.15–1.73)

2–12 years 3.8–5.0 (1.22–1.60) 3.8–5.0 (1.22–1.60)

12–16 years 3.4–4.6 (1.09–1.47) 3.4–4.6 (1.09–1.47)

16–25 years 3.33–5.9 (1.07–1.89) 3.18–6.41 (1.02–2.05)

25–45 years 3.09–4.18 (0.99–1.34) 2.97–4.45 (0.95–1.42)

45–65 years 2.78–4.18 (0.89–1.34) 2.72–4.39 (0.87–1.40)

65–75 years 2.47–4.18 (0.79–1.34) 2.47–4.18 (0.79–1.34)

aReferences (Stark et al. 1986, Alon & Hellerstein 1994,Payne 1998).


Localizing studies: functional imaging

As tumors can arise in bone or soft tissue, occur from

head to toe, and are typically very small in size, locating

these tumors is often quite challenging. We have seen

in our cohort of patients that tumors are found more

commonly in bone than in soft tissue.

We advocate a stepwise approach, first performing

functional tests. In our hands, F-18 fluorodeoxyglucose

positron emission tomography, with computed tomo-

graphy (FDG-PET/CT), has proven to be most sensitive

for localizing TIO tumors (Dupond et al. 2005b,

Andreopoulou et al. 2010a, Jagtap et al. 2010). However,

while FDG-PET/CT may be very sensitive, it is also

non-specific and identifies areas of metabolic activity

A B

C

Figure 5 Subcutaneous TIO tumor detectable on physical examinatshown in Fig. 1) revealed a subcutaneous nodule (A). This nodule won functional imaging, FDG-PET (B). The lesion was visualized on(C, arrow). On the low-power view, it can be seen that the tumor wahigh-power view, it was revealed that the calcification in the lesion wTIO resolved after excision.

R62

that are not tumors. This is especially true in patients with

many areas of active fracture healing (Fig. 6).

Another important functional imaging modality is111Indium octreotide scintigraphy, ideally combined with

single photon emission CT and CT (SPECT/CT).

Somatostatin receptors have been found to be present

on many TIO tumors (Duet et al. 2008) and 111Indium-

octreotide has a high affinity for the somatostatin receptor,

especially subtype 2 and to a lesser extent subtype 5. As

with FDG PET/CT, emphasis should be placed on making

sure these imaging tests cover the entire body, from

head to toe, including the hands and feet. Standard

PET/CT and octreotide often exclude portions of the

extremities and may exclude portions of the head.

Addition of co-registered CT to both FDG-PET and

octreotide significantly increases the ability to localize

tumors, and whenever possible it should be performed.

More recently, 68Ga-DOTANOC PET/CT has been

explored as a means of finding TIO tumors (Hesse et al.

2007a, von Falck et al. 2008). This scan combines the

specificity of octreotide scanning with the sensitivity of

PET/CT. It utilizes a modified octreotide molecule

(DOTANOC) that has increased affinity for both

somatostatin receptor 2 and 5 (Wild et al. 2003,

2005). Labeling this compound with the positron

emitter 68Ga results in a PET compound that may be

more specific than FDG. However, studies comparing68Ga-DOTANOC PET/CT with standard octreotide

SPECT/CT in the diagnosis of TIO have not been done.

D

E

ion. Physical examination of a patient with TIO (the same patientas implicated as the culprit tumor by the fact that it was detectedCT scan, which also suggested intralesional calcifications completely contained in the subcutaneous tissue (D), and on aas actually ossification and contained areas of lamellar bone (E).



A B

C

D

E

Figure 6Multiple imaging modalities may be needed to localize TIO tumors. In this patient, FDG PET/CT revealed multiple areas ofincreased uptake (A). Octreotide scan only demonstrated a single lesion (B–D). MRI revealed a tumor in the area identified onfunctional imaging (E). TIO resolved after excision of the lesion.


201Thallium and 99Technetium MIBI scintigraphy

have been used in TIO (Kimizuka et al. 2004, Hodgson

et al. 2006), but we have not found them to add

anything to FDG-PET or octreotide scanning.99Tc-MDP bone scintigraphy (bone scans) has not

proven to be a useful study in localization of TIO

tumors (Lee et al. 1995, Garcia & Spencer 2002). It

often reveals multiple foci of uptake at areas of fracture

and may actually misdirect the effort to localize the

tumor. Of interest, though, is that 99Tc-MDP bone

scans often show uptake at the costochondral junctions

(a sort of adult rachitic rosary) and areas of the bone in

skeletally mature adults where the growth plates were

previously located (Fig. 7). This finding should suggest

the diagnosis of TIO, and may represent a sort of

‘pseudo-reactivation’ of growth plates in the adult

skeleton. The pathophysiology underlying this inter-

esting and frequently observed phenomenon is unclear

at this time. Importantly, this finding should not be

misinterpreted as evidence of metastatic tumor, as it

sometimes is.

Localizing studies: anatomical imaging

Once suspicious lesions have been identified with

functional imaging, one should proceed to anatomical

imaging to confirm the location of the tumor. Anatomic

imaging studies include X-rays, CT, and/or magnetic


resonance imaging (MRI) scans. Some investigators

advocate total body MRI as an initial imaging study.

However, we have not found this approach to be

fruitful. It should also be noted that there are ‘blind’

spots on both FDG-PET and octreoscan; brain uptake

on FDG-PET may obscure intracranial tumors, and

liver and spleen uptake of octreotide may obscure

potential lesions in these regions. Therefore, ana-

tomical imaging of these areas may be indicated if a

tumor has not been identified.

Venous sampling

Usually, the combination of functional and anatomical

imaging is successful in localizing the FGF23-

secreting tumor. However, there are certain circum-

stances in which more certainty and testing are

indicated. Often, more than one lesion is found on

functional imaging, particularly FGD-PET, each with a

reasonable degree of suspicion or the suspicious lesion

is located in an area where the indicated operation is

associated with a high level of potential morbidity. In

these cases, additional certainty and testing are

indicated. Of particular utility is selective venous

sampling with measurement of FGF23 (Andreopoulou

et al. 2010b). Examples of the utility of venous

sampling in distinguishing between multiple sites and

difficult sites are shown in Fig. 8.

R63


A

B

C

Figure 7 ‘Pseudo-reactivation’ of growth plate. X-ray (A) andbone scan (B) of a patient with TIO showing areas of intensetracer uptake and evidence of ‘growth plates’ in a 54-year-oldman who had senesced his growth plates decades before. Abone scan of another adult patient with TIO (C) revealed intensetracer uptake at multiple costochondral junctions, creating thenuclear medicine equivalent of an adult rachitic rosary.


Venous sampling has been attempted in localizing

tumors in the absence of any suspicious lesions

identified on either functional or anatomical imaging,

the so called ‘blind sampling’. In a trial designed to test

this, we were unable to localize tumors by venous

sampling without a ‘target’ lesion suggested by

anatomical or functional imaging, and concluded this

was not a useful approach (Andreopoulou et al.

2010b). Van Boekel et al. (2008) advocated a two-

step approach to venous sampling. They suggested that

if a suspected tumor cannot be localized by imaging,

whole body venous sampling can be performed with

assessment of the average values for samples from

different anatomical regions. If the average values in

samples from a region appear to be higher, more

detailed sampling is performed in the smaller branches

of the veins in that region. In the one patient studied by

this approach, it appeared to suggest a particular

region. However, in retrospect, the tumor was evident

on an MRI that had been performed prior to venous

sampling, so the utility of this approach is not clear.

An additional approach that can be used for

confirmation that a suspicious lesion identified on

functional or anatomical imaging is the culprit tumor is

aspiration of the lesion. Elevated FGF23 in the aspirate

R64

is diagnostic of a culprit lesion. Inspection of cells in

the aspirate may reveal cellular morphology consistent

with that of a phosphaturic mesenchymal tumor,

further supporting that the aspirated lesion represents

the culprit lesion (Sciubba et al. 2009).

Despite all of the advances in imaging that are

available today, tumor localization may not be

successful. If this is the case, imaging studies should

be repeated in hopes that a tumor may be more evident

with time. This can be done every 1–2 years.

Treatment

Surgical resection

The treatment of choice for TIO is resection of the

tumor with a wide margin to insure complete resection.

Resection with a wide surgical margin is of utmost

importance, as recurrences of these tumors have been

reported (Clunie et al. 2000, Ogose et al. 2001,

Uramoto et al. 2009). Tumor resection is almost

always curative, and following complete resection of

the tumor, there is relatively rapid improvement.

FGF23 has a halflife of w45 min and disappears

rapidly from the circulation (Khosravi et al. 2007). The

majority of patients demonstrate surgical cure, as

evidenced by the return of serum phosphate to normal,

by post-operative day 5. Some patients may take as

long as 10 days and, in children, we have seen

phosphate return to normal in as few as 2 days. In fact,

it is return of serum phosphorus to normal after tumor

resection that confirms the diagnosis of TIO. Most

patients feel better within days to weeks of tumor

removal. Bone healing starts immediately, but depend-

ing on the severity of the disease, it may take up to a

year or more for significant clinical improvement.

Late recurrence due to metastatic disease is rare but

possible. This probably occurs in !5% of the patients

with TIO (Ogose et al. 2001, Folpe et al. 2004). Lung is

a common site for metastasis (Fig. 3), and as such

should be closely evaluated when there is a late

recurrence without evidence of local disease. The

lesions can be quite small and difficult to visualize.

Therefore, high-resolution CT is recommended as the

imaging modality of choice. More advanced disease

may present with a miliary pattern. The course after

metastasis is quite variable, and survival of up to 30

years has been reported (Harvey et al. 1992). In our

series of 31 cases of TIO, we have seen two cases of

recurrence due to tumor metastasis in the lung (Fig. 3).

There is no chemotherapeutic regimen with any

demonstrated efficacy in treating metastatic TIO.



600

700C

L acetabular lesion

A

400

500

R patellar lesion

200

300

FG

F23

(pg

/ml)

0

100B

D E F

90100G H

4050607080

0102030

FG

F23

(pg

/ml)

Catheter

Catheter tip

Venous sampling

r pop

abo

ve p

atell

a

Periph

eral

Right a

nter

ior fa

cial

Right s

inus

Right ju

gular

(low

)

Super

ior sa

gitta

l sinu

s (m

id)

Super

ior sa

gitta

l sinu

s (m

id)

Super

ior sa

gitta

l sinu

s (po

sterio

r)

Super

ior sa

gitta

l sinu

s (an

terio

r)

Right p

etro

sal

r sfv

high

r dee

p fe

m lo

w

r com

mon

iliac

r sfv

lower

r int

erna

l iliac

r hep

atic

r low

er p

op ve

ry lo

w

r pop

abo

ve kn

ee

r pop

very

high

R pop

low

I ver

tebr

al

I sfv

prox

I sfv

very

low d

istal

I circ

umfle

x pro

x

I com

mon

iliac

I com

mon

fem

I int il

iac is

ch b

orde

r

I int il

iac lo

w

I inte

rnal

iliac s

mall

I inte

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iliac l

arge

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..

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rnal

iliac l

arge

bra

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nch.

.

I int il

iac m

id

Figure 8 Utility of selective venous sampling in TIO. Selective venous sampling is useful in distinguishing between multiple suspectlesions, as in this patient who had uptake at both the region of the acetabulum (A) and patella (B). Elevated FGF23 in the veinsdraining the acetabular region (C) identified the lesion in this region as the causative lesion. Selective venous sampling is also usefulin identifying lesions in places difficult to image or to approach surgically. The brain shows generalized increased uptake on FDGPET/CT (D) making identification of a lesion in this area difficult. A lesion was seen on octreotide scan (E) and MRI (F). It was felt thatthis could be a TIO tumor or a meningioma, which are also octreotide positive. Venous sampling (G) demonstrated elevated FGF23(H), confirming that the lesion was the FGF23-secreting tumor. This material is reproduced from Andreopoulou et al. 2010b withpermission of John Wiley & Sons, Inc. r, right; l, left; pop, popliteal; sfv, superficial femoral vein; fem, femoral; prox, proximal; comm,common; int, internal; isch, ischial; mid, middle.


Radiofrequency ablation (RFA) has also been

reported as a possible treatment modality (Hesse et al.

2007b). Hesse et al. reported use of RFA in a 40-year-old

woman with TIO, in whom the tumor was located in

the femoral head. In order to preserve the hip joint,

CT-guided RFA was performed in two rounds of


treatment. The patient showed complete biochemical

and symptomatic recovery within weeks, and had

unremarkable follow-up at 1 year. While this is

promising, long-term follow-up and effectiveness in

other cases remains to be seen. Again, the need for a wide

margin is advocated to avoid recurrence or metastasis.

R65



Medical treatment

When the tumor cannot be localized or is not surgically

resectable, medical therapy with phosphate supple-

mentation and calcitriol or alfacalcidiol is used. The

treatment regimen that follows is essentially the same

as that used in non-TIO causes of hypophosphatemia.

When initiating treatment, it is prudent to check

weekly labs to guide titration of medications until

treatment targets are reached.

Phosphorus supplementation is the mainstay of

treatment. However, since phosphorus is rapidly

absorbed and cleared, multiple doses throughout the

day are necessary (at least 3–4 times per day) in an

attempt to try and get the serum phosphorus to the

lower end of the age-appropriate normal range.

Treatment to the lower end of the age-appropriate

range has been shown by bone biopsy to improve bone

disease. Whether treatment to targets below the normal

range is effective remains unclear. GI upset and

diarrhea may develop as a result of phosphate

supplementation. GI side effects can sometimes be

alleviated with divided dosing and administration with

food; however, they should not be provided with

calcium-rich foods. GI side effects can also sometimes

be avoided by using concentrated oral preparations that

were developed for treatment of constipation or for

bowel preparation prior to endoscopy. Various

phosphorus supplement preparations are listed in

Table 3. Secondary hyperparathyroidism can be seen

on presentation, due to suppression of 1,25-vitamin D

by FGF23, or it can develop as a result of phosphorus

supplementation. Active vitamin D (calcitriol or

alfacalcidiol) is used to prevent or treat secondary

hyperparathyroidism. The dose is titrated to keep the

PTH in the normal range. In the early phases of the

treatment of severe bone disease, additional calcium

supplementation may be necessary to provide mineral

ion substrate to heal the bone. Addition of calcium

supplements or increases in calcitriol and/or alfacalci-

diol are indicated for difficult to suppress PTH, very

Table 3 Phosphorus supplements

Phosphorus source Amount of elemental phosphorus

Neutra-Phos 8 mmol (248 mg) per capsule/packet

Neutro-Phos K 8 mmol (248 mg) per capsule/packet

K-Phos Neutral 8 mmol (248 mg) per tablet

K Phos Original 3.68 mmol (114 mg) per tablet

Fleet’s Phospho Soda 4.15 mmol (128.65 mg) per ml

Joulies Solution Varies depending on compounding

pharmacy

Adapted fromhttp://www.globalrph.com/phosphate_supplements.htm; http://www.newbornnetworks.org.uk/staffs/Nutrition.pdf.

R66

low urinary calcium, or hypocalcemia. As bone healing

progresses, the regimen needs to be modified. Calcium

supplementation and/or active vitamin D treatment

usually need to be decreased. One consequence of

over-treatment with active vitamin D is the develop-

ment of hypercalciuria and the risk for nephrocalci-

nosis/nephrolithiasis. While on chronic treatment,

periodic measurement of urine calcium should be

performed. Prolonged phosphorus supplementation can

lead to the development of tertiary hyperparathy-

roidism. This may require partial parathyroidectomy,

or treatment with the calcium-sensing receptor

agonist, cinacalcet.

The treatment regimen is to give 15–60 mg/kg per

day of elemental phosphorus (typically 1–3 g/day)

divided into 4–6 doses. Various formulations with

varying amounts of phosphorus are available (Table 3).

Calcitriol or alfacalcidiol is given at 15–60 ng/kg

per day, with a typical starting dose of 1.5 mg/day in

an adult.

A new treatment approach that holds promise, but

needs additional study for confirmation of efficacy and

establishment of safety, is cinacalcet, an agonist of the

calcium-sensing receptor that lowers blood PTH levels

(Geller et al. 2007). The use of cinacalcet was

advocated on the basis of evidence that FGF23 action

was PTH-dependent. Gupta et al. (2004) found that

both FGF23 and serum phosphorus were high in the

blood of patients with hypoparathyroidism, indicating

that in the absence of PTH, FGF23 was unable to

adequately lower blood phosphorus level. This led to

the notion that medically induced hypoparathyroidism

may be a potential treatment for TIO (Geller et al.

2007). In this paper, we were able to show that

cinacalcet increased %TRP and serum phosphorus,

allowed for a decrease in phosphate supplementation,

and led to bone healing, as assessed by iliac crest bone

biopsy. However, hypercalciuria developed, necessi-

tating the addition of a thiazide diuretic to lower

urinary calcium. Similarly, cinacalcet has shown

promise in treating patients with XLH, which is

also a disorder of excess FGF23 (Alon et al. 2008,

Yavropoulou et al. 2010). In patients with TIO

treated with cinacalcet, urinary calcium must be

monitored carefully to avoid nephrocalcinosis and/or

nephrolithiasis.

A previously advocated treatment for TIO was the

somatostatin analog, octreotide (Seufert et al. 2001).

This appeared to be a logical treatment, given the

presence of somatostatin receptors on the cell surface

of TIO tumors and the ability to detect the tumors with

radiolabeled octreotide. However, most clinicians have

not been able to reproduce the success that Seufert



http://www.globalrph.com/phosphate_supplements.htm

http://www.globalrph.com/phosphate_supplements.htm

http://www.newbornnetworks.org.uk/staffs/Nutrition.pdf


et al. had in the single patient they reported. Paglia

et al. (2002) reported their lack of success in a single

patient, and we saw no effect in five patients and have

abandoned further attempts (unpublished data).

Few reports are available on the role of external

beam radiation or chemotherapy in the treatment of

these patients. In the few reports that mention radiation

therapy, there does not appear to be any clear benefit

(Fuentealba et al. 2003, Uramoto et al. 2009).

Chemotherapy regimens that have been reported

include the combination of cisplatin, doxorubicin,

and methotrexate (Terek & Nielsen 2001) as well as

the use of dasatinib (Peters et al. 2010). In the first case,

chemotherapy was pursued as the first option as the

patient was felt to have an osteosarcoma. Following

treatment, the patient’s phosphate normalized (Terek

& Nielsen 2001). In the second case, the patient had

recurrent disease that could not be completely resected.

Due to strongly positive immunohistochemical stain-

ing of platelet-derived growth factor receptor, the

patient was started on dasatinib and has been stable on

this therapy (Peters et al. 2010). Given the limited

evidence for either radiation or chemotherapy, their

roles in treating these patients are not known at this

time. Given the slowly proliferating nature of these

tumors, we would expect that these treatments would

have little efficacy.

Medical treatment: monitoring

A baseline ultrasound should be obtained, and blood

and urine studies should be monitored approximately

every 3 months. For urine tests, checking the second

morning void for calcium and creatinine is suggested to

assess for hypercalciuria. If the calcium/creatinine is

R0.2, urinalysis should be done to check for the

presence of blood in the urine. If this is present,

calcitriol should be decreased and a 24 h urine for

calcium and creatinine should be checked with a goal

of obtaining normal urinary calcium/creatinine ratio. If

this remains elevated, calcitriol should be decreased

further. If calcium/creatinine is !0.2 and the serum

phosphorus and PTH are within targets, the current

regimen can be maintained. A summary of medical

therapy and monitoring is provided in Box 1.

Future directions

Treatment with calcitonin has also been explored as a

method to suppress FGF23 (van Boekel et al. 2008). A

single s.c. injection of calcitonin was able to suppress

FGF23 levels by 44.6% at 9 h post-injection. Long-

term treatment, however, was not pursued as focus was


given to localization of the tumor. We were unable to

replicate these findings in a single patient in whom we

attempted this treatment (unpublished data). Whether

calcitonin is truly an effective treatment awaits further

investigation.

Future treatment will likely be guided by a better

understanding of the biology of FGF23 and the nature

of these tumors. Recent investigations have led to a

rudimentary understanding of FGF23 synthesis, post-

translational modification, and signaling. While eluci-

dation of the transcriptional and translational

regulation of FGF23 is still lacking, it has become

evident that posttranslational glycosylation by UDP-N-

acetyl-alpha-D-galactosamine:polypeptide N-acetylga-

lactosaminyltransferase 3 (GalNAc-T3) is essential for

the secretion of biologically active FGF23 (Topaz et al.

2004, Benet-Pages et al. 2005, Frishberg et al. 2005,

Dumitrescu et al. 2009). The fact that patients null for

GalNAc-T3 have a phenotype that is completely

confined to abnormalities in mineral metabolism

suggests that GalNAc-T3 may eventually be a

therapeutic target for diseases of FGF23 excess, such

as TIO. A promising therapeutic currently in clinical

trials are monoclonal antibodies that target the FGF23–

FGFR1 interaction (Aono et al. 2009, 2010). A

monoclonal antibody that disrupts the interaction of

FGF23 with the FGFR appears to be the mechanism of

action with this approach.

Conclusion

TIO is a fascinating paraneoplastic syndrome caused

by unregulated over-secretion of the recently identified

phosphate and vitamin D regulating hormone, FGF23.

It is a debilitating disease that is cured with excision of

the tumors. The benign-appearing histopathology

typically seen in these tumors can be misleading, as

even clinically proven metastatic disease can have

benign cellular features. While the tumors can be

difficult to locate, a step-wise approach that involves

functional imaging, followed by anatomical imaging,

and, if necessary, selective venous sampling or

aspiration for confirmation is usually successful.

Excision with wide margins is important to avoid late

recurrence. When tumors cannot be identified, medical

treatment can be successful though periodic surveil-

lance is necessary.

Declaration of interest

The authors declare that there is no conflict of interest that

could be perceived as prejudicing the impartiality of the

research reported.

R67



Funding

This work was supported by the funding from the Division of

Intramural Research, National Institutes of Dental and

Craniofacial Research, National Institutes of Health,

Bethesda, Maryland, USA.

References

ADHR Consortium 2000 Autosomal dominant hypopho-

sphataemic rickets is associated with mutations in FGF23.

The ADHR Consortium. Nature Genetics 26 345–348.

(doi:10.1038/81664)

Ahn JM, Kim HJ, Cha CM, Kim J & Yim SG 2007

Oncogenic osteomalacia: induced by tumor, cured by

surgery. Oral Surgery, Oral Medicine, Oral Pathology,

Oral Radiology, and Endodontics 103 636–641. (doi:10.

1016/j.tripleo.2005.12.027)

Albright F & Reifenstein E 1948 Clinical hyperparathyroid-

ism. In Parathyroid Glands & Metabolic Bone Disease,

ch 3, p 56. Baltimore, MD, USA: The Williams & Wilkins

Company.

Albright F, Butler AM & Bloomber E 1937 Rickets resistant

to vitamin D therapy. American Journal of Diseases of

Children 54 529–547.

Alon U & Hellerstein S 1994 Assessment and interpretation

of the tubular threshold for phosphate in infants and

children. Pediatric Nephrology 8 250–251. (doi:10.1007/

BF00865491)

Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S &

Quarles LD 2008 Calcimimetics as an adjuvant treatment

for familial hypophosphatemic rickets. Clinical

Journal of the American Society of Nephrology 3

658–664. (doi:10.2215/CJN.04981107)

Andreopoulou P, Dumitrescu CE, Kelly MH, Brillante B,

Cutler CM, Wodajo FM, Chang R & Collins MT 2010a

Selective venous catheterization for the localization of

phosphaturic mesenchymal tumors. Journal of Bone and

Mineral Research [in press]. (doi:10.1002/jbmr.316)

Andreopoulou P, Millo C, Reynolds J, Kelly M, Brillante B,

Wodajo FM, Chang R, Chen CC & Collins MT 2010b

Multimodality Diagnosis and Treatment of Tumor

Induced Osteomalacia. Endocrine Reviews

31 (Supplement 1) OR08–6 S49.

Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H,

Urakawa I, Fujita T, Wada M, Yamashita T, Fukumoto S

et al. 2009 Therapeutic effects of anti-FGF23 antibodies

in hypophosphatemic rickets/osteomalacia. Journal of

Bone and Mineral Research 24 1879–1888. (doi:10.1359/

jbmr.090509)

Aono Y, Hasegawa H, Yamazaki Y, Shimada T, Fujita T,

Yamashita T & Fukumoto S 2010 Anti-FGF23

neutralizing antibodies ameliorate muscle weakness and

decreased spontaneous movement of Hyp mice.

Journal of Bone and Mineral Research 26 803–810.

(doi:10.1002/jbmr.275)

Aranami F, Segawa H, Furutani J, Kuwahara S, Tominaga R,

Hanabusa E, Tatsumi S, Kido S, Ito M & Miyamoto K

R68

2010 Fibroblast growth factor 23 mediates the phos-

phaturic actions of cadmium. Journal of Medical

Investigation 57 95–108. (doi:10.2152/jmi.57.95)

Auethavekiat P, Roberts JR, Biega TJ, Toney MO,

Christensen RS, Belnap CM & Berenberg JL 2005 Case 3.

Oncogenic osteomalacia associated with hemangioper-

icytoma localized by octreotide scan. Journal of Clinical

Oncology 23 3626–3628. (doi:10.1200/JCO.2005.05.043)

Bahrami A, Weiss SW, Montgomery E, Horvai AE, Jin L,

Inwards CY & Folpe AL 2009 RT-PCR analysis for

FGF23 using paraffin sections in the diagnosis of

phosphaturic mesenchymal tumors with and without

known tumor induced osteomalacia. American Journal of

Surgical Pathology 33 1348–1354. (doi:10.1097/PAS.

0b013e3181aa2311)

Baroncelli GI, Angiolini M, Ninni E, Galli V, Saggese R &

Giuca MR 2006 Prevalence and pathogenesis of dental

and periodontal lesions in children with X-linked

hypophosphatemic rickets. European Journal of

Paediatric Dentistry 7 61–66.

Baronofsky SI, Kalbhen CL, Demos TC & Sizemore GW

1999 Oncogenic osteomalacia secondary to a hemangio-

pericytoma of the hip: case report. Canadian Association

of Radiologists Journal 50 26–28.

Barth JH, Jones RG & Payne RB 2000 Calculation of renal

tubular reabsorption of phosphate: the algorithm performs

better than the nomogram. Annals of Clinical Biochemistry

37 79–81. (doi:10.1258/0004563001901371)

Beech TJ, Rokade A, Gittoes N & Johnson AP 2007 A

haemangiopericytoma of the ethmoid sinus causing

oncogenic osteomalacia: a case report and review of the

literature. International Journal of Oral and Maxillofacial

Surgery 36 956–958. (doi:10.1016/j.ijom.2007.03.005)

Benet-Pages A, Orlik P, Strom TM & Lorenz-Depiereux B

2005 An FGF23 missense mutation causes familial

tumoral calcinosis with hyperphosphatemia. Human

Molecular Genetics 14 385–390. (doi:10.1093/hmg/

ddi034)

Bergwitz C & Juppner H 2010 Regulation of phosphate

homeostasis by PTH, vitamin D, and FGF23. Annual

Review of Medicine 61 91–104. (doi:10.1146/annurev.

med.051308.111339)

Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe

M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO,

Anderson D et al. 2006 SLC34A3 mutations in patients

with hereditary hypophosphatemic rickets with hyper-

calciuria predict a key role for the sodium-phosphate

cotransporter NaPi-IIc in maintaining phosphate homeo-

stasis. American Journal of Human Genetics 78 179–192.

(doi:10.1086/499409)

van Boekel G, Ruinemans-Koerts J, Joosten F, Dijkhuizen P,

van Sorge A & de Boer H 2008 Tumor producing

fibroblast growth factor 23 localized by two-staged

venous sampling. European Journal of Endocrinology

158 431–437. (doi:10.1530/EJE-07-0779)

Bonnardeaux A & Bichet D 2008 Inherited disorders

associated with generalized dysfunction of the proximal



http://dx.doi.org/10.1038/81664

http://dx.doi.org/10.1016/j.tripleo.2005.12.027


http://dx.doi.org/10.1007/BF00865491

http://dx.doi.org/10.1007/BF00865491

http://dx.doi.org/10.2215/CJN.04981107

http://dx.doi.org/10.1002/jbmr.316




http://dx.doi.org/10.2152/jmi.57.95

http://dx.doi.org/10.1200/JCO.2005.05.043

http://dx.doi.org/10.1097/PAS.0b013e3181aa2311

http://dx.doi.org/10.1097/PAS.0b013e3181aa2311

http://dx.doi.org/10.1258/0004563001901371

http://dx.doi.org/10.1016/j.ijom.2007.03.005

http://dx.doi.org/10.1093/hmg/ddi034

http://dx.doi.org/10.1093/hmg/ddi034

http://dx.doi.org/10.1146/annurev.med.051308.111339

http://dx.doi.org/10.1146/annurev.med.051308.111339

http://dx.doi.org/10.1086/499409

http://dx.doi.org/10.1530/EJE-07-0779


tubule (renal Fanconi syndrome). In Brenner & Rectors:

The Kidney, 8 edn, pp 1390–1399. Ed B Brenner.

Philadelphia, PA: Saunders Elsevier.

Cai Q, Hodgson SF, Kao PC, Lennon VA, Klee GG,

Zinsmiester AR & Kumar R 1994 Brief report: inhibition

of renal phosphate transport by a tumor product in a

patient with oncogenic osteomalacia. New England

Journal of Medicine 330 1645–1649. (doi:10.1056/

NEJM199406093302304)

Carey DE, Drezner MK, Hamdan JA, Mange M, Ahmad MS,

Mubarak S & Nyhan WL 1986 Hypophosphatemic

rickets/osteomalacia in linear sebaceous nevus syndrome:

a variant of tumor-induced osteomalacia. Journal of

Pediatrics 109 994–1000. (doi:10.1016/S0022-3476(86)

80283-9)

Casari S, Rossi V, Varenna M, Gasparini M, Parafioriti A,

Failoni S & Sinigaglia L 2003 A case of oncogenic

osteomalacia detected by 111In-pentetreotide total body

scan. Clinical and Experimental Rheumatology 21

493–496.

Chadha V & Alon US 2009 Hereditary renal tubular

disorders. Seminars in Nephrology 29 399–411. (doi:10.

1016/j.semnephrol.2009.03.013)

Cheung FM, Ma L, Wu WC, Siu TH, Choi PT & Tai YP 2006

Oncogenic osteomalacia associated with an occult

phosphaturic mesenchymal tumour: clinico-radiologico-

pathological correlation and ultrastructural studies. Hong

Kong Medical Journal 12 319–321.

Chouhan V, Agrawal K, Vinothkumar TK & Mathesul A

2010 Bilateral insufficiency fracture of the femoral head

and neck in a case of oncogenic osteomalacia. Journal of

Bone and Joint Surgery. British Volume 92 1028–1031.

(doi:10.1302/0301-620X.92B7.24526)

Clunie GP, Fox PE & Stamp TC 2000 Four cases of acquired

hypophosphataemic (‘oncogenic’) osteomalacia.

Problems of diagnosis, treatment and long-term management.

Rheumatology 39 1415–1421. (doi:10.1093/rheumatology/

39.12.1415)

Collins MT, Chebli C, Jones J, Kushner H, Consugar M,

Rinaldo P, Wientroub S, Bianco P & Robey PG 2001

Renal phosphate wasting in fibrous dysplasia of bone is

part of a generalized renal tubular dysfunction similar to

that seen in tumor-induced osteomalacia. Journal of Bone

and Mineral Research 16 806–813. (doi:10.1359/jbmr.

2001.16.5.806)

Collins MT, Lindsay JR, Jain A, Kelly MH, Cutler CM,

Weinstein LS, Liu J, Fedarko NS & Winer KK 2005

Fibroblast growth factor-23 is regulated by

1alpha,25-dihydroxyvitamin D. Journal of Bone

and Mineral Research 20 1944–1950. (doi:10.1359/

JBMR.050718)

Colt E, Gopan T & Chong HS 2005 Oncogenic osteomalacia

cured by removal of an organized hematoma. Endocrine

Practice 11 190–193.

Dash T, Parker MG & Lafayette RA 1997 Profound

hypophosphatemia and isolated hyperphosphaturia in


two cases of multiple myeloma. American Journal of

Kidney Diseases 29 445–448. (doi:10.1016/S0272-6386

(97)90207-9)

Davis S, Kessler W, Haddad BM & Maesaka JK 1980 Acute

renal tubular dysfunction following cis-dichlorodiammine

platinum therapy. Journal of Medicine 11 133–141.

De Beur SM, Finnegan RB, Vassiliadis J, Cook B, Barberio D,

Estes S, Manavalan P, Petroziello J, Madden SL, Cho JY

et al. 2002 Tumors associated with oncogenic osteomalacia

express genes important in bone and mineral metabolism.


(doi:10.1359/jbmr.2002.17.6.1102)

Dehghani M, Dabaghmanesh MH & Omrani GH 2010

Photoclinic. Oncogenic osteomalacia. Archives of Iranian

Medicine 13 253–254.

Dent CE & Gertner JM 1976 Hypophosphataemic osteoma-

lacia in fibrous dysplasia. Quarterly Journal of Medicine

45 411–420.

Dewitt CA, Collins MT & Cowen EW 2007 Diffuse pain,

hypophosphatemia, and a subcutaneous nodule.

Journal of the American Academy of Dermatology 57

509–512. (doi:10.1016/j.jaad.2007.05.010)

Dissanayake AM, Wilson JL, Holdaway IM & Reid IR 2003

Oncogenic osteomalacia: culprit tumour detection whole

body magnetic resonance imaging. Internal Medicine

Journal 33 615–616. (doi:10.1111/j.1445-5994.2003.

00488.x)

Dowman JK & Khattak FH 2006 Oncogenic hypopho-

sphataemic osteomalacia mimicking bone metastases on

isotope bone scan. Annals of Rheumatic Disease 65 1664.

(doi:10.1136/ard.2006.057943)

Drezner M 1999 Tumor-induced osteomalacia. In Primer on

the Metabolic Bone Diseases and Disorders of Mineral

Metabolism, 4 edn, Ed M Favus. Philadelphia, PA:

Lippincott Williams & Wilkins

Drezner MK 2001 Tumor-induced osteomalacia. Reviews in

Endocrine & Metabolic Disorders 2 175–186. (doi:10.

1023/A:1010006811394)

Duet M, Kerkeni S, Sfar R, Bazille C, Liote F & Orcel P 2008

Clinical impact of somatostatin receptor scintigraphy in

the management of tumor-induced osteomalacia. Clinical

Nuclear Medicine 33 752–756. (doi:10.1097/RLU.

0b013e31818866bf)

Dumitrescu CE, Kelly MH, Khosravi A, Hart TC, Brahim J,

White KE, Farrow EG, Nathan MH, Murphey MD &

Collins MT 2009 A case of familial tumoral calcino-

sis/hyperostosis-hyperphosphatemia syndrome due to

a compound heterozygous mutation in GALNT3

demonstrating new phenotypic features. Osteoporosis

International 20 1273–1278. (doi:10.1007/s00198-008-

0775-z)

Dupond JL, Mahammedi H, Magy N, Blagosklonov O,

Meaux-Ruault N & Kantelip B 2005a Detection of a

mesenchymal tumor responsible for hypophosphatemic

osteomalacia using FDG-PET. European Journal of

Internal Medicine 16 445–446. (doi:10.1016/j.ejim.2005.

07.003)

R69


http://dx.doi.org/10.1056/NEJM199406093302304


http://dx.doi.org/10.1016/S0022-3476(86)80283-9

http://dx.doi.org/10.1016/S0022-3476(86)80283-9

http://dx.doi.org/10.1016/j.semnephrol.2009.03.013

http://dx.doi.org/10.1016/j.semnephrol.2009.03.013

http://dx.doi.org/10.1302/0301-620X.92B7.24526

http://dx.doi.org/10.1093/rheumatology/39.12.1415

http://dx.doi.org/10.1093/rheumatology/39.12.1415

http://dx.doi.org/10.1359/jbmr.2001.16.5.806


http://dx.doi.org/10.1359/JBMR.050718


http://dx.doi.org/10.1016/S0272-6386(97)90207-9

http://dx.doi.org/10.1016/S0272-6386(97)90207-9


http://dx.doi.org/10.1016/j.jaad.2007.05.010

http://dx.doi.org/10.1111/j.1445-5994.2003.00488.x

http://dx.doi.org/10.1111/j.1445-5994.2003.00488.x

http://dx.doi.org/10.1136/ard.2006.057943

http://dx.doi.org/10.1023/A:1010006811394

http://dx.doi.org/10.1023/A:1010006811394

http://dx.doi.org/10.1097/RLU.0b013e31818866bf

http://dx.doi.org/10.1097/RLU.0b013e31818866bf

http://dx.doi.org/10.1007/s00198-008-0775-z

http://dx.doi.org/10.1007/s00198-008-0775-z

http://dx.doi.org/10.1016/j.ejim.2005.07.003



Dupond JL, Mahammedi H, Prie D, Collin F, Gil H,

Blagosklonov O, Ricbourg B, Meaux-Ruault N &

Kantelip B 2005b Oncogenic osteomalacia: diagnostic

importance of fibroblast growth factor 23 and F-18

fluorodeoxyglucose PET/CT scan for the diagnosis and

follow-up in one case. Bone 36 375–378. (doi:10.1016/j.

bone.2005.01.001)

Earle KE, Seneviratne T, Shaker J & Shoback D 2004

Fanconi’s syndrome in HIVC adults: report of three cases

and literature review. Journal of Bone and Mineral

Research 19 714–721. (doi:10.1359/jbmr.2004.19.5.714)

Econs MJ & Drezner MK 1994 Tumor-induced osteomalacia

– unveiling a new hormone. New England Journal of

Medicine 330 1679–1681. (doi:10.1056/NEJM19940609

3302310)

Econs MJ & McEnery PT 1997 Autosomal dominant

hypophosphatemic rickets/osteomalacia: clinical

characterization of a novel renal phosphate-wasting

disorder. Journal of Clinical Endocrinology and

Metabolism 82 674–681. (doi:10.1210/jc.82.2.674)

Elston MS, Stewart IJ, Clifton-Bligh R & Conaglen JV 2007

A case of oncogenic osteomalacia with preoperative

secondary hyperparathyroidism: description of the

biochemical response of FGF23 to octreotide therapy

and surgery. Bone 40 236–241. (doi:10.1016/j.bone.2006.

07.027)

Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D,

Minagawa M, Sugimoto T, Yamauchi M, Michigami T

et al. 2008 Clinical usefulness of measurement of

fibroblast growth factor 23 (FGF23) in hypophosphatemic

patients: proposal of diagnostic criteria using FGF23

measurement. Bone 42 1235–1239. (doi:10.1016/j.bone.

2008.02.014)

von Falck C, Rodt T, Rosenthal H, Langer F, Goesling T,

Knapp WH & Galanski M 2008 (68)Ga-DOTANOC

PET/CT for the detection of a mesenchymal tumor

causing oncogenic osteomalacia. European Journal of

Nuclear Medicine and Molecular Imaging 35 1034.

(doi:10.1007/s00259-008-0755-8)

Farrow EG, Davis SI, Summers LJ & White KE 2009

Initial FGF23-mediated signaling occurs in the distal

convoluted tubule. Journal of the American Society of

Nephrology 20 955–960. (doi:10.1681/ASN.

2008070783)

Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X,

Rauch F, Davis SI, Zhang S et al. 2006 Loss of DMP1

causes rickets and osteomalacia and identifies a role for

osteocytes in mineral metabolism. Nature Genetics 38

1310–1315. (doi:10.1038/ng1905)

Ferrari SL, Bonjour JP & Rizzoli R 2005 Fibroblast growth

factor-23 relationship to dietary phosphate and renal

phosphate handling in healthy young men. Journal of

Clinical Endocrinology and Metabolism 90 1519–1524.

(doi:10.1210/jc.2004-1039)

Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M,

Bertoni F, Cho JY, Econs MJ, Inwards CY, Jan de Beur

SM, Mentzel T et al. 2004 Most osteomalacia-associated

R70

mesenchymal tumors are a single histopathologic entity:

an analysis of 32 cases and a comprehensive review of the

literature. American Journal of Surgical Pathology 28

1–30. (doi:10.1097/00000478-200401000-00001)

Friedlaender MM, Wald H, Dranitzki-Elhalel M, Zajicek HK,

Levi M & Popovtzer MM 2001 Vitamin D reduces renal

NaPi-2 in PTH-infused rats: complexity of vitamin D action

on renal P(i) handling. American Journal of Physiology.

Renal Physiology 281 F428–F433.

Frishberg Y, Topaz O, Bergman R, Behar D, Fisher D,

Gordon D, Richard G & Sprecher E 2005 Identification of

a recurrent mutation in GALNT3 demonstrates that

hyperostosis-hyperphosphatemia syndrome and familial

tumoral calcinosis are allelic disorders. Journal of

Molecular Medicine 83 33–38. (doi:10.1007/s00109-004-

0610-8)

Fuentealba C, Pinto D, Ballesteros F, Pacheco D, Boettiger O,

Soto N, Fernandez W, Gabler F, Gonzales G & Reginato AJ

2003 Oncogenic hypophosphatemic osteomalacia associ-

ated with a nasal hemangiopericytoma. Journal of Clinical

Rheumatology 9 373–379. (doi:10.1097/01.rhu.00001019

06.15276.ed)

Fukumoto S, Takeuchi Y, Nagano A & Fujita T 1999

Diagnostic utility of magnetic resonance imaging skeletal

survey in a patient with oncogenic osteomalacia. Bone 25

375–377. (doi:10.1016/S8756-3282(99)00170-2)

Furco A, Roger M, Mouchet B, Richard O, Martinache X &

Fur A 2002 Osteomalacia cured by surgery. European

Journal of Internal Medicine 13 67–69. (doi:10.1016/

S0953-6205(01)00196-0)

Garcia CA & Spencer RP 2002 Bone and In-111 octreotide

imaging in oncogenic osteomalacia: a case report.

Clinical Nuclear Medicine 27 582–583. (doi:10.1097/

00003072-200208000-00007)

Gascon A, Cobeta-Garcia JC, Iglesias E, Lazaro JM &

Muniesa JA 1999 Oncogenic osteomalacia in a patient

with a fibrocystic nodule of the breast. Nephrology,

Dialysis, Transplantation 14 1561–1563. (doi:10.1093/

ndt/14.6.1561)

Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS &

Collins MT 2007 Cinacalcet in the management of tumor-

induced osteomalacia. Journal of Bone and Mineral

Research 22 931–937. (doi:10.1359/jbmr.070304)

Gershinsky M, Croitoru S, Dickstein G, Bardicef O, Gelman R

& Barmeir E 2007 Imaging of oncogenic osteomalacia.

Israel Medical Association Journal 9 566–567.

Gore MO, Welch BJ, Geng W, Kabbani W, Maalouf NM,

Zerwekh JE, Moe OW & Sakhaee K 2009 Renal

phosphate wasting due to tumor-induced osteomalacia:

a frequently delayed diagnosis. Kidney International 76

342–347. (doi:10.1038/ki.2008.355)

Gupta A, Winer K, Econs MJ, Marx SJ & Collins MT 2004

FGF-23 is elevated by chronic hyperphosphatemia.

Journal of Clinical Endocrinology and Metabolism 89

4489–4492. (doi:10.1210/jc.2004-0724)

Habra MA, Jimenez C, Huang SC, Cote GJ, Murphy WA Jr,

Gagel RF & Hoff AO 2008 Expression analysis of



http://dx.doi.org/10.1016/j.bone.2005.01.001





http://dx.doi.org/10.1210/jc.82.2.674





http://dx.doi.org/10.1007/s00259-008-0755-8

http://dx.doi.org/10.1681/ASN.2008070783

http://dx.doi.org/10.1681/ASN.2008070783

http://dx.doi.org/10.1038/ng1905

http://dx.doi.org/10.1210/jc.2004-1039

http://dx.doi.org/10.1097/00000478-200401000-00001

http://dx.doi.org/10.1007/s00109-004-0610-8

http://dx.doi.org/10.1007/s00109-004-0610-8

http://dx.doi.org/10.1097/01.rhu.0000101906.15276.ed

http://dx.doi.org/10.1097/01.rhu.0000101906.15276.ed

http://dx.doi.org/10.1016/S8756-3282(99)00170-2

http://dx.doi.org/10.1016/S0953-6205(01)00196-0

http://dx.doi.org/10.1016/S0953-6205(01)00196-0

http://dx.doi.org/10.1097/00003072-200208000-00007

http://dx.doi.org/10.1097/00003072-200208000-00007

http://dx.doi.org/10.1093/ndt/14.6.1561

http://dx.doi.org/10.1093/ndt/14.6.1561


http://dx.doi.org/10.1038/ki.2008.355

http://dx.doi.org/10.1210/jc.2004-0724


fibroblast growth factor-23, matrix extracellular phos-

phoglycoprotein, secreted frizzled-related protein-4, and

fibroblast growth factor-7: identification of fibroblast

growth factor-23 and matrix extracellular phosphoglyco-

protein as major factors involved in tumor-induced

osteomalacia. Endocrine Practice 14 1108–1114.

Haeusler G, Freilinger M, Dominkus M, Egerbacher M,

Amann G, Kolb A, Schlegel W, Raimann A &

Staudenherz A 2010 Tumor-induced hypophosphatemic

rickets in an adolescent boy – clinical presentation,

diagnosis, and histological findings in growth plate and

muscle tissue. Journal of Clinical Endocrinology and

Metabolism 95 4511–4517. (doi:10.1210/jc.2010-0543)

Halperin F, Anderson RJ & Mulder JE 2007 Tumor-induced

osteomalacia: the importance of measuring serum

phosphorus levels. Nature Clinical Practice.

Endocrinology & Metabolism 3 721–725. (doi:10.1038/

ncpendmet0639)

Hannan FM, Athanasou NA, Teh J, Gibbons CL, Shine B &

Thakker RV 2008 Oncogenic hypophosphataemic

osteomalacia: biomarker roles of fibroblast growth

factor 23, 1,25-dihydroxyvitamin D3 and lymphatic

vessel endothelial hyaluronan receptor 1. European

Journal of Endocrinology 158 265–271. (doi:10.1530/

EJE-07-0485)

Harbeck B, Schocklmann H, Seekamp A, Czech N &

Monig H 2009 Tumor-induced osteomalacia: successful

treatment by radio-guided tumor surgery. Journal of

Clinical Rheumatology 15 31–34. (doi:10.1097/RHU.

0b013e3181960483)

Harish S, Jurriaans E, Jan E, Sur M & Colterjohn N 2008

Giant cell tumour of soft tissue causing oncogenic

osteomalacia: report demonstrating the use of octreotide

scintigraphy in tumour localization. Clinical Radiology

63 101–107. (doi:10.1016/j.crad.2007.05.017)

Harvey JN, Gray C & Belchetz PE 1992 Oncogenous

osteomalacia and malignancy. Clinical Endocrinology 37

379–382. (doi:10.1111/j.1365-2265.1992.tb02342.x)

Hasegawa T, Shimoda T, Yokoyama R, Beppu Y, Hirohashi

S & Maeda S 1999 Intracortical osteoblastic osteosar-

coma with oncogenic rickets. Skeletal Radiology 28

41–45. (doi:10.1007/s002560050470)

Hesse E, Moessinger E, Rosenthal H, Laenger F, Brabant G,

Petrich T, Gratz KF & Bastian L 2007a Oncogenic

osteomalacia: exact tumor localization by co-registration

of positron emission and computed tomography.


(doi:10.1359/jbmr.060909)

Hesse E, Rosenthal H & Bastian L 2007b Radiofrequency

ablation of a tumor causing oncogenic osteomalacia. New

England Journal of Medicine 357 422–424. (doi:10.1056/

NEJMc070347)

Heylen A, Dasnoy D, Hustin J & Pochet JM 1999 Tumor-

related osteomalacia followed after treatment by

hyperparathyroidism. Revue du Rhumatisme (English ed.)

66 53–57.


Hodgson SF, Clarke BL, Tebben PJ, Mullan BP, Cooney WP III

& Shives TC 2006 Oncogenic osteomalacia: localization

of underlying peripheral mesenchymal tumors with use

of Tc 99m sestamibi scintigraphy. Endocrine Practice 12

35–42.

Ichikawa S, Sorenson AH, Imel EA, Friedman NE, Gertner

JM & Econs MJ 2006 Intronic deletions in the SLC34A3

gene cause hereditary hypophosphatemic rickets

with hypercalciuria. Journal of Clinical

Endocrinology and Metabolism 91 4022–4027. (doi:10.

1210/jc.2005-2840)

Imel EA, Peacock M, Pitukcheewanont P, Heller HJ, Ward LM,

Shulman D, Kassem M, Rackoff P, Zimering M, Dalkin A

et al. 2006 Sensitivity of fibroblast growth factor 23

measurements in tumor-induced osteomalacia. Journal of


(doi:10.1210/jc.2005-2105)

Imel EA, Hui SL & Econs MJ 2007 FGF23 concentrations

vary with disease status in autosomal dominant hypo-

phosphatemic rickets. Journal of Bone and Mineral


Inokuchi G, Tanimoto H, Ishida H, Sugimoto T, Yamauchi M,

Miyauchi A & Nibu K 2006 A paranasal tumor associated

with tumor-induced osteomalacia. Laryngoscope 116

1930–1933. (doi:10.1097/01.mlg.0000231295.67060.89)

Ishii A, Imanishi Y, Kobayashi K, Hashimoto J, Ueda T,

Miyauchi A, Koyano HM, Kaji H, Saito T, Oba K et al.

2010 The levels of somatostatin receptors in causative

tumors of oncogenic osteomalacia are insufficient for their

agonist to normalize serum phosphate levels. Calcified

Tissue International 86 455–462. (doi:10.1007/s00223-

010-9369-9)

Ito N, Fukumoto S, Takeuchi Y, Takeda S, Suzuki H,

Yamashita T & Fujita T 2007 Effect of acute changes of

serum phosphate on fibroblast growth factor (FGF) 23

levels in humans. Journal of Bone and Mineral

Metabolism 25 419–422. (doi:10.1007/s00774-007-

0779-3)

Ito N, Shimizu Y, Suzuki H, Saito T, Okamoto T, Hori M,

Akahane M, Fukumoto S & Fujita T 2010 Clinical utility

of systemic venous sampling of FGF23 for identifying

tumours responsible for tumour-induced osteomalacia.

Journal of Internal Medicine 268 390–394. (doi:10.1111/

j.1365-2796.2010.02262.x)

Ivker R, Resnick SD & Skidmore RA 1997 Hypopho-

sphatemic vitamin D-resistant rickets, precocious pub-

erty, and the epidermal nevus syndrome. Archives of

Dermatology 133 1557–1561. (doi:10.1001/archderm.

133.12.1557)

Izzedine H, Launay-Vacher V, Isnard-Bagnis C & Deray G

2003 Drug-induced Fanconi’s syndrome. American

Journal of Kidney Diseases 41 292–309. (doi:10.1053/

ajkd.2003.50037)

Jacob JJ, Finny P, Thomas M, Thomas N & John M 2007

Oncogenic osteomalacia. Journal of Association of

Physicians of India 55 231–233.

R71


http://dx.doi.org/10.1210/jc.2010-0543

http://dx.doi.org/10.1038/ncpendmet0639

http://dx.doi.org/10.1038/ncpendmet0639



http://dx.doi.org/10.1097/RHU.0b013e3181960483

http://dx.doi.org/10.1097/RHU.0b013e3181960483

http://dx.doi.org/10.1016/j.crad.2007.05.017

http://dx.doi.org/10.1111/j.1365-2265.1992.tb02342.x

http://dx.doi.org/10.1007/s002560050470


http://dx.doi.org/10.1056/NEJMc070347

http://dx.doi.org/10.1056/NEJMc070347

http://dx.doi.org/10.1210/jc.2005-2840

http://dx.doi.org/10.1210/jc.2005-2840

http://dx.doi.org/10.1210/jc.2005-2105


http://dx.doi.org/10.1097/01.mlg.0000231295.67060.89

http://dx.doi.org/10.1007/s00223-010-9369-9

http://dx.doi.org/10.1007/s00223-010-9369-9

http://dx.doi.org/10.1007/s00774-007-0779-3

http://dx.doi.org/10.1007/s00774-007-0779-3

http://dx.doi.org/10.1111/j.1365-2796.2010.02262.x

http://dx.doi.org/10.1111/j.1365-2796.2010.02262.x

http://dx.doi.org/10.1001/archderm.133.12.1557

http://dx.doi.org/10.1001/archderm.133.12.1557

http://dx.doi.org/10.1053/ajkd.2003.50037

http://dx.doi.org/10.1053/ajkd.2003.50037


Jagtap VS, Sarathi V, Lila AR, Malhotra G, Sankhe SS,

Bandgar T, Menon P & Shah NS 2010 Tumor induced

osteomalacia: a single center experience. Endocrine

Practice 16 1–19. (doi:10.4158/10024.GL)

Jan de Beur SM 2005 Tumor-induced osteomalacia.

Journal of the American Medical Association 294

1260–1267. (doi:10.1001/jama.294.10.1260)

Jan de Beur SM, Streeten EA, Civelek AC, McCarthy EF,

Uribe L, Marx SJ, Onobrakpeya O, Raisz LG, Watts NB,

Sharon M et al. 2002 Localisation of mesenchymal

tumours by somatostatin receptor imaging. Lancet 359

761–763. (doi:10.1016/S0140-6736(02)07846-7)

Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T,

Imanishi Y, Yamamoto T, Hampson G, Koshiyama H,

Ljunggren O et al. 2003 Fibroblast growth factor 23 in

oncogenic osteomalacia and X-linked hypophosphatemia.

New England Journal of Medicine 348 1656–1663.

(doi:10.1056/NEJMoa020881)

Jung GH, Kim JD, Cho Y, Chung SH, Lee JH & Sohn KR

2010 A 9-month-old phosphaturic mesenchymal tumor

mimicking the intractable rickets. Journal of Pediatric

Orthopaedics. Part B/ European Paediatric Orthopaedic

Society, Pediatric Orthopaedic Society of North America

19 127–132. (doi:10.1097/BPB.0b013e32832f59cb)

Kaul M, Silverberg M, Dicarlo EF, Schneider R, Bass AR &

Erkan D 2007 Tumor-induced osteomalacia. Clinical

Rheumatology 26 1575–1579. (doi:10.1007/s10067-006-

0468-y)

Kaylie DM, Jackson CG & Gardner EK 2006 Oncogenic

osteomalacia caused by phosphaturic mesenchymal tumor

of the temporal bone. Otolaryngology – Head and Neck

Surgery 135 653–654. (doi:10.1016/j.otohns.2005.03.086)

Kenealy H, Holdaway I & Grey A 2008 Occult nasal sinus

tumours causing oncogenic osteomalacia. European

Journal of Internal Medicine 19 516–519. (doi:10.1016/j.

ejim.2008.01.011)

Kenny AP & Glen AC 1973 Tests of phosphate reabsorption.

Lancet 2 158. (doi:10.1016/S0140-6736(73)93112-7)

Khadgawat R, Singh Y, Kansara S, Tandon N, Bal C, Seith A

& Kotwal P 2009 PET/CT localisation of a scapular

haemangiopericytoma with tumour-induced osteomala-

cia. Singapore Medical Journal 50 e55–e57.

Khosravi A, Cutler CM, Kelly MH, Chang R, Royal RE,

Sherry RM, Wodajo FM, Fedarko NS & Collins MT 2007

Determination of the elimination half-life of fibroblast

growth factor-23. Journal of Clinical Endocrinology and

Metabolism 92 2374–2377. (doi:10.1210/jc.2006-2865)

Kimizuka T, Ozaki Y & Sumi Y 2004 Usefulness of 201Tl

and 99mTc MIBI scintigraphy in a case of oncogenic

osteomalacia. Annals of Nuclear Medicine 18 63–67.

(doi:10.1007/BF02985616)

Kobayashi K, Nakao K, Kawai K, Ito K, Hukumoto S,

Asakage T, Oota S & Motoi R 2010 Tumor-induced

osteomalacia originating from the temporal bone: a case

report. Head & Neck [in press]. (doi:10.1002/hed.21355)

Konishi K, Nakamura M, Yamakawa H, Suzuki H, Saruta T,

Hanaoka H & Davatchi F 1991 Hypophosphatemic

R72

osteomalacia in von Recklinghausen neurofibromatosis.

American Journal of the Medical Sciences 301 322–328.

(doi:10.1097/00000441-199105000-00006)

Koriyama N, Nishimoto K, Kodama T, Nakazaki M, Kurono

Y, Yoshida H & Tei C 2006 Oncogenic osteomalacia in a

case with a maxillary sinus mesenchymal tumor.

American Journal of the Medical Sciences 332 142–147.

(doi:10.1097/00000441-200609000-00010)

Kurien R, Manipadam MT & Rupa V 2010 Oncogenic

osteomalacia in a patient with an ethmoid sinus tumour.

Journal of Laryngology and Otology 124 799–803.

(doi:10.1017/S0022215109992313)

Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A,

Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW

et al. 2006 Regulation of fibroblast growth factor-23

signaling by klotho. Journal of Biological Chemistry 281

6120–6123. (doi:10.1074/jbc.C500457200)

Ladha SS, Whitaker MD & Bosch EP 2006 Oncogenic

osteomalacia: muscular weakness and multiple fractures.

Neurology 67 364–365. (doi:10.1212/01.wnl.

0000225057.56863.33)

Lamont EB, Cavaghan MK & Brockstein BE 1999

Oncogenic osteomalacia as a harbinger of recurrent

osteosarcoma. Sarcoma 3 95–99. (doi:10.1080/

13577149977712)

Larsson T, Nisbeth U, Ljunggren O, Juppner H & Jonsson KB

2003 Circulating concentration of FGF-23 increases as

renal function declines in patients with chronic kidney

disease, but does not change in response to variation

in phosphate intake in healthy volunteers. Kidney

International 64 2272–2279. (doi:10.1046/j.1523-1755.

2003.00328.x)

Lee HK, Sung WW, Solodnik P & Shimshi M 1995 Bone

scan in tumor-induced osteomalacia. Journal of Nuclear

Medicine 36 247–249.

Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N,

Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S,

Hadad Y, Goding J et al. 2010 Autosomal-recessive

hypophosphatemic rickets is associated with an inacti-

vation mutation in the ENPP1 gene. American Journal of

Human Genetics 86 273–278. (doi:10.1016/j.ajhg.2010.

01.010)

Lewiecki EM, Urig EJ Jr & Williams RC Jr 2008 Tumor-

induced osteomalacia: lessons learned. Arthritis and

Rheumatism 58 773–777. (doi:10.1002/art.23278)

Lichter-Konecki U, Broman KW, Blau EB & Konecki DS

2001 Genetic and physical mapping of the locus for

autosomal dominant renal Fanconi syndrome, on

chromosome 15q15.3. American Journal of Human

Genetics 68 264–268. (doi:10.1086/316923)

Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach

B, Scheinman SJ, Harding B, Bolino A, Devoto M,

Goodyer P et al. 1996 A common molecular basis for

three inherited kidney stone diseases. Nature 379

445–449. (doi:10.1038/379445a0)

Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M,

Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser



http://dx.doi.org/10.4158/10024.GL

http://dx.doi.org/10.1001/jama.294.10.1260

http://dx.doi.org/10.1016/S0140-6736(02)07846-7

http://dx.doi.org/10.1056/NEJMoa020881

http://dx.doi.org/10.1097/BPB.0b013e32832f59cb

http://dx.doi.org/10.1007/s10067-006-0468-y

http://dx.doi.org/10.1007/s10067-006-0468-y

http://dx.doi.org/10.1016/j.otohns.2005.03.086



http://dx.doi.org/10.1016/S0140-6736(73)93112-7

http://dx.doi.org/10.1210/jc.2006-2865

http://dx.doi.org/10.1007/BF02985616

http://dx.doi.org/10.1002/hed.21355

http://dx.doi.org/10.1097/00000441-199105000-00006

http://dx.doi.org/10.1097/00000441-200609000-00010

http://dx.doi.org/10.1017/S0022215109992313

http://dx.doi.org/10.1074/jbc.C500457200

http://dx.doi.org/10.1212/01.wnl.0000225057.56863.33

http://dx.doi.org/10.1212/01.wnl.0000225057.56863.33

http://dx.doi.org/10.1080/13577149977712

http://dx.doi.org/10.1080/13577149977712

http://dx.doi.org/10.1046/j.1523-1755.2003.00328.x

http://dx.doi.org/10.1046/j.1523-1755.2003.00328.x

http://dx.doi.org/10.1016/j.ajhg.2010.01.010


http://dx.doi.org/10.1002/art.23278

http://dx.doi.org/10.1086/316923

http://dx.doi.org/10.1038/379445a0


SM, Rittmaster RS, Shlossberg AH et al. 2006a DMP1

mutations in autosomal recessive hypophosphatemia

implicate a bone matrix protein in the regulation of

phosphate homeostasis. Nature Genetics 38 1248–1250.

(doi:10.1038/ng1868)

Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-

Rakover Y, Wagenstaller J, Tiosano D, Gershoni-Baruch R,

Albers N, Lichtner P, Schnabel D et al. 2006b Hereditary

hypophosphatemic rickets with hypercalciuria is caused

by mutations in the sodium-phosphate cotransporter gene

SLC34A3. American Journal of Human Genetics 78

193–201. (doi:10.1086/499410)

Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G &

Strom TM 2010 Loss-of-function ENPP1 mutations

cause both generalized arterial calcification of infancy

and autosomal-recessive hypophosphatemic rickets.

American Journal of Human Genetics 86 267–272.

(doi:10.1016/j.ajhg.2010.01.006)

Lui CY, Khoo R, Law TC & Chong SF 2002 Case report.

Tumour-induced osteomalacia in a patient with osseous

haemangioma. Clinical Radiology 57 1125–1127.

(doi:10.1053/crad.2002.1091)

Malabanan AO, Turner AK, Rosenberg IN & Holick MF 1998

Oncogenic osteomalacia: clinical presentation, densito-

metric findings, and response to therapy. Journal of

Clinical Densitometry 1 77–80. (doi:10.1385/JCD:1:1:77)

Mannstadt M, Lorente C & Juppner H 2008 Rapid detection

of intact FGF-23 in tumor tissue from patients with

oncogenic osteomalacia. Clinical Chemistry 54

1252–1254. (doi:10.1373/clinchem.2007.102418)

Marshall AE, Martin SE, Agaram NP, Chen JH, Horn EM,

Douglas-Akinwande AC & Hattab EM 2010 A 61-year-

old woman with osteomalacia and a thoracic spine lesion.

Brain Pathology 20 499–502. (doi:10.1111/j.1750-3639.

2009.00360.x)

McCance R 1947 Osteomalacia with Looser’s nodes

(Milkman’s syndrome) due to a raised resistance to

vitamin D acquired about the age of 15 years. Quarterly

Journal of Medicine 16 33–46.

Meyer RA Jr, Meyer MH & Gray RW 1989 Parabiosis

suggests a humoral factor is involved in X-linked

hypophosphatemia in mice. Journal of Bone and Mineral


Miyauchi A, Fukase M, Tsutsumi M & Fujita T 1988

Hemangiopericytoma-induced osteomalacia: tumor

transplantation in nude mice causes hypophosphatemia

and tumor extracts inhibit renal 25-hydroxyvitamin D

1-hydroxylase activity. Journal of Clinical Endocrinology

and Metabolism 67 46–53. (doi:10.1210/jcem-67-1-46)

Moran M & Paul A 2002 Octreotide scanning in the

detection of a mesenchymal tumour in the pubic

symphysis causing hypophosphataemic osteomalacia.

International Orthopaedics 26 61–62. (doi:10.1007/

s00264-001-0318-0)

Mori Y, Ogasawara T, Motoi T, Shimizu Y, Chikazu D,

Tamura K, Fukumoto S & Takato T 2010 Tumor-induced

osteomalacia associated with a maxillofacial tumor


producing fibroblast growth factor 23: report of a case and

review of the literature. Oral Surgery, Oral Medicine,

Oral Pathology, Oral Radiology, and Endodontics 109

e57–e63. (doi:10.1016/j.tripleo.2009.10.052)

Mount D &Yu A 2008 Phosphate transport. In Brenner &

Rectors: The Kidney, 8 edn, pp 196–204. Ed B Brenner.

Philadelphia, PA: Saunders Elsevier

Mussig K, Oksuz MO, Pfannenberg C, Adam P, Zustin J,

Beckert S & Petersenn S 2009 Somatostatin receptor

expression in an epitheloid hemangioma causing

oncogenic osteomalacia. Journal of Clinical


1210/jc.2009-0927)

Nakahama H, Nakanishi T, Uno H, Takaoka T, Taji N,

Uyama O, Kitada O, Sugita M, Miyauchi A, Sugishita T

et al. 1995 Prostate cancer-induced oncogenic hypopho-

sphatemic osteomalacia. Urologia Internationalis 55

38–40. (doi:10.1159/000282746)

Narvaez J, Domingo-Domenech E, Narvaez JA, Nolla JM &

Valverde J 2005 Acquired hypophosphatemic osteoma-

lacia associated with multiple myeloma. Joint, Bone,

Spine 72 424–426. (doi:10.1016/j.jbspin.2004.10.012)

Nasu T, Kurisu S, Matsuno S, Tatsumi K, Kakimoto T,

Kobayashi M, Nakano Y, Wakasaki H, Furuta H, Nishi M

et al. 2008 Tumor-induced hypophosphatemic osteoma-

lacia diagnosed by the combinatory procedures of

magnetic resonance imaging and venous sampling for

FGF23. Internal Medicine 47 957–961. (doi:10.2169/

internalmedicine.47.0745)

Nawrot-Wawrzyniak K, Varga F, Nader A, Roschger P,

Sieghart S, Zwettler E, Roetzer KM, Lang S, Weinkamer

R, Klaushofer K et al. 2009 Effects of tumor-induced

osteomalacia on the bone mineralization process.

Calcified Tissue International 84 313–323. (doi:10.1007/

s00223-009-9216-z)

Nayak A, Sharma SG, Tandon N & Ray R 2004 Phosphaturic

mesenchymal tumor: a case report. Indian Journal of

Pathology & Microbiology 47 530–533.

Nelson AE, Mason RS, Robinson BG, Hogan JJ, Martin EA,

Ahlstrom H, Astrom G, Larsson T, Jonsson K, Wibell L

et al. 2001 Diagnosis of a patient with oncogenic

osteomalacia using a phosphate uptake bioassay of serum

and magnetic resonance imaging. European Journal of

Endocrinology 145 469–476. (doi:10.1530/eje.0.

1450469)

Nelson AE, Bligh RC, Mirams M, Gill A, Au A, Clarkson A,

Juppner H, Ruff S, Stalley P, Scolyer RA et al. 2003

Clinical case seminar: fibroblast growth factor 23: a new

clinical marker for oncogenic osteomalacia. Journal of


(doi:10.1210/jc.2002-021919)

Nesbitt T, Coffman TM, Griffiths R & Drezner MK 1992

Crosstransplantation of kidneys in normal and Hyp mice.

Evidence that the Hyp mouse phenotype is unrelated to an

intrinsic renal defect. Journal of Clinical Investigation 89

1453–1459. (doi:10.1172/JCI115735)

R73



http://dx.doi.org/10.1086/499410


http://dx.doi.org/10.1053/crad.2002.1091

http://dx.doi.org/10.1385/JCD:1:1:77

http://dx.doi.org/10.1373/clinchem.2007.102418

http://dx.doi.org/10.1111/j.1750-3639.2009.00360.x

http://dx.doi.org/10.1111/j.1750-3639.2009.00360.x


http://dx.doi.org/10.1210/jcem-67-1-46

http://dx.doi.org/10.1007/s00264-001-0318-0

http://dx.doi.org/10.1007/s00264-001-0318-0


http://dx.doi.org/10.1210/jc.2009-0927

http://dx.doi.org/10.1210/jc.2009-0927

http://dx.doi.org/10.1159/000282746

http://dx.doi.org/10.1016/j.jbspin.2004.10.012

http://dx.doi.org/10.2169/internalmedicine.47.0745


http://dx.doi.org/10.1007/s00223-009-9216-z

http://dx.doi.org/10.1007/s00223-009-9216-z

http://dx.doi.org/10.1530/eje.0.1450469

http://dx.doi.org/10.1530/eje.0.1450469

http://dx.doi.org/10.1210/jc.2002-021919

http://dx.doi.org/10.1172/JCI115735


Nguyen BD 2006 Coexisting hyperparathyroidism

and oncogenic osteomalacia: sestamibi and

somatostatin receptor scintigraphy. Clinical Nuclear

Medicine 31 648–651. (doi:10.1097/01.rlu.0000238192.

37389.28)

Nguyen BD & Wang EA 1999 Indium-111 pentetreotide

scintigraphy of mesenchymal tumor with oncogenic

osteomalacia. Clinical Nuclear Medicine 24 130–131.

(doi:10.1097/00003072-199902000-00016)

Nishida Y, Taketani Y, Yamanaka-Okumura H, Imamura F,

Taniguchi A, Sato T, Shuto E, Nashiki K, Arai H,

Yamamoto H et al. 2006 Acute effect of oral phosphate

loading on serum fibroblast growth factor 23 levels in

healthy men. Kidney International 70 2141–2147.

(doi:10.1038/sj.ki.5002000)

Nordstrom H, Lennquist S, Lindell B & Sjoberg HE 1977

Hypophosphataemia in severe burns. Acta Chirurgica

Scandinavica 143 395–399.

Ogose A, Hotta T, Emura I, Hatano H, Inoue Y, Umezu H &

Endo N 2001 Recurrent malignant variant of phosphaturic

mesenchymal tumor with oncogenic osteomalacia.

Skeletal Radiology 30 99–103. (doi:10.1007/

s002560000306)

Ogura E, Kageyama K, Fukumoto S, Yagihashi N, Fukuda Y,

Kikuchi T, Masuda M & Suda T 2008 Development of

tumor-induced osteomalacia in a subcutaneous tumor,

defined by venous blood sampling of fibroblast growth

factor-23. Internal Medicine 47 637–641. (doi:10.2169/


Ohashi K, Ohnishi T, Ishikawa T, Tani H, Uesugi K &

Takagi M 1999 Oncogenic osteomalacia presenting as

bilateral stress fractures of the tibia. Skeletal Radiology 28

46–48. (doi:10.1007/s002560050471)

Oka M, Kamo T, Sasaki E, Kaji H, Nishizawa H, Imanishi Y

& Nishigori C 2007 A case of phosphaturic mesenchymal

tumour (mixed connective tissue variant) that developed

in the subcutaneous tissue of a patient with oncogenic

osteomalacia and produced fibroblast growth factor 23.

British Journal of Dermatology 157 198–200. (doi:10.

1111/j.1365-2133.2007.07940.x)

Omdahl JL & DeLuca HF 1971 Strontium induced rickets:

metabolic basis. Science 174 949–951. (doi:10.1126/

science.174.4012.949)

Oudet C, Martin-Coignard D, Pannetier S, Praud E,

Champion G & Hanauer A 1997 A second family with

XLRH displays the mutation S244L in the CLCN5

gene. Human Genetics 99 781–784. (doi:10.1007/

s004390050448)

Paglia F, Dionisi S & Minisola S 2002 Octreotide for tumor-

induced osteomalacia. New England Journal of Medicine

346 1748–1749 (author reply 1748–1749). (doi:10.1056/

NEJM200205303462215)

Park JM, Woo YK, Kang MI, Kang CS & Hahn ST 2001

Oncogenic osteomalacia associated with soft tissue

chondromyxoid fibroma. European Journal of Radiology

39 69–72. (doi:10.1016/S0720-048X(00)00279-5)

R74

Payne RB 1998 Renal tubular reabsorption of phosphate

(TmP/GFR): indications and interpretation. Annals of

Clinical Biochemistry 35 201–206.

Pedrazzoli M, Colletti G, Ferrari M, Rossetti G, Moneghini L

& Autelitano L 2010 Mesenchymal phosphaturic neo-

plasm in the maxillary sinus: a case report. International

Journal of Oral and Maxillofacial Surgery 39 1027–1032.

(doi:10.1016/j.ijom.2010.04.039)

Peters KB, McLendon R, Morse MA & Vredenburgh JJ 2010

Treatment of recurrent intracranial hemangiopericytoma

with SRC-related tyrosine kinase targeted therapy: a case

report. Case Reports in Oncology 3 93–97. (doi:10.1159/

000307468)

Peterson NR, Summerlin DJ & Cordes SR 2010 Multiple

phosphaturic mesenchymal tumors associated with

oncogenic osteomalacia: case report and review of the

literature. Ear, Nose, & Throat Journal 89 E11–E15.

Pirola E, Vergani F, Casiraghi P, Leone EB, Guerra P &

Sganzerla EP 2009 Oncogenic osteomalacia caused by a

phosphaturic mesenchymal tumor of the thoracic spine.

Journal of Neurosurgery. Spine 10 329–333. (doi:10.

3171/2009.1.SPINE08351)

Policarpio-Nicolas ML, Abbott TE, Dalkin AC, Bennett-

Wick J & Frierson HF Jr 2008 Phosphaturic mesenchymal

tumor diagnosed by fine-needle aspiration and core

biopsy: a case report and review of literature. Diagnostic

Cytopathology 36 115–119. (doi:10.1002/dc.20772)

Pook MA, Wrong O, Wooding C, Norden AG, Feest TG &

Thakker RV 1993 Dent’s disease, a renal Fanconi

syndrome with nephrocalcinosis and kidney stones, is

associated with a microdeletion involving DXS255 and

maps to Xp11.22. Human Molecular Genetics 2

2129–2134. (doi:10.1093/hmg/2.12.2129)

Prader A, Illig R, Uehlinger E & Stalder G 1959 Rickets

following bone tumor. Helvetica Paediatrica Acta 14

554–565.

Radaideh AR, Jaradat D, Abu-Kalaf MM & Nusier MK 2009

Resolution of severe oncogenic hypophosphatemic

osteomalacia after resection of a deeply located soft-tissue

tumour. Current Oncology 16 87–90.

Rao DS, Parfitt AM, Villanueva AR, Dorman PJ &

Kleerekoper M 1987 Hypophosphatemic osteomalacia

and adult Fanconi syndrome due to light-chain nephro-

pathy. Another form of oncogenous osteomalacia.

American Journal of Medicine 82 333–338. (doi:10.1016/

0002-9343(87)90081-7)

Ratanasuwan T, Chetsurakarn S, Ongphiphadhanakul B &

Damrongkitchaiporn S 2008 A case report of tumor-

induced osteomalacia: eight year followed-up. Journal of

the Medical Association of Thailand 91 1900–1902.

Razzaque MS 2009 The FGF23-Klotho axis: endocrine

regulation of phosphate homeostasis. Nature Reviews.

Endocrinology5 611–619. (doi:10.1038/nrendo.2009.196)

Reese DM & Rosen PJ 1997 Oncogenic osteomalacia

associated with prostate cancer. Journal of Urology 158

887. (doi:10.1016/S0022-5347(01)64351-9)



http://dx.doi.org/10.1097/01.rlu.0000238192.37389.28


http://dx.doi.org/10.1097/00003072-199902000-00016

http://dx.doi.org/10.1038/sj.ki.5002000

http://dx.doi.org/10.1007/s002560000306

http://dx.doi.org/10.1007/s002560000306



http://dx.doi.org/10.1007/s002560050471

http://dx.doi.org/10.1111/j.1365-2133.2007.07940.x

http://dx.doi.org/10.1111/j.1365-2133.2007.07940.x

http://dx.doi.org/10.1126/science.174.4012.949

http://dx.doi.org/10.1126/science.174.4012.949

http://dx.doi.org/10.1007/s004390050448

http://dx.doi.org/10.1007/s004390050448



http://dx.doi.org/10.1016/S0720-048X(00)00279-5

http://dx.doi.org/10.1016/j.ijom.2010.04.039

http://dx.doi.org/10.1159/000307468

http://dx.doi.org/10.1159/000307468

http://dx.doi.org/10.3171/2009.1.SPINE08351


http://dx.doi.org/10.1002/dc.20772

http://dx.doi.org/10.1093/hmg/2.12.2129

http://dx.doi.org/10.1016/0002-9343(87)90081-7

http://dx.doi.org/10.1016/0002-9343(87)90081-7

http://dx.doi.org/10.1038/nrendo.2009.196

http://dx.doi.org/10.1016/S0022-5347(01)64351-9


Reis-Filho JS, Paiva ME & Lopes JM 2002 Pathologic quiz

case. A 36-year-old woman with muscle pain and

weakness. Phosphaturic mesenchymal tumor (mixed

connective tissue variant)/oncogenic osteomalacia.

Archives of Pathology & Laboratory Medicine 126

1245–1246.

Reis-Filho JS, Paiva ME & Lopes JM 2004 August 2003:

47-year-old female with a 7-year history of osteomalacia

and hypophosphatemia. Brain Pathology 14 111–112,

115.

Rendina D, De Filippo G, Tauchmanova L, Insabato L,

Muscariello R, Gianfrancesco F, Esposito T, Cioffi M,

Colao A, Strazzullo P et al. 2009 Bone turnover and the

osteoprotegerin-RANKL pathway in tumor-induced

osteomalacia: a longitudinal study of five cases. Calcified

Tissue International 85 293–300. (doi:10.1007/s00223-

009-9275-1)

Renkema KY, Alexander RT, Bindels RJ & Hoenderop JG

2008 Calcium and phosphate homeostasis: concerted

interplay of new regulators. Annals of Medicine 40 82–91.

(doi:10.1080/07853890701689645)

Rhee Y, Lee JD, Shin KH, Lee HC, Huh KB & Lim SK 2001

Oncogenic osteomalacia associated with mesenchymal

tumour detected by indium-111 octreotide scintigraphy.

Clinical Endocrinology 54 551–554. (doi:10.1046/j.1365-

2265.2001.01056.x)

Rico H, Fernandez-Miranda E, Sanz J, Gomez-Castresana F,

Escriba A, Hernandez ER & Krsnik I 1986 Oncogenous

osteomalacia: a new case secondary to a malignant tumor.

Bone 7 325–329. (doi:10.1016/8756-3282(86)90251-6)

Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A,

White KE, Waguespack S, Gupta A, Hannon T, Econs MJ

et al. 2003 FGF-23 in fibrous dysplasia of bone and its

relationship to renal phosphate wasting. Journal of

Clinical Investigation 112 683–692. (doi:10.1172/

JCI18399)

Roarke MC & Nguyen BD 2007 PET/CT localization of

phosphaturic mesenchymal neoplasm causing tumor-

induced osteomalacia. Clinical Nuclear Medicine 32

300–301. (doi:10.1097/01.rlu.0000257180.03964.51)

Romualdo-Silva DD, Silva BC, Caetano CV, Tiburcio AM,

Nunes MB, Chagas SA, Polito ET, Ferreira AR & Purisch S

2009 Tumor-induced osteomalacia: a case report. Arquivos

Brasileiros de Endocrinologia e Metabologia 53 378–382.

(doi:10.1590/S0004-27302009000300014)

Sahnoune I, Tazi-Mezalek Z, Essaadouni L, Harmouche H,

Ismael F, Adnaoui M, Aouni M, Kettani F & Maaouni A

2006 Oncogenic osteomalacia in a patient with heman-

gioma: a clinical diagnosis. Joint, Bone, Spine 73

115–118. (doi:10.1016/j.jbspin.2005.06.001)

Sakamoto A, Oda Y, Nagayoshi Y, Iwakiri K, Tamiya S,

Iwamoto Y & Tsuneyoshi M 2001 Glomangiopericytoma

causing oncogenic osteomalacia. A case report with

immunohistochemical analysis. Archives of Orthopaedic

and Trauma Surgery 121 104–108. (doi:10.1007/

s004020000187)


Santer R, Schneppenheim R, Dombrowski A, Gotze H,

Steinmann B & Schaub J 1997 Mutations in GLUT2, the

gene for the liver-type glucose transporter, in patients

with Fanconi-Bickel syndrome. Nature Genetics 17

324–326. (doi:10.1038/ng1197-324)

Sato K, Obara T, Yamazaki K, Kanbe M, Nakajima K,

Yamada A, Yanagisawa T, Kato Y, Nishikawa T &

Takano K 2001 Somatic mutations of the MEN1 gene and

microsatellite instability in a case of tertiary hyperpara-

thyroidism occurring during high phosphate therapy for

acquired, hypophosphatemic osteomalacia. Journal of


(doi:10.1210/jc.86.11.5564)

Savage CR & Zimmer LA 2009 Oncogenic osteomalacia

from pterygopalatine fossa mass. Journal of Laryngology

and Otology 123 1052–1054. (doi:10.1017/S0022215

109004927)

Saville PD, Nassim JR, Stevenson FH, Mulligan L & Carey M

1955 Osteomalacia in Von Recklinghausen’s neuro-

fibromatosis; metabolic study of a case. BMJ 1 1311–1313.

(doi:10.1136/bmj.1.4925.1311)

Scheinman SJ 1998 X-linked hypercalciuric nephrolithiasis:

clinical syndromes and chloride channel mutations.

Kidney International 53 3–17. (doi:10.1046/j.1523-1755.

1998.00718.x)

Sciubba DM, Petteys RJ, Shakur SF, Gokaslan ZL, McCarthy

EF, Collins MT, McGirt MJ, Hsieh PC, Nelson CS &

Wolinsky JP 2009 En bloc spondylectomy for treatment

of tumor-induced osteomalacia. Journal of Neurosurgery.

Spine 11 600–604. (doi:10.3171/2009.6.SPINE08120)

Seijas R, Ares O, Sierra J & Perez-Dominguez M 2009

Oncogenic osteomalacia: two case reports with surprisingly

different outcomes. Archives of Orthopaedic and Trauma

Surgery 129 533–539. (doi:10.1007/s00402-008-0808-2)

Seufert J, Ebert K, Muller J, Eulert J, Hendrich C, Werner E,

Schuuze N, Schulz G, Kenn W, Richtmann H et al. 2001

Octreotide therapy for tumor-induced osteomalacia. New

England Journal of Medicine 345 1883–1888. (doi:10.

1056/NEJMoa010839)

Sharkis DH, Devereux JP, Chako AC & Estep HL 1997

Reversible avascular necrosis of the femoral head in

tumor-induced osteomalacia. Endocrine Practice 3

137–139.

Shelekhova KV, Kazakov DV, Hes O, Treska V & Michal M

2006 Phosphaturic mesenchymal tumor (mixed connec-

tive tissue variant): a case report with spectral analysis.

Virchows Archiv 448 232–235. (doi:10.1007/s00428-005-

0149-2)

Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R,

Takeuchi Y, Fujita T, Nakahara K, Fukumoto S &

Yamashita T 2004 FGF-23 is a potent regulator of vitamin

D metabolism and phosphate homeostasis. Journal of

Bone and Mineral Research 19 429–435. (doi:10.1359/

JBMR.0301264)

Sommer S, Berndt T, Craig T & Kumar R 2007 The

phosphatonins and the regulation of phosphate transport

R75


http://dx.doi.org/10.1007/s00223-009-9275-1

http://dx.doi.org/10.1007/s00223-009-9275-1

http://dx.doi.org/10.1080/07853890701689645

http://dx.doi.org/10.1046/j.1365-2265.2001.01056.x

http://dx.doi.org/10.1046/j.1365-2265.2001.01056.x

http://dx.doi.org/10.1016/8756-3282(86)90251-6




http://dx.doi.org/10.1590/S0004-27302009000300014

http://dx.doi.org/10.1016/j.jbspin.2005.06.001

http://dx.doi.org/10.1007/s004020000187

http://dx.doi.org/10.1007/s004020000187

http://dx.doi.org/10.1038/ng1197-324

http://dx.doi.org/10.1210/jc.86.11.5564

http://dx.doi.org/10.1017/S0022215109004927

http://dx.doi.org/10.1017/S0022215109004927

http://dx.doi.org/10.1136/bmj.1.4925.1311

http://dx.doi.org/10.1046/j.1523-1755.1998.00718.x

http://dx.doi.org/10.1046/j.1523-1755.1998.00718.x


http://dx.doi.org/10.1007/s00402-008-0808-2



http://dx.doi.org/10.1007/s00428-005-0149-2

http://dx.doi.org/10.1007/s00428-005-0149-2




and vitamin D metabolism. Journal of Steroid Biochem-

istry and Molecular Biology 103 497–503. (doi:10.1016/j.

jsbmb.2006.11.010)

Stark H, Eisenstein B, Tieder M, Rachmel A & Alpert G 1986

Direct measurement of TP/GFR: a simple and reliable

parameter of renal phosphate handling. Nephron 44

125–128. (doi:10.1159/000184216)

Stone MD, Quincey C & Hosking DJ 1992 A neuroendocrine

cause of oncogenic osteomalacia. Journal of Pathology

167 181–185. (doi:10.1002/path.1711670204)

Szumera-Cieckiewicz A, Ptaszynski K, Pawelas A &

Rutkowski P 2009 Oncogenic osteomalacia associated

with phosphaturic mesenchymal tumour, mixed connec-

tive tissue type of the knee. Polish Journal of Pathology

60 193–198.

Taketani Y, Segawa H, Chikamori M, Morita K, Tanaka K,

Kido S, Yamamoto H, Iemori Y, Tatsumi S, Tsugawa N

et al. 1998 Regulation of type II renal NaC-dependent

inorganic phosphate transporters by 1,25-dihydroxyvita-

min D3. Identification of a vitamin D-responsive element

in the human NAPi-3 gene. Journal of Biological

Chemistry 273 14575–14581. (doi:10.1074/jbc.273.23.

14575)

Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki Y,

Yamashita T, Miyamoto Y, Okazaki H, Nakamura K,

Nakahara K et al. 2004 Venous sampling for fibroblast

growth factor-23 confirms preoperative diagnosis

of tumor-induced osteomalacia. Journal of Clinical


1210/jc.2004-0406)

Tartaglia F, Minisola S, Sgueglia M, Blasi S, Brunelli D,

Degli Effetti E, Maturo A, Cola A, Custureri F &

Campana FP 2006 Tumor-induced hypophosphatemic

osteomalacia associated with tertiary hyperparathyroid-

ism: a case report. Il Giornale di Chirurgia 27 9–13.

Taylor HC, Fallon MD & Velasco ME 1984 Oncogenic

osteomalacia and inappropriate antidiuretic hormone

secretion due to oat-cell carcinoma. Annals of Internal

Medicine 101 786–788.

Teasell RW & Shapiro AP 2002 Misdiagnosis of conversion

disorders. American Journal of Physical Medicine &

Rehabilitation 81 236–240. (doi:10.1097/00002060-

200203000-00015)

Terek R & Nielsen G 2001 Case records of the Massachusetts

General Hospital. Weekly clinicopathological exercises.

Case 29-2001. A 14-year-old with abnormal bones and a

sacral mass. New England Journal of Medicine 345

903–908. (doi:10.1056/NEJMcpc010029)

The HYP Consortium 1995 A gene (PEX) with homologies

to endopeptidases is mutated in patients with

X-linked hypophosphatemic rickets. The HYP

Consortium. Nature Genetics 11 130–136. (doi:10.1038/

ng1095-130)

Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak

P, Mizrachi M, Khamaysi Z, Behar D, Petronius D,

Friedman V et al. 2004 Mutations in GALNT3, encoding

R76

a protein involved in O-linked glycosylation, cause

familial tumoral calcinosis. Nature Genetics 36 579–581.

(doi:10.1038/ng1358)

Toyosawa S, Tomita Y, Kishino M, Hashimoto J, Ueda T,

Tsujimura T, Aozasa K, Ijuhin N & Komori T 2004

Expression of dentin matrix protein 1 in tumors causing

oncogenic osteomalacia. Modern Pathology 17 573–578.

(doi:10.1038/modpathol.3800084)

Umphrey LG, Whitaker MD, Bosch EP & Cook CB 2007

Clinical and bone density outcomes of tumor-induced

osteomalacia after treatment. Endocrine Practice 13

458–462.

Ungari C, Rocchi G, Rinna C, Agrillo A, Lattanzi A &

Pagnoni M 2004 Hypophosphaturic mesenchymal tumor

of the ethmoid associated with oncogenic osteomalacia.

Journal of Craniofacial Surgery 15 523–527. (doi:10.

1097/00001665-200405000-00036)

Uramoto N, Furukawa M & Yoshizaki T 2009 Malignant

phosphaturic mesenchymal tumor, mixed connective

tissue variant of the tongue. Auris, Nasus, Larynx 36

104–105. (doi:10.1016/j.anl.2008.01.003)

Vandergheynst F, Van Dorpe J, Goldman S & Decaux G

2006 Increased 18F fluorodeoxyglucose uptake of a

vertebral hemangioma responsible for oncogenic osteo-

malacia. European Journal of Internal Medicine 17 223.

(doi:10.1016/j.ejim.2005.11.008)

Vollbrecht JE & Rao DS 2008 Images in clinical

medicine. Tumor-induced osteomalacia. New England

Journal of Medicine 358 1282. (doi:10.1056/

NEJMicm066066)

Walton RJ & Bijvoet OL 1975 Nomogram for derivation of

renal threshold phosphate concentration. Lancet 2

309–310. (doi:10.1016/S0140-6736(75)92736-1)

Ward LM, Rauch F, White KE, Filler G, Matzinger MA,

Letts M, Travers R, Econs MJ & Glorieux FH 2004

Resolution of severe, adolescent-onset hypophosphatemic

rickets following resection of an FGF-23-producing

tumour of the distal ulna. Bone 34 905–911. (doi:10.1016/

j.bone.2003.12.025)

Weidner N 1991 Review and update: oncogenic osteomalacia-

rickets. Ultrastructural Pathology 15 317–333. (doi:10.

3109/01913129109016242)

Weidner N, Bar RS, Weiss D & Strottmann MP 1985

Neoplastic pathology of oncogenic osteomalacia/rickets.

Cancer 55 1691–1705. (doi:10.1002/1097-0142(19850415)

55:8!1691::AID-CNCR2820550814O3.0.CO;2-S)

Westerberg PA, Olauson H, Toss G, Wikstrom B, Morales O,

Linde T, Jonsson K, Ljunggren O & Larsson TE 2008

Preoperative tumor localization by means of venous

sampling for fibroblast growth factor-23 in a patient with

tumor-induced osteomalacia. Endocrine Practice 14

362–367.

White K, Evans W, O’Riordan JL, Speer M, Econs MJ,

Lorenz-Depiereux B, Grabowski M, Meitinger T &

Strom T 2000 Autosomal dominant hypophosphataemic

rickets is associated with mutations in FGF23. Nature

Genetics 26 345–348. (doi:10.1038/81664)



http://dx.doi.org/10.1016/j.jsbmb.2006.11.010

http://dx.doi.org/10.1016/j.jsbmb.2006.11.010

http://dx.doi.org/10.1159/000184216

http://dx.doi.org/10.1002/path.1711670204

http://dx.doi.org/10.1074/jbc.273.23.14575

http://dx.doi.org/10.1074/jbc.273.23.14575

http://dx.doi.org/10.1210/jc.2004-0406

http://dx.doi.org/10.1210/jc.2004-0406

http://dx.doi.org/10.1097/00002060-200203000-00015

http://dx.doi.org/10.1097/00002060-200203000-00015

http://dx.doi.org/10.1056/NEJMcpc010029

http://dx.doi.org/10.1038/ng1095-130

http://dx.doi.org/10.1038/ng1095-130


http://dx.doi.org/10.1038/modpathol.3800084

http://dx.doi.org/10.1097/00001665-200405000-00036

http://dx.doi.org/10.1097/00001665-200405000-00036

http://dx.doi.org/10.1016/j.anl.2008.01.003


http://dx.doi.org/10.1056/NEJMicm066066

http://dx.doi.org/10.1056/NEJMicm066066

http://dx.doi.org/10.1016/S0140-6736(75)92736-1



http://dx.doi.org/10.3109/01913129109016242

http://dx.doi.org/10.3109/01913129109016242

http://dx.doi.org/10.1002/1097-0142(19850415)55:8%3C1691::AID-CNCR2820550814%3E3.0.CO;2-S

http://dx.doi.org/10.1002/1097-0142(19850415)55:8%3C1691::AID-CNCR2820550814%3E3.0.CO;2-S

http://dx.doi.org/10.1038/81664


White KE, Jonsson KB, Carn G, Hampson G, Spector TD,

Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang

IM, Ljunggren O et al. 2001 The autosomal dominant

hypophosphatemic rickets (ADHR) gene is a secreted

polypeptide overexpressed by tumors that cause phos-

phate wasting. Journal of Clinical Endocrinology and

Metabolism 86 497–500. (doi:10.1210/jc.86.2.497)

White KE, Larsson TE & Econs MJ 2006 The roles of

specific genes implicated as circulating factors involved

in normal and disordered phosphate homeostasis: frizzled

related protein-4, matrix extracellular phosphoglycopro-

tein, and fibroblast growth factor 23. Endocrine Reviews

27 221–241. (doi:10.1210/er.2005-0019)

Wild D, Schmitt J, Ginj M, Macke H, Bernard B, Krenning E,

De Jong M, Wenger S & Reubi J 2003 DOTA-NOC, a

high-affinity ligand of somatostatin receptor subtypes 2, 3

and 5 fo labelling with various radiometals. European

Journal of Nuclear Medicine and Molecular Imaging 30

1338–1347. (doi:10.1007/s00259-003-1255-5)

Wild D, Macke HR, Waser B, Reubi JC, Ginj M, Rasch H,

Muller-Brand J & Hofmann M 2005 68Ga-DOTANOC: a

first compound for PET imaging with high affinity for

somatostatin receptor subtypes 2 and 5. European

Journal of Nuclear Medicine and Molecular Imaging 32

724. (doi:10.1007/s00259-004-1697-4)

Wilkins GE, Granleese S, Hegele RG, Holden J, Anderson DW

& Bondy GP 1995 Oncogenic osteomalacia: evidence for

a humoral phosphaturic factor. Journal of Clinical


1210/jc.80.5.1628)

Williams K, Flanagan A, Folpe A, Thakker R & Athanasou

NA 2007 Lymphatic vessels are present in phosphaturic

mesenchymal tumours. Virchows Archiv 451 871–875.

(doi:10.1007/s00428-007-0471-y)

Woo VL, Landesberg R, Imel EA, Singer SR, Folpe AL,

Econs MJ, Kim T, Harik LR & Jacobs TP 2009

Phosphaturic mesenchymal tumor, mixed connective

tissue variant, of the mandible: report of a case and review

of the literature. Oral Surgery, Oral Medicine, Oral

Pathology, Oral Radiology, and Endodontics 108

925–932. (doi:10.1016/j.tripleo.2009.07.005)

Woznowski M, Quack I, Stegbauer J, Buchner N, Rump LC

& Schieren G 2008 Oncogenic osteomalacia, a rare

paraneoplastic syndrome due to phosphate wasting – a

case report and review of the literature. Clinical

Nephrology 70 431–438.

Wyman AL, Paradinas FJ & Daly JR 1977 Hypophosphataemic

osteomalacia associated with a malignant tumour of the

tibia: report of a case. Journal of Clinical Pathology 30

328–335. (doi:10.1136/jcp.30.4.328)


Xia WB, Jiang Y, Li M, Xing XP, Wang O, Hu YY, Zhang HB,

Liu HC, Meng XW & Zhou XY 2010 Levels and dynamic

changes of serum fibroblast growth factor 23 in hypo-

phosphatemic rickets/osteomalacia. Chinese Medical

Journal 123 1158–1162.

Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K,

Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita

T et al. 2002 Increased circulatory level of biologically

active full-length FGF-23 in patients with hypopho-

sphatemic rickets/osteomalacia. Journal of Clinical


1210/jc.2002-021105)

Yang IM, Park YK, Hyun YJ, Kim DY, Woo JT, Kim SW,

Kim JW, Kim YS & Choi YK 1997 Oncogenic

osteomalacia caused by a phosphaturic mesenchymal

tumor of the oral cavity: a case report. Korean Journal of

Internal Medicine 12 89–95.

Yavropoulou MP, Kotsa K, Gotzamani Psarrakou A, Papazisi

A, Tranga T, Ventis S & Yovos JG 2010 Cinacalcet in

hyperparathyroidism secondary to X-linked hypopho-

sphatemic rickets: case report and brief literature review.

Hormones 9 274–278.

Yoshioka K, Nagata R, Ueda M, Yamaguchi T, Konishi Y,

Hosoi M, Inoue T, Yamanaka K, Iwai Y & Sato T 2006

Phosphaturic mesenchymal tumor with symptoms related

to osteomalacia that appeared one year after tumorect-

omy. Internal Medicine 45 1157–1160. (doi:10.2169/


Yun KI, Kim DH & Pyo SW 2009 A phosphaturic

mesenchymal tumor of the floor of the mouth with

oncogenic osteomalacia: report of a case. Journal of Oral

and Maxillofacial Surgery 67 402–405. (doi:10.1016/

j.joms.2008.01.007)

Zimering MB, Caldarella FA, White KE & Econs MJ 2005

Persistent tumor-induced osteomalacia confirmed by

elevated postoperative levels of serum fibroblast growth

factor-23 and 5-year follow-up of bone density changes.

Endocrine Practice 11 108–114.

Zura RD, Minasi JS & Kahler DM 1999 Tumor-induced

osteomalacia and symptomatic looser zones secondary

to mesenchymal chondrosarcoma. Journal of Surgical

Oncology 71 58–62. (doi:10.1002/(SICI)1096-9098

(199905)71:1!58::AID-JSO12O3.0.CO;2-F)

Received in final form 11 March 2011Accepted 12 April 2011Made available online as an Accepted Preprint13 April 2011

R77


http://dx.doi.org/10.1210/jc.86.2.497

http://dx.doi.org/10.1210/er.2005-0019

http://dx.doi.org/10.1007/s00259-003-1255-5

http://dx.doi.org/10.1007/s00259-004-1697-4

http://dx.doi.org/10.1210/jc.80.5.1628

http://dx.doi.org/10.1210/jc.80.5.1628

http://dx.doi.org/10.1007/s00428-007-0471-y


http://dx.doi.org/10.1136/jcp.30.4.328

http://dx.doi.org/10.1210/jc.2002-021105

http://dx.doi.org/10.1210/jc.2002-021105



http://dx.doi.org/10.1016/j.joms.2008.01.007

http://dx.doi.org/10.1016/j.joms.2008.01.007

http://dx.doi.org/10.1002/(SICI)1096-9098(199905)71:1%3C58::AID-JSO12%3E3.0.CO;2-F

http://dx.doi.org/10.1002/(SICI)1096-9098(199905)71:1%3C58::AID-JSO12%3E3.0.CO;2-F

tumor-induced osteomalacia · tumor-induced osteomalacia (tio) is a rare and fascinating...

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