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Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to "private" found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.

Kniest dysplasia is a heritable chondrodysplasia that severely affects skeletal growth. Recent evidence suggests that the etiology is based on mutations in COL2A1, the gene for collagen type II. We report the detection and partial characterization of an identical defect in type II collagen in two unrelated patients with Kniest dysplasia. Analysis of cyanogen bromide (CB)-digested cartilage samples from both probands by SDS-PAGE revealed an abnormal band for peptide alpha 1(II)CB12. The peptide was purified and digested with endoproteinase Asp-N. Fragments unique to the Kniest tissues were identified by reverse-phase high-pressure liquid chromatography and by sequence analysis. The results established a deletion of amino acids 102-108 of the alpha 1(II) triple-helical domain, which disrupted the (gly-X-Y)n repeat needed for helix formation. This was confirmed by sequence analysis of DNA amplified from both probands, revealing the molecular basis to be a single nucleotide mutation at a CpG dinucleotide (GCG-->GTG) in the codon for alanine 102. The mutation created a new splice donor site, which would account for the absence of the last seven amino acids from the 3' end of exon 12 in alpha 1(II)CB12. Light and electron micrographs of the probands' cartilage showed the perilacunar foamy matrix ("Swiss cheese") characteristic of Kniest dysplasia and chondrocytes containing dilated rough endoplasmic reticulum, which earlier studies had shown were filled with type II procollagen. These two cases strengthen the concept that Kniest dysplasia is based on mutations of COL2A1 and belongs within the broad spectrum of chondrodysplasias caused by type II collagenopathies.

Knowledge of the structure of cartilage vascular canals is important for a more thorough understanding of the development of cartilage and the growth plate in the human neonate and growing child. We have studied the costochondral junction of 6 normal neonates and 12 normal children (age 4 months-16 years) and utilised quantitative histomorphometry to define the percentage tissue area occupied by canals and the number of canals/mm2. Both percentage canal area and the number of canals/mm2 were significantly greater in newborn vs. older children (percentage area: 0.42 +/- 0.15 (mean +/- S.E.M.) vs. 0.08 +/- 0.04, P = 0.003; number/mm2: 0.2 +/- 0.09 vs. 0.04 +/- 0.02, P = 0.02). Eight newborn patients with achondrogenesis II-hypochondrogenesis were also studied. Both percentage canal area and number were significantly elevated above normal (percentage area: 5.22 +/- 1.01, P less than 0.001; number/mm2: 1.45 +/- 0.26, P less than 0.001). Results presented here demonstrate that: (i) quantitative differences in vascular canal area and numbers occur during development; (ii) 10-fold increases in vascular canal area and number are present in achondrogenesis II-hypochondrogenesis. Data from normal subjects will provide normative values against which vascular abnormalities in other skeletal dysplasias can be compared.