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Pseudoachondroplasia

Pseudo Achondroplastic Spondyloepiphyseal Dysplasia Syndrome

Pseudoachondroplasia is a type of skeletal dysplasia occurring due to mutations in the cartilage oligomeric matrix protein (COMP) gene, resulting in the appearance of a short stature, extensive laxity of the joints and ligaments, and an early onset of degenerative arthritis. A comprehensive clinical and radiologic workup is necessary in order to distinguish between several disorders presenting with similar symptoms, and genetic studies are required to confirm the diagnosis.


Presentation

Signs and symptoms of pseudoachondroplasia (PSACH) arise because of mutations in the COMP gene that codes for a family of proteins essential for numerous physiological processes in the extracellular matrix of chondrocytes and other soft tissue cells [1]. These mutations lead to premature death of chondrocytes during bone growth, resulting in the transformation of cartilage into bone and subsequent impairment in musculoskeletal growth [1]. Unlike many disorders of insufficient growth in which symptoms present from birth, pseudoachondroplasia (PSACH) is distinguished by a slightly delayed onset of symptoms, as newborns and infants suffering from this condition do not exhibit any signs until early childhood [1] [2]. Short stature, often severe enough to be termed dwarfism, appears during the second year of life, along with various musculoskeletal abnormalities [1] [2] [3]. Deceleration of linear growth, lower extremity bowing and a waddling gait, all lead to rhizomelic dwarfism, while the adult heights range between 82-130 cm with shortening of limbs [1] [4] [5]. In addition, joint changes include profound laxity, pain and a significant reduction in mobility due to osteoarthritis, a cardinal feature of PSACH that affects all joints, particularly the shoulders, elbows, and hips [1]. In fact, severe joint pain and degenerative osteoarthritis in PSACH frequently require hip replacement [1]. Brachydactyly, a knock knee, lumbar lordosis, scoliosis, ulnar deviation of the hands are other notable signs of this genetic disease [1] [6]. Normal head circumference and size, the absence of facial changes and preserved mental growth are important characteristics of PSACH, as craniofacial and intellectual abnormalities are more common in other similar disorders (for eg. achondroplasia) [1] [6].

Short Stature
  • Mutations in exon 13 (encoding the seventh calmodulin-like repeat) have been associated with severe short stature (-6 SD) in PSACH. We examined an Inuit boy with PSACH and severe short stature.[ncbi.nlm.nih.gov]
  • The degree of short stature was related to the site of the mutation in the COMP gene, but there was no correlation between bony deformity and height or gene mutation.[ncbi.nlm.nih.gov]
  • This mutation produced a severe PSACH phenotype with marked short stature and deformities of the spine and extremities.[ncbi.nlm.nih.gov]
  • PSACH is a dominant condition characterized by disproportionate short stature, joint laxity, and early-onset osteoarthritis.[ncbi.nlm.nih.gov]
  • Short stature, often severe enough to be termed dwarfism, appears during the second year of life, along with various musculoskeletal abnormalities.[symptoma.com]
Short Finger
  • Despite the radioclinical similarities between pseudoachondroplasia and multiple epiphyseal dysplasia, the latter is less severe. [3] Signs and symptoms [ edit ] Disproportionate short stature, deformity of the lower limbs, short fingers, and ligamentous[en.wikipedia.org]
Fishing
  • The size of the deletion was estimated at 0.8-7.3 Mb using fluorescent in situ hybridization (FISH). This deletion may contain or disrupt a second PSACH locus.[ncbi.nlm.nih.gov]
  • D19S212 and D19S215, genetic markers flanking the EDM1/PSACH locus, have been localized in a chromosome 19 physical map consisting of cosmid contigs ordered by high-resolution FISH.[ncbi.nlm.nih.gov]
Difficulty Walking
  • They often have difficulty walking (waddling gait) or have a deformed thoracic cavity and sternum; the thoracic cavity sticks out dramatically in the front of the torso.[aqppt.org]
Lordosis
  • With age, her rhizomelic dwarfism became increasingly visible, and since completed 15 months of age, when she started to walk, the disease was complicated with genu varum, lumbar lordosis and abnormal gait.[ncbi.nlm.nih.gov]
  • As the growth rate slows, the trunk appears long with lumbar lordosis and rhizomelic shortening of the limbs. Final adult height is 80-130cm. A height curve is available for individuals with pseudoachondroplasia.[web.archive.org]
  • The case of the current report also had lumbar lordosis ( Figure 1 ). Lumbar lordosis is observed in around 50% of affected individuals ( 4 ).[comprped.com]
  • Brachydactyly, a knock knee, lumbar lordosis, scoliosis, ulnar deviation of the hands are other notable signs of this genetic disease.[symptoma.com]
  • […] conditions; the most common is pseudoachondroplastic spondyloepiphyseal dysplasia Clinical Early onset with limb growth–irregular 'mushroomed' metaphyses, small, irregular and fragmented epiphyses, short bowed diaphyses, flattened vertebrae, lumbar lordosis[medical-dictionary.thefreedictionary.com]
Genu Valgum
  • Legs are malaligned with a variety of knee deformities noted, including bow-legs (genu varum), knock-knees (genu valgum), and windswept deformities (bow-leg on one side and knock-knee on the other side).[web.archive.org]
  • […] pseu·do·a·chon·dro·pla·si·a ( sū'dō-ă-kon'drō-plā'sē-ă ), A skeletal dysplasia characterized by short-limb dwarfism with leg deformities associated with genu varum or genu valgum and ligamentous laxity, allowing the joints to telescope; normal appearing[medical-dictionary.thefreedictionary.com]
  • The patient was also noted to have genu varum on the right and genu valgum on the left, along with a prominent lumbar lordosis and a mild dextroscoliosis of the thoracic spine.[appliedradiology.com]
  • Other known clinical features include, genu valgum/varum, brachydactyly (short fingers), supple flexion deformity of the hips, knees, hyperlordosis of lumbar spine, rocker bottom feet and broadening of the metaphyseal ends of long bones especially around[en.wikipedia.org]
Short Arm
  • The disease genes in families with PSACH and MED have been localized to an 800 kilobase interval on the short arm of chromosome 19. Recently the gene for cartilage oligomeric matrix protein (COMP) was localized to chromosome 19p13.1.[ncbi.nlm.nih.gov]
  • This process is due to mutations in the gene cause COMP, located on the short arm of chromosome 19 (19p13.1). This gene encodes a protein that is essential for normal cartilage development and for conversion to bone.[ivami.com]
  • Symptoms of pseudoachondroplasia include short arms and legs that do not become apparent until the child is age 3 to 5, bowed legs, scoliosis (curved spine), joint pain, limited range of motion of the joints and other symptoms.[nicklauschildrens.org]
  • Other characteristic features of pseudoachondroplasia include short arms and legs, a waddling walk, early-onset joint pain (osteoarthritis), and a limited range of motion at the elbows and hips.[littlepeopledoc.com]
  • Characteristic features of pseudoachondroplasia include short arms and legs, a waddling walk, early-onset joint pain (osteoarthritis), and a limited range of motion at the elbows and hips.[sumerdoc.blogspot.com]
Brachydactyly
  • A 2.75-year-old Chinese boy presented with typical clinical features of pseudoachondroplasia, including disproportionate short-limb short stature, brachydactyly, genu varus and waddling gait.[ncbi.nlm.nih.gov]
  • Beside visibly short forearms, short, broad and ulnar deviation of the hands, brachydactyly and joint hyperlaxity, the radiographic picture showed markedly flared metaphyses, small and irregular epiphyses and poorly formed acetabulum.[ncbi.nlm.nih.gov]
  • Definition A skeletal dysplasia usually manifesting in the second year of life and characterized by moderate to severe disproportionate short stature, deformity of the lower limbs, brachydactyly, ligamentous laxity, and degenerative joint disease.[uniprot.org]
  • Brachydactyly, a knock knee, lumbar lordosis, scoliosis, ulnar deviation of the hands are other notable signs of this genetic disease.[symptoma.com]
Arthralgia
  • Esra Döğer, Aysun Bideci, Öznur Boyunağa, Aylin Kılınç Uğurlu, Emine Demet Akbaş, Orhun Çamurdan & Peyami Cinaz Aim: Pseudoacondroplasia is a short extremity dwarfism characterized by lifelong arthralgia and early onset osteoarthritis.[abstracts.eurospe.org]
  • Osteoarthritis in early adulthood is a universal finding usually developing into chronic joint pain (arthralgia). The hips, ankles, shoulder, elbows and wrists are particularly affected.[rarediseases.org]
Distractibility
  • Distraction osteogenesis was used in 20 segments and acute deformity correction was done in six segments. External fixation was applied to all segments.[ncbi.nlm.nih.gov]
Waddling Gait
  • 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.[ncbi.nlm.nih.gov]
  • A characteristic waddling gait is seen due to hip involvement.[web.archive.org]
  • A 2.75-year-old Chinese boy presented with typical clinical features of pseudoachondroplasia, including disproportionate short-limb short stature, brachydactyly, genu varus and waddling gait.[ncbi.nlm.nih.gov]
  • Abstract We have identified a large family with a dominantly inherited chondrodysplasia characterized by a waddling gait, short limbs, and early onset osteoarthritis.[ncbi.nlm.nih.gov]
Abnormal Gait
  • With age, her rhizomelic dwarfism became increasingly visible, and since completed 15 months of age, when she started to walk, the disease was complicated with genu varum, lumbar lordosis and abnormal gait.[ncbi.nlm.nih.gov]
  • By this point the abnormal gait is present and measurements show the short stature to suggest pseudoachondroplasia. Diagnosis is typically made between 1 and 4 years of age. Disease-specific charts should be used to monitor growth.[web.archive.org]
  • By this point the abnormal gait is present and measurements suggest pseudoachondroplasia. Diagnosis is typically made between 1 and 4 years of age and is based on clinical examination and characteristic X-ray appearances.[nemours.org]
  • Patients with PSACH usually present at 2 to 4 years of age with abnormal gait or extremities and are subsequently noted to have a shortened stature and disproportionately shortened limbs.[appliedradiology.com]
Cervical Cord Compression
  • Death is usually secondary to respiratory compromise or from cervical cord compression by a very small foramen magnum.[ommbid.mhmedical.com]
  • Cervical cord compression myelopathy is a complication of this condition.[genedx.com]
Vertigo
  • At 26 years of age he complained of pain in the knees, swallowing difficulties, and vertigo. Renal ultrasonographic examination showed a large cortical cyst of the right kidney and smaller cysts in both kidney.[ncbi.nlm.nih.gov]

Workup

The diagnosis of PSACH is difficult to make at birth and during infancy due to the absence of typical features, but when signs of short stature and accompanying joint-related symptoms appear, a detailed workup is necessary to determine the underlying cause [6]. Firstly, a thorough patient history is necessary, primarily to assess the appearance of symptoms and their course. A family history, however, may be vital, as autosomal dominant (but also recessive) patterns of inheritance have been assumed, but because many mutations arise de novo (sporadically), the absence of a positive family history should not rule out PSACH from the differential diagnosis [2] [6]. Physical examination of the child can provide sufficient details to form valid clinical suspicion, in which case radiographic studies should be advised. Plain radiography of all bones in the body must be carried out, as prominent shortening of the proximal segments of long bones (the humerus and femur are predominantly affected), flared and irregular metaphyses, flattened femoral heads, incomplete formation of the acetabulum, a widened pubic symphysis, kyphoscoliosis and a normal radiography of the skull are notable features on X-ray [1] [6]. When clinical and radiologic findings point to PSACH as a probable cause, genetic studies are indicated, when mutations in the COMP gene, mapped on chromosome 4q35, are identified through molecular analysis [2] [6].

Treatment

  • Toward identifying potential treatments, drugs known to decrease cellular stress (lithium, phenylbutyric acid, and valproate) were assessed.[ncbi.nlm.nih.gov]
  • Management and treatment Treatment is based on physiotherapy, management of the spinal deformation and corrective orthopedic surgery. Intensive physical activity should be avoided.[orpha.net]
  • 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.[ncbi.nlm.nih.gov]
  • The authors advocate the Ilizarov method as the treatment of choice for severe juxtaarticular osseous deformities, where the technical limits of a standard osteotomy with internal fixation are being exceeded.[ncbi.nlm.nih.gov]
  • Treatment Pseudoachondroplasia affects many body systems in any given child, so each treatment plan is personalized to the patient on a case-by-case basis.[verywellhealth.com]

Prognosis

  • Prognosis The final height prognosis is variable but the short stature may be moderately severe. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • The description and natural history of the double heterozygote phenotype may be useful in counseling families regarding risk and prognosis.[ncbi.nlm.nih.gov]
  • Prognosis The prognosis for most people with pseudoachondroplasia is very good. In general, they have minimal medical problems, normal IQ, and most achieve success and have a long life, regardless of their stature.[encyclopedia.com]
  • Pseudoachondroplasia Source/Author: Scott, Charles; Alfred I. duPont Hospital for Children/Nemours Medical Review Excellent overview of this condition including: how it happens, its genetics, physical features, diagnosis, medical management, prognosis[lpamrs.memberclicks.net]

Etiology

  • Etiology The disorder is caused by small mutations or deletions in the COMP gene (19p13.1) coding for the cartilage oligomeric matrix protein.[orpha.net]
  • […] synonyms: Pseudoachondroplasia ICD-9 756.4 Chondrodystrophy Pseudoachondroplasia Etiology / Epidemiology / Natural History Disproportionate short-limbed dwarfism and ligamentous laxity Caused by deletion or alteration of the gene coding for Cartilage[eorif.com]
  • H00477 Pseudoachondroplasia Gene COMP [HSA: 1311 ] [KO: K04659 ] Other DBs ICD-11: LD24.60 ICD-10: Q77.8 MeSH: C535819 OMIM: 177170 Reference PMID: 11891674 Authors Unger S, Hecht JT Title Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic[genome.jp]
  • Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments. Source/Author: Unger S, Hecht JT. Am J Med Genet. 2001 Winter;106(4):244-50. Abstract Discussion of the genetic etiology of MED and pseudoachondroplasia.[lpamrs.memberclicks.net]

Epidemiology

  • Summary Epidemiology Prevalence is estimated at around 1/60,000. Clinical description The disorder is usually discovered during the second year of life with the onset of slow growth and walking difficulties.[orpha.net]
  • […] synonyms: Pseudoachondroplasia ICD-9 756.4 Chondrodystrophy Pseudoachondroplasia Etiology / Epidemiology / Natural History Disproportionate short-limbed dwarfism and ligamentous laxity Caused by deletion or alteration of the gene coding for Cartilage[eorif.com]
  • Epidemiology [ edit ] Pseudoachondroplasia is one of the most common skeletal dysplasias affecting all racial groups. However, no precise incidence figures are currently available (Suri et al. 2004).[en.wikipedia.org]
  • Summary Epidemiology The prevalence is approximately 1 per 100,000 live births. Males and females are equally affected.[orpha.net]
Sex distribution
Age distribution

Pathophysiology

  • Pathophysiology [ edit ] COMP is an extracellular calcium binding protein directly involved in chondrocyte migration and proliferation. It is observed at a high frequency in chondrocytes in developing bone and tendon.[en.wikipedia.org]

Prevention

  • COMP trapped in the ER builds an intracellular matrix network that may prevent the normal cellular clearance mechanisms.[ncbi.nlm.nih.gov]
  • We strive to maximize children’s mobility, correct deformity, and prevent future complications.[nemours.org]
  • Early death of the chondrocytes prevents normal bone growth and causes the short stature and bone abnormalities seen in pseudoachondroplasia.[ghr.nlm.nih.gov]
  • The premature death of chondrocytes prevents normal growth of bones, causing bone abnormalities observed in the disease. A particular mutation is found in about 30 percent of affected individuals.[ivami.com]

References

Article

  1. Posey KL, Alcorn JL, Hecht JT. Pseudoachondroplasia/COMP — translating from the bench to the bedside. Matrix biology : journal of the International Society for Matrix Biology. 2014;0:167-173.
  2. Jackson GC, Mittaz-Crettol L, Taylor JA, et al. Pseudoachondroplasia and Multiple Epiphyseal Dysplasia: A 7-Year Comprehensive Analysis of the Known Disease Genes Identify Novel and Recurrent Mutations and Provides an Accurate Assessment of Their Relative Contribution. Hum Mutat. 2012;33(1):144-157.
  3. Kennedy J, Jackson G, Ramsden S, et al. COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia. European journal of human genetics : Eur J Hum Genet. 2005;13(5):547-555.
  4. Elliott AM, Bocangel P, Reed MH, Greenberg CR. A novel COMP mutation in an Inuit patient with pseudoachondroplasia and severe short stature. Genet Mol Res. 2010;9(3):1785-1790.
  5. Tandon A, Bhargava SK, Goel S, Bhatt S. Pseudoachondroplasia: A rare cause of rhizomelic dwarfism. Indian Journal of Orthopaedics. 2008;42(4):477-479.
  6. Radlović V, Smoljanić Z, Radlović N, et al. Pseudoachondroplasia: a case report. Srp Arh Celok Lek. 2013;141(9-10):676-699.

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Last updated: 2019-07-11 21:10