Four hundred fifty-six different conditions were included and placed in 40 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 316 (2006 revision: 215) were associated with one or more of 226 (2006 revision: 140) different genes. The results are presented in . Within a group, disorders with known molecular basis have been listed preceding those with lesser degree of evidence; however, variants of the same disorder have been kept together.
The organization of groups has been further changed in comparison to the 2006 version. Two new groups based on a common affected molecule or biochemical pathway have been created (TRPV4 group and Aggrecan group). The TRPV4 group includes disorders that are relatively common and that constitute a new prototypic spectrum ranging from mild to lethal. Aggrecan is one of the important structural molecules in cartilage and it would not be surprising if more disorders would find their way into this group in the future. Thus, groups 1–8 are based on a common underlying gene or pathway.
Groups 9–17 are based on the localization of radiographic changes to specific bone structures (vertebrae, epiphyses, metaphyses, diaphysis, or combination thereof) or of the involved segment (rhizo, meso, or acro). Groups 18–20 are defined by macroscopic criteria in combination with clinical features (bent bones, slender bones, presence of multiple dislocations). Groups 21–25 and 28 take into account features of mineralization (increased or reduced bone density, impaired mineralization, stippling, osteolysis). Group 27 encompasses the large group of lysosomal disorders with skeletal involvement. Group 29 comprises disorders with so-called abnormal (previously “anarchic”) development of skeletal components such as exostoses, ecnhondromas, and ectopic calcification. It is particularly heterogeneous and may need to be revised in the future with the help of newer molecular data.
Group 23, comprising the osteopetrosis (OP) variants and related disorders, has been expanded following the identification of distinct genetic defects in various variants of osteopetrosis. The diversity of molecular mechanisms involved and the presence of clinical, biochemical and/or histologic features that distinguish between the various OP forms justify the subdivision of the “OP phenotype” in the many subtypes.
Group 25 (Osteogenesis Imperfecta and decreased bone density group) has had special attention. The Sillence classification, published 30 years ago, provided a first systematic clinical classification and made correlations to the inheritance pattern of individual clinical types [Sillence and Rimoin, 1978
; Sillence et al., 1979a
]. Today, a surprising genetic complexity of the molecular bases of OI has been revealed, and at the same time the extensive phenotypic variation arising from single loci has been documented clearly. It seemed therefore untenable to try and maintain tight correlations between “Sillence types” and their molecular basis. It was agreed upon to retain the Sillence classification as the prototypic and universally accepted way to classify the degree of severity in OI; and to free the Sillence classification from any direct molecular reference. Thus, the many genes that may cause osteogenesis imperfecta have been listed separately. The proliferation of “OI types” to reflect each gene separately, advocated by some scholars, is more confusing than helpful in clinical practice.
Group 26 has seen the identification of several novel molecular mechanisms leading to hypophosphatemic rickets.
In Group 29 (Disorganized Development of Skeletal Components), neurofibromatosis type 1 has been included following the points made by Stevenson and others that although the main clinical features of NF1 are neurologic and cutaneous, the skeletal features are frequent, diagnostically helpful and clinically relevant [Stevenson et al., 2007
Groups 30 (Overgrowth syndromes with significant skeletal involvement) and Group 31 (Genetic inflammatory/rheumatoid-like osteoarthropathies) have been newly added. Group 30 comprises disorders that present as overgrowth syndromes and have a significant skeletal component that is part of the diagnostic criteria for a specific condition. One condition has been tentatively included because of its conspicuous skeletal features [Nishimura et al., 2004
; Schmidt et al., 2007
]; however this condition remains incompletely delineated. Group 31 includes disorders with features of inflammation and skeletal involvement. The creation of these two groups has been suggested by the frequent diagnostic overlap between these disorders and primary skeletal disorders as well as by the identification of the genetic basis of such disorders in recent years, allowing for a more precise delineation of the phenotypes.
Finally, groups 32–40 are dedicated to the dysostoses and follow again anatomical criteria (cranium, face, axial skeleton, extremities) with additional criteria reflecting principles of embryonic development such as limb reduction or hypoplasia (proximal-distal growth) versus terminal differentiation and patterning of the digits or joint formation. These groups have seen a marked increase in conditions with identified molecular bases and there are indications of a much larger heterogeneity yet.
A single group, the Brachyolmias (formerly group 13), has been deleted. Following the inclusion of dominant brachyolmia in the TRPV4 group, the few remaining short-trunk disorders have been incorporated in the SED group.