Clinical and genetic landscape of Bruck syndrome in the Indian population

Clinical and genetic landscape of Bruck syndrome in the Indian population | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical and genetic landscape of Bruck syndrome in the Indian population Agnes Selina, Madhavi Kandagaddala, Sumita Danda, Vrisha Madhuri This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4379907/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 12 You are reading this latest preprint version Abstract Background Bruck syndrome (BS) is a rare form of Osteogenesis imperfecta (OI) with congenital large joint contractures and bone fragility fractures. Evaluation of phenotypic and genotypic profiles of 14 children with FKBP10 and PLOD2 gene variants causing Bruck syndrome (BS) and highlighting the severe deformities in response to poor surgical treatment in the Indian cohort. Methods Patients with bone fragility were clinically evaluated. After informed consent, genotyping was done by next-generation sequencing, and the variants were validated by Sanger sequencing. These children were treated surgically and pamidronate was administered. Results Out of 14 children, 12 were with FKBP10 gene variants, and two with PLOD2 gene variants. The age at diagnosis varied from birth to four years. All were classified as type III by modified Sillence classification. twelve had joint contractures, mainly in the knees and elbows. Clubfeet was identified in seven, scoliosis in three, and severe kyphoscoliosis in three. Two had skull deformities, six with wormian bones, one with basilar invagination and another showing severe cervical compression myelopathy. Rib fractures in six, vertebral compression in nine, and protrusion acetabulae in three were noted. Surgical correction of the deformities by soft tissue release and bone shortening was partially successful, while growth modulation was unsuccessful as the implant failed. Nine of the patients were non-ambulant. Bone density was decreased in all, and the response to pamidronate was partial. This cohort had four novel FKBP10 variants and two PLOD2 variants. Conclusion The study highlights the proportionate representation of the two genes in our population, the severe deformities with poor response to surgical treatment, and novel variants in the population. Bruck syndrome FKBP10 PLOD2 bone fragility joint contractures Figures Figure 1 Figure 2 Figure 3 Introduction Bruck syndrome (BS) is a rare autosomal recessive form of Osteogenesis imperfecta (OI) with congenital large joint contractures and bone fragility fractures [1]. First described by Alfred Bruck in 1897 as a syndrome with articular contractures and bone fragility, Viljoen and Beighton described 5 children from three unrelated families with contractures who developed fractures after walking age[2]. Wormian bones, white sclera, short stature, severe scoliosis, and varying diameters for collagen fibrils in osteoid in BS with defective mineralization were highlighted in 1993[3]. It is classified into type I and type II, based on the two causative genes FKBP10 and PLOD2 [4]. Bruck type I is due to FKBP10 gene variants located on chromosome 17p12 and type II is caused by PLOD2 gene variants, located on chromosome 3q23-q24[5]. Both these types are phenotypically indistinguishable and exhibit a wide range of phenotypes from mild OI to severe BS[6]. The phenotype of bruck syndrome includes an arthrogryposis-like syndrome with multiple, predominantly large joints such as knees and ankles, contractures with webbing, clubfeet with muscle atrophy and compensatory hypertrophy, osteopenia, progressive scoliosis and lumbar lordosis, short stature and low energy fractures. Some joint such as wrist and fingers, in contrast, have hypermobility. Teeth and hearing are normal[2, 7]. Older patients are extremely short with severe kyphoscoliosis affecting pulmonary function and lower limb contractures preventing ambulation[8]. Recently phenotype has been enlarged to include dental malocclusion, enamel hypoplasia, congenital dislocation of knee joint, and myopathy[9]. Metaphyseal corner fractures and posterior rib fractures have been reported in BS[10]. Sclera is white[2–4, 8], however mild blue sclera has been reported[11]. Radiographic studies show demineralized bones, severe deformity and cystic change at old fracture sites, and vertebral wedging[8]. Bruck syndrome is also known as Kuskokwim disease or arthrogryposis like disorder found in Inuit population[12]. The clinical presentation varies from mild to severe lethal ranging with only contractures or only fractures without contractures or with both[6, 13, 14]. FKBP10 pathogenic gene variants decreases post-translational cross-linking of collagen fibrils[15]. Collagen is stabilized into fibrils by lysyl oxidation of lysine to aldehyde allysine and hydroxylysine to aldehyde hydroxyallysine. Both processes form cross-links of hydroxylysylpyridinoline or lysylpyridinoline are formed[16]. PLOD2 gene variants similarly effect lysyl hydroxylase 2 hydroxylation. The molecular defect in bruck syndrome results in aberrant cross-linking of bone collagen owing to under-hydroxylation, whereas cartilage and ligamentous collagen maintained normal cross-linking[17]. Recessive forms of OI are common in India, however only 10 cases of BS are described from India[18–20]. Mrosk et al reported three novel variants out of four reported from an OI population of 50 cases and Madhuri et al reported six variants of which two were novel out of 54 OI cases[18, 20]. We report the genotype and phenotype in a series of 14 BS from India, the largest such series in the world. We report a single center experience of 14 patients with pathogenic variants in FKBP10 and PLOD2 genes and report on their clinical phenotype, progression and effect of bisphosphonates and surgery. Materials and methods Fourteen children diagnosed as BS based on clinical and molecular findings in the department of Paediatric Orthopaedics and Medical genetics, Christian Medical College Hospital were selected for the study. The study was approved by the institutional review board (IRB No 9330 &10384). Patients and the parents were given information sheets and informed consent were obtained. Pedigree analysis was done. Patients were classified based on the severity of the symptoms based on the Sillence classification system. All the patients were evaluated for scleral hue, recurrent fractures, decreased bone density, joint contractures, short stature, loss of hearing, and skeletal deformity. Patient assessment form includes birth history; Family history (Consanguinity, involving parents and siblings); anthropometric data; teeth examination; eye (color of the sclera); spine examination (scoliosis and kyphosis); joint contractures (hip, knee, ankle, shoulder, elbow, and wrist); deformities; Fracture history (first fracture, the total number of fractures, previous fracture). X-rays of long bones, skull, and spine were evaluated. Bisphosphonate dose, total body bone mineral density (BMD), BMD of the lumbar spine was measured using dual X-ray absorptiometry (DXA) and collected yearly where possible. Blood samples were collected from the patients and their parents for the exome sequencing. Results Clinical Findings A total of 14 children diagnosed as bruck syndrome phenotypically and genotypically by next generation sequencing were included in the study. Of the fourteen, six were males and eight were females. Nine were from consanguineous parentage. Based on the clinical and radiological findings all these fourteen subjects fall in the modified Sillence classification’s type III. Five children had blue sclera and none of the children had denitinogensis imperfecta (DI) or deafness. There were no prenatal fractures. Age at the first fracture ranged from birth (clavicle), to six months. Twelve of the children had joint contractures including hip, knee, ankle, elbow and wrist. Joint contractures were majorly seen in knees and elbows (Figure 1). In the skull, wormian bones were seen in six children. A rare skull deformity called the Tam o’ Shanter appearance (Figure 2a) due to widening of the skull in transverse plane above a flat small skull base was seen in one child and another child showed the ‘Darth Vader’ appearance (Figure 2b) due to occipital flattening in sagittal plane. Basilar invagination was present in one child. One child had abnormalities at basicervical junction (C1 and C2) and acute angulation at C3 vertebra causing compression with myelopathy. Scoliosis was seen in three, was mild during childhood and became severe later, kyphoscoliosis was seen in three severe cases who were adolescents the time of evaluation (Figure 3 a and b). All patient with severe scoliosis were adult at the time of last assessment, one with mild scoliosis was aged five. Rib fractures were seen in six and vertebral compression in nine (Figure 3a) were noted. One patient also had spondylolistheisis of L5 over S1 vertebra. In the pelvis, three children had acetabular protrusion deformity (Figure 3c). Very thin gracile bones were seen in four children. Congenital talipes equinovarus (CTEV) or clubfoot were present in six children. Hyperplastic callus formation was seen in femur of two children. All these children had deformity in the lower limb long bones and had undergone rush rod fixation and exchange. All the clinical phenotypes are given in Table 1. Surgery with soft tissue release and bone shortening gave partial correction of contractures in two cases. The four children who underwent growth modulation or knee osteotomy did not correct deformities. Most (nine) could not be ambulant even after surgery with rush rodding. Only five patients had bone mineral density of spine. The values are given in table 1. Genetic analysis: Out of fourteen patients, twelve were type I BS having FKBP10 mutation, two were type II BS having PLOD2 mutation. There was no phenotypic difference between the two gene variants. Six variants of these have been reported earlier[20]. In this series, there were six frameshift, one in-frame, four missense, and two stop codon mutation. There were 4 novel mutations in FKBP10. Four children had homozygous novel mutations namely c.501C>A, c.1339del T, c.1189A>T, and c.21dupC. There were two novel variants in PLOD2 gene. One child has a homozygous variant and the second was compound heterozygous with two novel heterozygous variants (C.2207C>T; c.1885A>g). All the genetic variants are presented in the table 2. In children with FKBP10 gene variants there were two additional gene variants which are not related to OI, one had CFTR gene variant known to causing Cystic fibrosis and the other had MYO7A gene causing Usher syndrome. Two more children had additional variants in SLC34A1 and BMP1 gene variants, which is explained the previous report[20]. Both syndromes are heterozygous, however there were no clinical manifestations seen in either of the two patients. Another one-year-old child with PLOD2 variant had PPA2 gene mutation known to cause infantile sudden unexpected cardiac arrest. The patient is presently four with no cardiac symptoms. Discussion A larger number of Bruck syndrome are being reported after the adoption of clinical exome sequencing in OI[21, 22]. In our study most of our patients were diagnosed with clinical exome sequencing which is preferred as most of the variants are novel in our population. In our Asian population the three common recessively transmitted genes are SERPINF1, FKBP10 , and LEPRE1 genes[23]. A large number of Chinese reports with BS has shown compound heterozygous genotype [21, 24, 25]. In our series two FKBP10 gene variants and one PLOD2 gene variant were compound heterozygous. The proportion of BS in our series is 21% of the recessive variants and 6.67% of all OI and is very high when compared to European population. Our patients showed mainly post-natal fractures though they all classed as type III OI with severe phenotype. Reported literature suggests a number of still births/miscarriages in PLOD2 variants with besides decreased fetal movements, contractures and fractures, there was significant cardiac and pulmonary pathology[26]. This makes it mandatory to rule out Bruck in arthrogrypotic stillbirths or newborns for genetic counselling, and for accurate diagnosis and early management with bisphosphonates when indicated. Congenital cardiac disease with valve prolapse and regurgitation and pulmonary hypertension and haemorrhage has been reported and represents abnormal collagen in the cardiac tissue[27]. We did not have cardiac or respiratory symptoms in any of our patients. The phenotype of Bruck does not vary greatly between Bruck I and II though in the reported literature most of the prenatal and neonatal deaths are associated with PLOD2 variants[24]. Besides joint contractures, bone fragility, white or light blue sclera, absence of deafness and DI, the phenotype has been enlarged to includes orodental findings, myopathy and poor muscle tone, prominent tailbone, and cervical abnormalities including cervical junction and upper cervical collapse and kyphosis [9, 28]. Protusio acetabuli is not a common feature of dominant OI. The type VI ( SERPINF1 gene) recessively transmitted OI where there are features of osteoporosis and osteomalacia. We had three patients who showed protrusio acetabuli. This has been reported earlier in BS[24]. Quadriparesis associated with upper cervical spine abnormality as seen in one of our cases has been described requiring multiple attempts at fusion and lifelong cervical orthosis. Gastroschisis has been described though not seen in our cases[29]. One of the severe phenotypes, associated with rhizomelia, and kyphosis of long bone was seen in one of our patients who also had hip, knee and ankle contractures. While the intellectually normal in most cases, associated microcephaly has been described[9]. A total of 87 unique public variants have been described in FKBP10 and 52 in PLOD2 (LOVD database). A large number of reports are from Chinese population[21, 22, 25, 30]. There are three reports from the south Asian population with no overlap and no recurrent mutation[18, 20, 26] .A recent Egyptian series reports 13 patients from nine families with five novel mutations[9]. Very few reports are from the western literature as there have mainly dominant form of OI[10, 24]. Our patients responded well in terms of fracture rate. The bone density values were available for only six patients because of inability to prefer the investigation because of multiple contractures and spinal deformities (Table 1 ). However, as reported elsewhere, despite the improvement in fracture rate and bone density the walking was significantly affected with only four out of 11 being mobile[31]. Surgical correction of the contracture using guided growth or osteotomy at the knee was not very successful in restoring mobility or correcting the deformity. In one patient significant correction could be achieved by shortening the bone to reduce the knee contracture to 10°. Limitations We had incomplete follow up mainly in the older patients who lacked mobility. Some features such as cardiac and pulmonary were not investigated by echocardiogram (ECHO) and pulmonary function test. Bone density was done only in five patients. Some patients were diagnosed as arthrogryposis initially and received treatment at a later age. There are totally 130 variants associated with BS reported in the LOVD database. Our study adds seven new previously unreported variants. The study highlights the varied phenotype and novel variants in the described population to the literature. The BS responds well to regular pamidronate therapy, however the kyphoscoliotic deformity progresses relentlessly. The treatment of contractures and preventing kyphoscoliosis is a priority and surgical techniques for correcting soft tissue contractures need to be explored further to improve ambulation in these patients. Declarations Ethics approval and consent to participate The study was approved by the institutional review board (IRB No 9330 &10384). Consent for publication Informed consent and photography consent was taken for all the patients participated in the study. Data availability: available on request Data (genetic polymorphism) has been submitted in Clinvar. It is still under review. Once it is accepted we will give the accession number. Conflict of interest: The authors declare no competing interests Funding: Department of Biotechnology, Government of India, Grant/Award Number: BT/IN/SWEDEN/09/VM/2017; Indian Council of Medical Research, Grant/Award Number: 54/9/2015-HUMBMS Author contribution: All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by A.S, M.K,S.D and V.M. The first draft of the manuscript was written by A.S and V.M and all authors commented on previous versions of the manuscript. 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Calcif Tissue Int 109:633–644. https://doi.org/10.1007/s00223-021-00879-4 Tables Table 1: Clinical, radiological and bone mineral density (BMD) of the 14 Bruck syndrome patients.(B/l – bilateral, LLD - limb length discrepancy, CTEV-Congenital talipes equinovarus, NA- not avalaible) AGE SEX GENE TYPE CONSANGUINITY BLUE SCLERA FIRST FRACTURE TOTAL FRACTURE DEVLOPMENTAL DELAY WORMAIAN BASILAR INVAGINATION skull shape CONTRACTURE CALLUS UPPER LIMB DEFORMITY SCOLIOSIS RIB FRACT VERE FRAC PROTRUSIO ACETABULI CTEV LOWER LIMB DEFORMITY PAMIDRO SURGERY OTHERS BMD Followup 1 7 Male FKBP10 III Yes White 40 Days >20 Yes Present Yes NA left knee 40° right knee 30° Hypertropic callus of b/l femur No No Present Present B/l femur and tibia LLD present 3 cycles(6 doses zolendronate) B/l femur and tibia rodding Gracile bones 0.461 -0.1 0.412 -2 2 13 Female FKBP10 III No White 3 Days >15 Yes NA NA NA B/l elbow, Knee and Ankle No Humerus deformity NA NA NA Right side Left foot B/l femur and tibia deformity, Varus on right and distal valgus on left Multiple cycles of pamidronate B/l femur and tibia correction and rodding. B/l distal femur anterior 8 plate implant and exit Gracile bones 0.51 0.1 0.522 -3 3 14 Female FKBP10 III Yes Blue 15 Days 15 No Present No Tam -O- shanter B/l Knee No No severe kyphoscoliosis No Present and mild listhesis of L5 over S1 B/l femur and tibia deformity 12 cycles of pamidronate and two dose of zolendronate B/l popetial contracture release, B/L femur rush rodding and dital anterior 8 plate 0.271 -5.4 0.487 -5.1 4 11 Male FKBP10 III Yes Light Blue 3 Days 4 Yes NA NA NA B/l elbow and knee No No No Present Present No b/l CTEV B/l femur deformity One dose, stopped on second day due to fever Left knee quadriceps plasty 0.309 -3.6 NA NA 5 8 Female FKBP10 III Yes Blue 6 months 4 Yes NA NA NA No NA NA NA Present NA NA B/l femur and tibia deformity NA NA NA NA NA NA 6 9 Male FKBP10 III Yes Light Blue Birth 12 Yes NA NA NA Right humerus NA Humerus defromity NA Present NA NA B/l femur and LLD present NA NA NA NA NA NA 7 5 Female FKBP10 III Yes 15 days 3 NA NA NA NA Left elbow and right knee NA single dose NA NA NA NA 8 10 Female FKBP10 III No White 4 years >10 No NA NA NA No NA No No No Present No No B/l femur deformity and LLD Multiple cycles of pamidronate B/l femur rush rodding 0.358 -2.8 0.57 -0.5 9 30 Male FKBP10 III Yes White 45 days >15 Yes Present No NA Right knee No Humerus, ulna and radius deformity Severe kyphoscoliosis Present Bilateral Severe femur and tibia deformity; LLD present 14 cycles B/l lower limbs and right humerus rush rodding Severe gracile bones and non-union of left femur with valgus deformity NA NA NA NA 10 23 Male FKBP10 III No NA NA NA No NA NA NA B/l knee Right femur No Left foot equinus LLD 5 cycles B/l femur and tibia rodding NA NA 0.808 -2.1 11 8 Female FKBP10 III No White 1 month 4 Yes NA Cerival compression myelopathy NA b/l knee scoliosis Present b/l CTEV Femur fractures 1 cycle Severe osteoporotic , very thin gracile bones, varus deformity 0.115 -12.9 NA NA 12 24 Male FKBP10 III Yes White 2 Months >15 Yes Present No Darth vader b/l knee No popliteal elbow pterygium Severe kyphoscoliosis Present Present Left side b/l CTEV B/l lower limbs Multiple cycles of pamidronate B/l tibia rodding and right femur rodding pectus excavatum 0.669 -3.9 13 5 Female PLOD2 III Yes Light Blue 4 Months >10 Yes Present No NA b/l elbow and wrist No Humerus deformity Mild scoliosis Present Present No b/l CTEV b/l anterior tibial deformity 6 cyles B/l femur rush rodding and hip spica and B/l percutaneous tentomy and corrective cast appilcation rhizomelic shortening, umblical hernia present, low set ears, small mouth, retrognathgia present 0.211 0.321 -3.7 14 27 Female PLOD2 III No White Birth >20 No Present No NA B/l elbow No Humerus deformity Scoliosis Present No No Tibial defromity 5 cycles Right femur ORIF with plate and, b/l tibia rod fixation and exchange 4times Atypical pubic fractures NA NA 1.229 1.8 Table 2: Genetic spectrum of the 14 bruck syndrome patients.(NA- not available, Homo- homozygous, Hetero-Heterozygous, VUS- variant of uncertain significance) STUDY ID Type GENE EXON c.DNA Protein change Mutation Type 1 III FKBP10 Exon 3 c.501C>A p.(Cys167*) Nonsense 2 III FKBP10 Exon 6: Intron 2 c.1024dup; c.391+1G>A p.(Thr342Asnfs*31): Splice site Frameshift: Splice Site 3 III FKBP10 Exon 1 c.21dupC p.(Ser8Glnfs*67) Frameshift 4 III FKBP10 Exon 3 c.523_552dup p.(Asp175_Thr184dup) in frame 5 III FKBP10 Intron 5 c.918-2A>G Splice site Missense 6 III FKBP10 Intron 5 c.918-2A>G Splice site Missense 7 III FKBP10 Exon 3 c.523_552dup p.(Asp175_Thr184dup) in frame 8 III FKBP10 Exon 1; Exon 5 c.21dup;c.773T>G p.(Ser8Glnfs*67); p.(Leu258Arg) Frameshift; Missense 9 III FKBP10 Exon 8 c.1339delT p.(Cys447Valfs*84) Frameshift 10 III FKBP10 Exon 7 c.1189A>T p.(Lys397*) Missense 11 III FKBP10 Exon 5 c.831del p.(Gly278Alafs*20) Frameshift 12 III FKBP10 Exon 1 c.21dupC p.(Ser8Glnfs*67) Frameshift 13 III PLOD2 Exon 1 c.32T>C p.(Leu11Pro) Missense 14 III PLOD2 Exon 20; Exon 18 c.2207C>A;c.1885A>G p.(Thr736Lys);p.(Thr629Ala) Missense;Missense Additional Declarations No competing interests reported. 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Madhavi","middleName":"","lastName":"Kandagaddala","suffix":""},{"id":307754389,"identity":"2c8b61fa-0b58-4fb5-b296-d053cf494ee2","order_by":2,"name":"Sumita Danda","email":"","orcid":"","institution":"Christian Medical College \u0026 Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sumita","middleName":"","lastName":"Danda","suffix":""},{"id":307754390,"identity":"9a86a529-f8cf-4599-bde9-4453bd7c7b68","order_by":3,"name":"Vrisha Madhuri","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYHACMyCWYGBgB7ErDoCFDjwgSgszM5A+c4CBB6QlgbAWBogWxjaIFgZ8WnTbD297zLvHIrG/mf/g48p5d+TsxQ4/BNpiJ6fbgMOKM2nlxjzPJBJnHGZmNjy77Zkxj3SaAVBLsrHZARxaDuSYSfMckMhtOMzMJtm47XBij3QCSMuBxG24tJx/A9Ey/zAz+8/GOSAt6R/wa7kBtWUD0BbGxgaQlhwCttx4ViY554BE/cbDzMaSDccOG/Pczik4kGCAxy/nk7dJvDlQZyx3vPHhx4aaw3Lss9M3f/hQYSeHSwsuYECa8lEwCkbBKBgFqAAAfpViUX9E6lsAAAAASUVORK5CYII=","orcid":"","institution":"Christian Medical College \u0026 Hospital","correspondingAuthor":true,"prefix":"","firstName":"Vrisha","middleName":"","lastName":"Madhuri","suffix":""}],"badges":[],"createdAt":"2024-05-07 03:23:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4379907/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4379907/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57729408,"identity":"160ab47d-9ee1-49f9-86c0-41cf60f22750","added_by":"auto","created_at":"2024-06-04 21:52:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1350349,"visible":true,"origin":"","legend":"\u003cp\u003ea) 4-year-old child with BS I shows severe knee and ankle contractures, b) 27 years girl with BS II having wrist and elbow contractures, c) 13 years old girl with BS I having knee contractures and left foot CTEV.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4379907/v1/71feb2a33ff12263e19ace31.png"},{"id":57729410,"identity":"d1124fcb-fb5a-4051-8f8e-5f2acb32cf0f","added_by":"auto","created_at":"2024-06-04 21:52:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1076288,"visible":true,"origin":"","legend":"\u003cp\u003ea) a 14-year-old girl showing a rare skull deformity Tam-O-shanter appearance and b) ‘Darth vader’ appearance due to occipital flattening in an adult.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4379907/v1/78cc06ca4b3321bb6cb44acf.png"},{"id":57729409,"identity":"ceaecf52-d8fd-4a5a-a5b3-bc93b907abf9","added_by":"auto","created_at":"2024-06-04 21:52:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1159358,"visible":true,"origin":"","legend":"\u003cp\u003ea) and b) a 27 years male with BS I showing severe kyphoscoliosis and rib fractures c) severe acetabular protrusion deformity\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4379907/v1/98bf95b9c022a4378725ec19.png"},{"id":57729412,"identity":"de4f216a-05a4-491f-86c9-bf5002a0c644","added_by":"auto","created_at":"2024-06-04 21:52:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5724751,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4379907/v1/bca12131-e000-46f1-84a9-ce74c580ab3c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical and genetic landscape of Bruck syndrome in the Indian population","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBruck syndrome (BS) is a rare autosomal recessive form of Osteogenesis imperfecta (OI) with congenital large joint contractures and bone fragility fractures [1]. First described by Alfred Bruck in 1897 as a syndrome with articular contractures and bone fragility, Viljoen and Beighton described 5 children from three unrelated families with contractures who developed fractures after walking age[2]. Wormian bones, white sclera, short stature, severe scoliosis, and varying diameters for collagen fibrils in osteoid in BS with defective mineralization were highlighted in 1993[3]. It is classified into type I and type II, based on the two causative genes \u003cem\u003eFKBP10\u003c/em\u003e and \u003cem\u003ePLOD2\u003c/em\u003e[4]. Bruck type I is due to \u003cem\u003eFKBP10\u003c/em\u003e gene variants located on chromosome 17p12 and type II is caused by \u003cem\u003ePLOD2\u003c/em\u003e gene variants, located on chromosome 3q23-q24[5]. Both these types are phenotypically indistinguishable and exhibit a wide range of phenotypes from mild OI to severe BS[6].\u003c/p\u003e \u003cp\u003eThe phenotype of bruck syndrome includes an arthrogryposis-like syndrome with multiple, predominantly large joints such as knees and ankles, contractures with webbing, clubfeet with muscle atrophy and compensatory hypertrophy, osteopenia, progressive scoliosis and lumbar lordosis, short stature and low energy fractures. Some joint such as wrist and fingers, in contrast, have hypermobility. Teeth and hearing are normal[2, 7]. Older patients are extremely short with severe kyphoscoliosis affecting pulmonary function and lower limb contractures preventing ambulation[8]. Recently phenotype has been enlarged to include dental malocclusion, enamel hypoplasia, congenital dislocation of knee joint, and myopathy[9]. Metaphyseal corner fractures and posterior rib fractures have been reported in BS[10]. Sclera is white[2\u0026ndash;4, 8], however mild blue sclera has been reported[11]. Radiographic studies show demineralized bones, severe deformity and cystic change at old fracture sites, and vertebral wedging[8]. Bruck syndrome is also known as Kuskokwim disease or arthrogryposis like disorder found in Inuit population[12]. The clinical presentation varies from mild to severe lethal ranging with only contractures or only fractures without contractures or with both[6, 13, 14].\u003c/p\u003e \u003cp\u003e \u003cem\u003eFKBP10\u003c/em\u003e pathogenic gene variants decreases post-translational cross-linking of collagen fibrils[15]. Collagen is stabilized into fibrils by lysyl oxidation of lysine to aldehyde allysine and hydroxylysine to aldehyde hydroxyallysine. Both processes form cross-links of hydroxylysylpyridinoline or lysylpyridinoline are formed[16]. \u003cem\u003ePLOD2\u003c/em\u003e gene variants similarly effect lysyl hydroxylase 2 hydroxylation. The molecular defect in bruck syndrome results in aberrant cross-linking of bone collagen owing to under-hydroxylation, whereas cartilage and ligamentous collagen maintained normal cross-linking[17].\u003c/p\u003e \u003cp\u003eRecessive forms of OI are common in India, however only 10 cases of BS are described from India[18\u0026ndash;20]. Mrosk et al reported three novel variants out of four reported from an OI population of 50 cases and Madhuri et al reported six variants of which two were novel out of 54 OI cases[18, 20]. We report the genotype and phenotype in a series of 14 BS from India, the largest such series in the world.\u003c/p\u003e \u003cp\u003eWe report a single center experience of 14 patients with pathogenic variants in \u003cem\u003eFKBP10\u003c/em\u003e and \u003cem\u003ePLOD2\u003c/em\u003e genes and report on their clinical phenotype, progression and effect of bisphosphonates and surgery.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eFourteen children diagnosed as BS based on clinical and molecular findings in the department of Paediatric Orthopaedics and Medical genetics, Christian Medical College Hospital were selected for the study. The study was approved by the institutional review board (IRB No 9330 \u0026amp;10384).\u003c/p\u003e \u003cp\u003ePatients and the parents were given information sheets and informed consent were obtained. Pedigree analysis was done. Patients were classified based on the severity of the symptoms based on the Sillence classification system. All the patients were evaluated for scleral hue, recurrent fractures, decreased bone density, joint contractures, short stature, loss of hearing, and skeletal deformity. Patient assessment form includes birth history; Family history (Consanguinity, involving parents and siblings); anthropometric data; teeth examination; eye (color of the sclera); spine examination (scoliosis and kyphosis); joint contractures (hip, knee, ankle, shoulder, elbow, and wrist); deformities; Fracture history (first fracture, the total number of fractures, previous fracture). X-rays of long bones, skull, and spine were evaluated. Bisphosphonate dose, total body bone mineral density (BMD), BMD of the lumbar spine was measured using dual X-ray absorptiometry (DXA) and collected yearly where possible.\u003c/p\u003e \u003cp\u003eBlood samples were collected from the patients and their parents for the exome sequencing.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eClinical Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 14 children diagnosed as bruck syndrome phenotypically and genotypically by next generation sequencing were included in the study. Of the fourteen, six were males and eight were females. Nine were from consanguineous parentage. Based on the clinical and radiological findings all these fourteen subjects fall in the modified Sillence classification\u0026rsquo;s type III.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFive children had blue sclera and none of the children had denitinogensis imperfecta (DI) or deafness. There were no prenatal fractures. Age at the first fracture ranged from birth (clavicle), to six months. Twelve of the children had joint contractures including hip, knee, ankle, elbow and wrist. Joint contractures were majorly seen in knees and elbows (Figure 1). In the skull, wormian bones were seen in six children. A rare skull deformity called the Tam o\u0026rsquo; Shanter appearance (Figure 2a) due to widening of the skull in transverse plane above a flat small skull base was seen in one child and another child showed the \u0026lsquo;Darth Vader\u0026rsquo; appearance (Figure 2b) due to occipital flattening in sagittal plane. Basilar invagination was present in one child. One child had abnormalities at basicervical junction (C1 and C2) and acute angulation at C3 vertebra causing compression with myelopathy. Scoliosis was seen in three, was mild during childhood and became severe later, kyphoscoliosis was seen in three severe cases who were adolescents the time of evaluation (Figure 3 a and b). All patient with severe scoliosis were adult at the time of last assessment, one with mild scoliosis was aged five. Rib fractures were seen in six and vertebral compression in nine (Figure 3a) were noted. One patient also had spondylolistheisis of L5 over S1 vertebra. In the pelvis, three children had acetabular protrusion deformity (Figure 3c). Very thin gracile bones were seen in four children. Congenital talipes equinovarus (CTEV) or clubfoot were present in six children.\u0026nbsp;Hyperplastic callus formation was seen in femur of two children. All these children had deformity in the lower limb long bones and had undergone rush rod fixation and exchange. All the clinical phenotypes are given in Table 1.\u003c/p\u003e\n\u003cp\u003eSurgery with soft tissue release and bone shortening gave partial correction of contractures in two cases. The four children who underwent growth modulation or knee osteotomy did not correct deformities. Most (nine) could not be ambulant even after surgery with rush rodding.\u003c/p\u003e\n\u003cp\u003eOnly five patients had bone mineral density of spine. The values are given in table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenetic analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOut of fourteen patients, twelve were type I BS having FKBP10 mutation, two were type II BS having PLOD2 mutation. There was no phenotypic difference between the two gene variants. Six variants of these have been reported earlier[20]. In this series, there were six frameshift, one in-frame, four missense, and two stop codon mutation. There were 4 novel mutations in FKBP10. Four children had homozygous novel mutations namely c.501C\u0026gt;A, c.1339del T, c.1189A\u0026gt;T, and c.21dupC.\u003c/p\u003e\n\u003cp\u003eThere were two novel variants in PLOD2 gene. One child has a homozygous variant and the second was compound heterozygous with two novel heterozygous variants (C.2207C\u0026gt;T; c.1885A\u0026gt;g). All the genetic variants are presented in the table 2.\u003c/p\u003e\n\u003cp\u003eIn children with FKBP10 gene variants there were two additional gene variants which are not related to OI, one had CFTR gene variant known to causing Cystic fibrosis and the other had MYO7A gene causing Usher syndrome. Two more children had additional variants in SLC34A1 and BMP1 gene variants, which is explained the previous report[20]. Both syndromes are heterozygous, however there were no clinical manifestations seen in either of the two patients. Another one-year-old child with PLOD2 variant had PPA2 gene mutation known to cause infantile sudden unexpected cardiac arrest. The patient is presently four with no cardiac symptoms.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eA larger number of Bruck syndrome are being reported after the adoption of clinical exome sequencing in OI[21, 22]. In our study most of our patients were diagnosed with clinical exome sequencing which is preferred as most of the variants are novel in our population. In our Asian population the three common recessively transmitted genes are \u003cem\u003eSERPINF1, FKBP10\u003c/em\u003e, and \u003cem\u003eLEPRE1\u003c/em\u003e genes[23].\u003c/p\u003e \u003cp\u003eA large number of Chinese reports with BS has shown compound heterozygous genotype [21, 24, 25]. In our series two \u003cem\u003eFKBP10\u003c/em\u003e gene variants and one \u003cem\u003ePLOD2\u003c/em\u003e gene variant were compound heterozygous. The proportion of BS in our series is 21% of the recessive variants and 6.67% of all OI and is very high when compared to European population.\u003c/p\u003e \u003cp\u003eOur patients showed mainly post-natal fractures though they all classed as type III OI with severe phenotype. Reported literature suggests a number of still births/miscarriages in \u003cem\u003ePLOD2\u003c/em\u003e variants with besides decreased fetal movements, contractures and fractures, there was significant cardiac and pulmonary pathology[26]. This makes it mandatory to rule out Bruck in arthrogrypotic stillbirths or newborns for genetic counselling, and for accurate diagnosis and early management with bisphosphonates when indicated. Congenital cardiac disease with valve prolapse and regurgitation and pulmonary hypertension and haemorrhage has been reported and represents abnormal collagen in the cardiac tissue[27]. We did not have cardiac or respiratory symptoms in any of our patients.\u003c/p\u003e \u003cp\u003eThe phenotype of Bruck does not vary greatly between Bruck I and II though in the reported literature most of the prenatal and neonatal deaths are associated with \u003cem\u003ePLOD2\u003c/em\u003e variants[24]. Besides joint contractures, bone fragility, white or light blue sclera, absence of deafness and DI, the phenotype has been enlarged to includes orodental findings, myopathy and poor muscle tone, prominent tailbone, and cervical abnormalities including cervical junction and upper cervical collapse and kyphosis [9, 28]. Protusio acetabuli is not a common feature of dominant OI. The type VI (\u003cem\u003eSERPINF1\u003c/em\u003e gene) recessively transmitted OI where there are features of osteoporosis and osteomalacia. We had three patients who showed protrusio acetabuli. This has been reported earlier in BS[24]. Quadriparesis associated with upper cervical spine abnormality as seen in one of our cases has been described requiring multiple attempts at fusion and lifelong cervical orthosis. Gastroschisis has been described though not seen in our cases[29]. One of the severe phenotypes, associated with rhizomelia, and kyphosis of long bone was seen in one of our patients who also had hip, knee and ankle contractures. While the intellectually normal in most cases, associated microcephaly has been described[9].\u003c/p\u003e \u003cp\u003eA total of 87 unique public variants have been described in \u003cem\u003eFKBP10\u003c/em\u003e and 52 in \u003cem\u003ePLOD2\u003c/em\u003e (LOVD database). A large number of reports are from Chinese population[21, 22, 25, 30]. There are three reports from the south Asian population with no overlap and no recurrent mutation[18, 20, 26] .A recent Egyptian series reports 13 patients from nine families with five novel mutations[9]. Very few reports are from the western literature as there have mainly dominant form of OI[10, 24].\u003c/p\u003e \u003cp\u003eOur patients responded well in terms of fracture rate. The bone density values were available for only six patients because of inability to prefer the investigation because of multiple contractures and spinal deformities (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). However, as reported elsewhere, despite the improvement in fracture rate and bone density the walking was significantly affected with only four out of 11 being mobile[31]. Surgical correction of the contracture using guided growth or osteotomy at the knee was not very successful in restoring mobility or correcting the deformity. In one patient significant correction could be achieved by shortening the bone to reduce the knee contracture to 10\u0026deg;.\u003c/p\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eWe had incomplete follow up mainly in the older patients who lacked mobility. Some features such as cardiac and pulmonary were not investigated by echocardiogram (ECHO) and pulmonary function test. Bone density was done only in five patients. Some patients were diagnosed as arthrogryposis initially and received treatment at a later age.\u003c/p\u003e \u003cp\u003eThere are totally 130 variants associated with BS reported in the LOVD database. Our study adds seven new previously unreported variants. The study highlights the varied phenotype and novel variants in the described population to the literature. The BS responds well to regular pamidronate therapy, however the kyphoscoliotic deformity progresses relentlessly. The treatment of contractures and preventing kyphoscoliosis is a priority and surgical techniques for correcting soft tissue contractures need to be explored further to improve ambulation in these patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the institutional review board (IRB No 9330 \u0026amp;10384).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent and photography consent was taken for all the patients participated in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e available on request\u003c/p\u003e\n\u003cp\u003eData (genetic polymorphism) has been submitted in Clinvar. It is still under review. Once it is accepted we will give the accession number.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Biotechnology, Government of India, Grant/Award Number: BT/IN/SWEDEN/09/VM/2017;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIndian Council of Medical Research, Grant/Award Number: 54/9/2015-HUMBMS\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution:\u003c/strong\u003e \u003cem\u003eAll authors contributed to the study\u0026apos;s conception and design. Material preparation, data collection, and analysis were performed by A.S, M.K,S.D and V.M. The first draft of the manuscript was written by A.S and V.M and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment:\u0026nbsp;\u003c/strong\u003eWe thank all the OI patients and their families for participating in this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMokete L, Robertson A, Viljoen D, Beighton P (2005) Bruck syndrome: congenital joint contractures with bone fragility. J Orthop Sci 10:641\u0026ndash;646. https://doi.org/10.1007/s00776-005-0958-9\u003c/li\u003e\n\u003cli\u003eViljoen D, Versfeld G, Beighton P (1989) Osteogenesis imperfecta with congenital joint contractures (Bruck Syndrome). Clinical Genetics 36:122\u0026ndash;126. https://doi.org/10.1111/j.1399-0004.1989.tb03174.x\u003c/li\u003e\n\u003cli\u003eBrenner RE, Vetter U, St\u0026ouml;ss H, et al (1993) Defective collagen fibril formation and mineralization in osteogenesis imperfecta with congenital joint contractures (Bruck syndrome). Eur J Pediatr 152:505\u0026ndash;508. https://doi.org/10.1007/BF01955060\u003c/li\u003e\n\u003cli\u003eShaheen R, Al-Owain M, Faqeih E, et al (2011) Mutations in FKBP10 cause both Bruck syndrome and isolated osteogenesis imperfecta in humans. Am J Med Genet A 155A:1448\u0026ndash;1452. https://doi.org/10.1002/ajmg.a.34025\u003c/li\u003e\n\u003cli\u003evan der Slot AJ, Zuurmond A-M, Bardoel AFJ, et al (2003) Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J Biol Chem 278:40967\u0026ndash;40972. https://doi.org/10.1074/jbc.M307380200\u003c/li\u003e\n\u003cli\u003eSantana A, Oleas-Santill\u0026aacute;n G, Franzone JM, et al (2019) Orthopedic Manifestations of Bruck Syndrome: A Case Series with Intermediate to Long-term Follow-Up. Case Reports in Orthopedics 2019:e8014038. https://doi.org/10.1155/2019/8014038\u003c/li\u003e\n\u003cli\u003eHa-Vinh R, Alanay Y, Bank RA, et al (2004) Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2. Am J Med Genet A 131:115\u0026ndash;120. https://doi.org/10.1002/ajmg.a.30231\u003c/li\u003e\n\u003cli\u003eMcPherson E, Clemens M (1997) Bruck syndrome (osteogenesis imperfecta with congenital joint contractures): review and report on the first North American case. Am J Med Genet 70:28\u0026ndash;31\u003c/li\u003e\n\u003cli\u003eOtaify GA, Abdel-Hamid MS, Hassib NF, et al (2022) Bruck syndrome in 13 new patients: Identification of five novel FKBP10 and PLOD2 variants and further expansion of the phenotypic spectrum. Am J Med Genet A 188:1815\u0026ndash;1825. https://doi.org/10.1002/ajmg.a.62718\u003c/li\u003e\n\u003cli\u003eBobyn A, Jetha M, Frohlich B, et al (2022) Metaphyseal and posterior rib fractures in osteogenesis imperfecta: Case report and review of the literature. Bone Rep 16:101171. https://doi.org/10.1016/j.bonr.2022.101171\u003c/li\u003e\n\u003cli\u003eSharma NL, Anand JS (1964) OSTEOGENESIS IMPERFECTA WITH ARTHROGRYPOSIS MULTIPLEX CONGENITA. J Indian Med Assoc 43:124\u0026ndash;126\u003c/li\u003e\n\u003cli\u003ePetajan JH, Momberger GL, Aase J, Wright DG (1969) Arthrogryposis syndrome (Kuskokwim disease) in the Eskimo. JAMA 209:1481\u0026ndash;1486\u003c/li\u003e\n\u003cli\u003eMoravej H, Karamifar H, Karamizadeh Z, et al (2015) Bruck syndrome - a rare syndrome of bone fragility and joint contracture and novel homozygous FKBP10 mutation. Endokrynol Pol 66:170\u0026ndash;174. https://doi.org/10.5603/EP.2015.0024\u003c/li\u003e\n\u003cli\u003eLuce L, Casale M, Waldron S (2020) A Rare Case of Bruck Syndrome Type 2 in Siblings With Broad Phenotypic Variability. Ochsner J 20:204\u0026ndash;208. https://doi.org/10.31486/toj.18.0145\u003c/li\u003e\n\u003cli\u003eBarnes AM, Cabral WA, Weis M, et al (2012) Absence of FKBP10 in Recessive Type XI Osteogenesis Imperfecta Leads to Diminished Collagen Cross-Linking and Reduced Collagen Deposition in Extracellular Matrix. Hum Mutat 33:1589\u0026ndash;1598. https://doi.org/10.1002/humu.22139\u003c/li\u003e\n\u003cli\u003eKelley BP, Malfait F, Bonafe L, et al (2011) Mutations in FKBP10 cause recessive osteogenesis imperfecta and bruck syndrome. J Bone Miner Res 26:666\u0026ndash;672. https://doi.org/10.1002/jbmr.250\u003c/li\u003e\n\u003cli\u003eEyre DR, Ann Weis M (2013) Bone Collagen: New Clues to its Mineralization Mechanism From Recessive Osteogenesis Imperfecta. Calcif Tissue Int 93:338\u0026ndash;347. https://doi.org/10.1007/s00223-013-9723-9\u003c/li\u003e\n\u003cli\u003eMrosk J, Bhavani GS, Shah H, et al (2018) Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. Bone 110:368\u0026ndash;377. https://doi.org/10.1016/j.bone.2018.02.029\u003c/li\u003e\n\u003cli\u003eDatta V, Sinha A, Saili A, Nangia S (2005) Bruck syndrome. Indian J Pediatr 72:441\u0026ndash;442. https://doi.org/10.1007/BF02731745\u003c/li\u003e\n\u003cli\u003eMadhuri V, Selina A, Loganathan L, et al (2020) Osteogenesis imperfecta: Novel genetic variants and clinical observations from a clinical exome study of 54 Indian patients. Annals of Human Genetics. https://doi.org/10.1111/ahg.12403\u003c/li\u003e\n\u003cli\u003eZhang J, Hu H, Mu W, et al (2021) Case Report: Exome Sequencing Identified a Novel Compound Heterozygous Variation in PLOD2 Causing Bruck Syndrome Type 2. Front Genet 12:619948. https://doi.org/10.3389/fgene.2021.619948\u003c/li\u003e\n\u003cli\u003eWang R, Ruan D, Hu Y, et al (2022) Genetic Analysis and Functional Study of a Pedigree With Bruck Syndrome Caused by PLOD2 Variant. Front Pediatr 10:878172. https://doi.org/10.3389/fped.2022.878172\u003c/li\u003e\n\u003cli\u003eLi S, Cao Y, Wang H, et al (2020) Genotypic and Phenotypic Analysis in Chinese Cohort With Autosomal Recessive Osteogenesis Imperfecta. Front Genet 11:984. https://doi.org/10.3389/fgene.2020.00984\u003c/li\u003e\n\u003cli\u003eMumm S, Gottesman GS, Wenkert D, et al (2020) Bruck syndrome 2 variant lacking congenital contractures and involving a novel compound heterozygous PLOD2 mutation. Bone 130:115047. https://doi.org/10.1016/j.bone.2019.115047\u003c/li\u003e\n\u003cli\u003eZhou P, Liu Y, Lv F, et al (2014) Novel Mutations in FKBP10 and PLOD2 Cause Rare Bruck Syndrome in Chinese Patients. PLoS ONE 9:e107594. https://doi.org/10.1371/journal.pone.0107594\u003c/li\u003e\n\u003cli\u003eParvin S, Dhali A, Biswas DN, Ray S (2021) Bruck syndrome: a rare cause of reduced fetal movements. BMJ Case Reports 14:. https://doi.org/10.1136/bcr-2021-246786\u003c/li\u003e\n\u003cli\u003eSandy JL, Perez D, Goh S, et al (2023) Expanding the phenotype of Bruck syndrome: Severe limb deformity, arthrogryposis, congenital cardiac disease and pulmonary hemorrhage. Am J Med Genet A 191:265\u0026ndash;270. https://doi.org/10.1002/ajmg.a.63007\u003c/li\u003e\n\u003cli\u003eMenezes AH, Traynelis VC (2022) Pediatric cervical kyphosis in the MRI era (1984\u0026ndash;2008) with long-term follow up: literature review. Childs Nerv Syst 38:361\u0026ndash;377. https://doi.org/10.1007/s00381-021-05409-z\u003c/li\u003e\n\u003cli\u003eAfşarlar \u0026Ccedil;E, Peltek-Kendirci HN, Erdoğan D, et al (2013) The first case of Bruck syndrome associated with gastroschisis. Turk J Pediatr 55:651\u0026ndash;654\u003c/li\u003e\n\u003cli\u003eLv F, Xu X, Song Y, et al (2018) Novel Mutations in PLOD2 Cause Rare Bruck Syndrome. Calcif Tissue Int 102:296\u0026ndash;309. https://doi.org/10.1007/s00223-017-0360-6\u003c/li\u003e\n\u003cli\u003eY\u0026uuml;ksel \u0026Uuml;lker A, Uludağ Alkaya D, Elkanova L, et al (2021) Long-Term Follow-Up Outcomes of 19 Patients with Osteogenesis Imperfecta Type XI and Bruck Syndrome Type I Caused by FKBP10 Variants. Calcif Tissue Int 109:633\u0026ndash;644. https://doi.org/10.1007/s00223-021-00879-4\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Clinical, radiological and bone mineral density (BMD) of the 14 Bruck syndrome patients.(B/l \u0026ndash; bilateral, LLD - \u0026nbsp;limb length discrepancy, CTEV-Congenital talipes equinovarus, NA- not avalaible)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3263855992420654%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"1.752723827569872%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAGE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.747513027001421%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSEX\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8896257697773566%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGENE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.9422074846044528%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTYPE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.068687825675036%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCONSANGUINITY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.263382283278068%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBLUE SCLERA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.4107058266224537%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFIRST FRACTURE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.4107058266224537%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOTAL FRACTURE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.9265750828991%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDEVLOPMENTAL DELAY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8844149692089056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWORMAIAN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.547607768829939%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBASILAR INVAGINATION\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6054002842254858%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eskull shape\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.547607768829939%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCONTRACTURE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.694931312174325%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCALLUS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7896731406916153%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUPPER LIMB DEFORMITY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.310753197536712%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSCOLIOSIS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6054002842254858%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRIB FRACT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.700142112742776%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVERE FRAC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.694931312174325%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePROTRUSIO ACETABULI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.700142112742776%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCTEV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.405495026054003%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLOWER LIMB DEFORMITY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.216011369019422%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePAMIDRO\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.916153481762198%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSURGERY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.158218853623875%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOTHERS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8844149692089056%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMD\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6001894836570347%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollowup\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e40 Days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eleft knee 40\u0026deg; right knee 30\u0026deg;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eHypertropic callus of b/l femur\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur and tibia LLD present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003e3 cycles(6 doses zolendronate)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur and tibia rodding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\n \u003cp\u003eGracile bones\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003e-0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.412\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003e-2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e3 Days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eB/l elbow, Knee and Ankle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eHumerus deformity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eRight side\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eLeft foot\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur and tibia deformity, Varus on right and distal valgus on left\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003eMultiple cycles of pamidronate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur and tibia correction and rodding. B/l distal femur anterior 8 plate implant and exit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\n \u003cp\u003eGracile bones\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.522\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003e-3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eBlue\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e15 Days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eTam -O- shanter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eB/l Knee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003esevere kyphoscoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003ePresent and mild listhesis of L5 over S1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur and tibia deformity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003e12 cycles of pamidronate and two dose of zolendronate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eB/l popetial contracture release, B/L femur rush rodding and dital anterior 8 plate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003e-5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.487\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003e-5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eLight Blue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e3 Days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eB/l elbow and knee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eb/l CTEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur deformity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003eOne dose, stopped on second day due to fever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eLeft knee quadriceps plasty\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.309\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003e-3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eBlue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur and tibia deformity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eLight Blue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003eBirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eRight humerus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eHumerus defromity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur and LLD present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e15 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eLeft elbow and right knee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003esingle dose\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e4 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur deformity and LLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003eMultiple cycles of pamidronate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur rush rodding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.358\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003e-2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003e-0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e45 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eRight knee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eHumerus, ulna and radius deformity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eSevere kyphoscoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eSevere femur and tibia deformity; LLD present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003e14 cycles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eB/l lower limbs and right humerus rush rodding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\n \u003cp\u003eSevere gracile bones and non-union of left femur with valgus deformity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eB/l knee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eRight femur\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eLeft foot equinus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eLLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003e5 cycles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur and tibia rodding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.808\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003e-2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e1 month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eCerival compression myelopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eb/l knee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003escoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eb/l CTEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eFemur fractures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003e1 cycle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\n \u003cp\u003eSevere osteoporotic , very thin gracile \u0026nbsp;bones, varus deformity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003e-12.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e2 Months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eDarth vader\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eb/l knee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003epopliteal elbow pterygium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eSevere kyphoscoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eLeft side\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eb/l CTEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eB/l lower limbs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003eMultiple cycles of pamidronate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eB/l tibia rodding and right femur rodding\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\n \u003cp\u003epectus excavatum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.669\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003e-3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003ePLOD2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eLight Blue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e4 Months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eb/l elbow and wrist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eHumerus deformity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eMild scoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eb/l CTEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eb/l anterior tibial deformity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003e6 cyles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eB/l femur rush rodding and hip spica and B/l percutaneous tentomy and corrective cast appilcation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\n \u003cp\u003erhizomelic shortening, umblical hernia present, low set ears, small mouth, retrognathgia present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e0.321\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003e-3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"1.3257575757575757%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7518939393939394%\" valign=\"top\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.746212121212121%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.8882575757575757%\" valign=\"top\"\u003e\n \u003cp\u003ePLOD2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.941287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.066287878787879%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.261363636363637%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003eBirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.924242424242424%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.882575757575758%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.545454545454546%\" valign=\"top\"\u003e\n \u003cp\u003eB/l elbow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.787878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eHumerus deformity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.308712121212121%\" valign=\"top\"\u003e\n \u003cp\u003eScoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6041666666666665%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6931818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.6988636363636362%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.403409090909091%\" valign=\"top\"\u003e\n \u003cp\u003eTibial defromity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.214015151515151%\" valign=\"top\"\u003e\n \u003cp\u003e5 cycles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.912878787878788%\" valign=\"top\"\u003e\n \u003cp\u003eRight femur ORIF with plate and, b/l tibia rod fixation and exchange 4times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.15530303030303%\" valign=\"top\"\u003e\n \u003cp\u003eAtypical pubic fractures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.7992424242424243%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1306818181818183%\" valign=\"top\"\u003e\n \u003cp\u003e1.229\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.4678030303030303%\" valign=\"top\"\u003e\n \u003cp\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2: Genetic spectrum of the 14 bruck syndrome patients.(NA- not available, Homo- homozygous, Hetero-Heterozygous, VUS- variant of uncertain significance)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"1566\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSTUDY ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eType\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGENE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEXON\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ec.DNA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eProtein change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMutation Type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.501C\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Cys167*)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 6: Intron 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.1024dup; c.391+1G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Thr342Asnfs*31): Splice site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eFrameshift: Splice Site\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.21dupC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Ser8Glnfs*67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.523_552dup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Asp175_Thr184dup)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003ein frame\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eIntron 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.918-2A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003eSplice site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eIntron 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.918-2A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003eSplice site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.523_552dup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Asp175_Thr184dup)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003ein frame\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 1;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eExon 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.21dup;c.773T\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Ser8Glnfs*67); p.(Leu258Arg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eFrameshift; Missense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.1339delT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Cys447Valfs*84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.1189A\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Lys397*)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.831del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Gly278Alafs*20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003eFKBP10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.21dupC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Ser8Glnfs*67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003ePLOD2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.32T\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Leu11Pro)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.850340136054422%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.02721088435374%\" valign=\"top\"\u003e\n \u003cp\u003ePLOD2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.517006802721088%\" valign=\"top\"\u003e\n \u003cp\u003eExon 20;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eExon 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.86394557823129%\" valign=\"top\"\u003e\n \u003cp\u003ec.2207C\u0026gt;A;c.1885A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.482993197278912%\" valign=\"top\"\u003e\n \u003cp\u003ep.(Thr736Lys);p.(Thr629Ala)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003eMissense;Missense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bruck syndrome, FKBP10, PLOD2, bone fragility, joint contractures","lastPublishedDoi":"10.21203/rs.3.rs-4379907/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4379907/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBruck syndrome (BS) is a rare form of Osteogenesis imperfecta (OI) with congenital large joint contractures and bone fragility fractures. Evaluation of phenotypic and genotypic profiles of 14 children with \u003cem\u003eFKBP10\u003c/em\u003e and \u003cem\u003ePLOD2\u003c/em\u003e gene variants causing Bruck syndrome (BS) and highlighting the severe deformities in response to poor surgical treatment in the Indian cohort.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients with bone fragility were clinically evaluated. After informed consent, genotyping was done by next-generation sequencing, and the variants were validated by Sanger sequencing. These children were treated surgically and pamidronate was administered.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOut of 14 children, 12 were with \u003cem\u003eFKBP10\u003c/em\u003e gene variants, and two with \u003cem\u003ePLOD2\u003c/em\u003e gene variants. The age at diagnosis varied from birth to four years. All were classified as type III by modified Sillence classification. twelve had joint contractures, mainly in the knees and elbows. Clubfeet was identified in seven, scoliosis in three, and severe kyphoscoliosis in three. Two had skull deformities, six with wormian bones, one with basilar invagination and another showing severe cervical compression myelopathy. Rib fractures in six, vertebral compression in nine, and protrusion acetabulae in three were noted. Surgical correction of the deformities by soft tissue release and bone shortening was partially successful, while growth modulation was unsuccessful as the implant failed. Nine of the patients were non-ambulant. Bone density was decreased in all, and the response to pamidronate was partial. This cohort had four novel \u003cem\u003eFKBP10\u003c/em\u003e variants and two \u003cem\u003ePLOD2\u003c/em\u003e variants.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe study highlights the proportionate representation of the two genes in our population, the severe deformities with poor response to surgical treatment, and novel variants in the population.\u003c/p\u003e","manuscriptTitle":"Clinical and genetic landscape of Bruck syndrome in the Indian population","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-04 21:52:44","doi":"10.21203/rs.3.rs-4379907/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-11T16:06:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-23T08:39:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-16T08:51:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230556807797972653503712709598584661888","date":"2024-08-14T21:26:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-13T08:48:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3286795117318542811355857993155475568","date":"2024-08-13T07:59:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8773610836573775257914374945736695206","date":"2024-08-06T15:44:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-06T14:36:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-24T10:35:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-20T13:32:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-20T13:32:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Musculoskeletal Disorders","date":"2024-05-07T03:18:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bc204c35-743a-4c3e-8701-a95996a5e27b","owner":[],"postedDate":"June 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T13:54:36+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-04 21:52:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4379907","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4379907","identity":"rs-4379907","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}