Clinical Profile:

A 26 year old man presented with complaints of generalized bodyache, progressive muscle weakness and bone pain since four years. The patient had had a trivial trauma to the left hip in 2016 resulting in a fracture of the neck of left femur and had been operated for the same. Since one year, the patient has not been able to walk without support

There was no history of alcohol intake, anti-seizure medication, chemotherapeutic drugs or antacid abuse.

No member of his family was known to suffer from any bone disorders.

The ultrasound of abdomen and pelvis was normal.

The serum calcium, PTH, Vit D3, RFT were Normal.

The serum phosphate was decreased

The serum ALP was increased

Radiological findings:T

Serial radiographs of hips show gradual reduction in bone density with coarse trabecular pattern and loss of cortico-medullary differentiation.. An old fracture of the neck of left femur with fixation screws is seen. An old healed fracture is seen in neck of the right femur.

Serial radiographs of the lumbar spine show reduction in bone density with coarse trabecular pattern and central wedging of the vertebral bodies. There is apparent sclerosis of the end plates of these vertebrae.

The lateral film of the skull shows the dorsum sellae to be poorly defined. In the mandible, there is resorption of the lamina dura. The film of the hand does not show any abnormality

Based on radiographic and biochemical findings, a diagnosis of hypophosphostemic osteomalacia was made.

Inherited causes were ruled out due to negative family history.

Causes like antacid abuse, chemotherapeutic agents were ruled out .

Renal function tests were normal This ruled out renal tubular acidosis .

Serum fibroblast growth factor(FGF-23) levels were done to rule out tumor induced osteomalacia

Serum Fibroblast growth factor(FGF-23) : 1067 RU/ml (Raised) .

A PET scan was advised to look for occult malignancy.

Somatostatin receptor PET Scan

Generalised osteopenia with mild heterogenously, increased tracer uptake in all bones with SUVmax-73.8. Fractures are seen in few ribs and both inferior pubic rami.

Intensely increased Ga-DOTATATE uptake (SUVmax-73.8) is seen in a ill defined soft tissue posterior to head of right tibia - just inferomedial to right superior tibiofibular joint.

These findings were diagnostic of a mesenchymal tumor causing tumor induced osteomalacia.

Final diagnosis :

Tumor induced osteomalacia

Treatment:

CT guided RFA was performed.

Biopsy samples were inconclusive.

Post operative PET scan showed no residual tumor.

On post operative day 01, there was a fall in FGF-23 levels to normal values (37 RU/ml) and normalization of serum phosphorus on post-op day 05.

Discussion:

•Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome with excessive production of fibroblast growth factor-23(FGF-23) .

•Phosphaturic mesenchymal tumor (PMT) is a polymorphous group of extremely rare mesenchymal tumors that often result in hypophosphatemic osteomalacia/rickets, caused by the overproduction of the phosphaturic hormone fibroblast growth factor 23.

Pathologically, four morphologic patterns of PMTs have been described and widely accepted: primitive-appearing mixed connective tissue, osteoblastoma-like, nonossifying fibroma-like, and ossifying fibroma-like

FGF-23

Mechanism of action: High circulating FGF-23 levels reduce the expression of the sodium -phosphate co-transporters, leading to renal phosphate wasting.

FGF23 is also a regulatory hormone for 1.25-vitamin D and leads to a decreased concentration of the vitamin in blood

Under physiological conditions, FGF23 is secreted predominantly by bone and undergoes degradation by proteolytic enzymes .

Excessive FGF23 action causes several hypophosphatemic diseases, including TIO, X-linked hypophosphatemic rickets (XLHR), autosomal dominant and recessive hypophosphatemic rickets (ADHR and ARHR) .

FGF 23 is phosphaturic agent in excess causes hyperphosphaturia and hypophosphatemia leading to osteomalacia .

Since the FGF -23 producing tumours are small in size and hard to detect diagnosis of this disease is a challenge.As a result, the time from osteomalacia to identifying the associated tumour averages a period of 5 years.

Patients with TIO often present with many years of symptoms before they are diagnosed. The symptoms usually are nonspecific and often progressive.

Differential diagnosis should always include renal Fanconi’s syndrome—a disorder of the proximal renal tubules, leading to impaired phosphate reabsorption and hypophosphatemia. The diagnosis can be confirmed by normal levels of FGF23 along with the presence of glycosuria, hypokalaemia, and metabolic acidosis

Surgical resection of the tumor is curative and improvement is dramatic. Hence, it’s important to be aware of the condition.

Treatment:

The treatment of choice for TIO is resection of a tumour with a wide margin to insure complete tumour removal, as recurrences of these tumours have been reported.

Tumour removal is always curative, and following complete resection of the tumour, the recovery and improvement of the patients is relatively quick, FGF23 disappears rapidly from the circulation, and serum phosphate returns to normal by day 5 post operation.

In case of incompletely resected tumours, subsequent radiotherapy can be used to avoid recurrence or metastasis.

References:

1.Shimada T, Mizutani S, Muto T, et al., Cloning and characterization of FGF23 as a causative factor of tumorinduced osteomalacia, Proc Natl Acad Sci U S A, 2001;98, 6500–5.

2.Pitt mj.Rickets and Osteomalacia. In: Resnick D diagnosis of bone and Disorder, 4^th edition. WB saunders company. 2002;2:1083-113.

3. 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 Eng J Med. 2003;348(17):1656-63.

4. Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F,Cho JY, et al. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity. An analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol. 2004;28(1):1-30.

6. Hypophosphatemic Rickets: Unraveling the Role of FGF23 John M. Pettifor • Kebashni Thandrayen

7. Hypophosphatemic rickets: case report Raquitismo hipofosfatêmico: relato de caso Marta Liliane de Almeida Maiaa, Ana Lucia Santos Abreub,

Paulo Cesar Koch Nogueirab, Maria Luiza Dautro Moreira do Valb,João Tomas de Abreu Carvalhaesb, Maria Cristina de Andradeb.

8. Phosphate wasting disorders in adults G. Marcucci1 & L. Masi1 & S. Ferrarì2 & D. Haffner3 & M.K. Javaid4 & P. Kamenický5 & J.-Y. Reginster6 & R. Rizzoli2 &M.L. Brandi1 .

9. Tumour-induced osteomalacia: a literature review and a case report :Jolanta Dadoniene, Marius Miglinas, Dalia Miltiniene et.al .