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We report on a family in which a brother and sister have pseudoachondroplasia and normal parents. The brother married a normal woman, and they have 2 daughters; one of them has typical changes of pseudoachondroplasia, the other is normal. The most likely explanation in this family is gonadal (germinal cell) mosaicism in one of the grandparents. Other reports of possible autosomal recessive pseudoachondroplasia are reviewed. It is likely that gonadal mosaicism is responsible for a small percentage of cases with what appears to be a new mutation for pseudoachondroplasia.

• Analysis of retrospective growth data from 72 patients with diastrophic dysplasia, 62 patients with spondyloepiphyseal dysplasia congenita and 61 patients with pseudoachondroplasia permitted the establishment of preliminary reference growth standards for height for each disorder. In addition, a comparison of mean height curves for these three disorders and achondroplasia revealed dissimilarities in growth patterns. (Am J Dis Child1982;136:316-319)

Seventy-seven persons with a variety of heritable chondrodysplasias were screened for gross rearrangements of the structural gene encoding the major cartilage collagen, collagen II. None was found. Segregation of the locus (COL2A1) was studied in 19 pedigrees using three restriction site dimorphisms (shown by PvuII, HindIII, and BamHI) and a length polymorphism as linkage markers. Discordant segregation between COL2A1 and the mutant locus was seen in pedigrees with multiple epiphyseal dysplasia, autosomal recessive spondyloepiphyseal dysplasia tarda, hypochondroplasia, pseudoachondroplasia, diaphyseal aclasis, and trichorhinophalangeal syndrome. One pedigree with diastrophic dysplasia was weakly concordant. Autosomal dominant spondyloepiphyseal dysplasia tarda and metaphyseal chondrodysplasia (type Schmid) were not informative. We conclude that mutations of the collagen II gene are not a common feature of the heritable chondrodysplasias. Since the chondrocyte binding protein, chondrocalcin, is also encoded at COL2A1 our conclusions apply equally to this gene.

We performed histochemical, immunohistochemical, electron-microscopic, and microchemical studies on cartilage growth plates from sixty-eight patients with nineteen different forms of human osteochondrodysplasia. Cartilage biopsies were obtained during orthopaedic procedures. Postmortem specimens were obtained within a short time after death. The combined morphological and biochemical studies revealed specific abnormalities suggestive of a particular biochemical defect in several chondrodysplasias. In pseudoachondroplasia, non-collagenous protein accumulated in the rough endoplasmic reticulum of chondrocytes and a proteoglycan species that normally is present in the extracellular matrix was not detected by gel electrophoresis. The accumulated material was stained with antibodies against the core protein of proteoglycan. This strongly suggested that in this syndrome an abnormal core protein of a proteoglycan species is not properly transferred to the Golgi system. In Kniest syndrome, intracytoplasmic accumulation of metachromatic material, dilatation of rough endoplasmic reticulum, and an abnormal gel-electrophoretic pattern of cartilage proteoglycans suggested an abnormality of cartilage proteoglycan metabolism. Abnormalities that probably are related to degradative lysosomal processes of proteoglycans in chondrocytes were found in spondylometaphyseal dysplasia of the Kozlowski type. An abnormal organization of type-II collagen was found in fibrochondrogenesis. In diastrophic dysplasia, an abnormal organization of collagen was found in areas of interterritorial matrix and around many degenerated cells, but also in the lacunae of cells without ultrastructural signs of degeneration. The segment-long-spacing form of collagen prepared from cartilage of three patients with diastrophic dysplasia showed an abnormal cross-striation pattern in a portion between bands 42 and 45, corresponding to the position of the alpha 1(II) cyanogen-bromide-derived 10,5 peptide. This suggested that in this syndrome there is a structural alteration of the type-II collagen molecule. There was an accumulation of intracellular lipid in pyknodysostosis and in hypochondrogenesis, and of glycoproteins in several atypical cases of spondyloepiphyseal dysplasia. In a pair of twins with an atypical form of spondyloepiphyseal dysplasia, the presence of many multinucleated chondrocytes suggested a primary impairment of cell division. Clinical Relevance: A knowledge of the pathogenic mechanisms in osteochondrodysplasias might improve the classification; aid in diagnosis, prognosis, and genetic counseling; and contribute to the understanding of normal endochondral growth.(ABSTRACT TRUNCATED AT 400 WORDS)

This survey reviews the diagnosis (predominantly radiological) of 32 cases of pseudoachondroplasia from 26 kindreds and illustrates the natural history and varying appearance of the disordered bone growth from infancy to adult life. In addition, an attempt has been made to detect phenotypic differences between autosomal dominant and recessive types (excluding isolated cases), analysing 10 kindreds of dominant inheritance (three in the current survey, seven from published reports) and six of recessive inheritance (three in the current survey, three from published reports). There appears to be no clinical or radiographical feature which clearly distinguishes them, but, using height as a criterion of severity, among those with autosomal recessive inheritance there was a disproportionate number of the most severely affected cases and there also appears to be very little intrafamilial variation. It is possible that pseudoachondroplasia can be subdivided into autosomal dominant mild and severe and autosomal recessive mild and severe, but full delineation must await elucidation of the basic defect at biochemical and molecular levels.

A 5-year-old boy was admitted to the hospital with failure to thrive since he was 2 years old, with weakness in his legs and a waddling gait. He has normal mental development. His parents are normal phenotypically and are unrelated. In analysing his pedigree only a grandfather is described to have waddling gait. He has a normal craniofacial appearance but a disproportionate body with normal trunk and short extremities with height below the 3rd percentile. The diagnosis of pseudoachondroplasia was made on clinical, radiological and laboratory findings. He also had immune deficiency characterised by low T-lymphocyte populations and a low level of serum immunoglobulin A.

We studied the clinical and radiological developments in a pseudoachondroplasia patient over a period of 30 years.

Pseudoachondroplasia (PSACH) is an autosomal dominant disorder characterized by disproportionate short stature and precocious osteoarthritis. Radiographic manifestations include epiphyseal, metaphyseal and vertebral abnormalities. Mutations in the cartilage oligomeric matrix protein (COMP) have been identified to cause PSACH. Most of them affect one of the eight calcium-binding domains of COMP. We describe a clinically and radiologically typical PSACH 4-year-old girl and her 31-year-old father. A novel mutation, 1345-1347CCC deletion in exon 13, of COMP was identified in both patients. The deletion would be expected to result in the loss of the conserved proline at codon 449 from the sixth calcium-binding domain. This result further supports that COMP is the only gene, discovered to date, responsible for PSACH across different populations and that the calcium-binding domains are important to the function of the normal COMP.

Pseudoachondroplasia (PSACH) and autosomal dominant multiple epiphyseal dysplasia (MED) are chondrodysplasias resulting in short-limbed dwarfism, joint pain and stiffness and early onset osteoarthritis. All PSACH, and the largest proportion of MED, result from mutations in cartilage oligomeric matrix protein (COMP). The first mutations in COMP were identified in 1995 in patients with both PSACH and MED and subsequently there has been over 30 publications describing COMP mutations in at least 250 PSACH–MED patients. However, despite these discoveries, a methodical analysis of the relationship between COMP mutations and phenotypes has not been undertaken. In particular, there has, to date, been little correlation between the type and location of a COMP mutation and the resulting phenotype of PSACH or MED. To determine if genotype to phenotype correlations could be derived for COMP, we collated 300 COMP mutations, including 25 recently identified novel mutations. The results of this analysis demonstrate that mutations in specific residues and/or regions of the type III repeats of COMP are significantly associated with either PSACH or MED. This newly derived genotype to phenotype correlation may aid in determining the prognosis of PSACH and MED, including the prediction of disease severity, and in the long term guide genetic counselling and contribute to the clinical management of patients with these diseases.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are skeletal disorders resulting from mutations in COMP, matrilin-3 or collagen IX and are characterised by short-limbed dwarfism and premature osteoarthritis. Interestingly, recent reports suggest patients can also manifest with muscle weakness. Here we present a detailed analysis of two mouse models of the PSACH/MED disease spectrum; ΔD469 T3-COMP (PSACH) and V194D matrilin-3 (MED). In grip test experiments T3-COMP mice were weaker than wild-type littermates, whereas V194D mice behaved as controls, confirming that short-limbed dwarfism alone does not contribute to PSACH/MED-related muscle weakness. Muscles from T3-COMP mice showed an increase in centronuclear fibers at the myotendinous junction. T3-COMP tendons became more lax in cyclic testing and showed thicker collagen fibers when compared with wild-type tissue; matrilin-3 mutant tissues were indistinguishable from controls. This comprehensive study of the myopathy associated with PSACH/MED mutations enables a better understanding of the disease progression, confirms that it is genotype specific and that the limb weakness originates from muscle and tendon pathology rather than short-limbed dwarfism itself. Since some patients are primarily diagnosed with neuromuscular symptoms, this study will facilitate better awareness of the differential diagnoses that might be associated with the PSACH/MED spectrum and subsequent care of PSACH/MED patients.

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia caused by mutations in cartilage oligomeric matrix protein (COMP) and characterised by short limbed dwarfism and early onset osteoarthritis. Mouse models of PSACH show variable retention of mutant COMP in the ER of chondrocytes, however, in each case a different stress pathway is activated and the underlying disease mechanisms remain largely unknown. T585M COMP mutant mice are a model of moderate PSACH and demonstrate a mild ER stress response. Although mutant COMP is not retained in significant quantities within the ER of chondrocytes, both BiP and the pro-apoptotic ER stress-related transcription factor CHOP are mildly elevated, whilst bcl-2 levels are decreased, resulting in increased and spatially dysregulated chondrocyte apoptosis. To determine whether the abnormal chondrocyte apoptosis observed in the growth plate of mutant mice is CHOP-mediated, we bred T585M COMP mutant mice with CHOP-null mice to homozygosity, and analysed the resulting phenotype. Although abnormal apoptosis was alleviated in the resting zone following CHOP deletion, the mutant growth plates were generally more disorganised. Furthermore, the bone lengths of COMP mutant CHOP null mice were significantly shorter at 9 weeks of age when compared to the COMP mutant mice, including a significant difference in the skull length. Overall, these data demonstrate that CHOP-mediated apoptosis is an early event in the pathobiology of PSACH and suggest that the lack of CHOP, in conjunction with a COMP mutation, may lead to aggravation of the skeletal phenotype via a potentially synergistic effect on endochondral ossification.

Mutations in genes encoding cartilage oligomeric matrix protein and matrilin-3 cause a spectrum of chondrodysplasias called multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH). The majority of these diseases feature classical endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) as a result of misfolding of the mutant protein. However, the importance and the pathological contribution of ER stress in the disease pathogenesis are unknown. The aim of this study was to investigate the generic role of ER stress and the UPR in the pathogenesis of these diseases. A transgenic mouse line (ColIITgcog) was generated using the collagen II promoter to drive expression of an ER stress-inducing protein (Tgcog) in chondrocytes. The skeletal and histological phenotypes of these ColIITgcog mice were characterised. The expression and intracellular retention of Tgcog induced ER stress and activated the UPR as characterised by increased BiP expression, phosphorylation of eIF2α and spliced Xbp1. ColIITgcog mice exhibited decreased long bone growth and decreased chondrocyte proliferation rate. However, there was no disruption of chondrocyte morphology or growth plate architecture and perturbations in apoptosis were not apparent. Our data demonstrate that the targeted induction of ER stress in chondrocytes was sufficient to reduce the rate of bone growth, a key clinical feature associated with MED and PSACH, in the absence of any growth plate dysplasia. This study establishes that classical ER stress is a pathogenic factor that contributes to the disease mechanism of MED and PSACH. However, not all the pathological features of MED and PSACH were recapitulated, suggesting that a combination of intra- and extra-cellular factors are likely to be responsible for the disease pathology as a whole.

Editor—Pseudoachondroplasia (PSACH) is an autosomal dominant chondrodysplasia. In the majority of clinically defined cases, mutations have been identified in the gene encoding cartilage oligomeric matrix protein ( COMP ).1 Mutations in the COMP gene have also been identified in some forms of multiple epiphyseal dysplasia (MED), a related skeletal dysplasia.1 All of the mutations associated with PSACH and MED have been found in exons encoding the type III repeat region or C-terminal domain of COMP . Clinically, PSACH is characterised by short limbed dwarfism, which first becomes apparent in infancy, short fingers, ligamentous laxity, scoliosis, and early onset osteoarthritis (OA).2Radiographic features include small irregular epiphyses with delayed ossification, flared metaphyses, anterior beaking of the vertebral bodies, and delayed maturation of the triradiate cartilage and acetabulum.3 We report three patients who had previously been given erroneous diagnoses, in whom mutations in exon 13 of the COMP gene have been identified. This emphasises the utility of molecular diagnosis, particularly in adult patients where radiological diagnosis can be difficult. All three affected subjects were born to unaffected parents. Each was of normal intelligence and normal facial appearance. Case 1 presented at 5 years because of pain in both hips. Numerous diagnoses, including spondyloepiphyseal dysplasia congenita with coxa vara and Morquio's syndrome, were considered following x ray examination. Extensive surgery over the following years included a left femoral osteotomy and bilateral Girdlestones operations to treat her osteoarthritis. She has had two unaffected children. Examination at 65 years showed her height at 136 cm (

Mesomelic shortening of the extremities lends itself as a useful clinical and/or radiologic sign to characterize a group of hereditary bone dysplasias. Table 1 and Figure 4 are presented to facilitate the comparison between the many different types of mesomelic dwarfism. Differential diagnosis between these types is not difficult because of the specific bone changes and extraskeletal malformations present. As in many hereditary syndromes, however, there may be wide clinical variability within a single entity, and meticulous clinical and radiologic examination must be done to arrive at the correct diagnosis. Certain other forms of chondrodystrophies, such as achondroplasia, hypochondroplasia, pseudoachondroplasia and distrophic dwarfism, can be easily differentiated from the mesomelic dysplasias by their clinical features and skeletal radiographs. Nothing is known about the pathogenesis of the various forms of mesomelic dysplasias. There is no available specific treatment, although corrective surgery has benefited selected patients. The correct diagnosis is, however, important both for prognostication and accurate genetic counseling.

PSEUDOACHONDROPLASIA is a term used by Lamy and Maroteaux in 1960 1 and later by Rubin 2 to describe a category of bone dysplasia which combines features of both achondroplasia and true Morquio's disease. It resembles achondroplasia in that there is marked shortening of the extremities. It differs from true achondroplasia, however, in that typical cranial and facial features are absent, discovery may be delayed until the second year of life, and abnormalities of the vertebrae and pelvis characteristic of Morquio's disease are present. Since these features can be explained by a primary defect in the articular cartilage of the epiphysis and vertebrae with secondary involvement of the epiphyseal plate, it is classified as a type of spondylo-epiphyseal dysplasia. 3 Recent investigations of cases of spondylo-epiphyseal dysplasia of Morquio's type have shown corneal opacities, dental abnormalities, and the presence of keratosulfate in the urine. 4-7 Similar investigations of pseudoachondroplasia have