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Purpose: Pseudoachondroplasia is a rare skeletal dysplasia caused by a mutation in the COMP gene. Infants with pseudoachondroplasia present with rhizomelic dwarfism. Pseudoachondroplasia can resemble achondroplasia, which also presents with a phenotype of rhizomelic dwarfism. The differentiation between these two conditions is important because while both can present with cervicomedullary compromise, the underlying pathophysiology and its management is entirely different. Results: We present a case of a 13-year-old female patient with pseudoachondroplasia who presented with cervical myelopathy and imaging evidence of atlantoaxial instability with an os odontoideum and a retro-odontoid cystic soft tissue mass, causing C1-2 canal stenosis and cervical cord compression. She underwent C1 decompression and C1-2 posterior cervical fixation. Post-operative imaging demonstrated improved alignment of the os odontoideum, and complete resolution of the retro-odontoid soft tissue mass. We contend that retro-odontoid masses are a marker of local C1-2 joint instability and restoration of atlanto-axial alignment with posterior fixation and fusion alone is likely to be sufficient for regression of the mass and associated compression. Conclusion: Pseudoachondroplasia can present with atlantoaxial instability and cervicomedullary compromise and with retro-odontoid masses. The differentiation from achondroplasia is crucially important for surgical decision-making and management should include surgical decompression and fixation. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH) is a rare, dominant genetic disorder affecting bone and cartilage development, characterized by short-limb short stature, brachydactyly, loose joints, joint stiffness, and pain. The disorder is caused by mutations in the COMP gene, which encodes a protein that plays a role in the formation of collagen fibers. In this study, we present the clinical and genetic characteristics of PSACH in two Chinese families. Whole-exome sequencing (WES) analysis revealed two novel missense variants in the COMP gene: NM_000095.3: c.1319G>T (p.G440V, maternal) and NM_000095.3: c.1304A>T (p.D435V, paternal-mosaic). Strikingly, both the G440V and D435V mutations were located in the same T3 repeat motif and exhibited the potential to form hydrogen bonds with each other. Upon further analysis using Missense3D and PyMOL, we ascertained that thesemutations showed the propensity to disrupt the protein structure of COMP, thus hampering its functioning. Our findings expand the existing knowledge of the genetic etiology underlying PSACH. The identification of new variants in theCOMP gene can broaden the range of mutations linked with the condition. This information can contribute to the diagnosis and genetic counseling of patients with PSACH. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 and pseudoachondroplasia are both rare autosomal dominant disorders, caused by pathogenic mutations in NF1 and COMP genes, respectively. Both neurofibromin 1 and cartilage oligomeric matrix protein (COMP) play a role in the development of the skeleton. Carrying both germline mutations has not been previously reported; however, it can affect the developing phenotype. Case presentation: The index patient, an 8-year-old female presented with several skeletal and dermatologic anomalies resembling the coexistence of multiple syndromes. Her mother had dermatologic symptoms characteristic for neurofibromatosis type 1, and her father presented with distinct skeletal anomalies. NGS-based analysis revealed a heterozygous pathogenic mutation in genes NF1 and COMP in the index patient. A previously unreported heterozygous variant was detected for the NF1 gene. The sequencing of the COMP gene revealed a previously reported, pathogenic heterozygous variant that is responsible for the development of the pseudoachondroplasia phenotype. Conclusions: Here, we present the case of a young female carrying pathogenic NF1 and COMP mutations, diagnosed with two distinct heritable disorders, neurofibromatosis type 1 and pseudoachondroplasia. The coincidence of two monogenic autosomal dominant disorders is rare and can pose a differential diagnostic challenge. To the best of our knowledge, this is the first reported co-occurrence of these syndromes. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 (MED1) are two rare skeletal disorders caused by cartilage oligomeric matrix protein (COMP) variants. This study aims to analyze the genotype and phenotype of patients with COMP variants. Clinical information for 14 probands was collected; DNA was extracted from blood for COMP variant detection. Clinical manifestations and radiology scoring systems were established to evaluate the severity of each patient's condition. Serum COMP levels in PSACH patients and healthy subjects were measured. Thirty-nine patients were included, along with 12 PSACH probands and two MED1 probands. Disproportionate short stature, waddling gait, early-onset osteoarthritis and skeletal deformities were the most common features. The height Z-score of PSACH patients correlated negatively with age at evaluation (r = − 0.603, p = 0.01) and the clinical manifestation score (r = − 0.556, p = 0.039). Over 50% of the PSACH patients were overweight/obese. The median serum COMP level in PSACH patients was 16.75 ng/ml, which was significantly lower than that in healthy controls (98.53 ng/ml; p < 0.001). The condition of MED1 patients was better than that of PSACH patients. Four novel variants of COMP were detected: c.874T>C, c.1123_1134del, c.1531G>A, and c.1576G>T. Height Z-scores and serum COMP levels were significantly lower in patients carrying mutations located in calmodulin-like domains 6, 7, and 8. As the two phenotypes overlap to different degrees, PSACH and MED1 are suggested to combine to produce "spondyloepiphyseal dysplasia, COMP type". Clinical manifestations and radiology scoring systems, serum COMP levels and genotype are important for evaluating patient condition severity. [ABSTRACT FROM AUTHOR]

Background: Cartilage oligomeric matrix protein (COMP) is an important extracellular matrix protein primarily functioning in the musculoskeletal tissues and especially endochondral bone growth. Mutations in COMP cause the skeletal dysplasia pseudoachondroplasia (PSACH) that is characterized by short limbs and fingers, joint laxity, and abnormalities but a striking lack of skull and facial abnormalities. Methods: This study examined both mice and humans to determine how mutant‐COMP affects face and skull growth. Results: Mutant COMP (MT‐COMP) mice were phenotypically distinct. Snout length and skull height were diminished in MT‐COMP mouse and the face more closely resembled younger controls. Three‐dimensional facial measurements of PSACH faces showed widely spaced eyes, reduced lower facial height, and decreased nasal protrusion, which correlated with a more juvenile appearing face. Neither MT‐COMP mice nor PSACH individuals show midface hypoplasia usually associated with abnormal endochondral bone growth. MT‐COMP mice do show delayed endochondral and membranous skull ossification that normalizes with age. Conclusion: Therefore, mutant‐COMP affects both endochondral and intramembranous bones of the skull resulting in a reduction of the nose and lower facial height in mice and humans, in addition to its well‐defined role in the growth plate chondrocytes. [ABSTRACT FROM AUTHOR]

Purpose In 1959, Maroteaux and Lamy initially designated pseudoachondroplasia as a distinct dysplasia different from achondroplasia the most common form of skeletal dysplasia. Pseudoachondroplasia is caused by a mutation in the collagen oligomeric matrix protein gene (COMP) gene on chromosome 19p13.1-p12 encoding the COMP. The COMP gene mutations result in rendering the articular and growth plate cartilages incapable of withstanding routine biomechanical loads with resultant deformity of the joints. The purpose of the study was to characterize the typical orthopaedic findings in pseudoachondroplasia. Methods The charts and radiographs of 141 patients with pseudoachondroplasia were analyzed. This cohort, to our knowledge, represents the largest group of patients describing the typical orthopaedic manifestations of pseudoachondroplasia. Results Patients with pseudoachondroplasia have normal craniofacial appearance with normal intelligence. Short stature is not present at birth and generally appears by two to four years of age. The condition is a form of spondyloepiphyseal dysplasia and the long bones are characterized by dysplastic changes in the epiphysis, metaphysis and vertebral bodies. Radiographically the long bones have altered the appearance and structure of the epiphyses with small irregularly formed or fragmented epiphyses or flattening. The metaphyseal regions of the long bones show flaring, widening or 'trumpeting'. The cervical (89%) and thoracic and lumbar vertebrae show either platyspondyly, ovoid, 'cod-fish' deformity or anterior 'beaking'. Kyphosis (28%), scoliosis (58%) and lumbar lordosis (100%) are commonly seen. The femoral head and acetabulum are severely dysplastic (100%). The knees show either genu valgum (22%), genu varum (56%) or 'windswept' deformity (22%). Conclusion Most commonly these distortions of the appendicular and the axial skeleton lead to premature arthritis particularly of the hips and often the knees not uncommonly in the 20- to 30-year-old age group. [ABSTRACT FROM AUTHOR]

Skeletal dysplasia is a heterogeneous group of abnormalities affecting growth and development of bone and cartilage characterized by disproportionate shortening of the limbs and/or spine. A systematic radiographic approach combined with pertinent clinical details can help guide specific genetic testing and treatment. We provide a discussion and examples of a few common and notable skeletal dysplasias to help familiarize general, pediatric, and musculoskeletal radiologists who do not commonly encounter children with these entities in their daily practices. [ABSTRACT FROM AUTHOR]

Pseudoachondroplastic dysplasia is a rare inherited disorder characterized by skeletal malformations resulting to short stature. These individuals are usually normal at birth but due to the abnormal skeletal growth or dysplasia, the skeleton becomes weakened and malformed. The skeletal deformities increase as the individual grows and gains weight. Affected individuals may have radiographic features simulating vitamin D deficiency. In addition, affected individuals may have spinal abnormalities including abnormally increased lumbar lordosis and kyphosis.This case is being presented because of its rarity and simulation of rickets in the growing young child. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH; MIM no. 177170) is an autosomal dominant osteochondrodysplasia characterized by short-limb short stature, brachydactyly and early-onset osteoarthropathy. Typically, at approximately two years of age, the rate of growth falls below the standard growth curve, causing a moderately severe form of disproportionate short-limb short stature. The current study described the clinical and radiographic observations of six Chinese patients with PSACH, and identified two de novo novel missense mutations [p.Asp326Asn (c.976G>A) and c.1585A>G (p.Thr529Ala)] in cartilage oligomeric matrix protein (COMP) in the patients. The current study expanded the mutation spectrum of the COMP gene, and contributes to the understanding of phenotype/ genotype of COMP-associated diseases. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH) is a well-described autosomal dominant short limb dwarfing condition caused by mutations in the cartilage oligomeric matrix protein gene ( COMP). The most debilitating complication of the disorder is joint pain starting in childhood, the extent and severity of which is poorly defined. The aim of this study was to fully assess the pain and identify additional clinical complications affecting those with PSACH. An online survey was distributed to individuals with PSACH. Of the 77 surveys analyzed, 83% reported chronic pain starting as early as the newborn period. Pain was most frequently reported in weight bearing joints including the knees, hips, and back, and significantly interfered with their overall quality of life. For pain relief, patients with PSACH used a wide variety of treatments. However, patients reported only a 60% resolution of pain with their current treatments. An increase in other comorbidities was not found, specifically osteoporosis was not increased. This study documents for the first time that pain is the most common presenting symptom in PSACH and is often overlooked until short stature becomes obvious. The recognition of chronic pain as one of the earliest manifestations of PSACH is important to allow for prompt diagnosis. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This historical report focuses on the first clinical description of pseudoachondroplasia and its radiographic findings. Only half a century ago, pseudoachondroplasia was recognized as a genetic disorder with a distinct but variable phenotype of short stature, normal facial features, and progressive joint problems starting in adolescence. Radiologically, the disease is particularly intriguing because the patients appear normal at birth. The patients develop the typical gait disturbances when they begin to walk. Radiographs show the characteristic anterior tongue-shaped lumbar vertebral body changes that develop after the first year of life. This account presents the most well-known group of individuals affected by pseudoachondroplasia, the Ovitz family, who narrowly escaped death in the concentration camp of Auschwitz in 1944 because of SS physician Dr. Josef Mengele's fascination with dwarfs. It was not until 1995 that the underlying genetic defect in the COMP gene was identified on chromosome 19. [ABSTRACT FROM AUTHOR]

Cartilage oligomeric matrix protein (COMP), or thrombospondin-5 (TSP-5), is a secreted glycoprotein that is important for growth plate organization and function. Mutations in COMP cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). In this study, we determined the structure of a recombinant protein that contains the last epidermal growth factor repeat, the type 3 repeats and the C-terminal domain (CTD) of COMP to 3.15-Å resolution limit by X-ray crystallography. The CTD is a βsandwich that is composed of 15 antiparallel β-strands, and the type 3 repeats are a contiguous series of calcium binding sites that associate with the CTD at multiple points. The crystal packing reveals an exposed potential metal-ion-dependent adhesion site (MIDAS) on one edge of the β-sandwich that is common to all TSPs and may serve as a binding site for collagens and other ligands. Disease-causing mutations in COMP disrupt calcium binding, disulfide bond formation, intramolecular interactions, or sites for potential ligand binding. The structure presented here and its unique molecular packing in the crystal identify potential interactive sites for glycosaminoglycans, integrins, and collagens, which are key to cartilage structure and function. [ABSTRACT FROM AUTHOR]

We present a child with irregular ossification of tubular bone epiphyses, short bones, and spine. The radiographic evolution of bones undergoing endochondral ossification was followed from the age of 1 year 9 months to 6 years. The unusual features demonstrated in this child made classification difficult: pseudoachondroplasia was excluded because no mutations of the COMP gene were found. Considering the evolution of the radiographic appearances, the most likely diagnosis would seem to be an unusual form of spondyloepiphyseal dysplasia, mimicking some aspects of multiple epiphyseal dysplasia. Endochondral ossification was diffusely altered with a mixture of epiphyseal ossification delay associated with acceleration and early fusion. This case was a unique presentation within the family, suggesting a mutation in the affected child. [ABSTRACT FROM AUTHOR]

We report on a 9-year-old-boy with the clinical and radiographic diagnosis of pseudoachondroplasia. An antero-posterior open mouth radiogram, showed an unduly long odontoid and a 3 CT scan confirmed the presence of a long, bifid odontoid. This is the first clinical report describing a dolicho-odontoid in a boy with pseudoachondroplasia. [ABSTRACT FROM AUTHOR]

Cartilage oligomeric matrix protein, also known as thrombospondin-5 (TSP-5), is an extracellular matrix protein found primarily in cartilage and musculoskeletal tissues. TSP-5 is of interest because mutations in the gene cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED/EDM1). Both PSACH and EDM1 have a characteristic chondrocyte phenotype distinguished by giant rough endoplasmic reticulum (rER) cisternae containing TSP-5 and other extracellular matrix proteins such as type IX collagen and matrilin-3. The accumulation of proteinaceous material in the rER compromises cellular function and leads to premature chondrocyte death. Both in vitro and in vivo models have been generated with varying degrees of success to study the cellular mechanisms of the disease process. Here we review and discuss in vitro and in vivo PSACH and MED model systems and describe two transgenic mouse lines expressing human mutant TSP-5 protein. These model systems have revealed several important features of the PSACH cellular pathology: unfolded protein response activation, upregulation of apoptosis and inappropriate assembly of matrix network in the rER. Some of these models are valuable reagents that may be of use in testing therapeutic interventions. (Part of a Multiauthor Review) [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH) is an autosomal-dominant osteochondrodysplasia due to mutations in the gene encoding cartilage oligomeric matrix protein (COMP). Clinical diagnosis of PSACH is based primarily on family history, physical examination, and radiographic evaluation, and is sometimes extremely difficult, particularly in adult patients. Genetic diagnosis based on DNA sequencing, on the other hand, can be expensive, time-consuming, and intensive because COMP mutations may be scattered throughout the gene. However, there is evidence that decreased plasma COMP concentration may serve as a diagnostic marker in PSACH, particularly in adult patients. Here, we report the serum and/or plasma COMP concentration-based differential diagnosis of a family with affected adult members. The mean serum and/or plasma COMP concentrations of the three affected family members alive (0.69±0.15 and/or 0.81±0.08 μg/ml, respectively) were significantly lower than those of an age-compatible control group of 21 adults (1.52±0.37 and/or 1.37±0.36 μg/ml, respectively; P<0.0001). Bidirectional fluorescent DNA sequencing-based genetic diagnosis of these patients revealed a heterozygous mutation for the nucleotide change 1532A>G in exon 14 of the COMP gene, resulting in a substitution of amino acid 511 from aspartic acid to glycine in COMP. Thus, serum and/or plasma COMP concentration may be suggested as an additional diagnostic marker to aid clinical and radiographic findings in suspected cases of PSACH.European Journal of Human Genetics (2007) 15, 1023–1028; doi:10.1038/sj.ejhg.5201882; published online 20 June 2007 [ABSTRACT FROM AUTHOR]

Skeletal dysplasia is a group of disorders of the skeleton that result from derangement of growth, development and/or differentiation of the skeleton. Nearly 300 disorders are included; most of them are monogenic diseases. Responsible genes for skeletal dysplasia have been identified in more than 150 diseases mainly through positional cloning. Identification of disease genes would improve patient care through genetic diagnosis as well as improving our understanding of the diseases and molecular mechanism of skeletal tissue formation. Studies of skeletal dysplasia would also help identify disease genes for common diseases affecting bones and joints. In this study, the author reviews recent advances and the current status of the genetic analysis of skeletal dysplasia and its impacts on research into skeletal biology. [ABSTRACT FROM AUTHOR]

This overview covers the group of disorders that presents radiographically as multiple epiphyseal dysplasia (MED). The disorders include "classic MED" (Ribbing and Fairbank types): MED that is caused by mutations in the cartilage oligomeric matrix protein (COMP), type IX collagen, and matrilin 3 genes (MATN3); and MED with multilayered patella, brachydactyly, and clubbed feet resultant from mutations in gene defect diastrophic dysplasia (DTDST). The recently identified gene/molecular abnormalities in these disorders have made more exact identification possible in many cases, although clinical testing is not always available. However, there are specific radiographic findings that allow the accurate diagnosis to be made, thus potentially guiding which molecular defect(s) should be investigated. The modes of inheritance of these distinct MED conditions are not identical. When a specific diagnosis is made, proper genetic counseling as well as prognostication, management issues and complications can be delineated to the patient and family. This review will include the mechanics of diagnostic and molecular triage for these disorders. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH), a short limb skeletal dysplasia associated with premature joint degeneration, is caused by misfolding mutations in cartilage oligomeric matrix protein (COMP). Here, we define mutant-COMP-induced stress mechanisms that occur in articular chondrocytes of MT-COMP mice, a murine model of PSACH. The accumulation of mutant-COMP in the ER occurred early in MT-COMP articular chondrocytes and stimulated inflammation (TNFα) at 4 weeks, and articular chondrocyte death increased at 8 weeks while ER stress through CHOP was elevated by 12 weeks. Importantly, blockage of autophagy (pS6), the major mechanism that clears the ER, sustained cellular stress in MT-COMP articular chondrocytes. Degeneration of MT-COMP articular cartilage was similar to that observed in PSACH and was associated with increased MMPs, a family of degradative enzymes. Moreover, chronic cellular stresses stimulated senescence. Senescence-associated secretory phenotype (SASP) may play a role in generating and propagating a pro-degradative environment in the MT-COMP murine joint. The loss of CHOP or resveratrol treatment from birth preserved joint health in MT-COMP mice. Taken together, these results indicate that ER stress/CHOP signaling and autophagy blockage are central to mutant-COMP joint degeneration, and MT-COMP mice joint health can be preserved by decreasing articular chondrocyte stress. Future joint sparing therapeutics for PSACH may include resveratrol. [ABSTRACT FROM AUTHOR]

As part of a larger survey of patients with chondrodysplasias, 197 patients or their parents were asked whether they had undergone orthopedic surgery related to their chondrodysplasia and, if so, to rate their impression of the outcome. Seventy-four patients (37.6%) had undergone a total of 152 procedures (221 if concurrent bilateral operations are counted separately). The percentage of patients treated surgically ranged from a low of 8.3% for hypochondroplasia to a high of 87.5% for diastrophic dysplasia. Of the patients who had surgery, the mean number of procedures per patient ranged from 1.0 for hypochondroplasia to 2.69 for pseudoachondroplasia. Of 180 individual procedures related to the limbs, the outcome in 88.8% was judged ‘a bit better’ or higher and in 68.8% ‘much better’ or higher. The responses ranged from a low of 70.4 and 66.7%, respectively for proximal femoral osteotomies to a high of 100 and 85.9% for hip replacement. The comparable figures for spine related surgery were 81.8 and 48.5% with a low of 58.3 and 50.0% for foramen magnum–cervical surgery and a high of 93.8 and 43.8% for thoracolumbar procedures. The expressed perception of lack of satisfaction varied not only by procedure but by diagnosis. Overall, patients perceived a high level of post-surgical improvement, although a number experienced subsequent deterioration and the need for further intervention. [ABSTRACT FROM AUTHOR]

Histochemical, immunohistochemical, electron microscopical and microchemical studies were performed on growth cartilage biopsies in 4 cases of pseudoachondroplasia and in 4 controls. An accumulation of a non collagenous protein material into the rough endoplasmic reticulum of chondrocytes and the missing of a proteoglycan population of the cartilage were detected. The accumulated material was stained with antibodies against the core proteins of proteoglycans. In pseudoachondroplasia, an abnormal synthesized or processed protein core of a proteoglycan population is not properly transfered to the Golgi system. [ABSTRACT FROM AUTHOR]

A 9-year-old boy from an incestuous union presented with mild clinical and roentgenological manifestations of pseudoachondroplasia. Tibial growth cartilage was obtained during a routine orthopedic procedure. Microscopic, histochemical and biochemical analysis showed changes identical to those of 6 sporadic cases of typical pseudoachondroplasia. The results support a concept of pathogenetic homogeneity of pseudoachondroplasia. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia is a rare rhizomelic short-limbed skeletal dysplasia. Its inheritance is varied; autosomal dominant pattern and germline or somatic mutations can occur. Children at 2.3 years of age present with short height, gait disturbances, or limb deformities. Characteristic skeletal changes include shortening of long bones, predominantly of femur and humerus with irregular, flared metaphysis and fragmented epiphysis. Platyspondyly is also present, but the interpedicular distance is normal. The diagnosis is essentially based on imaging, and thus, it is important to be aware of the radiological features. Here, we report a case of two brothers where the elder sibling had classical radiological features of pseudoachondroplasia, whereas the younger one had early changes of this disorder. [ABSTRACT FROM AUTHOR]