Tumor-Induced Rickets in a Child Witha Central Giant Cell Granuloma: A CaseReportElisa Fernández-Cooke, MDa, Jaime Cruz-Rojo, MDa, Carmen Gallego, MDb, Ana Isabel Romance, MDc, Rocio Mosqueda-Peña, MDa,Yolanda Almaden, MDd, Jaime Sánchez del Pozo, MDa

abstract Tumor-induced osteomalacia/rickets is a rare paraneoplastic disorderassociated with a tumor-producing fibroblast growth factor 23 (FGF23). Wepresent a child with symptoms of rickets as the first clinical sign of a centralgiant cell granuloma (CGCG) with high serum levels of FGF23, a hormoneassociated with decreased phosphate resorption. A 3-year-old boy presentedwith a limp and 6 months later with painless growth of the jaw. Onexamination gingival hypertrophy and genu varum were observed.Investigations revealed hypophosphatemia, normal 1,25 and 25 (OH) vitaminD, and high alkaline phosphatase. An MRI showed an osteolytic lesion of themaxilla. Radiographs revealed typical rachitic findings. Incisional biopsy of thetumor revealed a CGCG with mesenchymal matrix. The CGCG was initiallytreated with calcitonin, but the lesions continued to grow, making it necessaryto perform tracheostomy and gastrostomy. One year after onset thehyperphosphaturia worsened, necessitating increasing oral phosphatesupplements up to 100 mg/kg per day of elemental phosphorus. FGF23 levelswere extremely high. Total removal of the tumor was impossible, and partialreduction was achieved after percutaneous computed tomography–guidedradiofrequency, local instillation of triamcinolone, and oral propranolol.Compassionate use of cinacalcet was unsuccessful in preventing phosphaturia.The tumor slowly regressed after the third year of disease; phosphaturiaimproved, allowing the tapering of phosphate supplements, and FGF23 levelsnormalized. Tumor-induced osteomalacia/rickets is uncommon in childrenand is challenging for physicians to diagnose. It should be suspected inpatients with intractable osteomalacia or rickets. A tumor should be ruled outif FGF23 levels are high.

Tumor-induced osteomalacia/rickets(TIO) is a rare paraneoplastic disordercaused by overproduction of fibroblastgrowth factor 23 (FGF23) from theresponsible tumors.1,2 FGF23 isa hormone associated with decreasedresorption of phosphate that causeshyperphosphaturia, leading toosteomalacia or rickets.3–5 Tumors aretypically benign, small, and withmesenchymal origin.2,6–8 We report thefirst pediatric case of TIO in associationwith a central giant cell granuloma

(CGCG).9 Our case is unique becausethe child presented with clinical signsof rickets as the first sign of CGCG withhigh FGF23 serum levels.

PATIENT PRESENTATION

A previously healthy 3-year-old boywith no history of trauma or other jointproblems presented with an increasinglimp. Initial radiographs and basiclaboratory studies, including calciumand phosphate, were normal. Heinitially received a diagnosis of

Departments of aPediatrics, bRadiology, Division ofPediatrics, and cOral & Maxillofacial Surgery, Division ofPediatrics, Hospital Universitario 12 de Octubre, Madrid,Spain; and dLipid and Atherosclerosis Unit, IMIBIC/ReinaSofia University Hospital/University of Cordoba, and CIBERFisiopatologia Obesidad y Nutricion, Instituto de SaludCarlos III, Spain

Dr Fernández-Cooke was a pediatrician on the teamcaring for the patient, and she drafted and reviewedthe manuscript; Dr Cruz-Rojo was a pediatrician onthe team caring for the patient, and he contributedto the writing of the manuscript; Dr Gallego was theradiologist caring for the patient, and sheperformed and interpreted the scans for diagnosisand follow-up, performed percutaneous CT-guidedradiofrequency sessions, and contributed to thewriting of the manuscript; Dr Romance was themaxillofacial surgeon caring for the patient, and shereviewed the manuscript; Dr Mosqueda-Peña wasa pediatrician on the team caring for the patient,and she reviewed the manuscript; Dr Almaden wasthe physician at the referral hospital where FGF23levels were measured, and she reviewed themanuscript; Dr Sánchez del Pozo was the leadingpediatrician on the team caring for the patient andhis reference doctor, and he reviewed themanuscript; and all authors approved the finalmanuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-2218

DOI: 10.1542/peds.2014-2218

Accepted for publication Feb 10, 2015

Address correspondence to Elisa Fernández-Cooke,MD, Department of Pediatrics, Hospital Universitario12 de Octubre, Avenida de Córdoba SN 28041,Madrid, Spain. E-mail: elisafcooke@gmail.com

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,1098-4275).

Copyright © 2015 by the American Academy ofPediatrics

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transient synovitis. His family historywas negative.

Six months later he presented withinsidious and painless growth of thejaw. On examination, gingivalhypertrophy and mobile teeth wereobserved (Fig 1), and he presentedwith genu varum, with a waddlinggait. Laboratory tests revealed serumphosphate level 2.6 mg/dL (referencerange 3.7–5.3 mg/dL), 1,25-(OH)-vitamin-D 35.2 pg/mL (referencerange 15–65 pg/mL), 25-(OH)-vitamin D 15.1 ng/mL (referencerange 15–55 ng/mL), and parathyroidhormone (PTH) 7.5 pg/mL (referencerange 15–60 pg/mL). Serum boneformation markers were high:osteocalcin 52 ng/mL (referencerange 4–12 ng/mL), alkalinephosphatase 23 mg/L (referencerange 7.5–17 mg/L), and bone-specificalkaline phosphatase 36.5 mg/L(reference range 7.5–17 g/L). Tubular

reabsorption of phosphate measuredby ratio of the renal tubularmaximum reabsorption rate ofphosphate to the glomerular filtrationrate (TmP/GFR) was normal initially(Fig 3). MRI showed an osteolyticlesion measuring 28 3 19 mm at themaxilla. Skeletal radiographs revealedtypical rachitic findings (Fig 2), andbone mineral density scans showeda z score of 22.92 SD at the lumbarspine. Incisional biopsy of the tumorrevealed a CGCG with mesenchymalmatrix. Cherubism mutations werenegative.

The CGCG was treated initially withcalcitonin and phosphatesupplements, and calcitriol werestarted for the rickets (Fig 3summarizes treatment timelinealigned with laboratory tests andphosphate supplementrequirements). Despite treatment, themaxillary bone lesions continued to

grow, measuring 45 3 70 3 100 mmin the maxilla and 80 3 40 3 70 mmin the jaw by MRI (Fig 1 and 2C).Although the lesions were benign,they led to obstructive sleep apneaand malnutrition. Thesecomplications made it necessary toperform a tracheostomy andgastrostomy. Multiple pathologicfractures made the patientwheelchair-bound, and weakness ofthe thoracic cage was reflected ina reduction in lung volumeparameters (Fig 2A and 2B).

Additional studies 1 year after theonset of the disease revealedsignificant hyperphosphaturia, withTmP/GFR of 0.44 mg/dL at thelowest, necessitating increasing oralphosphate supplements starting at8 mg/kg per day (of elementalphosphorus; 500 mg = 16.1 mmol) atthe onset of the disease and up to100 mg/kg per day during follow-up.Osteocalcin was .300 ng/mL (theupper limit of detection of thelaboratory), and alkaline phosphatasewas 246 mg/L (7.5–17) (Fig 3). Twoyears into follow-up, bone mineraldensity worsened to a z score of 24.4SD at the lumbar spine.

The challenge was to find the linkbetween the tumor and rickets in anotherwise healthy child. Aftera literature search, TIO induced byFGF23 was our main suspecteddiagnosis despite being rare in children.

FGF23 levels were extremely high:intact FGF23 395.1 pg/mL (N , 40)and C-terminal peptides 1267.2 RU/mL (N , 60), as measured by ELISAKit (Kainos Laboratories, Tokyo,Japan). CGCG producing FGF23 wasthought to be the primary cause of hisrickets but was not confirmed bymessenger RNA on the surgerysamples because this was notavailable technique in our hospital.

Total removal of the tumor wasimpossible because of its extension,and the CGCG did not respond toconventional treatment withcalcitonin. An octreotide scan was

FIGURE 1Sequence of photographs showing the tumor’s growth (2008–2009) and improvement (2012).

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performed but was negative forsomatostatin receptors. Conservativetreatment of the CGCG includingbisphosphonates and simple curettagewas tried to reduce the volume, withpoor response. Partial reduction wasachieved after percutaneousCT-guided radiofrequency sessions, witha Cool Tip 15-10 (Tyco-Radionics-Covidie, Minneapolis, MN) and anumbrella-type electrode (Leeving4 cm; Boston Scientific, Marlborough,MA), with an overall decrease in sizeof 5 mm at all axes. Also, localinstillation of triamcinolone resultedin disappearance of 2 40-mm cysts2 months after therapy. Finally,propranolol was given for 6 monthsin an attempt to reduce the tumor’svascularization and therefore its

growth. Two months later anMRI scan showed tumor reduction(40 3 62 3 77 mm in the maxilla and57 3 38 3 70 mm in the jaw).

Together with the local control of thetumor, the main problem was tocontrol phosphate renal wasting andmore pathologic fractures.Compassionate use of cinacalcet,a calcimimetic drug that suppressesPTH secretion and by reducing PTH-induced phosphate excretion mayraise serum phosphate, was tried.This treatment was unsuccessful andwas discontinued after a monthbecause of hypocalcemia. The tumorwas then stable for more than a year,with no specific treatment, andphosphate wasting was managedwith phosphorus supplements and

calcitriol. The tumor spontaneouslyand slowly regressed the third yearafter onset. Bone mass, bonereabsorption parameters, and FGF23levels normalized. Because thesamples had to be sent away, wemeasured FGF23 only twice, atdiagnosis and after improvement, toprove normalization. Phosphatesupplements were tapered andgastrostomy and tracheostomy tubesremoved. The patient started to walkagain and is now back in school 4years after the onset of the disease.

DISCUSSION

To the best of our knowledge, this isthe first pediatric case of severeFGF23 tumor-induced rickets

FIGURE 2A and B, Radiologic images of rickets and pathologic fractures. Sequences of comparative radiographs taken 1 year apart (January 2008 and February2009) demonstrate progressive diffuse bone demineralization, widening of the growth plates, metaphyseal cupping and fraying, bowing of long bones,and multiple rib fractures with collapse of the thoracic cage. C, Images of the tumor in the maxillary bones. Axial T2-weighted images of facial MRI showa huge mass that involves both the mandible (white arrows) and the maxilla (white open arrows). Teeth (white arrowheads) are seen floating in themass. There are areas of cystic transformation with fluid levels (black arrowheads) related to hemorrhage.

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secondary to a CGCG of the maxillarybones. Retrospectively, we think theinitial limp was the first sign ofweakness associated with rickets. Weassumed that the tumor was thesource of production of FGF23because rickets started with the onsetof the CGCG, coinciding with anextremely high FGF23 serum level.Also, the rickets and the need forphosphorus supplementationimproved as the tumor’s size graduallydecreased. The limitation of our case isthat we could not provide the finalproof of concept, because we did notperform tests looking for FGF23production in the surgical samples.

TIO is a rare condition first describedby McCance1 in 1947 as

a paraneoplastic disordercharacterized by phosphaturia,hypophosphatemia, low serum levelsof 1,25-dihydroxy-vitamin D, andrickets or osteomalacia.7,10 Tumorsresponsible for this condition usuallyaffect patients .30 years old and aretypically benign, small, and ofmesenchymal origin.2,6–8 Very fewchildren with TIO have beenreported; the youngest wasa 9-month-old boy with a soft tissuetumor on his right thigh.6,11

In our case the tumor was a benignCGCG with a collagen fibroblastmatrix, located in the maxillary bones.In an extensive literature review onCGCG of the jaw by de Lange,9 none ofthe patients presented with

osteomalacia, suggesting that thetumors did not produce FGF23, unlikethat of our patient.

In 2000 FGF23 was implicated in thedevelopment of hypophosphatemicdiseases.12 FGF23 is a bone-derivedhormone that regulates and isregulated by blood levels ofphosphate and active vitamin D.FGF23 acts at renal tubule cells bybinding to an FGF receptor (probablyFGFR1) and its coreceptor Klotho todecrease the overall activity of theenzyme (1a hydroxylase), whichconverts inactive vitamin D to active1,25-D, and increasing the activity ofthe 24(OH)ase, which catabolizes thedegradation of 1,25-D. FGF23 alsoincreases phosphate transport into

FIGURE 3Timeline of medical and surgical treatment aligned with graph showing phosphate wasting parameters and phosphate daily intake. TmP/GFR, ratio of therenal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (mg/dL).

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the urine via the sodium-dependentphosphate transporters 2a and c.On the other hand, FGF23 productionis stimulated in response to elevationsin phosphorus and 1,25-D.13

MRI has been shown to be the besttool for searching for the primarytumor.14 Tumor localization isimproved by somatostatin receptorimaging, such as octreotidescintigraphy and octreotide single-photon emission CT/CT.8,15 Imagingmethods such as gallium-68 (68Ga)DOTA-NOC, 68Ga DOTA-TOC, and 68GaDOTA-TATE positron emissiontomography/CT show promising firstresults in patients with TIO andnegative octreotide scans.16

Our challenge was on one hand therapidly growing CGCG and on theother hand the consequences ofFGF23 overproduction. The mostcommon treatment of CGCG has beensurgical curettage, with highrecurrence rates. The most successfulpharmacologic agents have beenintralesional corticosteroid injectionsand systemic treatment withcalcitonin or interferon-a2.9 Otheragents such as imatinib17 ordenosumab,18 a monoclonal antibodywith antiresorptive effects developedfor osteoporosis, could be useful intreating CGCG. Radiofrequencythermal ablation is less invasive, and

in our experience it had a mild effectin reducing the tumor’s volume;therefore, we think it should beoffered when complete surgicalresection cannot be performed.19

Propanolol was our last treatmentattempt, intended to reducevascularization of the tumor andtherefore its growth.20 In ourexperience there was mildimprovement, with a reduction intumor size 2 months after weinitiated treatment.

The treatment of choice for TIO istotal removal of the tumor. When thetumor is completely removed, clinicalimprovement and resolution of thelaboratory abnormalities can beseen.2,6,7,10 There are reported casesof TIO that improved with octreotidetherapy when scans were positivefor somatostatin receptors. Gelleret al21 treated patients successfullywith cinacalcet, a calcimimetic agent.They hypothesized that medicallyinduced hypoparathyroidism withcinacalcet increases renal phosphatereabsorption and decreasesphosphate supplementation,showing evidence of bone healing.In our case this treatment did notwork and led to hypocalcemia,although other studies have shownits effectiveness.21–23 A phase 1clinical trial of an anti-FGF23

antibody has shown that it increasesserum phosphate in patients withX-linked hypophosphatemic ricketsand may open the door to treat otherFGF23-related hypophosphatemicdiseases.24

In conclusion, TIO is uncommon inchildren. The diagnosis is challengingfor physicians, and it should besuspected in patients with intractableosteomalacia or rickets. If FGF23levels are high, a tumor should belooked for. FGF23 levels in serum andhistologic samples are useful fordiagnosis and follow-up. Curativetreatment of TIO involves surgicalremoval of the tumor when possible.Propranolol is a treatment option ifthe primary tumor is wellvascularized and cannot be totallyremoved. When the tumor expressessomatostatin receptors, treatmentwith somatostatin analogs should betried. Cinacalcet may be useful forimproving phosphate wasting. CGCGthat does not respond to standardtreatment could be candidate fordenosumab or imatinib. In ourexperience, CGCG producing FGF23 isan aggressive disease that if notcompletely removed causes severeosteomalacia or rickets, with feweffective treatment options but withan encouraging natural historytoward regression.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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DOI: 10.1542/peds.2014-2218 originally published online May 25, 2015; 2015;135;e1518Pediatrics 

Rocio Mosqueda-Peña, Yolanda Almaden and Jaime Sánchez del PozoElisa Fernández-Cooke, Jaime Cruz-Rojo, Carmen Gallego, Ana Isabel Romance,

Case ReportTumor-Induced Rickets in a Child With a Central Giant Cell Granuloma: A

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