CLINICAL REPORT
Polyostotic Osteolysis and Hypophosphatemic Rickets with Elevated Serum Fibroblast Growth Factor 23: A Case Report Takeshi Sato,1,2 Koji Muroya,1* Yumi Asakura,1 Akihiro Yachie,3 Gen Nishimura,4 Noriko Aida,5 Jiro Machida,6 Yukichi Tanaka,7 Tomonobu Hasegawa,2 and Masanori Adachi1 1
Department of Endocrinology and Metabolism, Kanagawa Children’s Medical Center, Yokohama, Japan Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
2 3
Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan 4 Department of Radiology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan 5
Department of Radiology, Kanagawa Children’s Medical Center, Yokohama, Japan
6
Department of Orthopedic Surgery, Kanagawa Children’s Medical Center, Yokohama, Japan
7
Department of Pathology, Kanagawa Children’s Medical Center, Yokohama, Japan
Manuscript Received: 4 March 2015; Manuscript Accepted: 20 May 2015
We report on a boy who presented with hypophosphatemic rickets with elevated serum fibroblast growth factor 23 (FGF23) and polyostotic osteolytic lesions at age 2 years. Tumor-induced hypophosphatemic rickets was suspected; however, bone biopsy for osteolytic changes revealed no tumorous change, except for irregularly dilated vessels associated with osteoclasts and fibrous proliferation. Venous sampling failed to point to FGF23-producing foci. After alfacalcidol and phosphate supplementation, the rachitic skeletal changes improved, but FGF23 increased and new osteolytic lesions developed. Serum levels of neopterin and a few cytokines, including plasma transforming growth factor-b and soluble tumor necrosis factor receptor type II, were elevated. At age 4 years, high doses of phosphate resulted in increased serum phosphate levels, decreased neopterin and cytokines, decreased FGF23, and stabilization of osteolysis. We excluded germline mutations in PHEX, FGF23, DMP1, and ENPP1 (genes for hereditary hypophosphatemic rickets) and somatic mutations in the GNAS and HRAS/KRAS (the disease-causing genes for McCune-Albright syndrome and linear nevus sebaceous syndrome, respectively). We could not perform octreotide scintigraphy or fluorodeoxyglucose-positron emission tomography, and thus could not completely exclude occult FGF23-producing tumors. However, considering the course of the disease, it is intriguing to assume that dysregulation of osteoclast-macrophage lineage may have induced increased neopterin levels, increased cytokine levels, osteolytic process, and possibly FGF23 overproduction. © 2015 Wiley Periodicals, Inc.
Key words: polyostotic osteolysis; hypophosphatemic rickets; fibroblast growth factor 23
© 2015 Wiley Periodicals, Inc.
How to Cite this Article: Sato T, Muroya K, Asakura Y, Yachie A, Nishimura G, Aida N, Machida J, Tanaka Y, Hasegawa T, Adachi M. 2015. Polyostotic osteolysis and hypophosphatemic rickets with elevated serum fibroblast growth factor 23: A case report. Am J Med Genet Part A 167A:2430–2434.
INTRODUCTION Hypophosphatemic rickets/osteomalacia encompasses a heterogeneous group of hereditary and acquired disorders. The hereditary form is caused by germline mutations in the PHEX, FGF23, DMP1, and ENPP1 genes, which is associated with secondary elevation of fibroblast growth factor 23 (FGF23). The acquired form is mainly Conflict of interest: None Correspondence to: Koji Muroya, M.D., Ph.D., Department of Endocrinology and Metabolism, Kanagawa Children’s Medical Center, Mutsukawa 2-1384, Minami-ku, Yokohama 232-8555, Japan. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 8 June 2015 DOI 10.1002/ajmg.a.37193
2430
SATO ET AL. attributed to FGF23-producing mesenchymal tumors but is also associated with malformation syndromes such as McCune– Albright syndrome (MAS) and linear nevus sebaceous syndrome (LNSS) [Riminucci et al., 2003; Hoffman et al., 2005]. Non-hereditary, progressive osteolysis is termed Gorham-Stout disease [Hardegger et al., 1985]. The histological characteristics include a matrix of thin-walled vessels lined with a single layer of endothelium surrounded by extensive fibrovascular connective tissue [M€ oller et al., 1999]. Gorham-Stout disease associated with hypophosphatemia or hypophosphatemic rickets has not been reported. Here, we report on a 6-year-old boy who presented with FGF23associated hypophosphatemic rickets and Gorham-Stout diseaselike polyostotic osteolysis. He also showed increased cytokines that
2431 may have been responsible for the bone lesions and possibly for the rickets.
CLINICAL REPORT The proband is a 6-year-old boy. He is the second child of nonconsanguineous Japanese parents. His 12-year-old sister is healthy. After an uneventful pregnancy, he was delivered at 38 weeks of gestation. Early development was unremarkable. He presented with a limp at age 14 months. At age 2 years, radiographic examinations showed rachitic changes and polyostotic osteolytic lesions in his upper left arm, both hands, and left leg (Fig. 1A–E). Laboratory examinations revealed normocalcemia (9.6–9.7 mg/dl, reference for adult 9.1–10.2 mg/dl), hypophosphatemia (2.1–2.3 mg/dl, references
FIG. 1. Anteroposterior radiographs of the patient’s upper arms (A, F, K: right; B, G, L: left), hands (C, H, M: right; D, I, N: left), and legs (E, J, O) at age 2 years and 1 month (A–E), age 3 years and 10 months (F–J), and age 4 years and 3 months (K–O). At age 2 years and 1 month, rachitic findings and genu varum were apparent (E). Cortical thickening, sclerosis, and an aggressive periosteal reaction were observed in his left leg (E). Slight periosteal reaction was observed in his upper left arm (B) and the third metacarpus of his left hand (D). Osteolytic lesions were observed in the first proximal phalanx of his right hand (C). At age 3 years and 10 months, pre-existing osteolytic lesions deteriorated (G–J). New osteolytic lesions appeared in his upper right arm (F), the third proximal phalanx, and the second metacarpus of his left hand (I). Leg length discrepancy was apparent (J). At age 4 years and 3 months, rachitic findings improved without the progression of the osteolytic lesions (K–O).
2432 for 1- to 3-year-old children 3.8–6.5 mg/dl, 4- to 11-year-old children 3.7–5.6 mg/dl), elevated serum alkaline phosphatase (ALP; 2357– 2662 IU/L, reference for 1- to 9-year-old children 145–420 IU/L), and elevated serum FGF23 (73 pg/ml, reference 10–50 pg/ml). Serum levels of intact parathyroid hormone and vitamin D metabolites were within the normal range (data not shown). The laboratory data raised suspicion of tumor-induced, FGF23-associated hypophosphatemic rickets. Bone biopsy of a left tibial lesion was attempted, but a definitive histological diagnosis was not obtained. We initiated treatment for hypophosphatemic rickets with alfacalcidol at age 2 years and 3 months, and added phosphate at age 3 years and 1 month (Fig. 2). At age 3 years and 10 months, radiographic examination showed alleviation of rachitic changes but deterioration of the initial observed osteolytic lesions (Fig. 1F–J) as well as new osteolytic lesions in the upper right arm and left hand (Fig. 1F and I). FGF23 levels were further elevated (295 pg/ml) (Fig. 2). No tumor was identified on magnetic resonance imaging, computed tomography, technetium99 m bone scintigraphy, or gallium scintigraphy. Repeated venous sampling from multiple body sites (data not shown) could not help in localizing the source of FGF23. Repeated bone biopsy of the left femoral lesion revealed irregularly dilated vessels in marrow spaces associated with osteoclasts and fibrous proliferation (Fig. 3). Serum
AMERICAN JOURNAL OF MEDICAL GENETICS PART A levels of interleukin-6, interleukin-18, tumor necrosis factor-alpha, and soluble tumor necrosis factor receptor type I were within normal limits, while levels of plasma transforming growth factor-beta (TGFb), serum neopterin, and soluble tumor necrosis factor receptor type II (sTNFRII) were elevated (Table I). At that time, we increased alfacalcidol and phosphate supplementation doses, which led to increased serum levels of phosphate and decreased serum levels of ALP and tartrate-resistant acid phosphatase type 5b (924–965 mU/dl, reference 190–590 mU/dl) (Fig. 2). Levels of plasma TGF-b, serum neopterin, sTNFRII, and FGF23 were also decreased (Table I). At age 4 years and 3 months, radiographic examination revealed improvement of rachitic findings and no progression of the osteolytic lesions (Fig. 1K–O). After serum phosphate levels were found to be increased, oral phosphate supplementation was decreased (Fig. 2). At age 6 years, treatment with 1.6 mg of alfacalcidol and 300 mg of phosphate supplementation maintained serum phosphate levels above 3.0 mg/dl; however, serum FGF23 levels remained elevated (Fig. 2).
Genetic Analysis After obtaining written informed consent from the parents, we extracted genomic DNA from the patient’s peripheral blood and
FIG. 2. Clinical course of the proband. We initiated treatment with alfacalcidol at age 2 years and 3 months and added phosphate supplementation at age 3 years and 1 month. We increased alfacalcidol and phosphate supplementation doses at age 3 years and 11 months, which resulted in decreased alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase type 5b (TRACP-5b). At age 4 years and 6 months, serum phosphate levels gradually increased and the requirement for phosphate supplementation decreased. Serum fibroblast growth factor 23 (FGF23) levels remained elevated.
SATO ET AL.
2433
bone tissue by using standard protocols. Genomic DNA samples from peripheral blood were polymerase chain reaction (PCR)amplified for all coding exons and their splice sites of the PHEX, FGF23, DMP1, and ENPP1 genes. Genomic DNA samples from the bone tissue were PCR-amplified for exon 7 to exon 10, the mutation hotspots for fibrous dysplasia, and their splice sites of the GNAS gene; and all coding exons and their splice sites of the HRAS and KRAS genes. The PCR products were subjected to direct sequencing from both directions on an autosequencer. We found no mutation in these genes.
and cytokines. Octreotide scintigraphy and fluorodeoxyglucosepositron emission tomography were not feasible, and imaging assessment and venous sampling failed to identify occult FGF23-producing tumors. Other investigations did not reveal the pathogenesis of rickets and the osteolytic process and their causal relationship. We excluded germline mutations in hereditary hypophosphatemic rickets. The manifestation in the present child superficially resembled that observed in MAS and LNSS, both of which are hamartomatous syndromes sometimes associated with hypophosphatemic rickets. However, we did not identify somatic mutations in GNAS or KRAS/HRAS, which are responsible for MAS and LNSS, respectively [Groesser et al., 2012]. The polyostotic bone lesions were histologically similar to Gorham-Stout disease, which is associated with elevation of vasculogenic growth factors such as circulating platelet-derived growth factor-BB or vascular endothelial growth factor [Patel, 2005; Hagendoorn et al., 2006; Dupond et al., 2010; Venkatramani et al., 2011]. The levels of these angiogenic growth factors were examined but they were observed to be normal (data not shown). The polyostotic bone lesions showed initially rapid progression along with remarkably increased FGF23. However, high doses of phosphate stabilized osteolysis and alleviated hypophosphatemia, FGF23 production, neopterinemia, and cytokinemia (plasma TGFb and serum sTNFRII). Dysregulation of several hormones and cytokines leads to pathological osteoclastogenesis and bone destruction. TGF-b is indispensable in receptor activator of nuclear factor kappa-B ligand-induced osteoclastogenesis [Yasui et al., 2011]. Neopterin and sTNFRII are produced by macrophages [Berdowska and Zwirska-Korczala, 2001]. Thus, it is possible that dysregulation of osteoclast-macrophage lineage was responsible for the osteolysis in this child. Moreover, the abnormal osteoclastogenesis may have been related to abnormal FGF23 metabolism in this patient. Further study will be needed to clarify the association between polyostotic osteolysis and hypophosphatemic rickets.
DISCUSSION
ACKNOWLEDGMENTS
We encountered a child with FGF23-associated hypophosphatemic rickets and polyostotic osteolytic lesions with elevated neopterin
We thank the patient’s family for participating in this study. We also thank Dr. Junko Hanakawa for providing us with clinical
FIG. 3. A photomicrograph of a biopsy specimen obtained from his left femur (hematoxylin-eosin staining, original magnification 100). Dilated microvessels were noted in the bone marrow. No osteoclasts were found in this microscopic field.
TABLE I. Synopsis of Serum Concentrations of Neopterin and Cytokines
TGF-ba Neopterin IL-6 IL-18 TNF-a sTNFRI sTNFRII
ng/ml nmol/L pg/ml pg/ml pg/ml pg/ml pg/ml
Reference value 1.56–3.24b
Polyostotic Osteolysis and Hypophosphatemic Rickets with Elevated Serum Fibroblast Growth Factor 23: A Case Report Takeshi Sato,1,2 Koji Muroya,1* Yumi Asakura,1 Akihiro Yachie,3 Gen Nishimura,4 Noriko Aida,5 Jiro Machida,6 Yukichi Tanaka,7 Tomonobu Hasegawa,2 and Masanori Adachi1 1
Department of Endocrinology and Metabolism, Kanagawa Children’s Medical Center, Yokohama, Japan Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
2 3
Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan 4 Department of Radiology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan 5
Department of Radiology, Kanagawa Children’s Medical Center, Yokohama, Japan
6
Department of Orthopedic Surgery, Kanagawa Children’s Medical Center, Yokohama, Japan
7
Department of Pathology, Kanagawa Children’s Medical Center, Yokohama, Japan
Manuscript Received: 4 March 2015; Manuscript Accepted: 20 May 2015
We report on a boy who presented with hypophosphatemic rickets with elevated serum fibroblast growth factor 23 (FGF23) and polyostotic osteolytic lesions at age 2 years. Tumor-induced hypophosphatemic rickets was suspected; however, bone biopsy for osteolytic changes revealed no tumorous change, except for irregularly dilated vessels associated with osteoclasts and fibrous proliferation. Venous sampling failed to point to FGF23-producing foci. After alfacalcidol and phosphate supplementation, the rachitic skeletal changes improved, but FGF23 increased and new osteolytic lesions developed. Serum levels of neopterin and a few cytokines, including plasma transforming growth factor-b and soluble tumor necrosis factor receptor type II, were elevated. At age 4 years, high doses of phosphate resulted in increased serum phosphate levels, decreased neopterin and cytokines, decreased FGF23, and stabilization of osteolysis. We excluded germline mutations in PHEX, FGF23, DMP1, and ENPP1 (genes for hereditary hypophosphatemic rickets) and somatic mutations in the GNAS and HRAS/KRAS (the disease-causing genes for McCune-Albright syndrome and linear nevus sebaceous syndrome, respectively). We could not perform octreotide scintigraphy or fluorodeoxyglucose-positron emission tomography, and thus could not completely exclude occult FGF23-producing tumors. However, considering the course of the disease, it is intriguing to assume that dysregulation of osteoclast-macrophage lineage may have induced increased neopterin levels, increased cytokine levels, osteolytic process, and possibly FGF23 overproduction. © 2015 Wiley Periodicals, Inc.
Key words: polyostotic osteolysis; hypophosphatemic rickets; fibroblast growth factor 23
© 2015 Wiley Periodicals, Inc.
How to Cite this Article: Sato T, Muroya K, Asakura Y, Yachie A, Nishimura G, Aida N, Machida J, Tanaka Y, Hasegawa T, Adachi M. 2015. Polyostotic osteolysis and hypophosphatemic rickets with elevated serum fibroblast growth factor 23: A case report. Am J Med Genet Part A 167A:2430–2434.
INTRODUCTION Hypophosphatemic rickets/osteomalacia encompasses a heterogeneous group of hereditary and acquired disorders. The hereditary form is caused by germline mutations in the PHEX, FGF23, DMP1, and ENPP1 genes, which is associated with secondary elevation of fibroblast growth factor 23 (FGF23). The acquired form is mainly Conflict of interest: None Correspondence to: Koji Muroya, M.D., Ph.D., Department of Endocrinology and Metabolism, Kanagawa Children’s Medical Center, Mutsukawa 2-1384, Minami-ku, Yokohama 232-8555, Japan. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 8 June 2015 DOI 10.1002/ajmg.a.37193
2430
SATO ET AL. attributed to FGF23-producing mesenchymal tumors but is also associated with malformation syndromes such as McCune– Albright syndrome (MAS) and linear nevus sebaceous syndrome (LNSS) [Riminucci et al., 2003; Hoffman et al., 2005]. Non-hereditary, progressive osteolysis is termed Gorham-Stout disease [Hardegger et al., 1985]. The histological characteristics include a matrix of thin-walled vessels lined with a single layer of endothelium surrounded by extensive fibrovascular connective tissue [M€ oller et al., 1999]. Gorham-Stout disease associated with hypophosphatemia or hypophosphatemic rickets has not been reported. Here, we report on a 6-year-old boy who presented with FGF23associated hypophosphatemic rickets and Gorham-Stout diseaselike polyostotic osteolysis. He also showed increased cytokines that
2431 may have been responsible for the bone lesions and possibly for the rickets.
CLINICAL REPORT The proband is a 6-year-old boy. He is the second child of nonconsanguineous Japanese parents. His 12-year-old sister is healthy. After an uneventful pregnancy, he was delivered at 38 weeks of gestation. Early development was unremarkable. He presented with a limp at age 14 months. At age 2 years, radiographic examinations showed rachitic changes and polyostotic osteolytic lesions in his upper left arm, both hands, and left leg (Fig. 1A–E). Laboratory examinations revealed normocalcemia (9.6–9.7 mg/dl, reference for adult 9.1–10.2 mg/dl), hypophosphatemia (2.1–2.3 mg/dl, references
FIG. 1. Anteroposterior radiographs of the patient’s upper arms (A, F, K: right; B, G, L: left), hands (C, H, M: right; D, I, N: left), and legs (E, J, O) at age 2 years and 1 month (A–E), age 3 years and 10 months (F–J), and age 4 years and 3 months (K–O). At age 2 years and 1 month, rachitic findings and genu varum were apparent (E). Cortical thickening, sclerosis, and an aggressive periosteal reaction were observed in his left leg (E). Slight periosteal reaction was observed in his upper left arm (B) and the third metacarpus of his left hand (D). Osteolytic lesions were observed in the first proximal phalanx of his right hand (C). At age 3 years and 10 months, pre-existing osteolytic lesions deteriorated (G–J). New osteolytic lesions appeared in his upper right arm (F), the third proximal phalanx, and the second metacarpus of his left hand (I). Leg length discrepancy was apparent (J). At age 4 years and 3 months, rachitic findings improved without the progression of the osteolytic lesions (K–O).
2432 for 1- to 3-year-old children 3.8–6.5 mg/dl, 4- to 11-year-old children 3.7–5.6 mg/dl), elevated serum alkaline phosphatase (ALP; 2357– 2662 IU/L, reference for 1- to 9-year-old children 145–420 IU/L), and elevated serum FGF23 (73 pg/ml, reference 10–50 pg/ml). Serum levels of intact parathyroid hormone and vitamin D metabolites were within the normal range (data not shown). The laboratory data raised suspicion of tumor-induced, FGF23-associated hypophosphatemic rickets. Bone biopsy of a left tibial lesion was attempted, but a definitive histological diagnosis was not obtained. We initiated treatment for hypophosphatemic rickets with alfacalcidol at age 2 years and 3 months, and added phosphate at age 3 years and 1 month (Fig. 2). At age 3 years and 10 months, radiographic examination showed alleviation of rachitic changes but deterioration of the initial observed osteolytic lesions (Fig. 1F–J) as well as new osteolytic lesions in the upper right arm and left hand (Fig. 1F and I). FGF23 levels were further elevated (295 pg/ml) (Fig. 2). No tumor was identified on magnetic resonance imaging, computed tomography, technetium99 m bone scintigraphy, or gallium scintigraphy. Repeated venous sampling from multiple body sites (data not shown) could not help in localizing the source of FGF23. Repeated bone biopsy of the left femoral lesion revealed irregularly dilated vessels in marrow spaces associated with osteoclasts and fibrous proliferation (Fig. 3). Serum
AMERICAN JOURNAL OF MEDICAL GENETICS PART A levels of interleukin-6, interleukin-18, tumor necrosis factor-alpha, and soluble tumor necrosis factor receptor type I were within normal limits, while levels of plasma transforming growth factor-beta (TGFb), serum neopterin, and soluble tumor necrosis factor receptor type II (sTNFRII) were elevated (Table I). At that time, we increased alfacalcidol and phosphate supplementation doses, which led to increased serum levels of phosphate and decreased serum levels of ALP and tartrate-resistant acid phosphatase type 5b (924–965 mU/dl, reference 190–590 mU/dl) (Fig. 2). Levels of plasma TGF-b, serum neopterin, sTNFRII, and FGF23 were also decreased (Table I). At age 4 years and 3 months, radiographic examination revealed improvement of rachitic findings and no progression of the osteolytic lesions (Fig. 1K–O). After serum phosphate levels were found to be increased, oral phosphate supplementation was decreased (Fig. 2). At age 6 years, treatment with 1.6 mg of alfacalcidol and 300 mg of phosphate supplementation maintained serum phosphate levels above 3.0 mg/dl; however, serum FGF23 levels remained elevated (Fig. 2).
Genetic Analysis After obtaining written informed consent from the parents, we extracted genomic DNA from the patient’s peripheral blood and
FIG. 2. Clinical course of the proband. We initiated treatment with alfacalcidol at age 2 years and 3 months and added phosphate supplementation at age 3 years and 1 month. We increased alfacalcidol and phosphate supplementation doses at age 3 years and 11 months, which resulted in decreased alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase type 5b (TRACP-5b). At age 4 years and 6 months, serum phosphate levels gradually increased and the requirement for phosphate supplementation decreased. Serum fibroblast growth factor 23 (FGF23) levels remained elevated.
SATO ET AL.
2433
bone tissue by using standard protocols. Genomic DNA samples from peripheral blood were polymerase chain reaction (PCR)amplified for all coding exons and their splice sites of the PHEX, FGF23, DMP1, and ENPP1 genes. Genomic DNA samples from the bone tissue were PCR-amplified for exon 7 to exon 10, the mutation hotspots for fibrous dysplasia, and their splice sites of the GNAS gene; and all coding exons and their splice sites of the HRAS and KRAS genes. The PCR products were subjected to direct sequencing from both directions on an autosequencer. We found no mutation in these genes.
and cytokines. Octreotide scintigraphy and fluorodeoxyglucosepositron emission tomography were not feasible, and imaging assessment and venous sampling failed to identify occult FGF23-producing tumors. Other investigations did not reveal the pathogenesis of rickets and the osteolytic process and their causal relationship. We excluded germline mutations in hereditary hypophosphatemic rickets. The manifestation in the present child superficially resembled that observed in MAS and LNSS, both of which are hamartomatous syndromes sometimes associated with hypophosphatemic rickets. However, we did not identify somatic mutations in GNAS or KRAS/HRAS, which are responsible for MAS and LNSS, respectively [Groesser et al., 2012]. The polyostotic bone lesions were histologically similar to Gorham-Stout disease, which is associated with elevation of vasculogenic growth factors such as circulating platelet-derived growth factor-BB or vascular endothelial growth factor [Patel, 2005; Hagendoorn et al., 2006; Dupond et al., 2010; Venkatramani et al., 2011]. The levels of these angiogenic growth factors were examined but they were observed to be normal (data not shown). The polyostotic bone lesions showed initially rapid progression along with remarkably increased FGF23. However, high doses of phosphate stabilized osteolysis and alleviated hypophosphatemia, FGF23 production, neopterinemia, and cytokinemia (plasma TGFb and serum sTNFRII). Dysregulation of several hormones and cytokines leads to pathological osteoclastogenesis and bone destruction. TGF-b is indispensable in receptor activator of nuclear factor kappa-B ligand-induced osteoclastogenesis [Yasui et al., 2011]. Neopterin and sTNFRII are produced by macrophages [Berdowska and Zwirska-Korczala, 2001]. Thus, it is possible that dysregulation of osteoclast-macrophage lineage was responsible for the osteolysis in this child. Moreover, the abnormal osteoclastogenesis may have been related to abnormal FGF23 metabolism in this patient. Further study will be needed to clarify the association between polyostotic osteolysis and hypophosphatemic rickets.
DISCUSSION
ACKNOWLEDGMENTS
We encountered a child with FGF23-associated hypophosphatemic rickets and polyostotic osteolytic lesions with elevated neopterin
We thank the patient’s family for participating in this study. We also thank Dr. Junko Hanakawa for providing us with clinical
FIG. 3. A photomicrograph of a biopsy specimen obtained from his left femur (hematoxylin-eosin staining, original magnification 100). Dilated microvessels were noted in the bone marrow. No osteoclasts were found in this microscopic field.
TABLE I. Synopsis of Serum Concentrations of Neopterin and Cytokines
TGF-ba Neopterin IL-6 IL-18 TNF-a sTNFRI sTNFRII
ng/ml nmol/L pg/ml pg/ml pg/ml pg/ml pg/ml
Reference value 1.56–3.24b
