Classification of Osteogenesis Imperfecta revisited F.S. Van Dijk a, * , G. Pals a , R.R. Van Rijn b , P.G.J. Nikkels c , J.M. Cobben d a Department of Medical Genetics, VUMC Hospital, Amsterdam, The Netherlands b Department of Paediatric Radiology, Emma Children Hospital AMC, Amsterdam, The Netherlands c Department of Pathology, University Medical Centre Utrecht, The Netherlands d Department of Paediatric Genetics, Emma Children Hospital AMC, Amsterdam, The Netherlands article info Article history: Received 15 June 2009 Accepted 22 October 2009 Available online 28 October 2009 Keywords: Osteogenesis Imperfecta Collagen CRTAP LEPRE1 Classification abstract In 1979 Sillence proposed a classification of Osteogenesis Imperfecta (OI) in OI types I, II, III and IV. In 2004 and 2007 this classification was expanded with OI types VeVIII because of distinct clinical features and/or different causative gene mutations. We propose a revised classification of OI with exclusion of OI type VII and VIII since these types have been added because of genetic criteria (autosomal recessive inheritance) while the clinical and radiological features are indistinguishable from OI types IIeIV. Instead, we propose continued use of the Sillence criteria I, II-A, II-B, II-C, III and IV for clinical and radiological classification of OI with additional mentioning of the causative mutated gene to this classification. OI type V and VI are still part of this revised classification, because of the distinguishing clinical/radiological and/or histological features observed in these types. Ó 2009 Elsevier Masson SAS. All rights reserved. 1. Introduction The definition and classification of Osteogenesis Imperfecta (OI) have been the subject of ongoing debate in the literature. The most commonly used definition of OI is “a hereditary disorder with osteopenia and increased bone fractures.” Secondary features such as short stature, blue sclerae, dentinogenesis imperfecta and hearing loss may also exist in affected individuals. The prevalence of OI is approximately 6e7/100,000 [26]. The prevalence of lethal OI in the Netherlands was reported to be 5/100,000 [7]. Because of the extreme clinical variability in OI various authors have attempted to classify patients with this disease [3]. In 1979 a classification was introduced by the Australian physician David Sillence (the “Sillence classification”) that is still in use today [24]. 2. Classification of Osteogenesis Imperfecta 2.1. Original Sillence classification The original Sillence classification of OI in four types (OI type IeIV), was based on (i) clinical findings with a radiological subclas- sification of OI type II in A, B, C and (ii) mode of inheritance, thus assuming heterogeneity in OI [23,24]. However, after the discovery of heterozygous collagen type I gene mutations in all OI types [5,17], the Sillence criteria were used mainly to describe the severity continuum and differences in clinical expression of OI. Later it appeared that that not all patients with lethal or severe OI had a collagen type I mutation [27] which led eventually to expansion of the Sillence classification. 2.2. Expanded Sillence classification In 2004 The Lancet published a Seminar on Osteogenesis Imperfecta (OI), containing among others an “expanded Sillence classification” [22]. This classification recognizes seven types of OI, type IeVII. In 2007, OI type VIII was proposed as an additional type [6] (see Fig. 1). The addition of OI type V was based on distinct clinical/radio- logical and histological features in patients originally diagnosed as having OI type IV in the absence of COL1A1/2 mutations [11]. At the moment 36 cases with OI type V have been reported in the litera- ture and autosomal dominant inheritance is presumed [10,15,29]. OI type VI was added to the classification because of distinct histological features in the absence of COL1A1/2 mutations in patients originally diagnosed with OI type IV, but without abnor- malities of collagen type I on electrophoresis [12]. 11 patients with OI type VI have been reported in the literature [14]. Autosomal reces- sive heritance is presumed because of two consanguineous families with recurrence of OI in one of these families [12]. The initial reason to distinguish OI type VII was autosomal recessive inheritance of moderate deforming OI in 2 generations of 3 interrelated families [13,28]. In 2006 partial loss of function CRTAP mutations encoding cartilage-associated protein (CRTAP) were * Corresponding authors. Tel.: þ31 20 5669111; fax: þ31 20 6917735. E-mail address: j.m.cobben@amc.uva.nl (J.M. Cobben). Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg 1769-7212/$ e see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2009.10.007 European Journal of Medical Genetics 53 (2010) 1e5