Diagnosis of a patient with oncogenic osteomalacia using a phosphate uptake bioassay of serum and magnetic resonance imaging
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European Journal of Endocrinology (2001) 145 469±476 ISSN 0804-4643
CASE REPORT
Diagnosis of a patient with oncogenic osteomalacia using
a phosphate uptake bioassay of serum and magnetic
resonance imaging
Anne E Nelson1,2,3 , Rebecca S Mason1,2, Bruce G Robinson1,3, Jeremy J Hogan1,2, Erin A Martin1,2,
HaÊkan AhlstroÈm5, Gunnar A Ê stroÈm5, Tobias Larsson4, Kenneth Jonsson4, Lars Wibell4 and Osten Ljunggren4
1
Cancer Genetics Department, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney 2065, Australia, 2Department of Physiology
and Institute for Biomedical Research, 3Department of Medicine, University of Sydney, Sydney 2006, Australia, 4Department of Internal Medicine and
5
Department of Radiology, University Hospital, Uppsala, Sweden
(Correspondence should be addressed to Anne E Nelson, Cancer Genetics Department, Kolling Institute of Medical Research, Royal North Shore Hospital,
St Leonards, NSW 2065, Australia; Email: annen@med.usyd.edu.au)
Abstract
A previously healthy man with no family history of fractures presented with muscle pain, back pain
and height loss. Investigations revealed hypophosphataemia, phosphaturia, undetectable serum 1,25-
dihydroxyvitamin D and severe osteomalacia on bone biopsy, suggestive of a diagnosis of oncogenic
osteomalacia. Thorough physical examination did not locate a tumour. Support for the diagnosis was
obtained by detection of phosphate uptake inhibitory activity in a blinded sample of the patient's
serum using a renal cell bioassay. On the basis of detection of this bioactivity, a total body magnetic
resonance (MR) examination was performed. A small tumour was located in the right leg. Removal of
the tumour resulted in the rapid reversal of symptoms and the abnormal biochemistry typical of
oncogenic osteomalacia. Inhibitory activity was also demonstrated using the bioassay in serum from
two other patients with con®rmed or presumptive oncogenic osteomalacia, but not in serum from two
patients with hypophosphataemia of other origin. This is the ®rst case to be reported in which the
diagnosis of oncogenic osteomalacia was assisted by demonstration of inhibitory activity of the
patient's serum in a renal cell phosphate bioassay that provided an impetus for total body MR
imaging.
European Journal of Endocrinology 145 469±476
Introduction located and removed. If it can be located and
completely removed, there is usually rapid reversal of
Oncogenic osteomalacia is a condition that is often the abnormal biochemistry and alleviation of symp-
dif®cult to diagnose and to manage (reviewed in (1±3)). toms. The search for the tumour usually starts with a
Patients frequently present with vague symptoms of very thorough physical examination, then radiographic
bone and muscle pain and muscle weakness. The survey and bone scans. Computed tomography (CT)
typical biochemical ®ndings are hypophosphataemia, and magnetic resonance (MR) examinations of any
renal phosphate wasting, low serum concentration of clinically suspicious areas have also been used (5±8).
1,25-dihydroxyvitamin D (1,25(OH)2D) and frequently In the case reported here, a patient presented with
increased serum alkaline phosphatase. Impaired miner- symptoms and signs suggestive of oncogenic osteo-
alisation of bone presents as rickets or osteomalacia, as malacia; however, no tumour could be located by
indicated by bone biopsy, and patients may have physical examination. A renal cell phosphate uptake
recurrent fractures. The tumour responsible for the bioassay, with which we have previously demonstrated
symptoms and signs of oncogenic osteomalacia may be inhibition of renal phosphate uptake by conditioned
located in almost any part of the body, with a large media from cultured oncogenic osteomalacia tumour
proportion occurring in the upper and lower extremi- cells (9), was used to test a blinded sample of the
ties and around the head. The tumours are often small patient's serum against age- and sex-matched controls.
and slowly growing. They are of a wide variety of Detection of phosphate uptake inhibitory activity in the
histological types and are mostly benign and of patient's serum provided the impetus for carrying out a
mesenchymal origin (reviewed in (4)). whole-body MR examination.
Location of the tumour is often dif®cult, and the The renal phosphate uptake assay was also used to
diagnosis cannot be con®rmed until the tumour is test sera from other patients with hypophosphataemia,
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with or without other symptoms and signs of In 1997, a sample of the patient's serum and sera
oncogenic osteomalacia, to determine its usefulness in from two age- and sex-matched normal controls were
assisting in the diagnosis of this condition. tested in a blinded manner, in the phosphate uptake
assay. Phosphate uptake inhibitory activity was
detected in the serum from patient 1 compared with
the control sera in the renal cell bioassay. Detection of
Case reports this activity was further evidence that the patient's
Patient 1 symptoms were due to oncogenic osteomalacia. On the
basis of this evidence, a further search for the tumour
Patient 1 presented in 1993 at age 26 years with was carried out using a whole-body MR examination.
muscle pain. He was a previously healthy man, a part- In that examination a small, subcutaneous, highly
time body-builder, with no family history of fractures. vascularised tumour was detected in the right leg
X-ray examination in 1994 detected no vertebral 20 cm proximal to the knee.
fractures. Over the next 2 years, the patient also The tumour was removed in January 1998 and was
suffered muscle ache, generalised stiffness and severe classi®ed histologically as angiodysplasia. Serum phos-
back pain and he lost 8 cm in height between 1995 phate returned to within the normal range 10 h after
and 1996. Multiple vertebral fractures were shown by the operation, and the serum concentration of
X-ray examination in February 1996. 1,25(OH)2D also normalised. The patient had full
In June 1996, he was seen after referral to the clinic mobility within 3 days after operation and had no
at Uppsala. Biochemical investigations indicated low pain or stiffness. His myopathy, which had been only
serum phosphate concentration of 0.43 mmol/l partially improved by treatment, vanished within 2
(normal range 0.76±1.44 mmol/l), high urinary days. He returned to full-time work, and at follow-up
phosphate clearance of 32.7 ml/min (normal range after 1 year he remained well. The changes in
4±12 ml/min), low tubular phosphate reabsorption biochemistry are summarised in Table 1.
of 69% (normal range 87±94%), undetectable
1,25(OH)2D and increased alkaline phosphatase of
26 ukat/l (normal range 0.8±4.8 ukat/l). The serum Patient 2
concentrations of 25-hydroxyvitamin D (27 nmol/l;
normal range 25±105 nmol/l), parathyroid hormone Patient 2 has been reported previously (10). In this
(PTH) (33 ng/l; normal range 12±55 ng/l) and cal- patient, the diagnosis of oncogenic osteomalacia was
cium (2.34 mmol/l; normal range 2.20±2.60 mmol/l), con®rmed by clinical improvement after removal of a
and other biochemical measurements were all within prostate adenocarcinoma. Serum was collected from
normal ranges. There was no evidence of amino- patient 2 before and after surgical removal of the
aciduria or skeletal dysmorphism. The patient had a tumour.
severe myopathy. Bone biopsy indicated severe osteo-
malacia. The patient's history and physical ®ndings
were suggestive of a diagnosis of oncogenic osteo-
Patient 3
malacia, though no tumour could be located on This female patient ®rst presented in 1985 at age 36
physical examination. The patient was treated from years with generalised bone and muscle pain, hypo-
June 1996 with phosphate and 1,25(OH)2D, which phosphataemia (0.4 mmol/l, normal range 0.8±
relieved his symptoms. 1.5 mmol/l), low serum concentration of 1,25(OH)2D
Table 1 Changes in biochemical measurements from patient 1 before treatment and after surgical removal of tumour.
Biochemical measurement Before treatment Immediately before surgery, After surgery Follow-up
(normal range) (June 1996) on treatment (January 1998) (without treatment) (May 1998)
Serum phosphate 0.43 mmol/l 0.55 mmol/l 0.91 mmol/l 1.36 mmol/l
(0.76±1.44 mmol/l)
Phosphate clearance 32.7 ml/min 17.3 ml/min 16.7 ml/min
(4±12 ml/min)
Tubular phosphate reabsorption 69% 79% 84%
(87±94%)
1,25(OH)2D ND 51 pmol/l (treated with 107 pmol/l
(40±130 pmol/l) 1,25(OH)2D 2 mg/day)
25(OH)D 27 nmol/l 23 nmol/l 31 nmol/l
(NR 25±105 nmol/l) (NR 19±124 nmol/l) (NR 19±124 nmol/l)
Biochemical measurements for patient 1 are summarized before treatment in June 1996, immediately before surgery to remove the tumour in January 1998,
after surgery, and at follow-up in May 1998. The normal range for each measurement is shown in the ®rst column, except for 25(OH)D, for which the
laboratory normal range changed in 1997 and the relevant values (NR) are shown for each time of measurement. ND, not detectable.
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via free accessEUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145 Oncogenic osteomalacia case report 471
and osteomalacia on bone biopsy. Careful physical 1 mol/l acetic acid. The eluants were then diluted
examinations and bone scans have failed to locate a with serum-free DMEM medium with bovine serum
causative tumour and she has been treated since 1985 albumin added to a ®nal concentration of 0.1%, then
with phosphate and 1,25(OH)2D, which alleviate her tested in the phosphate uptake bioassay.
symptoms. If treatment is interrupted, symptoms of
muscle pain recur after only a few days. The patient
was unwilling to undergo MR examination. In 1999, Magnetic resonance imaging
octreotide scintigraphy was carried out using the The MR examinations were carried out on a 0.5T
somatostatin receptor analog octreotide, which has scanner (Gyroscan T5-NT, Philips, Best, The Nether-
been used to locate other tumours in patients with lands). Fat-suppressed T2-weighted STIR images (repe-
oncogenic osteomalacia (11). No tumour was located. tition time (TR) 2500 ms, echo time (TE) 120 ms,
Inversion time (TI) 120 ms, matrix 203±256/256)
with a ®eld of view of 275±450 cm and a slice
Materials and methods thickness of 6±8 mm, gap 0.8±1.6 mm, were obtained
Materials in the frontal plane at the following locations: neck,
thorax and upper abdomen, pelvis and proximal part of
The OK 3B2 cells were kindly provided by Professor the upper leg, distal part of the upper leg and proximal
H Murer, Zurich, Switzerland. Tissue culture media and part of lower leg, distal part of the lower leg and the
additives were obtained from Gibco BRL Life Tech- foot. Complementary T2-STIR and T1-weighted
nologies (Gaithersburg, MD, USA) and Trace Bio- sequences in the axial and frontal plane were
sciences (Melbourne, Victoria, Australia). The isotope performed in areas suspected of containing the tumour.
[32P]orthophosphoric acid was obtained from Gene- Contrast-enhanced (20 ml of 0.5 mmol/kg gadolinium
Works, Adelaide, Australia and Norit A charcoal from diethylene triamino pentacetic acid-bismethylamide
ICN, Cleveland, Ohio, USA. All other chemicals were (GdDTPA)-BMA) T1-weighted images were obtained in
obtained from Sigma Chemical Co, St Louis, MO, USA. the tumour area of the upper leg.
Phosphate uptake assay Statistical analysis
A renal phosphate uptake assay was used (9) in which The results are expressed as the mean^S.D. Signi®cant
we have previously detected inhibitory activity in differences between means were determined using
conditioned media from oncogenic osteomalacia Student's two sample t-test, assuming equal variance.
tumour cells, using OK 3B2 cells, which are particu-
larly sensitive to PTH. Phosphate uptake was measured
as previously described (9) in cells grown to con¯uence Results
in 24-well plates; they were changed to serum-free
medium 24 h before the uptake assay. Patients' serum
Testing of patients' sera in renal phosphate
samples were tested compared with serum samples uptake bioassay
from two age- and sex-matched controls each. The A sample of serum from patient 1 with blinded identity
serum samples were heat-inactivated at 56 8C for was tested in the phosphate uptake assay at 5±20% v/v
30 min to overcome the cytotoxic effects of unheated dilutions compared with sera from two age- and sex-
serum, then diluted to 5±20% v/v in serum-free DMEM matched controls. Signi®cant inhibition of renal
medium. The OK 3B2 cells were preincubated with the phosphate uptake was detected in the patient 1
diluted serum samples for 20 h, the preincubation time serum (Table 2). The activity detected in the blinded
for maximal inhibitory activity with conditioned sample was small (from 3% to 9% inhibition of control
medium (12). Uptake of [32P]orthophosphate was uptake) but signi®cant P , 0:05 and detected in
then measured after incubation with 32P-uptake three different assays.
solution for 15 min. The total protein per well was Signi®cant inhibitory activity was also detected in
measured using the Bio-Rad protein assay (Bio-Rad serum from patient 2, in whom the diagnosis of
Laboratories, Hercules, CA, USA). oncogenic osteomalacia was subsequently con®rmed
by the clinical improvement that occurred after
removal of a prostate adenocarcinoma. Signi®cant
Charcoal extraction of serum inhibition of phosphate uptake compared with control
Serum samples were charcoal extracted by a method was detected in the preoperative serum ± up to 24%
based on that described by Lajeunesse et al. (13). The inhibition of control at 20% v/v dilution (Table 2) ± but
patients' and control serum samples were ®rst heat no signi®cant inhibition was detected in postoperative
inactivated and then 5 ml serum was added to 0.5 g serum.
washed charcoal. After mixing, the charcoal was Signi®cant inhibitory activity was also detected in
recovered by centrifugation and eluted in 750 ml serum from patient 3 (Fig. 1) with symptoms and signs
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Table 2 Effect of patient serum on renal phosphate uptake by OK 3B2 cells.
Phosphate uptake (c.p.m./mg protein103)
Serum dilution Inhibition by patient serum
Patient (% v/v) Patient serum Control serum compared with control serum (%)
Patients with diagnosis of OOM con®rmed by tumour removal
Patient 1 15 1792^33 1963^55 9*
20 2035^46 2098^10 3*
Patient 2 10 3177^48 3991^98 20*
20 2492^24 3282^35 24*
Patient with symptoms and signs of OOM but diagnosis not con®rmed
Patient 3 15 1198^87 1451^56 17*
20 823^54 1205^200 32*
Patients with hypophosphataemia of other origin
Patient 4 10 1424^174 1289^42 No inhibition
20 1377^125 1092^83 No inhibition
Patient 5 10 1537^287 1500^78 No inhibition
20 1541^108 1200^36 No inhibition
Phosphate uptake was measured in triplicate in con¯uent OK 3B2 cells that had been incubated with heat-inactivated serum at 10±20% v/v dilution for 20 h.
OOM, oncogenic osteomalacia.
*Signi®cantly different from control P , 0:05:
typical of oncogenic osteomalacia, but in whom no 1,25(OH)2D concentration, no muscle pain and no
tumour has been located. Signi®cant inhibitory activity evidence of osteomalacia or rickets. His hypophos-
up to 32% inhibition of control has been detected in phataemia is as yet unexplained. Patient 5 is a 12-year
serum from this patient (Table 2). Similar signi®cant old girl with hypophosphataemia and rickets, with an
inhibitory activity has been demonstrated in three increased serum 1,25(OH)2D concentration and hyper-
different serum samples collected from her over a 2- calciuria. Her clinical presentation is consistent with a
year period. diagnosis of hereditary hypophosphataemic rickets
Sera from two other patients with hypophosphatae- with hypercalciuria (14), and there are two other
mia, but without other signs of oncogenic osteomalacia, affected family members. No inhibition of phosphate
were also tested in the bioassay. Patient 4 is a 36-year uptake was detected in sera from these two patients
old man with hypophosphataemia, but normal serum compared with control sera at dilutions of 5±20% v/v
(Table 2). Some stimulation of phosphate uptake
compared with control sera was detected in sera from
these patients, up to 1.4-fold control by the serum of
patient 5.
Charcoal extraction of serum
After determining that phosphate uptake inhibitory
activity was present in sera of patients with proven or
presumptive oncogenic osteomalacia, the sera were
next tested to determine whether the activity could be
extracted with charcoal and eluted with acetic acid, as
described with the inhibitory activity in sera from Hyp
mice (13). This was shown to be the case for serum
from patients 1 and 3. There was insuf®cient pre-
operative serum available from Patient 2 for charcoal
extraction. Acetic acid eluants of charcoal extracts
from patients 1 and 3 both signi®cantly inhibited
phosphate uptake compared with eluants from control
sera (Table 3).
Figure 1 Inhibition of phosphate uptake by OK 3B2 cells by serum
from patient 3 with symptoms and signs of oncogenic
osteomalacia. Phosphate uptake was measured in triplicate in OK
3B2 cells after preincubation for 20 h with heat-inactivated serum MR imaging
from patient 3, or control serum, at 10±20% v/v dilution, and
corrected for total protein content per well. Each bar represents the In patient 1 an oval area 10 8 5 mm with very high
mean of triplicates^S.D. Patient 3 was signi®cantly different from signal intensity, located subcutaneously approximately
each control P , 0:05: 20 cm proximal to the knee joint, was seen on the
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Table 3 Charcoal extraction of patient serum.
Phosphate uptake (c.p.m./mg protein103) Inhibition by patient serum
Serum dilution compared with control
Patient (% v/v) Patient serum Control serum serum (%)
Patient 1
Unextracted serum 20 4019^47 4131^65 3*
Charcoal-extracted serum eluant 5 2338^63 2576^139 9*
Patient 3
Unextracted serum 20 823^54 1205^200 32*
Charcoal-extracted serum eluant 10 687^46 1162^267 41*
Phosphate uptake was measured in triplicate in con¯uent OK 3B2 cells that had been incubated with heat-inactivated serum or acetic acid eluants of charcoal
extracts of serum at 10±20% v/v dilution for 20 h.
*Signi®cantly different from control P , 0:05:
T2-weighted STIR images in the frontal plane (Fig. 2A). patient's serum compared with control serum in this
Complementary axial T2-weighted STIR images and pre- assay provided further evidence for the diagnosis of
and post-contrast T1-weighted images (Fig. 2B±D) oncogenic osteomalacia, and on this basis a whole-
con®rmed this ®nding and the signal intensity pattern body MR scan was carried out. As most tumours have a
corresponded to a highly vascularised tumour. high signal intensity on T2-weighted images because of
high water content, we used the highly water-sensitive
fat-suppressed T2-weighted STIR sequence in this
Discussion patient. With a large ®eld of view (450 cm) it is
This case report describes the use of a renal phosphate possible to get an overview and screen for tumours,
uptake bioassay of serum and whole-body MR imaging using only this sequence with relatively few investi-
for the diagnosis of oncogenic osteomalacia and gated areas, even if, as in our patient, the tumour
localisation of the tumour. The patient presented with location is completely unknown. MR imaging was
increasing muscle ache and pain, and had demon- successful in identifying a small subcutaneous tumour
strated hypophosphataemia, high urinary phosphate in the right leg. Surgical removal of the tumour
excretion, undetectable serum 1,25(OH)2D and severe resulted in normalisation of the abnormal biochemistry
osteomalacia typical of oncogenic osteomalacia. No and resolution of the patient's symptoms.
tumour, however, could be located. Localising the There has been one previous report of testing serum
tumour, which is needed for a de®nite diagnosis, is from a patient with oncogenic osteomalacia; the serum
commonly a problem in patients presenting with was shown in fact to stimulate phosphate uptake by the
clinical signs and symptoms suggestive of oncogenic PTH-sensitive OK/E cell line to a greater extent than
osteomalacia. The tumours responsible for the condi- control serum after incubation for 4 h (21). As
tion can be located in almost any part of the body and discussed by the authors, their inability to detect
are often small and slowly growing (reviewed, (3, 4)). inhibitory activity may have been due to the short
Dif®culty in locating the tumour may result in delays of time course used. In the studies reported here, the OK
several years between the original presentation and 3B2 cells were incubated with diluted serum for 20 h ±
presumptive diagnosis, and treatment by removal of the the time course we have used with conditioned media
tumour (15±18). In some cases (19), including patient (12) ± before measurement of phosphate uptake.
3 of this report, no tumour has been located despite Inhibition of phosphate uptake compared with
diligent searching. control serum was also demonstrated in our studies
MR imaging has been reported to have been useful in by serum from a second patient in whom the diagnosis
localising the tumour in several previous cases, often by was subsequently con®rmed by removal of the tumour,
de®ning the tumour after a suspicious area has already and in a third patient with clinical signs consistent with
been identi®ed (5, 6, 20, 21). If no suspicious area is oncogenic osteomalacia and biopsy-proven osteomala-
identi®ed, however, the issue becomes whether to cia, but in whom no tumour has yet been located. In
proceed with an expensive whole-body scan. In two the latter patient, inhibitory activity up to 32%
previous reports, skeletal MR surveys have been used to inhibition of control at 20% v/v dilution was demon-
locate the tumour (7, 22). strated in several samples collected over a 2-year
In the studies presented here, a sample of serum from interval. The lower percentage inhibition in response
patient 1 was ®rst tested in a blinded manner in a renal to patient 1 serum compared with serum from patients
phosphate bioassay, in which we have shown inhibition 2 and 3 (Table 2) was most probably attributable to the
of renal phosphate uptake by conditioned medium from inherent variability of a bioassay system. In this study,
cultured oncogenic osteomalacia tumour cells (9). the sera were each compared with age- and sex-
Detection of phosphate uptake inhibition in the matched controls and there was also variability in the
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Figure 2 MR images from patient 1. Fat-suppressed T2-weighted
STIR images (TR 2500 ms, TE 120 ms, TI 120 ms, matrix 203±
256/256) with a ®eld of view of 275±450 cm and a slice thickness
of 6±8 mm, gap 0.8±1.6 mm, were obtained in the frontal plane.
Complementary T2-STIR and T1-weighted sequences in the axial
and frontal plane were performed in areas suspected of harboring
the tumour. Contrast-enhanced (20 ml of 0.5 mmol/kg GdDTPA-
BMA) T1-weighted images were obtained in the tumour area of the
upper leg. (A) Frontal fat-suppressed T2-weighted `screening'
image of the distal part of the upper leg with the tumour located
subcutaneously (arrow). (B) Axial fat-suppressed T2-weighted
image of the distal part of the upper leg with the tumour located
subcutaneously (arrow). (C) Axial T1-weighted spin echo image
over the tumour area (arrow). (D) Contrast-enhanced axial T1-
weighted SE image over the tumour area (arrow).
baseline responses. Therefore, the responses were phosphate uptake compared with control serum
evaluated on an intra-assay basis, which reproducibly samples.
showed signi®cant inhibitory activity of serum from Lajeunesse et al. (23) have studied renal phosphate
patients 1, 2 and 3 compared with their appropriate uptake inhibitory activity in serum from Hyp mice, the
controls. We also tested sera from two other patients with mouse model of X-linked hypophosphataemic rickets.
clinical features suggestive of oncogenic osteomalacia, The clinical similarities between oncogenic osteomala-
but who were not included in this report because they cia and the inherited condition, X-linked hypophos-
did not have biopsy-proven osteomalacia. Sera from phataemic rickets, and evidence for the involvement of
these patients did not inhibit phosphate uptake in the a humoral factor in both, have led to proposals that
bioassay. Two further patients with hypophosphatae- similar mechanisms may be involved in the two
mia, but without other signs of oncogenic osteomala- conditions (2, 24). Lajeunesse et al. (23) reported a
cia, were included in this study to assess the speci®city maximal effect of inhibition of renal phosphate uptake
of the assay. Serum from these patients did not inhibit by serum from Hyp mice with a longer time course of
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via free accessEUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145 Oncogenic osteomalacia case report 475
24 h of incubation, similar to the time course used in 5 Leicht E, Kramann B, Seitz G, Trentz O & Remberger K.
this study. The phosphate uptake inhibitory activity of Oncogenic osteomalacia: imaging studies. Bildgebung 1993 60
13±17.
serum from patients with oncogenic osteomalacia was 6 Lee HK, Sung WW, Solodnik P & Shimshi M. Bone scan in tumor-
also extracted by charcoal and was recovered by elution induced osteomalacia. Journal of Nuclear Medicine 1995 36 247±
in acetic acid in this study, in a manner similar to that 249.
described by Lajeunesse et al. (13) with Hyp mice 7 Avila NA, Skarulis M, Rubino DM & Doppman JL. Oncogenic
osteomalacia ± lesion detection by MR skeletal survey. American
serum. The similarity in properties of the phosphate Journal of Roentgenology 1996 167 343±345.
uptake inhibitory activity between the oncogenic 8 David K, Revesz T, Path MRC, Kratimenos G, Krausz T, Path FRC
osteomalacia patient serum and Hyp mice serum, in et al. Oncogenic osteomalacia associated with a meningeal
time course and after charcoal extraction, supports the phosphaturic mesenchymal tumor ± case report. Journal of
hypothesis of a common phosphate regulating factor in Neurosurgery 1996 84 288±292.
9 Nelson AE, Namkung HJ, Patava J, Wilkinson MR, Chang ACM,
the two conditions. Reddel RR et al. Characteristics of tumor cell bioactivity in
In conclusion, this case report describes the ®rst oncogenic osteomalacia. Molecular and Cellular Endocrinology
patient in whom detection of phosphate uptake 1996 124 17±23.
inhibitory activity in the serum assisted in the diagnosis 10 Nelson AE, Mason RS, Hogan JJ, Diamond T & Robinson BG.
Tumor expression studies indicate that HEM-1 is unlikely to be
and prompted subsequent localisation of the tumour by the active factor in oncogenic osteomalacia. Bone 1998 23 549±
whole-body MR imaging. Although some candidate 553.
genes for oncogenic osteomalacia have recently been 11 Jan de Beur SM, Streeten EA, Civelek AC, McCarthy EF, Sweeney
described (25, 26) the causative circulating factor has DC, Sharon M et al. Identi®cation of tumors producing oncogenic
not yet been identi®ed and there is not yet available a osteomalacia using somatostatin-receptor imaging. Proceedings of
the Endocrine Society, 80th Annual Meeting, New Orleans, LA,
de®nitive diagnostic serum test for the presence of this USA, 1998, 420±421.
factor. The ®nal diagnosis of oncogenic osteomalacia is 12 Nelson AE, Hogan JJ, Holm IA, Robinson BG & Mason RS.
dependent on the localisation of the tumour, which is Phosphate wasting in oncogenic osteomalacia: PHEX is normal
also essential for the successful management of the and the tumor-derived factor has unique properties. Bone 2001
28 430±439.
patient. Localisation can present a clinical problem, 13 Lajeunesse D, Delandre A & Loignon M. Evidence for the
however, if the tumour is not found by routine involvement of a charcoal extractable humoral factor responsible
investigations and more sophisticated tests have to be for hypophosphatemia in the Hyp mouse. Journal of Bone and
considered. In this case, the advantage of the bioassay Mineral Research 1997 12 S113.
result was the con®rmation of the provisional diag- 14 Tieder M, Arie R, Bab I, Maor J & Liberman UA. A new kindred
with hereditary hypophosphatemic rickets with hypercalciuria:
nosis, which then prompted the whole-body MR scan. implications for correct diagnosis and treatment. Nephron 1992
The diagnosis was ®nally con®rmed when the tumour, 62 176±181.
located by the MR scan, was removed and the patient's 15 Reid IR, Teitelbaum SL, Dusso A & Whyte MP. Hypercalcemic
symptoms and signs were normalised. hyperparathyroidism complicating oncogenic osteomalacia.
Effect of successful tumor resection on mineral homeostasis.
American Journal of Medicine 1987 83 350±354.
Acknowledgements 16 Nitzan DW, Horowitz AT, Darmon D, Friedlaender MM,
Rubinger D, Stein P et al. Oncogenous osteomalacia: a case
We thank Dr A Ê ke Tenerz, Professor S Posen, Dr T study. Bone and Mineral 1989 6 191±197.
Diamond, Dr M Epstein, Associate Professors S Boyages 17 Gonzalez-Compta X, Manos-Pujol M, Foglia-Fernandez M, Peral E,
and R Cuneo and Professor A Kung for referring their Condom E, Claveguera T et al. Oncogenic osteomalacia: case
report and review of head and neck associated tumours. Journal
patients to us for study. Professor H Murer of Zurich, of Laryngology and Otology 1998 112 389±392.
Switzerland is thanked for providing us with the OK 18 Heylen A, Dasnoy D, Hustin J & Pochet JM. Tumor-related
3B2 cells. This research was supported by grants from osteomalacia followed after treatment by hyperparathyroidism.
the NH & MRC Australia, the University of Sydney Revue de Rhumatisme 1999 66 53±57.
19 Paterson CR, Naismith KI & Young JA. Severe unexplained
Cancer Research Fund, and the Swedish Cancer Society. hypophosphatemia. Clinical Chemistry 1992 38 104±107.
20 McGuire MH, Merenda JT, Etzkorn JR & Sundaram M. Oncogenic
osteomalacia. A case report. Clinical Orthopedics 1989 244 305±
References 308.
21 Shane E, Parisien M, Henderson JE, Dempster DW, Feldman F,
1 Hewison M. Tumor-induced osteomalacia. Current Opinion in Hardy MA et al. Tumor-induced osteomalacia: clinical and basic
Rheumatology 1994 6 340±344. studies. Journal of Bone and Mineral Research 1997 12 1502±
2 Nelson AE, Robinson BG & Mason RS. Oncogenic osteomalacia: is 1511.
there a new phosphate regulating hormone? Clinical Endocrin- 22 Fukumoto S, Takeuchi Y, Nagano A & Fujita T. Diagnostic utility
ology 1997 47 635±642. of magnetic resonance imaging skeletal survey in a patient with
3 Drezner MK. Tumor-induced osteomalacia. In Primer on the oncogenic osteomalacia. Bone 1999 25 375±377.
Metabolic Bone Diseases and Disorders of Mineral Metabolism, edn 23 Lajeunesse D, Meyer RA & Hamel L. Direct demonstration of a
4, pp 331±337. Ed MJ Favus. Philadelphia: Lippincott Williams & humorally-mediated inhibition of renal phosphate transport in
Wilkins, 1999. the Hyp mouse. Kidney International 1996 50 1531±1538.
4 Nuovo MA, Dorfman HD, Sun CC & Chalew SA. Tumor-induced 24 Rowe PSN. The role of the PHEX gene (PEX) in families with
osteomalacia and rickets. American Journal of Surgical Pathology X-linked hypophosphataemic rickets. Current Opinion in Nephrology
1989 13 588±599. and Hypertension 1998 7 367±376.
www.eje.org
Downloaded from Bioscientifica.com at 07/06/2022 09:57:09AM
via free access476 A E Nelson and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145
25 Rowe PSN, de Zoysa PA, Dond R, Wang HR, White KE, Econs MJ tumors that cause phosphate wasting. Journal of Clinical
et al. MEPE, a new gene expressed in bone marrow and tumors Endocrinology and Metabolism 2001 86 497±500.
causing osteomalacia. Genomics 2000 67 54±68.
26 White KE, Jonsson KB, Carn G, Hampson G, Spector TD,
Mannstadt M et al. The autosomal dominant hypophosphatemic Received 8 November 2000
rickets (ADHR) gene is a secreted polypeptide overexpressed by Accepted 1 June 2001
www.eje.org
Downloaded from Bioscientifica.com at 07/06/2022 09:57:09AM
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