Multiple epiphyseal dysplasia

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Multiple epiphyseal dysplasia
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Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
DurationLifelong

Multiple epiphyseal dysplasia (MED), also known as Fairbank's disease, is a rare genetic disorder (dominant form: 1 in 10,000 births) that affects the growing ends of bones. Long bones normally elongate by expansion of cartilage in the growth plate (epiphyseal plate) near their ends. As it expands outward from the growth plate, the cartilage mineralizes and hardens to become bone (ossification). In MED, this process is defective.

Contents

Signs and symptoms

Children with autosomal dominant MED experience joint pain and fatigue after exercising. Their x-rays show small and irregular ossification centers, most apparent in the hips and knees. There are very small capital femoral epiphyses and hypoplastic, poorly formed acetabular roofs. [1] A waddling gait may develop. Knees have metaphyseal widening and irregularity while hands have brachydactyly (short fingers) and proximal metacarpal rounding. Flat feet are very common. [2] The spine is normal but may have a few irregularities, such as scoliosis.[ citation needed ]

By adulthood, people with MED are of short stature or in the low range of normal and have short limbs relative to their trunks. Frequently, movement becomes limited at the major joints, especially at the elbows and hips. However, loose knee and finger joints can occur. Signs of osteoarthritis usually begin in early adulthood. [3]

Children with recessive MED experience joint pain, particularly of the hips and knees, and commonly have deformities of the hands, feet, knees, or vertebral column (like scoliosis). Approximately 50% of affected children have abnormal findings at birth (such as club foot or twisted metatarsals, cleft palate, inward curving fingers due to underdeveloped bones and brachydactyly, or ear swelling caused by injury during birth). Height is in the normal range before puberty. As adults, people with recessive MED are only slightly more diminished in stature, but within the normal range. Lateral knee radiography can show multi-layered patellae. [3]

Genetics

Multiple epiphyseal dysplasia (MED) encompasses a spectrum of skeletal disorders, in which are inherited in an autosomal dominant form. However, there is an autosomal recessive form. [4]

Associated genes include COL9A1, [5] COL9A2, [6] COL9A3, [7] COMP, [8] and MATN3. [9]

Types include:

Type OMIM Gene
EDM1 132400 COMP
EDM2 600204 COL9A2
EDM3 600969 COL9A3
EDM4 226900 DTDST
EDM5 607078 MATN3
EDM6 120210 COL9A1

In the dominant form, mutations in five genes are causative: COMP (chromosome 19), COL9A1 (chromosome 6), COL9A2 (chromosome 1), COL9A3 (chromosome 20), and MATN3 (chromosome 2). However, in approximately 10%–20% of samples analyzed, a mutation cannot be identified in any of the five genes above, suggesting that mutations in other as-yet unidentified genes are involved in the pathogenesis of dominant MED. [10]

The COMP gene is mutated in 70% of the molecularly confirmed MED patients. Mutations are in the exons encoding the type III repeats (exons 8–14) and C-terminal domain (exons 15–19). [11] The most common mutations in COL9A1 are in exons 8-10, in COL9A2 in exons 2-4, and in COL9A3 in exons 2-4. Altogether, those mutations cover 10% of the patients. The other 20% of affected people have mutations in MATN3 gene, all found within exon 2. The following testing regime has been recommended by the European Skeletal Dysplasia Network:[ citation needed ]

All those genes are involved in the production of the extracellular matrix (ECM). The role of COMP gene remains unclear. It is a noncollagenous protein of the ECM. [12] Mutations in this gene can cause the pseudoachondroplasia (PSACH). It should play a role in the structural integrity of cartilage by its interaction with other extracellular matrix proteins and can be part of the interaction of the chondrocytes with the matrix and it is also a potent suppressor of apoptosis in chondrocytes. Another role is maintaining a vascular smooth muscle cells contractile under physiological or pathological stimuli. [13]

Since 2003, the European Skeletal Dysplasia Network has used an online system to diagnose cases referred to the network before mutation analysis to study the mutations causing PSACH or MED. [14]

COL9A1, COL9A2, COL9A3 are genes coding for collagen type IX, that is a component of hyaline cartilage. MATN3 protein may play a role in the formation of the extracellular filamentous networks and in the development and homeostasis of cartilage and bone. [15]

In the recessive form, the DTDST gene, also known as SLC26A2, is mutated in almost 90% of the patients, causing diastrophic dysplasia. It is a sulfate transporter, transmembrane glycoprotein implicated in several chondrodysplasias. It is important for sulfation of proteoglycans and matrix organization. [16]

Diagnosis

Diagnosis should be based on the clinical and radiographic findings and a genetic analysis can be assessed. [17]

Treatment

Symptomatic individuals should be seen by an orthopedist to assess the possibility of treatment (physiotherapy for muscular strengthening, cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs). Although there is no cure, surgery is sometimes used to relieve symptoms. [18] Surgery may be necessary to treat misalignment of the hip (osteotomy of the pelvis or the collum femoris) and, in some cases, malformation (e.g., genu varum or genu valgum). [19] In some cases, total hip replacement may be necessary. However, surgery is not always necessary or appropriate. [20]

Sports involving joint overload are to be avoided, while swimming or cycling are strongly suggested. [21] Cycling has to be avoided in people having ligamentous laxity.

Weight control is suggested. [22] [ citation needed ]

The use of crutches, other deambulatory aids or wheelchair is useful to prevent hip pain. [23] Pain in the hand while writing can be avoided using a pen with wide grip. [24]

History

Multiple epiphyseal dysplasia was described separately by Seved Ribbing and Harold Arthur Thomas Fairbank in the 1930s. [3]

In 1994, Ralph Oehlmann's group mapped MED to the peri-centromeric region of chromosome 19, using genetic linkage analysis. [25] Michael Briggs' group mapped PSACH to the same area. [26] COMP gene was firstly linked to MED and PSACH in 1995. [27] In 1995, the group led by Knowlton did a "high-resolution genetic and physical mapping of multiple epiphyseal dysplasia and pseudoachondroplasia mutations at chromosome 19p13.1-p12." [28]

Research on COMP led to mouse models of the pathology of MED. In 2002, Svensson's group generated a COMP-null mouse to study the COMP protein in vivo. These mice showed no anatomical, histological, or even ultrastructural abnormalities and none of the clinical signs of PSACH or MED. Lack of COMP was not compensated for by any other protein in the thrombospondin family. This study confirmed that the disease is not caused by reduced expression of COMP. [29]

In 2007, Piròg-Garcia's group generated another mouse model carrying a mutation previously found in a human patient. With this new model, they were able to demonstrate that reduced cell proliferation and increased apoptosis are significant pathological mechanisms involved in MED and PSACH. [30] In 2010, this mouse model allowed a new insight into myopathy and tendinopathy, which are often associated with PSACH and MED. These patients show increased skeletal muscle stress, as indicated by the increase in myofibers with central nuclei. Myopathy in the mutant mouse results from underlying tendinopathy, because the transmission of forces is altered from the normal state. There is a higher proportion of larger diameter fibrils of collagen, but the cross-sectional area of whole mutant tendons was also significantly less than that of the wild-type tendons causing joint laxity and stiffness, easy tiring and weakness. This study is important because those diseases are often mistaken for neurological problems, since the doctor can detect a muscle weakness. This includes many painful and useless clinical neurological examination before the correct diagnosis. In this work, the researchers suggest to the pediatric doctor to perform x-rays before starting the neurological assessment, to exclude the dysplasia. [31]

COL9A1 mutation was discovered in 2001. [32]

Culture

Prominent people with this condition

Related Research Articles

<span class="mw-page-title-main">Spondyloepimetaphyseal dysplasia, Strudwick type</span> Medical condition

Spondyloepimetaphyseal dysplasia, Strudwick type is an inherited disorder of bone growth that results in dwarfism, characteristic skeletal abnormalities, and problems with vision. The name of the condition indicates that it affects the bones of the spine (spondylo-) and two regions near the ends of bones. This type was named after the first reported patient with the disorder. Spondyloepimetaphyseal dysplasia, Strudwick type is a subtype of type II collagenopathies.

<span class="mw-page-title-main">Collagen, type II, alpha 1</span>

Collagen, type II, alpha 1 , also known as COL2A1, is a human gene that provides instructions for the production of the pro-alpha1(II) chain of type II collagen.

<span class="mw-page-title-main">Collagen, type XI, alpha 2</span> Protein found in humans

Collagen alpha-2(XI) chain is a protein that in humans is encoded by the COL11A2 gene.

<span class="mw-page-title-main">Autosomal recessive multiple epiphyseal dysplasia</span> Medical condition

Autosomal recessive multiple epiphyseal dysplasia (ARMED), also called epiphyseal dysplasia, multiple, 4 (EDM4), multiple epiphyseal dysplasia with clubfoot or –with bilayered patellae, is an autosomal recessive congenital disorder affecting cartilage and bone development. The disorder has relatively mild signs and symptoms, including joint pain, scoliosis, and malformations of the hands, feet, and knees.

<span class="mw-page-title-main">Larsen syndrome</span> Congenital disorder

Larsen syndrome (LS) is a congenital disorder discovered in 1950 by Larsen and associates when they observed dislocation of the large joints and face anomalies in six of their patients. Patients with Larsen syndrome normally present with a variety of symptoms, including congenital anterior dislocation of the knees, dislocation of the hips and elbows, flattened facial appearance, prominent foreheads, and depressed nasal bridges. Larsen syndrome can also cause a variety of cardiovascular and orthopedic abnormalities. This rare disorder is caused by a genetic defect in the gene encoding filamin B, a cytoplasmic protein that is important in regulating the structure and activity of the cytoskeleton. The gene that influences the emergence of Larsen syndrome is found in chromosome region, 3p21.1-14.1, a region containing human type VII collagen gene. Larsen syndrome has recently been described as a mesenchyme disorder that affects the connective tissue of an individual. Autosomal dominant and recessive forms of the disorder have been reported, although most cases are autosomal dominant. Reports have found that in Western societies, Larsen syndrome can be found in one in every 100,000 births, but this is most likely an underestimate because the disorder is frequently unrecognized or misdiagnosed.

An osteochondrodysplasia, or skeletal dysplasia, is a disorder of the development of bone and cartilage. Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Nonetheless, if taken collectively, genetic skeletal dysplasias or osteochondrodysplasias comprise a recognizable group of genetically determined disorders with generalized skeletal affection. These disorders lead to disproportionate short stature and bone abnormalities, particularly in the arms, legs, and spine. Skeletal dysplasia can result in marked functional limitation and even mortality.

<span class="mw-page-title-main">Pseudoachondroplasia</span> Inherited disorder of bone growth

Pseudoachondroplasia is an inherited disorder of bone growth. It is a genetic autosomal dominant disorder. It is generally not discovered until 2–3 years of age, since growth is normal at first. Pseudoachondroplasia is usually first detected by a drop of linear growth in contrast to peers, a waddling gait or arising lower limb deformities.

<span class="mw-page-title-main">Sulfate transporter</span> Protein-coding gene in the species Homo sapiens

The sulfate transporter is a solute carrier family protein that in humans is encoded by the SLC26A2 gene. SLC26A2 is also called the diastrophic dysplasia sulfate transporter (DTDST), and was first described by Hästbacka et al. in 1994. A defect in sulfate activation described by Superti-Furga in achondrogenesis type 1B was subsequently also found to be caused by genetic variants in the sulfate transporter gene. This sulfate (SO42−) transporter also accepts chloride, hydroxyl ions (OH−), and oxalate as substrates. SLC26A2 is expressed at high levels in developing and mature cartilage, as well as being expressed in lung, placenta, colon, kidney, pancreas and testis.

<span class="mw-page-title-main">Cartilage associated protein</span> Protein found in humans

Cartilage associated protein is a protein that in humans is encoded by the CRTAP gene.

<span class="mw-page-title-main">Cartilage oligomeric matrix protein</span> Protein found in humans

Cartilage oligomeric matrix protein (COMP), also known as thrombospondin-5, is an extracellular matrix (ECM) protein primarily present in cartilage. In humans it is encoded by the COMP gene.

<span class="mw-page-title-main">Collagen, type VII, alpha 1</span> Protein found in humans

Collagen alpha-1(VII) chain is a protein that in humans is encoded by the COL7A1 gene. It is composed of a triple helical, collagenous domain flanked by two non-collagenous domains, and functions as an anchoring fibril between the dermal-epidermal junction in the basement membrane. Mutations in COL7A1 cause all types of dystrophic epidermolysis bullosa, and the exact mutations vary based on the specific type or subtype. It has been shown that interactions between the NC-1 domain of collagen VII and several other proteins, including laminin-5 and collagen IV, contribute greatly to the overall stability of the basement membrane.

<span class="mw-page-title-main">Collagen, type IX, alpha 1</span> Protein found in humans

Collagen alpha-1(IX) chain is a protein that in humans is encoded by the COL9A1 gene.

<span class="mw-page-title-main">Collagen, type XI, alpha 1</span> Protein found in humans

Collagen alpha-1(XI) chain is a protein that in humans is encoded by the COL11A1 gene.

<span class="mw-page-title-main">Collagen, type IX, alpha 2</span> Protein found in humans

Collagen alpha-2(IX) chain is a protein that in humans is encoded by the COL9A2 gene.

<span class="mw-page-title-main">Collagen, type IX, alpha 3</span> Protein found in humans

Collagen alpha-3(IX) chain is a protein that in humans is encoded by the COL9A3 gene.

<span class="mw-page-title-main">Matrilin-3</span> Protein-coding gene in the species Homo sapiens

Matrilin-3 is a protein that in humans is encoded by the MATN3 gene. It is linked to the development of many types of cartilage, and part of the Matrilin family, which includes Matrilin-1, Matrilin-2, Matrilin-3, and Matrilin-4, a family of filamentous-forming adapter oligomeric extracellular proteins that are linked to the formation of cartilage and bone, as well as maintaining homeostasis after development. It is considered an extracellular matrix protein that functions as an adapter protein where the Matrilin-3 subunit can form both homo-tetramers and hetero-oligomers with subunits from Matrilin-1 which is the cartilage matrix protein. This restricted tissue has been strongly expressed in growing skeletal tissue as well as cartilage and bone.

<span class="mw-page-title-main">MMP20</span>

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<span class="mw-page-title-main">Boomerang dysplasia</span> Medical condition

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<span class="mw-page-title-main">Cranio-lenticulo-sutural dysplasia</span> Medical condition

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<span class="mw-page-title-main">Spondyloenchondrodysplasia</span> Medical condition

Spondyloenchondrodysplasia is the medical term for a rare spectrum of symptoms that are inherited following an autosomal recessive inheritance pattern. Skeletal anomalies are the usual symptoms of the disorder, although its phenotypical nature is highly variable among patients with the condition, including symptoms such as muscle spasticity or thrombocytopenia purpura. It is a type of immunoosseous dysplasia.

References

  1. ↑ EL-Sobky, TA; Shawky, RM; Sakr, HM; Elsayed, SM; Elsayed, NS; Ragheb, SG; Gamal, R (15 November 2017). "A systematized approach to radiographic assessment of commonly seen genetic bone diseases in children: A pictorial review". J Musculoskelet Surg Res. 1 (2): 25. doi: 10.4103/jmsr.jmsr_28_17 . S2CID   79825711.
  2. ↑ Canepa, Giuseppe; Maroteaux, Pierre; Pietrogrande, Vincenzo (2001). Dysmorphic-syndromes and constitutional diseases of the skeleton. Padova: Piccin. ISBN   978-88-299-1502-6.
  3. 1 2 3 Lachman, Ralph S.; Krakow, Deborah; Cohn, Daniel H.; Rimoin, David L. (21 October 2004). "MED, COMP, multilayered and NEIN: an overview of multiple epiphyseal dysplasia". Pediatric Radiology. 35 (2): 116–123. doi:10.1007/s00247-004-1323-4. PMID   15503005. S2CID   7728788.
  4. ↑ "Multiple Epiphyseal Dysplasia (MED) – Pediatrics – Orthobullets".
  5. ↑ "COL9A1 collagen type IX alpha 1 [ Homo sapiens (human) ]".
  6. ↑ "COL9A2 collagen type IX alpha 2 [ Homo sapiens (human) ]".
  7. ↑ "COL9A3 collagen type IX alpha 3".
  8. ↑ "COMP cartilage oligomeric matrix protein [ Homo sapiens (human) ]".
  9. ↑ "MATN3 matrilin 3 [ Homo sapiens (human) ]".
  10. ↑ d Briggs, Michael; Wright, Michael J; Mortier, Geert R (July 25, 2013) [2003]. "Multiple Epiphyseal Dysplasia, Autosomal Dominant". GeneReviews. University of Washington, Seattle. PMID   20301302. Archived from the original on May 3, 2014. Retrieved May 3, 2014.
  11. ↑ Briggs, Michael D.; Chapman, Kathryn L. (May 2002). "Pseudoachondroplasia and multiple epiphyseal dysplasia: Mutation review, molecular interactions, and genotype to phenotype correlations". Human Mutation. 19 (5): 465–478. doi:10.1002/humu.10066. PMID   11968079. S2CID   37593399.
  12. ↑ Paulsson M, Heinegård D (1981). "Purification and structural characterization of a cartilage matrix protein". Biochem J. 197 (2): 367–75. doi:10.1042/bj1970367. PMC   1163135 . PMID   7325960.
  13. ↑ "GeneCards".
  14. ↑ Jackson, Gail C.; Mittaz-Crettol, Laureane; Taylor, Jacqueline A.; Mortier, Geert R.; Spranger, Juergen; Zabel, Bernhard; Le Merrer, Martine; Cormier-Daire, Valerie; Hall, Christine M.; Offiah, Amaka; Wright, Michael J.; Savarirayan, Ravi; Nishimura, Gen; Ramsden, Simon C.; Elles, Rob; Bonafe, Luisa; Superti-Furga, Andrea; Unger, Sheila; Zankl, Andreas; Briggs, Michael D. (January 2012). "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". Human Mutation. 33 (1): 144–157. doi:10.1002/humu.21611. PMC   3272220 . PMID   21922596.
  15. ↑ "MATN3 review".
  16. ↑ "SLC26A2 solute carrier family 26".
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  18. ↑ Trehan R, Dabbas N, Allwood D, Agarwal M, Kinmont C (2008). "Arthroscopic decompression and notchplasty for long-standing anterior cruciate ligament impingement in a patient with multiple epiphyseal dysplasia: a case report". J Med Case Rep. 2: 172. doi: 10.1186/1752-1947-2-172 . PMC   2412893 . PMID   18498631.
  19. ↑ Linden, Suzanne K. Campbell, Robert J. Palisano, Darl W. Vander (2005). Physical therapy for children (3rd ed.). Philadelphia, Pa.: Elsevier Saunders. ISBN   978-0-7216-0378-0.{{cite book}}: CS1 maint: multiple names: authors list (link)
  20. ↑ Bajuifer S, Letts M (April 2005). "Multiple epiphyseal dysplasia in children: beware of overtreatment!" (PDF). Can J Surg. 48 (2): 106–9. PMC   3211605 . PMID   15887789. Archived from the original (PDF) on 2018-12-07. Retrieved 2009-02-15.
  21. ↑ Juergen Maeurer (2006). Imaging strategies for the knee. Thieme. ISBN   978-3-13-140561-6.
  22. ↑ Paans, Nienke; van den Akker-Scheek, Inge; van der Meer, Klaas; Bulstra, Sjoerd K; Stevens, Martin (23 February 2009). "The effects of exercise and weight loss in overweight patients with hip osteoarthritis: design of a prospective cohort study". BMC Musculoskeletal Disorders. 10 (1): 24. doi: 10.1186/1471-2474-10-24 . PMC   2649885 . PMID   19236692.
  23. ↑ L.Echternach, Ed.John (1990). Physical therapy of the hip. New York...[etc.]: Churchill Livingstone. ISBN   978-0-443-08650-2.
  24. ↑ Michael Benson; John Fixsen; Malcolm Macnicol; Klausdieter Parsch, eds. (February 2, 2010). Children's Orthopaedics and Fractures. Springer. ISBN   978-1-84882-610-6 . Retrieved May 3, 2014.
  25. ↑ Oehlmann, R; Summerville, GP; Yeh, G; Weaver, EJ; Jimenez, SA; Knowlton, RG (January 1994). "Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19". American Journal of Human Genetics. 54 (1): 3–10. PMC   1918067 . PMID   8279467.
  26. ↑ Briggs, Michael D.; Merete Rasmussen, I.; Weber, James L.; Yuen, Juliet; Reinker, Kent; Garber, Ann P.; Rimoin, David L.; Cohn, Daniel H. (December 1993). "Genetic linkage of mild pseudoachondroplasia (PSACH) to markersin the pericentromeric region of chromosome 19". Genomics. 18 (3): 656–660. doi:10.1016/s0888-7543(05)80369-6. PMID   8307576.
  27. ↑ Briggs MD, Hoffman SM, King LM, Olsen AS, Mohrenweiser H, Leroy JG, et al. (1995). "Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene". Nat Genet. 10 (3): 330–6. doi:10.1038/ng0795-330. PMID   7670472. S2CID   43867448.
  28. ↑ Knowlton RG, Cekleniak JA, Cohn DH, Briggs MD, Hoffman SM, Brandriff BF, et al. (1995). "High-resolution genetic and physical mapping of multiple epiphyseal dysplasia and pseudoachondroplasia mutations at chromosome 19p13.1-p12". Genomics. 28 (3): 513–9. doi:10.1006/geno.1995.1183. PMID   7490089.
  29. ↑ Svensson L, Aszódi A, Heinegård D, Hunziker EB, Reinholt FP, Fässler R, et al. (2002). "Cartilage oligomeric matrix protein-deficient mice have normal skeletal development". Mol Cell Biol. 22 (12): 4366–71. doi:10.1128/mcb.22.12.4366-4371.2002. PMC   133870 . PMID   12024046.
  30. ↑ Piróg-Garcia KA, Meadows RS, Knowles L, Heinegård D, Thornton DJ, Kadler KE, et al. (2007). "Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP". Hum Mol Genet. 16 (17): 2072–88. doi:10.1093/hmg/ddm155. PMC   2674228 . PMID   17588960.
  31. ↑ Piróg KA, Jaka O, Katakura Y, Meadows RS, Kadler KE, Boot-Handford RP, et al. (2010). "A mouse model offers novel insights into the myopathy and tendinopathy often associated with pseudoachondroplasia and multiple epiphyseal dysplasia". Hum Mol Genet. 19 (1): 52–64. doi:10.1093/hmg/ddp466. PMC   2792148 . PMID   19808781.
  32. ↑ Czarny-Ratajczak M, Lohiniva J, Rogala P, et al. (November 2001). "A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity". Am. J. Hum. Genet. 69 (5): 969–80. doi:10.1086/324023. PMC   1274373 . PMID   11565064.
  33. ↑ Jenkins, Mark (26 September 2013). "For Richer And For Poorer, But What Of That Vanishing Middle?". NPR. Retrieved 5 October 2015.
  34. ↑ Joseph, Pat (2013-09-10). "Lights, Camera, Economics Robert Reich brings his message to the big screen". Berkeley. Retrieved 5 October 2015.
  35. ↑ Leibovitch, Mark (March 14, 2002). "The True Measure of a Man". The Washington Post . Archived from the original on April 23, 2003. Retrieved November 8, 2008.
  36. ↑ David Wetherill; Parasport Archived 2012-12-24 at archive.today
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