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Case Description JOURNAL ARTICLE

Discussion Severe Hypophosphatemia: The Hidden Truth !

Farzahna Mohamed # , Frederick J Raal Author Notes
Case Resolution
Clinical Chemistry, Volume 69, Issue 5, May 2023, Pages 450–453,
Nonstandard Abbreviations
https://doi.org/10.1093/clinchem/hvad028
Human Genes Published: 28 April 2023 Article history "

Author Contributions
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Authors’ Disclosures or
Potential Conflicts of Interest Advertisement

Employment or Leadership Issue Section: Clinical Case Study

Consultant or Advisory Role

VIEWS ALTMETRIC
Stock Ownership

Honoraria
Case Description 331

Research Funding
A 52-year-old woman presented with a 14-year history of progressive proximal More metrics information

Expert Testimony muscle weakness and myalgia. She had been wheelchair-bound for the previous 10

Patents years, with a significant loss of height since the onset of symptoms. She was
previously healthy, with no family history of metabolic bone disease. Clinical
Other Remuneration examination revealed a proximal myopathy, short stature with marked Email alerts
References kyphoscoliosis and pectus carinatum. Her admission laboratory investigations
Article activity alert
showed severe hypophosphatemia, with a serum phosphate of 0.87 mg/dL (0.28
Author notes Advance article alerts
mmol/L [reference interval 2.5–4.5 mg/dL; 0.8–1.4 mmol/L]). 25-Hydroxy
vitamin D (25-OHD) was reduced with a normal 1,25-dihydroxy vitamin D (1,25- New issue alert
< Previous Next > OHD). Laboratory results are summarized in Table 1. Of note, the tubular
maximum reabsorption of phosphate for glomerular filtration rate (TmP/GFR) Receive exclusive offers and updates
was 0.8 mg/dL (0.22 mmol/L [reference interval 2.0–3.4 mg/dL; 0.80–1.35 from Oxford Academic
mmol/L]), suggestive of renal phosphate wasting. Fibroblast growth factor 23
(FGF-23) was elevated at 9207 pg/mL (reference interval 12–49 pg/mL). Despite
phosphate and vitamin D replacement, the hypophosphatemia persisted.
See also
Table 1. Biochemical results at the time of admission (all serum unless specified otherwise). COMMENTARY
Commentary on Severe Hypophosphatemia:
Analyte Reference interval Result The Hidden Truth

Adjusted calcium 8.8–10 mg/dL 8.8 Commentary on Severe Hypophosphatemia:

The Hidden Truth
Phosphate 2.5–4.5 mg/dL 0.87

Magnesium 1.5–2.6 mg/dL 1.97

Citing articles via
Albumin 3.5–5.2 g/dL 4.4
Google Scholar
Parathyroid hormone 14–72 pg/mL 622

25-hydroxy vitamin D <20 ng/mL—deficient; >30 ng/mL—sufficient 13 Latest Most Read Most Cited

1,25-dihydroxy vitamin D 17–65 pg/mL 53 A Single Reference Interval for Interpreting

Serum Free Light Chains across Patients with
Alkaline phosphatase 42–98 IU/L 460
Varying Renal Function

Bone-specific alkaline phosphatase 14–42 IU/L 305 Analytical and Non-Analytical Variation May
Lead to Inappropriate Antimicrobial Dosing in
Creatinine 0.55–1.02 mg/dL 0.43
Neonates: An In Silico Study
2
Estimated glomerular filtration rate 90–120 mL/min/1.73m 117 A Case of Yellow Airway Secretions and Oral
Fluid
TmP/GFR 2.0–3.4 mg/dL 0.8
Severe Hypophosphatemia: The Hidden Truth
Fibroblast growth factor 23 12–49 pg/mL 9207
Commentary on Severe Hypophosphatemia:
Open in new tab The Hidden Truth

More from Oxford Academic

Questions to Consider Biochemistry Biological Sciences

1. What are the causes of urine phosphate wasting? Medical Skills Medicine and Health

2. What is the most likely cause of persistent hypophosphatemia in the Pathology

setting of a normal or low plasma calcitriol level (1,25-OHD)?
Research Methods in Life Sciences
3. What is the most common phosphatonin responsible for diseases
Science and Mathematics Books
characterized by urine phosphate wasting?

Journals
4. What is the diagnostic localization image of choice in this case?

Discussion

A diagnosis of tumor-induced osteomalacia (TIO) was considered and localization

of the tumor was pursued. Localization images included a Gallium 68 DOTATATE
68
positron emission tomography/ computed tomography ( Ga DOTATATE PET/CT),
which showed a 2 cm soft tissue density inferior to the right 2nd and 3rd
metatarsophalangeal joint (Fig. 1 A). MRI of the right foot revealed a
corresponding soft tissue mass (Fig. 1 B). A bone densitometry scan showed
severely reduced bone mineral density with a T-score of -4.4 and -6.4 at the
lumbar spine and left neck of femur respectively. This was in keeping with
osteomalacia. The whole body bone scan showed typical findings of TIO, such as
the ‘tie sign,’ ‘rachitic rosary sign,’ and ‘pseudo-reactivation’ of growth plates (1)
(Fig. 1 C).

Fig. 1.

Open in new tab Download slide

68
(A), Gallium 68 DOTATATE positron emission tomography/ computed tomography ( Ga DOTATATE
PET CT): soft tissue density (1.8 cm×1.8 cm), inferior to the right metatarsophalangeal joint of the
2nd and 3rd digit, with avid uptake of tracer (white arrow); (B), MRI right foot: soft tissue mass
plantar to the 2nd and 3rd metatarsal heads (open arrow). (C) Bone scan: ‘tie sign’ (black arrow),
‘rachitic rosary sign’ (black open arrow), ‘pseudo-reactivation’ of growth plates (black curved
arrow).

Hypophosphatemia is defined as a plasma phosphate less than 2.5 mg/dL (0.8

mmol/L). Phosphate is important for optimal cellular function and serum
phosphorous concentration is predominantly determined by proximal renal
tubular reabsorption via parathyroid hormone regulation (2, 3). Intestinal
phosphorous absorption contributes to a lesser extent to phosphate homeostasis,
with a low phosphate diet and low 1,25-OHD being the 2 most important
regulators for intestinal phosphate absorption (2, 3). Hence, phosphate deficiency
can occur secondary to reduced input, either from insufficient intake or
absorption, or due to increased renal losses and abnormalities in vitamin D
homeostasis. Clinical manifestations of hypophosphatemia depend on the severity
and chronicity of phosphate deficiency, with severe hypophosphatemia (≤1.0
mg/dL [0.3 mmol/L]) being associated with rhabdomyolysis, respiratory failure,
hemolysis, and left ventricular dysfunction (3).

Chronic severe hypophosphatemia is typically caused by rare disorders, including

X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic
rickets, and TIO (3). TIO, also known as oncogenic osteomalacia, is a rare
paraneoplastic syndrome of unknown prevalence, with 1000 cases reported
worldwide to date (4, 5). It is usually caused by a phophaturic mesenchymal tumor
(PMT), which is generally a slow-growing and typically benign mesenchymal or
mixed connective tissue neoplasm that affects bone or soft tissue (2, 4). The most
common phosphatonin secreted by these tumors is FGF-23; however, rarely, other
phosphatonins can be secreted. These include frizzled-related protein-4, FGF-7,
and matrix extracellular phosphoglycoprotein (MEPE), none of which is routinely
measured (4, 6).

FGF-23 acts predominantly at the renal tubule, impairing phosphate reabsorption

and 1-alpha hydroxylation of 25-OHD. Thus, the biochemical hallmarks of TIO are
severe hypophosphatemia secondary to phosphaturia and inappropriately normal
or low 1,25-OHD, with normal serum levels of calcium, parathyroid hormone, and
25-OHD. This biochemical phenotype should direct FGF-23 testing to support the
diagnosis of TIO. The renal phosphate leak is defined by a TmP/GFR result below
the lower reference interval, with the reference range being age and sex dependent
(2, 4, 7, 8). TmP/GFR measures maximum renal tubular phosphate reabsorption in
mass per unit volume of glomerular filtrate, with an increase in TmP/GFR when
plasma phosphate is low and vice versa (8). In a non-disease state, the TmP/GFR
will be high when there is hypophosphatemia, but in TIO, it is abnormally low,
confirming phosphaturia (2).

Due to the lack of awareness of this condition, there is often a prolonged lag time
between the onset of symptoms and diagnosis. Oncogenic osteomalacia, like X-
linked hypophosphatemia, exhibits decreased mineralization of newly formed
bone, and a useful clinical discriminator between the 2 diseases is the age of onset,
whereby X-linked hypophosphatemia typically manifests in the second year of life
(7). The predominant clinical presentation of TIO includes muscle weakness and
severe bone pain that is an unusual symptom for X-linked hypophosphatemia (7).
TIO may also present with or without bone deformities and pathological fractures
or pseudo-fractures.

These tumors are usually small and hence challenging to localize, with successful
localization achieved in only 61% of subjects utilizing a combination of functional
111
imaging including In-pentetreotide single-photon emission computer
tomography (Octreoscan-SPECT), fluorodeoxyglucose-positron emission
18 68
tomography ( F FDG-PET/CT), and anatomical imaging (9). Ga-DOTATATE
PET/CT showed greater sensitivity and specificity in TIO localization when
18
compared to Octreoscan-SPECT/CT and F FDG-PET/CT (9).

The therapeutic modality of choice for TIO is surgical resection of the neoplasm. A
resection with wide margins is recommended to avoid persistent disease, local or
multifocal relapse, and/or distant metastasis when small amounts of residual
tissue remain (4). Therapeutic options for irresectable tumors include primary or
adjuvant radiotherapy and chemotherapy (4). Targeted therapy is based on the
expression of somatostatin receptors on PMTs. Octreotide and peptide receptor
177
radionuclide therapy (PRRT) with Lu DOTATATE has been proposed, with a
variable but modest response (4). Alternative medical therapies utilized in FGF-
23–mediated renal phosphaturia include burosamab or cinacalcet (4). Burosumab
is a fully human monoclonal antibody that inhibits FGF-23 (10). Data from an open
label phase 2 study, in patients with TIO, showed a significant increase in serum
phosphate from baseline, as well as an improvement in all measures of
osteomalacia at 48 weeks (10). Cinacalcet reduces renal phosphate wasting by
inducing a functional hypophosphatemia (4). Furthermore, vitamin D metabolites,
preferably calcitriol, and oral phosphate salts are recommended in those where the
tumor is not identified or irresectable (7).

A recent systematic review of 1725 TIO cases showed a male predominance, with
male patients also showing a higher incidence of fractures compared to women
(4). Almost 80% of TIOs were benign and a neoplasm was identified in 87% of
cases, with somatostatin receptor-based imaging modalities having the highest
sensitivity (4). The neoplasm is most frequently located in the lower limbs (53%
[femur, acetabulum, or feet]) and the head (30% [paranasal sinuses, maxilla, or
oral cavity]), with a preferential localization in the lower limbs seen in men,
compared to women predominantly localizing in the head (4, 9). The reason for
these site preferences is unknown, but sexual differentiation may be linked to
variations of expression of the FN1-FGFR1 fusion gene (4). Malignant TIO was
observed in 3.8% of patients and was associated with a higher risk of pseudo-
fractures, lower TmP/GFR, and higher calcium levels compared to non-malignant
TIO (4). Multifocal TIO occurred in only 6 patients and showed no biochemical or
clinical difference in presentation to unifocal TIO, except for a higher risk of
pseudo-fractures (4). Surgery was the therapeutic modality of choice (98.7%) in
patients with an identifiable tumor (4).

Case Resolution

Our patient proceeded to surgery, and a well-circumscribed mass measuring 12 ×

10 × 9 mm was excised, with a 1 mm clear margin of resection. Histology was
compatible with a benign PMT, specifically the non-ossifying fibroma-like variant
whereby trabeculae of woven bone, spindle cells with nuclear pleomorphisms, and
osteoclast-like giant cells were noted. Phosphate and vitamin D replacement was
discontinued and the phosphate level normalized 1 week postoperatively, with a
68% reduction in FGF-23 levels. The patient no longer required phosphate and
vitamin D replacement and showed an overall improvement in muscle strength.

TIO is a paraneoplastic syndrome caused by over-secretion of FGF-23 from a PMT.

The clinical and biochemical presentation of TIO is important to recognize as it is
an endocrine neoplasm which may have debilitating consequences, yet can have a
very gratifying outcome if cured.

Points to Remember

Severe hypophosphatemia requires prompt evaluation for renal phosphate

wasting, allowing early diagnosis and treatment.

Tumor-induced osteomalacia is a paraneoplastic syndrome caused by

over-secretion of FGF-23 from a phosphaturic mesenchymal tumor.

These tumors are usually benign and are typically small, thus proving a
diagnostic challenge.

Treatment of choice is surgical excision of the tumor.

Nonstandard Abbreviations

OHD, hydroxy vitamin D; TmP/GFR, tubular maximum reabsorption of phosphate

for glomerular filtration rate; FGF-23,fibroblast growth factor 23; TIO, tumor-
induced osteomalacia; PET/CT, positron emission tomography/ computed
tomography; PMT, phophaturic mesenchymal tumor.

Human Genes

FN1-FGFR1

Author Contributions

All authors confirmed they have contributed to the intellectual content of this paper and
have met the following 4 requirements: (a) significant contributions to the conception
and design, acquisition of data, or analysis and interpretation of data; (b) drafting or
revising the article for intellectual content; (c) final approval of the published article;
and (d) agreement to be accountable for all aspects of the article thus ensuring that
questions related to the accuracy or integrity of any part of the article are appropriately
investigated and resolved.

Farzahna Mohamed (Conceptualization, Writing—original draft, Writing—review

& editing), Frederick J. Raal (Supervision, Funding acquisition)

Authors’ Disclosures or Potential Conflicts of Interest

Upon manuscript submission, all authors completed the author disclosure form.
Disclosures and/or potential conflicts of interest:

Employment or Leadership

None declared.

Consultant or Advisory Role

F.J. Raal, fees for advisory board presentations on lipid-lowering therapy and
honoraria from Amgen, Sanofi-Aventis, Regeneron, Novartis, and LIB
Therapeutics. No conflict of interest for the publication above.

Stock Ownership

None declared.

Honoraria

F.J. Raal, fees for lectures on lipid-lowering therapy and honoraria from Amgen,
Sanofi-Aventis, Regeneron, Novartis, and LIB Therapeutics. No conflict of interest
for the publication above.

Research Funding

None declared.

Expert Testimony

None declared.

Patents

None declared.

Other Remuneration

F.J. Raal, support for attending meetings and/or travel from Amgen, Sanofi-
Aventis, Regeneron, Novartis, and LIB Therapeutics.

References

1 Chakraborty PP, Bhattacharjee R, Mukhopadhyay S, Chowdhury S. ‘Rachitic rosary sign’ and ‘tie
sign’ of the sternum in tumour-induced osteomalacia. BMJ Case Rep 2016;2016:bcr2016214766.
Google Scholar WorldCat

2 Chong WH, Molinolo AA, Chen CC, Collins MT. Tumor-induced osteomalacia. Endocr Relat Cancer
2011;18:53–77.
Google Scholar Crossref WorldCat

3 Amanzadeh J, Reilly RF Jr. Hypophosphatemia: an evidence-based approach to its clinical

consequences and management. Nat Clin Pract Nephrol 2006;2:136–48.
Google Scholar Crossref PubMed WorldCat

4 Rendina D, Abate V, Cacace G, D'Elia L, De Filippo G, Del Vecchio S, et al. Tumor-induced

osteomalacia: a systematic review and individual patient's data analysis. J Clin Endocrinol
Metab 2022;107:3428–3436.
Google Scholar Crossref PubMed WorldCat

5 Dahir K, Zanchetta MB, Stanciu I, Robinson C, Lee JY, Dhaliwal R, et al. Diagnosis and
management of tumour-induced osteomalacia: perspectives from clinical experience. J Endocr
Soc 2021;5:bvab099.
Google Scholar Crossref PubMed WorldCat

6 Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, et al. Fibroblast growth
factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med
2003;348:1656–63.
Google Scholar Crossref PubMed WorldCat

7 Carpenter TO. Oncogenic osteomalacia—a complex dance of factors. N Engl J Med

2003;348:1705–8.
Google Scholar Crossref PubMed WorldCat

8 Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation.
Ann Clin Biochem 1998;35:201–6.
Google Scholar Crossref PubMed WorldCat

68
9 El-Maouche D, Sadowski SM, Papadakis GZ, Guthrie L, Cottle-Delisle C, Merkel R, et al. Ga-
DOTATATE for tumor localization in tumor-induced osteomalacia. J Clin Endocrinol Metab
2016;101:3575–81.
Google Scholar Crossref PubMed WorldCat

10 Jan de Beur SM, Miller PD, Weber TJ, Peacock M, Insogna K, Kumar R, et al. Burosumab for the
treatment of tumor-induced osteomalacia. J Bone Miner Res 2021;36:627–635.
Google Scholar Crossref PubMed WorldCat

Author notes

Previous Presentation: Portions of this manuscript were presented as a poster at the 52nd Society
of Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA) Congress, May 2017, in
Johannesburg, South Africa.

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