Hereditary multiple exostoses

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Hereditary multiple osteochondromas
Other namesHereditary multiple exostoses
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Photograph of the legs of a 26-year-old male showing multiple lumps leading to deformity
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Hereditary multiple osteochondromas (HMO), also known as hereditary multiple exostoses, is a disorder characterized by the development of multiple benign osteocartilaginous masses (exostoses) in relation to the ends of long bones of the lower limbs such as the femurs and tibias and of the upper limbs such as the humeri and forearm bones. They are also known as osteochondromas. Additional sites of occurrence include on flat bones such as the pelvic bone and scapula. The distribution and number of these exostoses show a wide diversity among affected individuals. Exostoses usually present during childhood. The vast majority of affected individuals become clinically manifest by the time they reach adolescence. [1] [2] The incidence of hereditary multiple exostoses is around 1 in 50,000 individuals. [3] [4] [5] Hereditary multiple osteochondromas is the preferred term used by the World Health Organization. A small percentage of affected individuals are at risk for development of sarcomas as a result of malignant transformation. The risk that people with hereditary multiple osteochondromas have a 1 in 20 to 1 in 200 lifetime risk of developing sarcomas. [6]

Contents

Presentation

A noticeable lump in relation to an extremity may be the first presenting symptom. Multiple deformities can arise, namely coronal plane deformities around the knees, ankles, shoulders, elbows, and wrists. For example, genu valgum (knock knees), ankle valgus, ulnar bowing and shortening, and radial head subluxation are encountered. The majority of affected individuals have clinically manifest osteochondromas around the knee. Forearm involvement in HMO is considerable. [1] [7] Intra-articular osteochondromas of the hip can induce limitation of range of motion, joint pain and acetabular dysplasia. [2] Likewise joint pain at other locations and neurovascular compression can occur. Furthermore, functional disability in regard to activities of daily living can be a presenting feature. Spinal deformity pain or neurological compromise should arouse suspicion of involvement of the vertebrae. [3] [8] Furthermore, short stature may occur and is generally disproportionate. Such manifestations usually result from disruption of physeal growth especially that osteochondromas typically arise at the metaphyseal ends of long bones in close proximity to the physis. [1] [7]

Pain

According to self-reports, a far majority of patients experience pain, and about half experience generalized pain. Individuals who had HME-related complications were five times more likely to have pain, while those who had surgery were 3.8 times more likely to have pain. No differences were found between males and females with respect to pain, surgery, or HME-related complications. [9]

Possible connection to autism

Some parents of children with HME have observed autism-like social problems in their children. To explore those observations more deeply, a 2012 study by the Sanford-Burnham Medical Research Institute used a mouse model of HME to observe cognitive function. The findings indicated that the mutant mice endorsed three autistic characteristics: social impairment, impairments in ultrasonic vocalization, and repetitive behavior. [10]

Heparan sulfate connections

MHE stems from an inability to biosynthesize heparan sulfate, a proteoglycan. As Cuellar et al. note: "[E]ncoding glycosyltransferases involved in the biosynthesis of ubiquitously expressed heparan sulphate (HS) chains, are associated with MHE." [11] [12]

Genetics

HME is an autosomal dominant hereditary disorder. This means that individuals with HME have a 50% chance of transmitting this disorder to their children. Most individuals with HME have a parent who also has the condition; however, approximately 10–20% of individuals with HME have the condition as a result of a spontaneous mutation and are thus the first person in their family to be affected.[ citation needed ]

HME has thus far been linked with mutations in three genes:

Mutations in these genes typically lead to the synthesis of a truncated EXT protein which does not function normally. It is known that EXT proteins are important enzymes in the synthesis of heparan sulfate proteoglycans; however, the exact mechanism by which altered synthesis of heparan sulfate that could lead to the abnormal bone growth associated with HME is unclear. It is thought that normal chondrocyte proliferation and differentiation may be affected, leading to abnormal bone growth. [16] [17] Since the HME genes are involved in the synthesis of a glycan (heparan sulfate), HME may be considered a congenital disorder of glycosylation according to the new CDG nomenclature suggested in 2009. [18]

For individuals with HME who are considering starting a family, preimplantation genetic testing and prenatal diagnosis are available to determine if their unborn child has inherited the disease. HME has a 96% penetrance, which means that if the affected gene is indeed transmitted to a child, the child will have a 96% of actually manifesting the disease, and 4% chance of having the disease but never manifesting it. The 96% penetrance figure comes from only one study. [19] Other studies have observed both incomplete and variable penetrance but without calculating the % penetrance, e.g. [20] In both the aforementioned studies the symptomless individuals carrying the faulty gene were predominantly female, leading to speculation that incomplete penetrance is more likely to be exhibited in females. Indeed, other work has shown that males tend to have worse disease than females, as well as that the number of exostoses in affected members of the same family can vary greatly. [21] It is also possible for females to be severely affected. Severity of symptoms varies between individuals, even in the same family.[ citation needed ]

Symptoms are more likely to be severe if the mutation is on the ext1 gene rather than ext2 or ext3; ext1 is also the most commonly affected gene in patients of this disorder. [21]

Pathophysiology

It is characterized by the growth of cartilage-capped benign bone tumours around areas of active bone growth, particularly the metaphysis of the long bones. Typically five or six exostoses are found in upper and lower limbs. Image depicts adult regrowth after knee replacement.

Skeleton of 92-year-old woman with MHE who had knee replacements at age 70. See FIRS Colorado Mesa University. MHE example of regrowth after age 70.png
Skeleton of 92-year-old woman with MHE who had knee replacements at age 70. See FIRS Colorado Mesa University.

Most common locations are: [4]

HME can lead to the shortening and bowing of bones; affected individuals often have a short stature. Depending on their location the exostoses can cause problems including: pain or numbness from nerve compression, vascular compromise, inequality of limb length, irritation of tendon and muscle, Madelung's deformity [22] as well as a limited range of motion at the joints upon which they encroach. A person with HME has an increased risk of developing a rare form of bone cancer called chondrosarcoma as an adult. [22] Problems may be had in later life and these could include weak bones and nerve damage. [23] [24] [5] The reported rate of transformation ranges from as low as 0.57% [19] to as high as 8.3% of people with HME. [25] Some authors have described an association between HME and the presence of popliteal pseudoaneurysms. [26]

Diagnosis

The diagnosis of HMO is based upon establishing an accurate correlation between the above-mentioned clinical features and the characteristic radiographic features. Family history can provide an important clue to the diagnosis. This is supplemented by testing for the two genes in which pathogenic variants are known to cause HMO namely EXT1 and EXT2. A combination of sequence analysis and deletion analysis of the entire coding regions of both EXT1 and EXT2 detects pathogenic variants in 70–95% of affected individuals. [3] [7] The hallmark of radiographic diagnosis is the presence of osteochondromas at the metaphyseal ends of long bones in which the cortex and medulla of the osteochondroma represent a continuous extension of the host bone. This is readily demonstrable in radiographs of the knees. [3] [1]

Treatment

The indications for surgical intervention in individuals with HMO vary across the medical literature. In general surgical treatment of HMO includes one or more of the following procedures: ostechondroma excision, gradual or acute bone lengthening such as the ulna lengthening, corrective osteotomies, temporary hemiepiphysiodesis to correct angular joint deformities such as distal radius hemiepiphysiodesis and medial distal tibial hemiepiphysiodesis. [1] [3] The success of surgery is not well-correlated with specific patient or disease characteristics, making it challenging to predict who will benefit most from intervention. Surgery may be most appropriate for patients with severe functional impairments, pain, or progressive deformities. [1] [2] To enhance the amount of evidence in the medical literature certain recommendations have been put forward. The construction of well-designed prospective studies that can provide a more clear relationship between surgical procedures, patient characteristics and outcomes is on high demand. Otherwise, following the current study designs will continue to raise more questions than answers. [1] [2] Total hip arthroplasty has been used to remedy severe and painful HMO of the hip joint. Total hip arthroplasty in individuals with HMO is challenging because of distortion of anatomy and repeated surgeries performed to address complaints related to exostosis. [27]

Epidemiology

HME is estimated to occur in 1 in 50,000 people. [4] [5]

Additional images

References

  1. 1 2 3 4 5 6 7 El-Sobky TA, Samir S, Atiyya AN, Mahmoud S, Aly AS, Soliman R (21 March 2018). "Current paediatric orthopaedic practice in hereditary multiple osteochondromas of the forearm: a systematic review". SICOT-J. 4: 10. doi:10.1051/sicotj/2018002. PMC   5863686 . PMID   29565244.
  2. 1 2 3 4 Makhdom AM, Jiang F, Hamdy RC, Benaroch TE, Lavigne M, Saran N (20 May 2014). "Hip joint osteochondroma: systematic review of the literature and report of three further cases". Advances in Orthopedics. 2014: 180254. doi: 10.1155/2014/180254 . PMC   4054980 . PMID   24963411.
  3. 1 2 3 4 5 Wuyts W, Schmale GA, Chansky HA, Raskind WH (21 November 2013). "Hereditary Multiple Osteochondromas.". GeneReviews. University of Washington, Seattle. PMID   20301413 . Retrieved 24 March 2018.
  4. 1 2 3 Buckwalter JA, Weinstein SL, eds. (2005). "Chapter 9: Idiopathic and Heritable Disorders: Defects in Tumor Suppressor Genes: Hereditary Multiple Exostoses". Turek's orthopaedics principles and their application (6th ed.). Philadelphia: Lippincott Williams & Wilkins. p. 263. ISBN   9780781742986.
  5. 1 2 3 Schmale GA, Conrad EU, Raskind WH (July 1994). "The natural history of hereditary multiple exostoses". The Journal of Bone and Joint Surgery. American Volume. 76 (7): 986–992. doi:10.2106/00004623-199407000-00005. PMID   8027127. Archived from the original on 2014-09-20.
  6. ↑ "Hereditary multiple osteochondromas". Medline. National Library of Medicine. Retrieved 14 July 2024.
  7. 1 2 3 Alvarez CM, De Vera MA, Heslip TR, Casey B (September 2007). "Evaluation of the anatomic burden of patients with hereditary multiple exostoses". Clinical Orthopaedics and Related Research. 462: 73–79. doi:10.1097/BLO.0b013e3181334b51. PMID   17589361. S2CID   39999620.
  8. ↑ Monroig-Rivera C, Bockhorn L, Thornberg D, Santillan B, Rathjen KE (January–March 2025). "Prevalence of Osteochondromas in the Spine in Patients with Multiple Hereditary Exostoses". JB & JS Open Access. 10 (1): e24.00072. doi:10.2106/JBJS.OA.24.00072. ISSN   2472-7245. PMC   11905973 . PMID   40104245.
  9. ↑ Darilek S, Wicklund C, Novy D, Scott A, Gambello M, Johnston D, et al. (May 2005). "Hereditary multiple exostosis and pain". Journal of Pediatric Orthopedics. 25 (3): 369–376. doi:10.1097/01.bpo.0000150813.18673.ad. PMID   15832158. S2CID   27884079.
  10. ↑ Irie F, Badie-Mahdavi H, Yamaguchi Y (March 2012). "Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate". Proceedings of the National Academy of Sciences of the United States of America. 109 (13): 5052–5056. Bibcode:2012PNAS..109.5052I. doi: 10.1073/pnas.1117881109 . PMC   3323986 . PMID   22411800.
  11. ↑ Cuellar A, Reddi AH (August 2013). "Cell biology of osteochondromas: bone morphogenic protein signalling and heparan sulphates". International Orthopaedics. 37 (8): 1591–1596. doi:10.1007/s00264-013-1906-5. PMC   3728397 . PMID   23771188.
  12. ↑ Jones KB, Pacifici M, Hilton MJ (April 2014). "Multiple hereditary exostoses (MHE): elucidating the pathogenesis of a rare skeletal disorder through interdisciplinary research". Connective Tissue Research. 55 (2): 80–88. doi:10.3109/03008207.2013.867957. PMID   24409815.
  13. ↑ Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, et al. (July 1993). "Genetic heterogeneity in families with hereditary multiple exostoses". American Journal of Human Genetics. 53 (1): 71–79. PMC   1682231 . PMID   8317501.
  14. ↑ Wu YQ, Heutink P, de Vries BB, Sandkuijl LA, van den Ouweland AM, Niermeijer MF, et al. (January 1994). "Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11". Human Molecular Genetics. 3 (1): 167–171. doi:10.1093/hmg/3.1.167. PMID   8162019.
  15. ↑ Le Merrer M, Legeai-Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H, et al. (May 1994). "A gene for hereditary multiple exostoses maps to chromosome 19p". Human Molecular Genetics. 3 (5): 717–722. CiteSeerX   10.1.1.1028.5356 . doi:10.1093/hmg/3.5.717. PMID   8081357.
  16. ↑ Zak BM, Crawford BE, Esko JD (December 2002). "Hereditary multiple exostoses and heparan sulfate polymerization". Biochimica et Biophysica Acta (BBA) - General Subjects. 1573 (3): 346–355. doi:10.1016/S0304-4165(02)00402-6. PMID   12417417.
  17. ↑ Stieber JR, Dormans JP (2005). "Manifestations of hereditary multiple exostoses". The Journal of the American Academy of Orthopaedic Surgeons. 13 (2): 110–120. doi:10.5435/00124635-200503000-00004. PMID   15850368. S2CID   29077708.
  18. ↑ Jaeken J, Hennet T, Matthijs G, Freeze HH (September 2009). "CDG nomenclature: time for a change!". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1792 (9): 825–826. doi:10.1016/j.bbadis.2009.08.005. PMC   3917312 . PMID   19765534.
  19. 1 2 Legeai-Mallet L, Munnich A, Maroteaux P, Le Merrer M (July 1997). "Incomplete penetrance and expressivity skewing in hereditary multiple exostoses". Clinical Genetics. 52 (1): 12–16. doi:10.1111/j.1399-0004.1997.tb02508.x. PMID   9272707. S2CID   44423092.
  20. ↑ Faiyaz-Ul-Haque M, Ahmad W, Zaidi SH, Hussain S, Haque S, Ahmad M, et al. (August 2004). "Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis)". Clinical Genetics. 66 (2): 144–151. doi:10.1111/j.1399-0004.2004.00275.x. PMID   15253765. S2CID   10431219.
  21. 1 2 Porter DE, Lonie L, Fraser M, Dobson-Stone C, Porter JR, Monaco AP, et al. (September 2004). "Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study". The Journal of Bone and Joint Surgery. British Volume. 86 (7): 1041–1046. doi:10.1302/0301-620x.86b7.14815. hdl: 20.500.11820/8754788e-ceea-4613-8e65-60d34fcf9edc . PMID   15446535. S2CID   7129239.
  22. 1 2 Davies AM, Pettersson H (2002). Pettersson H, Ostensen H (eds.). Radiography of the Musculoskeletal System (PDF). Geneva: World Health Organization. pp. 177, 189. ISBN   978-92-4-154555-6. Archived from the original (PDF) on 11 February 2014.
  23. ↑ Cannon JF (December 1954). "Hereditary multiple exostoses". American Journal of Human Genetics. 6 (4): 419–425. PMC   1716573 . PMID   14349947.
  24. ↑ McBride WZ (September 1988). "Hereditary multiple exostoses". American Family Physician. 38 (3): 191–192. PMID   3046271.
  25. ↑ Kivioja A, Ervasti H, Kinnunen J, Kaitila I, Wolf M, Böhling T (March 2000). "Chondrosarcoma in a family with multiple hereditary exostoses". The Journal of Bone and Joint Surgery. British Volume. 82 (2): 261–266. doi: 10.1302/0301-620X.82B2.0820261 . PMID   10755438.
  26. ↑ Duarte OA, Neira JG, Herazo VD, Lara MF, Polanco AL, Omaña AF, et al. (January 2022). "Popliteal artery pseudoaneurysm caused by non-penetrating trauma in a patient with hereditary multiple osteochondromatosis". Radiology Case Reports. 17 (1): 185–189. doi:10.1016/j.radcr.2021.10.025. PMC   8593258 . PMID   34815824.
  27. ↑ Vaishya R, Swami S, Vijay V, Vaish A (January 2015). "Bilateral total hip arthroplasty in a young man with hereditary multiple exostoses". BMJ Case Reports. 2015: bcr2014207853. doi:10.1136/bcr-2014-207853. PMC   4289752 . PMID   25564594.
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