Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2019

Open Access 01-12-2019 | Osteogenesis Imperfecta | Review

The evolving therapeutic landscape of genetic skeletal disorders

Authors: Ataf Hussain Sabir, Trevor Cole

Published in: Orphanet Journal of Rare Diseases | Issue 1/2019

Login to get access

Abstract

Background

Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials.

Methods

A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.​gov respectively. Over 140 articles and 80 trials were generated for review.

Results

Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP.

Discussion

It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.
Literature
1.
Tosi LL, Warman ML. Mechanistic and therapeutic insights gained from studying rare skeletal diseases. Bone. 2015;76:67–75.PubMedCrossRef
2.
Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Gen Part A. 2015;167(12):2869–92.CrossRef
3.
Yap P, Savarirayan R. Emerging targeted drug therapies in skeletal disorders. Am J Med Genet Part A. 2016;170(10):2596–604.PubMedCrossRef
4.
5.
Nikkel SM. Skeletal Disorders: What Every Bone Health Clinician Needs to Know. Curr Osteoporosis Rep. 2017;15(5):419–24.CrossRef
6.
Bacon S, Crowley R. Developments in rare bone diseases and mineral disorders. Ther Adv Chronic Dis. 2018;9(1):51–60.PubMedCrossRef
7.
Yasoda A, et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med. 2004;10(1):80–6.PubMedCrossRef
8.
Duarte SP, Rocha ME, Bidondo MP, Liascovich R, Barbero P, Groisman B. Bone disorders in 1.6 million births in Argentina. Eur J Med Genet. 2018.
9.
10.
11.
Wynn J, King TM, Gambello MJ, Waller DK, Hecht JT. Mortality in achondroplasia study: A 42-year follow-up. Am J Med Genets Part A. 2007;143(21):2502–11.CrossRef
12.
Arenas MA, del Pino M, Fano V. FGFR3-related hypochondroplasia: longitudinal growth in 57 children with the p. Asn540Lys mutation. J Pediatr Endocrinol Metab. 2018;31(11):1279–84.PubMed
13.
Pauli RM, Botto LD. Achondroplasia. In: Management of Genetic Syndromes. 4th ed. New York: Wiley; 2018.
14.
Mortier G, Nuytinck L, Craen M, Renard JP, Leroy JG, De Paepe A. Clinical and radiographic features of a family with hypochondroplasia owing to a novel Asn540Ser mutation in the fibroblast growth factor receptor 3 gene. J Med Genet. 2000;37(3):220–4.PubMedPubMedCentralCrossRef
15.
Peake NJ, Hobbs AJ, Pingguan-Murphy B, Salter DM, Berenbaum F, et al. Role of C-type natriuretic peptide signalling in maintaining cartilage and bone function. Osteoarth Cartilage. 2014;22(11):1800–7.CrossRef
16.
17.
Noonberg S. BMN 111: vosoritide for achondroplasia. Biomarin R&D Day. 2016:98–135.
18.
Savarirayan R, Irving M, Bacino CA, Bostwick B, Charrow J, Cormier-Daire V, et al. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med. 2019;381(1):25–35.PubMedCrossRef
19.
Olney RC, Prickett TC, Espiner EA, Mackenzie WG, Duker AL, Ditro C, et al. C-type natriuretic peptide plasma levels are elevated in subjects with achondroplasia, hypochondroplasia, and thanatophoric dysplasia. J Clin Endocrinol Metab. 2015;100:E355–9.PubMedCrossRef
20.
Wendt DJ, Dvorak-Ewell M, Bullens S, Lorget F, Bell SM, Peng J, et al. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3–related dwarfism. J Pharmacol Exp Ther. 2015;353:132–49.PubMedCrossRef
21.
22.
Webster MK, d'Avis PY, Robertson SC, Donoghue DJ. Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Mol Cell Biol. 1996;16(8):4081–7.PubMedPubMedCentralCrossRef
23.
Monsonego-Ornan E, Adar R, Feferman T, Segev O, Yayon A. The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Mol Cell Biol. 2000;20(2):516–22.PubMedPubMedCentralCrossRef
24.
25.
Garcia S, Dirat B, Tognacci T, Rochet N, Mouska X, Bonnafous S, et al. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med. 2013;5(203):203ra124.PubMedCrossRef
26.
27.
Matsushita M, Hasegawa S, Kitoh H, Mori K, Ohkawara B, Yasoda A, Masuda A, et al. Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene. Endocrinology. 2014;156(2):548–54.PubMedCrossRef
28.
29.
Kombla-Ebri D, et al. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest. 2016;126(5):1871–84.CrossRef
30.
De Ridder R, Boudin E, Mortier G, Van Hul W. Human Genetics of Sclerosing Bone Disorders. Curr Osteoporos Rep. 2018;16(3):256–68.PubMedCrossRef
31.
Bollerslev J, Henriksen K, Frost M, Brixen K, Van Hul W. Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol. 2013;EJE-13.
32.
33.
Thudium CS, Moscatelli I, Flores C, Thomsen JS, Brüel A, Gudmann NS, et al. A comparison of osteoclast-rich and osteoclast-poor osteopetrosis in adult mice sheds light on the role of the osteoclast in coupling bone resorption and bone formation. Calcif Tissue Int. 2014;95(1):83–93.PubMedCrossRef
34.
35.
Key LL Jr, Rodriguiz RM, Willi SM, Wright NM, Hatcher HC, Eyre DR, et al. Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med. 1995;332(24):1594–9.PubMedCrossRef
36.
Key L, Carnes D, Cole S, Holtrop M, Bar-Shavit Z, Shapiro F, Arceci R, Steinberg J, Gundberg C, Kahn A, Teitelbaum S. Treatment of congenital osteopetrosis with high-dose calcitriol. N Engl J Med. 1984;310(7):409–15.PubMedCrossRef
37.
Wu CC, Econs MJ, LA DM, Insogna KL, Levine MA, Orchard PJ, et al. Diagnosis and Management of Osteopetrosis: Consensus Guidelines from the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017.
38.
Maurizi A, Capulli M, Patel R, Curle A, Rucci N, Teti A. RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development. Bone. 2018;110:343–54.PubMedCrossRef
39.
Goessl C, Katz L, Dougall WC, et al. The development of denosumab for the treatment of diseases of bone loss and cancer-induced bone destruction. Ann N Y Acad Sci. 2012;1263:29–40.PubMedCrossRef
40.
Chung PY, van Hul W. Paget's disease of bone: evidence for complex pathogenetic interactions. Semin Arthritis Rheum. 2012;41(5):619–41.PubMedCrossRef
41.
Lo Iacono N, Pangrazio A, Abinun M, Bredius R, Zecca M, Blair HC, et al. RANKL cytokine: from pioneer of the osteoimmunology era to cure for a rare disease. Clin Dev Immunol. 2013;15:2013.
42.
Streeten EA, McBride D, Puffenberger E, Hoffman ME, Pollin TI, et al. Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates. Bone. 2008;43(3):584–90.PubMedPubMedCentralCrossRef
43.
Papapoulos SE. Bisphosphonates: how do they work? Best Pract Res Clin Endocrinol Metab. 2008;22(5):831–47.PubMedCrossRef
44.
Clément-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssière B, Belleville C, Estrera K, et al. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci. 2005;102(48):17406–11.PubMedCrossRefPubMedCentral
45.
46.
Kedlaya R, Veera S, Horan DJ, Moss RE, Ayturk UM, Jacobsen CM, et al. Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome. Sci Transl Med. 2013;5(211):211ra158.PubMedPubMedCentralCrossRef
47.
48.
Xu XJ, Lv F, Song YW, Li LJ, Wei XX. Zhao XL, et al Novel mutations in BMP1 induce a rare type of osteogenesis imperfecta. Clin Chim Acta. 2019;489:21–8.PubMedCrossRef
49.
Sillence DO, Rimoin DL, Danks DM. Clinical variability in osteogenesis imperfecta- variable expressivity or genetic heterogeneity. Birth Defects Orig Artic Ser. 1979;15:113–29.PubMed
50.
Van Dijk FS, Sillence DO. Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment. Am J Med Genet Part A. 2014;164A:1470–81.PubMedCrossRef
51.
Shapiro J. Osteogenesis Imperfecta: A Translational Approach to Brittle Bone Disease. Academic Press. Chapter 2; 2014. p. 15–22.CrossRef
52.
Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2016;10.
53.
Drake MT, Collins MT, Hsiao EC. The Rare Bone Disease Working Group: report from the 2016 American Society for Bone and Mineral Research Annual Meeting. Bone. 2017;102:80–4.PubMedCrossRef
54.
55.
56.
Kobayashi T, Nakamura Y, Suzuki T, Yamaguchi T, Takeda R, Takagi M, et al. Efficacy and Safety of Denosumab Therapy for Osteogenesis Imperfecta Patients with Osteoporosis—Case Series. J Clin Med. 2018;7(12):479.PubMedCentralCrossRef
57.
Glorieux FH, Devogelaer JP, Durigova M, Goemaere S, Hemsley S. Jakob Fet al. BPS804 anti-sclerostin antibody in adults with moderate osteogenesis imperfecta: results of a randomized phase 2a trial. J Bone Miner Res. 2017;32(7):1496–504.PubMedCrossRef
58.
Wu M, Chen G, Li YP. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009.PubMedPubMedCentralCrossRef
59.
Grafe I, Yang T, Alexander S, Homan EP, Lietman C, Jiang MM, Bertin T, Munivez E, Chen Y, Dawson B, Ishikawa Y. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat Med. 2014;20(6):670.PubMedPubMedCentralCrossRef
60.
61.
Le Blanc K, Gotherstrom C, Ringden O, Hassan M, McMahon R, Horwitz E, et al. Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation. 2005;79(11):1607–14.PubMedCrossRef
62.
Gotherstrom C, Westgren M, Shaw SW, Astrom E, Biswas A, Byers PH, et al. Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience. Stem Cells Transl Med. 2014;3(2):255–64.PubMedCrossRef
63.
64.
65.
Chevrel G, Cimaz R. Osteogenesis imperfecta: new treatment options. Curr Rheumatol Rep. 2006;8(6):474–9.PubMedCrossRef
66.
Shapiro JR, Rowe DW. Genetic approach to treatment of osteogenesis imperfecta in Osteogenesis imperfecta. 1st ed. London: Elsevier Science and Technology; 2013.
67.
Berman AG, Wallace JM, Bart ZR, Allen MR. Raloxifene reduces skeletal fractures in an animal model of osteogenesis imperfecta. Matrix Biol. 2016;52:19–28.PubMedCrossRef
68.
69.
Bowden SA, Foster BL. Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy. Drug Des Devel Ther. 2018;12:3147.PubMedPubMedCentralCrossRef
70.
71.
Nishioka T, Tomatsu S, Gutierrez MA, Miyamoto KI, Trandafirescu GG, Lopez PL, et al. Enhancement of drug delivery to bone: characterization of human tissue-nonspecific alkaline phosphatase tagged with an acidic oligopeptide. Mol Genet Metab. 2006;88:244–55.PubMedPubMedCentralCrossRef
72.
Uçaktürk SA, Elmaogullari S, Ünal S, Gönülal D, Mengen E. Enzyme Replacement Therapy in Hypophosphatasia. J Coll Physicians Surg Pak. 2018;28(9):S198–200.PubMedCrossRef
73.
Shapiro JR, Lewiecki EM. Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res. 2017;32(10):1977–80.PubMedCrossRef
74.
Iijima O, Miyake K, Watanabe A, Miyake N, Igarashi T. Kanokoda C, et al Prevention of lethal murine hypophosphatasia by neonatal ex vivo gene therapy using lentivirally transduced bone marrow cells. Hum Gene Ther. 2015;26(12):801–12.PubMedPubMedCentralCrossRef
75.
Kaunitz JD, Yamaguchi DT. TNAP, TrAP, ecto-purinergic signaling, and bone remodeling. J Cell Biochem. 2008;105(3):655–62.PubMedCrossRef
76.
Seefried L, Baumann J, Hemsley S, Hofmann C, Kunstmann E, Kiese B, et al. Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia. J Clin Invest. 2017;127(6):2148–58.PubMedPubMedCentralCrossRef
77.
Endo I, Fukumoto S, Ozono K, Namba N, Inoue D, Okazaki R, et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr J. 2015:EJ15–0275.
78.
Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol. 2016;174(2):125–36.PubMedCrossRef
79.
80.
81.
DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20–33.PubMedCrossRef
82.
Squires LA, Prangley J. Neonatal diagnosis of Schwartz-Jampel syndrome with dramatic response to carbamazepine. Pediatr Neurol. 1996;15(2):172–4.PubMedCrossRef
83.
Mullan LA, Mularczyk EJ, Kung LH, Forouhan M, Wragg JM, Goodacre R, et al. Increased intracellular proteolysis reduces disease severity in an ER stress–associated dwarfism. J Clin Invest. 2017;127(10):3861–5.PubMedPubMedCentralCrossRef
84.
Meng Q, Chen X, Sun L, Zhao C, Sui G, Cai L. Carbamazepine promotes Her-2 protein degradation in breast cancer cells by modulating HDAC6 activity and acetylation of Hsp90. Mol Cell Biochem. 2011;348(1-2):165–71.PubMedCrossRef
85.
86.
Caja L, Bellomo C, Moustakas A. Transforming growth factor β and bone morphogenetic protein actions in brain tumors. FEBS Lett. 2015;589(14):1588–97.PubMedCrossRef
87.
Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015;7(303):303ra137.PubMedPubMedCentralCrossRef
88.
Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, et al. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci U S A. 2015;112(50):15438–43.PubMedPubMedCentralCrossRef
89.
Pacifici M. Retinoid roles and action in skeletal development and growth provide the rationale for an ongoing heterotopic ossification prevention trial. Bone. 2018;109:267–75.PubMedCrossRef
90.
Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011;17(4):454–60.PubMedPubMedCentralCrossRef
91.
Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, et al. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) mutation. J Bone Miner Res. 2016;31(9):1666–75.PubMedCrossRef
92.
Kaplan F. HE, Baujat G., Keen R., Grogan D., Pignolo R. Efficacy and Safety of Palovarotene in Fibrodysplasia Ossificans Progressiva (FOP): A Randomized, PlaceboControlled, Double-Blind Study. J Bone Miner Res. 2017. 32 (Suppl1).
93.
Wentworth KL, Masharani U, Hsiao EC. Therapeutic Advances for Blocking Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva. Brit J Clin Pharmacol. 2018.
94.
Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, et al. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone. 2018;109:276–80.PubMedCrossRef
95.
Shrivats AR, Hollinger JO. The delivery and evaluation of RNAi therapeutics for heterotopic ossification pathologies. Biomimetics and Stem Cells. New York: Humana Press; 2013. p. 149–60.
96.
97.
Pacifici M. Hereditary multiple exostoses: new insights into pathogenesis, clinical complications, and potential treatments. Curr Osteopor Rep. 2017;15(3):142–52.CrossRef
98.
Mcfarlane J, Knight T, Sinha A, Cole T, Kiely N, Freeman R. Exostoses, enchondromatosis and metachondromatosis; diagnosis and management. Acta Orthop Belg. 2016;82(1).
99.
Burgetova A, Matejovsky Z, Zikan M, Slama J, Dundr P, Skapa P, et al. The association of enchondromatosis with malignant transformed chondrosarcoma and ovarian juvenile granulosa cell tumor (Ollier disease). Taiwan J Obstet Gyne. 2017;56(2):253–7.CrossRef
100.
Fei L, Ngoh C, Porter DE. Chondrosarcoma transformation in hereditary multiple exostoses: A systematic review and clinical and cost-effectiveness of a proposed screening model. J Bone Oncol. 2018;13:114–22.PubMedPubMedCentralCrossRef
101.
Prokopchuk O, Andres S, Becker K, Holzapfel K, Hartmann D, Friess H. Maffucci syndrome and neoplasms: a case report and review of the literature. BMC Res Notes. 2016;9:126.PubMedPubMedCentralCrossRef
102.
Riou S, Morelon E, Guibaud L, Chotel F, Dijoud F, Marec-Berard P. Efficacy of rapamycin for refractory hemangioendotheliomas in Maffucci's syndrome. J Clin Oncol. 2012;30(23):e213–5.PubMedCrossRef
103.
Li Z, Zhao B, Zhang Y, Tu C, Zheng Y, He X, Xiao S. Failure of rapamycin in the treatment of multiple haemangiomas associated with Maffucci syndrome. Clin Exp Dermatol. 2015;40(8):951–4.PubMedCrossRef
104.
105.
Shih F, Inubushi T, Lemire I, Gossen R, Grogan D, Yamaguchi Y. Efficacy of palovarotene on prevention of osteochondroma formation in the Fsp1-Ext1 conditional knockout mouse model of Multiple Osteochondromas (MO). Poster presentation at the 13th meeting of ISDS, 2017. 2017. Available from: https://​clementiapharma.​com/​our-pipeline/​#palovarotene-mo. [cited December 4 2018].
106.
107.
108.
109.
Herper, M. Spark Therapeutics Sets Price Of Blindness-Treating Gene Therapy At $850,000. Forbes. 2018. [cited January 4 2019].
110.
111.
Personal Reference. Mooney P. Drug Development for Rare Disease [oral presentation]. Glaxosmith Kline, National Rare Disease Symposium, University of Birmingham. May17 2018.
Metadata
Title
The evolving therapeutic landscape of genetic skeletal disorders
Authors
Ataf Hussain Sabir
Trevor Cole
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2019
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-019-1222-2

Other articles of this Issue 1/2019

Orphanet Journal of Rare Diseases 1/2019 Go to the issue

Research

Comparison of structural progression between ciliopathy and non-ciliopathy associated with autosomal recessive retinitis pigmentosa

Research

Cardiac and autonomic function in patients with Wilson’s disease

Research

New simple and quick method to analyze serum variant transthyretins: direct MALDI method for the screening of hereditary transthyretin amyloidosis

Research

Clinical burden of illness in patients with phenylketonuria (PKU) and associated comorbidities - a retrospective study of German health insurance claims data

Review

Epidemiological and clinical characteristics of symptomatic hereditary transthyretin amyloid polyneuropathy: a global case series

Research

Demography of vascular Behcet’s disease with different gender and age: an investigation with 166 Chinese patients