Short report A novel homozygous 5 bp deletion in FKBP10 causes clinically Bruck syndrome in an Indonesian patient E.D. Setijowati a, b , F.S. van Dijk a , J.M. Cobben c , R.R. van Rijn d , E.A. Sistermans a , S.M.H. Faradz b , S. Kawiyana d , G. Pals a, * a Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands b Center of Biomolecular Research, Faculty of Medicine, Diponegoro University, Indonesia c Department of Pediatric Genetics, Emma Children’s Hospital/AMC, Amsterdam, the Netherlands d Department of Orthopaedics and Traumatology, Sanglah Hospital, Denpasar, Indonesia article info Article history: Received 1 July 2011 Accepted 6 October 2011 Available online 24 October 2011 Keywords: Bruck syndrome FKBP10 Collagen type I abstract We report an Indonesian patient with bone fragility and congenital joint contractures. The initial diag- nosis was Osteogenesis Imperfecta type III (OI type III) based on clinical and radiological findings. Because of (i) absence of COL1A1/2 mutations, (ii) a consanguineous pedigree with a similarly affected sibling and (iii) the existence of congenital joint contractures with absence of recessive variants in PLOD2, mutation analysis was performed of the FKBP10 gene, recently associated with Bruck syndrome and/or recessive OI. A novel homozygous deletion in FKBP10 was discovered. Our report of the first Indonesian patient with clinically Bruck syndrome, confirms the role of causative recessive FKBP10 mutations in this syndrome. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Bruck syndrome (BS) (OMIM %259450 and #609220) is char- acterized clinically by congenital contractures with pterygia, onset of fractures in infancy or early childhood, postnatal short stature, severe limb deformity, and progressive scoliosis [1] and bio- chemically by aberrant collagen type I cross-linking in bone. BS is named after the first physician (Alfred Bruck) who described a male patient with Osteogenesis Imperfecta (OI) and arthrogryposis in 1897 [2]. Later it appeared that the condition described by Bruck was in fact different from BS since the contractures in the initial patient were not congenital. In 2003 recessive variants in procollagen-lysine, 2-oxoglutarate 5- dioxygenase II (PLOD2) linked to 3q23e24, encoding lysyl hydrox- ylase 2 (LH2) were identified as the cause of BS in two families [3]. However, in a single consanguineous family with BS [4] linkage to 17p12 [5] had been found and no causative variants in PLOD2 were detected [3] indicating genetic heterogeneity in Bruck syndrome. Therefore, Bruck syndrome with linkage to 17p12 was classified as Bruck syndrome type 1 (BS 1) and Bruck syndrome caused by recessive variants in PLOD2 was classified as Bruck syndrome type 2 (BS 2) [3]. BS 1 and BS 2 are phenotypically and biochemically indistinguishable with their hallmarks congenital contractures and aberrant cross-linking of bone collagen type I. Formation of inter- and intramolecular cross-links is the final step in collagen biosyn- thesis necessary to generate fibrils with tensile properties. Cross- links are formed by two routes namely (i) the allysine route (pre- dominating in the skin), characterized by the conversion of a telo- peptide lysine to allysine and (ii) the hydroxyallysine route (predominating in the stiff connective tissues), characterized by conversion of telopeptide hydroxylysine to hydroxyallysine. The pyridinoline cross-links lysylpiridinolines (LP) and hydrox- ylysylpyridinolines (HP) are derived only via the hydroxyallysine route and can be regarded as a measure of telopeptide lysyl hydroxylation. In Bruck syndrome (1 and 2), decreased hydrox- yallysine route derived cross-links (HP and LP) and increased ally- sine route derived cross-links are observed only in collagen type I from bone [6] (Fig. 1). The (HP þ LP)/Hyp ratio of urinary collagen degradation products has been shown to be a good diagnostic marker for BS patients with healthy children showing an average ratio of 2.80 (range: 1.83e4.31) whereas in BS patients, it is below 1 [7]. Interestingly, causative variants in FKBP10 (gene map locus 17q21.2) were first described in OI most closely resembling OI type III [8], but are recently reported also to cause BS [9] based on the * Corresponding author. Centre for Connective Tissue Research, Department of Clinical Genetics, VU University Medical Center, De Boelelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands. Tel.: þ31 20 4448346. E-mail address: g.pals@vumc.nl (G. Pals). Contents lists available at SciVerse ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg 1769-7212/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2011.10.002 European Journal of Medical Genetics 55 (2012) 17e21