hereditary multiple exostoses

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.{{cite journal | vauthors = Alvarez CM, De Vera MA, Heslip TR, Casey B | title = Evaluation of the anatomic burden of patients with hereditary multiple exostoses | journal = Clinical Orthopaedics and Related Research | volume = 462 | pages = 73–79 | date = September 2007 | pmid = 17589361 | doi = 10.1097/BLO.0b013e3181334b51 | s2cid = 39999620 }} Intra-articular osteochondromas of the hip can induce limitation of range of motion, joint pain and acetabular dysplasia. 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.{{Cite journal |last=Monroig-Rivera |first=Carlos |last2=Bockhorn |first2=Lauren |last3=Thornberg |first3=David |last4=Santillan |first4=Brenda |last5=Rathjen |first5=Karl E. |date=January–March 2025 |title=Prevalence of Osteochondromas in the Spine in Patients with Multiple Hereditary Exostoses |url=https://journals.lww.com/jbjsoa/fulltext/2025/03000/prevalence_of_osteochondromas_in_the_spine_in.27.aspx |journal=JB & JS Open Access |language=en-US |volume=10 |issue=1 |pages=e24.00072 |doi=10.2106/JBJS.OA.24.00072 |issn=2472-7245|pmc=11905973 }} 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.

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.{{cite journal | vauthors = Darilek S, Wicklund C, Novy D, Scott A, Gambello M, Johnston D, Hecht J | title = Hereditary multiple exostosis and pain | journal = Journal of Pediatric Orthopedics | volume = 25 | issue = 3 | pages = 369–376 | date = May 2005 | pmid = 15832158 | doi = 10.1097/01.bpo.0000150813.18673.ad | s2cid = 27884079 }}

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.{{cite journal | vauthors = Irie F, Badie-Mahdavi H, Yamaguchi Y | title = Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 13 | pages = 5052–5056 | date = March 2012 | pmid = 22411800 | pmc = 3323986 | doi = 10.1073/pnas.1117881109 | doi-access = free | bibcode = 2012PNAS..109.5052I }}

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."{{cite journal | vauthors = Cuellar A, Reddi AH | title = Cell biology of osteochondromas: bone morphogenic protein signalling and heparan sulphates | journal = International Orthopaedics | volume = 37 | issue = 8 | pages = 1591–1596 | date = August 2013 | pmid = 23771188 | pmc = 3728397 | doi = 10.1007/s00264-013-1906-5 }}{{cite journal | vauthors = Jones KB, Pacifici M, Hilton MJ | title = Multiple hereditary exostoses (MHE): elucidating the pathogenesis of a rare skeletal disorder through interdisciplinary research | journal = Connective Tissue Research | volume = 55 | issue = 2 | pages = 80–88 | date = April 2014 | pmid = 24409815 | doi = 10.3109/03008207.2013.867957 }}

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|date=September 2020}}

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

• EXT1 which maps to chromosome 8q24.1{{cite journal | vauthors = Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G | title = Genetic heterogeneity in families with hereditary multiple exostoses | journal = American Journal of Human Genetics | volume = 53 | issue = 1 | pages = 71–79 | date = July 1993 | pmid = 8317501 | pmc = 1682231 }}
• EXT2 which maps to 11p13{{cite journal | vauthors = Wu YQ, Heutink P, de Vries BB, Sandkuijl LA, van den Ouweland AM, Niermeijer MF, Galjaard H, Reyniers E, Willems PJ, Halley DJ | title = Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11 | journal = Human Molecular Genetics | volume = 3 | issue = 1 | pages = 167–171 | date = January 1994 | pmid = 8162019 | doi = 10.1093/hmg/3.1.167 }}
• EXT3 which maps to the short arm of chromosome 19 (though its exact location has yet to be precisely determined){{cite journal | vauthors = Le Merrer M, Legeai-Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H, Toutain A, Achard F, Munnich A, Maroteaux P | title = A gene for hereditary multiple exostoses maps to chromosome 19p | journal = Human Molecular Genetics | volume = 3 | issue = 5 | pages = 717–722 | date = May 1994 | pmid = 8081357 | doi = 10.1093/hmg/3.5.717 | citeseerx = 10.1.1.1028.5356 }}

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.{{cite journal | vauthors = Zak BM, Crawford BE, Esko JD | title = Hereditary multiple exostoses and heparan sulfate polymerization | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1573 | issue = 3 | pages = 346–355 | date = December 2002 | pmid = 12417417 | doi = 10.1016/S0304-4165(02)00402-6 }}{{cite journal | vauthors = Stieber JR, Dormans JP | title = Manifestations of hereditary multiple exostoses | journal = The Journal of the American Academy of Orthopaedic Surgeons | volume = 13 | issue = 2 | pages = 110–120 | year = 2005 | pmid = 15850368 | doi = 10.5435/00124635-200503000-00004 | s2cid = 29077708 }} 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.{{cite journal | vauthors = Jaeken J, Hennet T, Matthijs G, Freeze HH | title = CDG nomenclature: time for a change! | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1792 | issue = 9 | pages = 825–826 | date = September 2009 | pmid = 19765534 | pmc = 3917312 | doi = 10.1016/j.bbadis.2009.08.005 }}

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. Other studies have observed both incomplete and variable penetrance but without calculating the % penetrance, e.g.{{cite journal | vauthors = Faiyaz-Ul-Haque M, Ahmad W, Zaidi SH, Hussain S, Haque S, Ahmad M, Cohn DH, Tsui LC | title = Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis) | journal = Clinical Genetics | volume = 66 | issue = 2 | pages = 144–151 | date = August 2004 | pmid = 15253765 | doi = 10.1111/j.1399-0004.2004.00275.x | s2cid = 10431219 }} 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.{{cite journal | vauthors = Porter DE, Lonie L, Fraser M, Dobson-Stone C, Porter JR, Monaco AP, Simpson AH | title = Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study | journal = The Journal of Bone and Joint Surgery. British Volume | volume = 86 | issue = 7 | pages = 1041–1046 | date = September 2004 | pmid = 15446535 | doi = 10.1302/0301-620x.86b7.14815 | hdl-access = free | s2cid = 7129239 | hdl = 20.500.11820/8754788e-ceea-4613-8e65-60d34fcf9edc }} It is also possible for females to be severely affected. Severity of symptoms varies between individuals, even in the same family.{{citation needed|date=August 2021}}

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.

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. File:MHE example of regrowth after age 70.png.]]

Most common locations are:{{cite book | vauthors = | chapter = Chapter 9: Idiopathic and Heritable Disorders: Defects in Tumor Suppressor Genes: Hereditary Multiple Exostoses | veditors = Buckwalter JA, Weinstein SL |title=Turek's orthopaedics principles and their application |year=2005 |publisher=Lippincott Williams & Wilkins |location=Philadelphia |isbn=9780781742986 |pages=263 |edition=6th}}

• Distal femur (70%)
• Proximal tibia (70%)
• Humerus (50%)
• Proximal fibula (30%)

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{{cite book | vauthors = Davies AM, Pettersson H | veditors = Pettersson H, Ostensen H |year=2002 |title=Radiography of the Musculoskeletal System |publisher=World Health Organization |location=Geneva |isbn=978-92-4-154555-6 |pages=177, 189 |url=http://whqlibdoc.who.int/publications/2002/9241545550_eng.pdf | archive-url = https://web.archive.org/web/20140211092822/http://whqlibdoc.who.int/publications/2002/9241545550_eng.pdf | archive-date = 11 February 2014 }} 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. Problems may be had in later life and these could include weak bones and nerve damage.{{cite journal | vauthors = Cannon JF | title = Hereditary multiple exostoses | journal = American Journal of Human Genetics | volume = 6 | issue = 4 | pages = 419–425 | date = December 1954 | pmid = 14349947 | pmc = 1716573 }}{{cite journal | vauthors = McBride WZ | title = Hereditary multiple exostoses | journal = American Family Physician | volume = 38 | issue = 3 | pages = 191–192 | date = September 1988 | pmid = 3046271 }}{{cite journal | vauthors = Schmale GA, Conrad EU, Raskind WH | title = The natural history of hereditary multiple exostoses | journal = The Journal of Bone and Joint Surgery. American Volume | volume = 76 | issue = 7 | pages = 986–992 | date = July 1994 | pmid = 8027127 | doi = 10.2106/00004623-199407000-00005 | url = http://www.jbjs.org/cgi/pmidlookup?view=long&pmid=8027127 | url-status = dead | archive-url = https://archive.today/20140920144109/http://www.jbjs.org/cgi/pmidlookup?view=long&pmid=8027127 | archive-date = 2014-09-20 }} The reported rate of transformation ranges from as low as 0.57%{{cite journal | vauthors = Legeai-Mallet L, Munnich A, Maroteaux P, Le Merrer M | title = Incomplete penetrance and expressivity skewing in hereditary multiple exostoses | journal = Clinical Genetics | volume = 52 | issue = 1 | pages = 12–16 | date = July 1997 | pmid = 9272707 | doi = 10.1111/j.1399-0004.1997.tb02508.x | s2cid = 44423092 }} to as high as 8.3% of people with HME.{{cite journal | vauthors = Kivioja A, Ervasti H, Kinnunen J, Kaitila I, Wolf M, Böhling T | title = Chondrosarcoma in a family with multiple hereditary exostoses | journal = The Journal of Bone and Joint Surgery. British Volume | volume = 82 | issue = 2 | pages = 261–266 | date = March 2000 | pmid = 10755438 | doi = 10.1302/0301-620X.82B2.0820261 | doi-access = free }} Some authors have described an association between HME and the presence of popliteal pseudoaneurysms.{{cite journal | vauthors = Duarte OA, Neira JG, Herazo VD, Lara MF, Polanco AL, Omaña AF, Ortiz AF | title = Popliteal artery pseudoaneurysm caused by non-penetrating trauma in a patient with hereditary multiple osteochondromatosis | journal = Radiology Case Reports | volume = 17 | issue = 1 | pages = 185–189 | date = January 2022 | pmid = 34815824 | pmc = 8593258 | doi = 10.1016/j.radcr.2021.10.025 }}

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. 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.

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. 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. 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. 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.{{cite journal | vauthors = Vaishya R, Swami S, Vijay V, Vaish A | title = Bilateral total hip arthroplasty in a young man with hereditary multiple exostoses | journal = BMJ Case Reports | volume = 2015 | pages = bcr2014207853 | date = January 2015 | pmid = 25564594 | pmc = 4289752 | doi = 10.1136/bcr-2014-207853 }}

HME is estimated to occur in 1 in 50,000 people.

File:EXT (1).jpg|Multiple osteochondromas causing deformity of the forearm (shortening of the radius with secondary bowing of the ulna)

File:EXT (2).jpg|Multiple osteochondromas at the pelvis

File:Multiple osteochondromas around the knee.jpg|Multiple osteochondromas around the knee

File:MO CT-scan1.JPG|CT of osteochondroma in MO

File:Bone_growth_after_hip_replacement.png|Skeleton of 92-year old woman 20 years after hip replacement

{{Reflist}}

• [https://web.archive.org/web/20070929092222/http://www.geneclinics.org/profiles/ext GeneReviews: Hereditary Multiple Exostoses]

{{Medical resources

| DiseasesDB = 33342

| ICD10 = {{ICD10|Q|78|6|q|65}}

| ICD9 = {{ICD9|756.59}}

| ICDO =

| OMIM = 133700

| OMIM_mult = {{OMIM|133701||none}}

| MedlinePlus =

| eMedicineSubj =

| eMedicineTopic =

| MeshID = D005097

}}

{{Osteochondrodysplasia}}

{{Mucopolysaccharidoses}}

Category:Proteoglycan metabolism disorders

Category:Rare diseases

Category:Skeletal disorders