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Achondroplasia and Enchondromatosis: Report Hironori Kobayashi Yukihiro Hasegawa of Three Boys Masanori Adachi Ok Hwa Kim Gen Nishimura

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Achondroplasia and Enchondromatosis: Report Hironori Kobayashi Yukihiro Hasegawa of Three Boys Masanori Adachi Ok Hwa Kim Gen Nishimura Skeletal Radiol (2007) 36: S29–S33 DOI 10.1007/s00256-006-0161-x CASE REPORT Chikahiko Numakura Achondroplasia and enchondromatosis: report Hironori Kobayashi Yukihiro Hasegawa of three boys Masanori Adachi Ok Hwa Kim Gen Nishimura patients are less likely to represent the Received: 4 December 2005 M. Adachi Revised: 18 April 2006 Department of Endocrinology & coincidence of both disorders, but Accepted: 28 April 2006 Metabolism, Clinical Research Institute, rather to result from a rare conse- Published online: 9 June 2006 Kanagawa Children’s Medical Center, quence of the FGFR3 mutation. # ISS 2006 Kanagawa, Japan Impaired FGFs/FGFR3 signaling O. H. Kim pathway in achondroplasia inhibits Department of Radiology, chondrocytic proliferation, which Ajou University Hospital, accounts for most characteristics of Seoul, South Korea achondroplasia. On the other hand, it C. Numakura (*) G. Nishimura causes conflicting biological conse- Department of Pediatrics, Department of Radiology, quences that can suppress or stimulate Yamagata University School of Medicine, Tokyo Metropolitan Kiyose ’ chondrocytic maturation. In a small Yamagata, Japan Children s Hospital, subset of achondroplastic individuals, e-mail: [email protected] Tokyo, Japan Tel.: +81-23-6285329 the suppression of chondrocytic Fax: +81-23-6285332 Abstract We report on three boys maturation may outweigh the stimu- suffering from achondroplasia con- lation, which leads to cartilaginous . C. Numakura Y. Hasegawa current with enchondromatosis-like overgrowth into the metaphysis, Endocrinology and Metabolism Unit, Tokyo Metropolitan Kiyose metaphyseal changes. Two boys who eventually causing the metaphyseal Children’s Hospital, were examined by molecular analysis dysplasia found in the present patients. Tokyo, Japan harbored a mutation of FGFR3, which occurs in most achondroplastic indi- Keywords Achondroplasia . H. Kobayashi viduals. Given the prevalence of Enchondromatosis . Metaphyseal Department of Pediatrics, . Shimane University School of Medicine, achondroplasia and enchondromato- dysplasia FGFR3 IHH SOX9 Shimane, Japan sis, the metaphyseal changes in these Introduction elucidated that the FGFs/FGFR3 signaling pathway inhibits cartilaginous bone growth. FGFR3 mutations in achondro- Achondroplasia is the most common skeletal dysplasia, plasia and allelic disorders (thanatophoric dysplasia and which occurs as a result of mutations in one copy of the hypochondroplasia) activate the signaling pathway, and fibroblast growth factor receptor 3 gene (FGFR3)[1, 2]. eventually suppress endochondral bone growth [4]. The Over 97% of achondroplasia arises from a common decreased endochondral bone growth explains most clinical mutation, i.e., a mutation that causes transition from and radiological characteristics in these disorders. guanine to adenine at the nucleotide 1138 (G1138A), We report here on three achondroplastic boys who had which substitutes arginine for glycine at the codon 380 unusual metaphyseal alterations but showed otherwise (Gly380Arg) [3]. This fact accounts for the phenotypic typical achondroplastic manifestations. Two boys under- homogeneity of achondroplasia. went molecular analysis, which revealed the common FGFR3 is one of four receptors for a large group of mutation of FGFR3 for achondroplasia. A similar case was fibroblast growth factors (FGFs). Recent investigations have previously reported by Nizankowska-Blaz et al. [5]. S30 Case reports radiological findings fulfilled the diagnostic criteria of achondroplasia. In addition to these characteristic features Patient 1 of achondroplasia, metaphyseal abnormalities that resem- ble those of enchondromatosis attracted attention (Fig. 1). The patient was a 17-year-old Japanese boy. The family Brain CT revealed hydrocephalus and narrowing of the history was unremarkable. His healthy, nonconsanguin- foramen magnum. He received growth hormone therapy eous father and mother were 170 cm and 158 cm tall, (0.35 mg/kg/week) from 6 to 16 years of age, which respectively. He was vaginally delivered at 42 weeks’ accelerated his growth from the mean to + 1.0 SD on the gestation after an unremarkable pregnancy. Birth length Japanese achondroplastic growth [6]. At 16 years of age, was 50 cm, and weight 3,829 g. A diagnosis of achondro- the metaphyseal changes remained unchanged. Molecular plasia was made on radiological grounds at 4 months of analysis showed the common mutation of FGFR3 for age. He was referred to us at 5 years of age. Physical and achondroplasia (G1138A). Fig. 1 Radiographs of the right hand (a), lower extremities (b), a magnified view of the right knee (c), and vertebrae (d)at 6 years of age. Typical achon- droplastic features, such as bul- let-shaped vertebral bodies (d) and metaphyseal cupping of the tubular bones (a, b, c) were observed. Metaphyseal dyspla- sia was apparent in the radii (a), distal femora, and proximal tibiae (b, c) S31 Fig. 2 Radiographs of the left hand (a), lower extremities (b), and a magnified view of the right knee (c) at 7 years of age. Metaphyseal dysplasia, along with achondroplastic features, was observed Patient 2 did not enhance his growth, which remained at −1.0 SD on the Japanese achondroplastic chart [6]. Molecular analysis The patient was a 16-year-old Japanese boy. His healthy, revealed the common mutation of achondroplasia. nonconsanguineous father and mother were 168 cm and 150 cm tall, respectively. He was born at full term with a birth weight of 3,240 g. He was radiologically diagnosed as Patient 3 having achondroplasia at 7 years of age. In addition to the typical radiological findings of achondroplasia, metaphys- The patient was a Korean boy. His healthy, nonconsangui- eal abnormalities of the long bones came to our attention neous father and mother were 170 cm and 150 cm tall, (Fig. 2). He was treated with growth hormone (0.25 mg/kg/ respectively. At 14 years of age, he was radiologically week) from 8 to 10 years of age. Growth hormone therapy diagnosed as having achondroplasia with atypical meta- Fig. 3 Radiographs of the right knee at 14 years of age (a, b). Metaphyseal cupping and meta- physeal dysplasia were observed S32 physeal changes (Fig. 3). His height was 117 cm (less than and radiological characteristics of achondroplasia. Enchon- the 3rd percentile of the Korean population). Although his dromatosis results from cartilaginous overgrowth, i.e., mid-face hypoplasia was mild, other physical and radio- failure of chondrocytic maturation [11, 12]. The manifesta- logical findings fulfilled the diagnostic criteria of achon- tions in our patients implicated that the common FGFR3 droplasia. Thereafter, he was lost to follow-up. Molecular mutation has a negative effect for chondrocytic maturation analysis was not performed. in these patients. Invagination of physeal cartilage into the metaphysis can occur as a result of growth-plate injuries, such as trauma and radiation. The metaphyseal enchon- Discussion dromatosis in our patients may ensue as a consequence of mechanical stress on abnormal cartilage in achondroplasia. The three boys whom we described here showed a It is known that FGFR3 mutations provide complex distinctive metaphyseal alteration resembling that of biological effects on chondrocytic maturation. They down- enchondromatosis. Otherwise, however, their clinical and regulate the “Indian hedgehog” (IHH) and enhance radiological manifestations fulfilled the diagnostic char- chondrocytic maturation [13, 14]. On the other hand, they acteristics of achondroplasia, and two harbored the upregulate the SRY-related HMG-box gene 9 protein common FGFR3 mutation for achondroplasia. A similar (SOX9), and may suppress chondrocytic maturation [15]. case was recently reported with the coexistence of A loss of function mutation of the SOX9 gene creates metaphyseal enchondromatosis and achondroplasia [5]. campomelic dysplasia, which histologically shows prema- Enchondromatosis comprises a heterogeneous group of ture endochondral ossification [16]. Thus, one of the normal disorders [7]. Ollier disease is a well-known, common functions of SOX9 is deemed to inhibit chondrocytic variant of enchondromatosis. Other entities, such as maturation [17]. The existence of conflicting FGFs/FGFR3 spondyloenchondrodysplasia and genochondromatosis, metabolic pathways that can stimulate or suppress chon- are exceedingly rare. It remains to be definitively drocytic maturation explains the appearance in our three determined whether the metaphyseal changes in these cases, i.e., upregulation of SOX9 may play a pivotal role in cases represent simply the coincidence of two disorders or the development of enchondromatosis in our patients. a rare consequence of the FGFR3 mutation. Given the Prevalence of enchondromatosis in achondroplasia prevalence of achondroplasia (approximately 1 in 26,000– remains to be determined. However, one of the authors 28,000) and Ollier disease (about 1 in 1,000,000), the latter has encountered an additional two cases in his career as a assumption is more likely [8, 9]. bone dysplasia specialist. He personally estimates that The pathogenesis of achondroplasia is an increased about 5% of achondroplastic individuals may have the activity of FGFs/FGFR3 signaling. FGFR3 mutations metaphyseal alteration. We also find an illustration of activate the signal transducer and activator of transcription achondroplasia with similar metaphyseal changes in a 1 (STAT1), and inhibit chondrocytic proliferation [10]. The textbook [18]. Thus, the metaphyseal
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