Hereditary Multiple Exostoses

Hereditary Multiple Exostoses is a rare disease. It is also referred to as Multiple Hereditary Exostoses, hereditary multiple osteochondromas, and Multiple Osteochondromedas.

Bone Issues

The first sign of HME is usually multiple bone tumors. See the online Multiple Osteochondromas Mutation Database for an overview of the reported variants. In MHE, the lack of HSPG causes patients to develop exostoses, which are benign tumors in multiple locations throughout the body (Brown 2008, Thompson 2011, and Mansouri et al. 2017). The severity (number and size of tumors and other complications) for MHE varies from patient to patient. Exostoses themselves can cause numerous problems including: irritation of tendons and muscles resulting in pain and loss of motion, skeletal deformity, short stature, limb length discrepancy, subluxations, and angular deformity, with a chance for chondrosarcoma (Fei et al. 2018). Problems directly associated with these exostoses include:

• Chronic pain and issues with quality of life (Goud et al. 2012, Bathen et al. 2019, Tremorsini 2025)
• Inflammation, immune responses (Callaghan et al. 2018, Collins and Troeberg 2019)  
• Bursa formation (Rueda et al. 2025) and resulting bursitis as well as early onset arthritis
• Breathing and lung issues when on ribs protruding into the thoracic cavity (Mazza et al. 2017)
• Irritation of a nearby nerve (pain, weakness, numbness, tingling)
• Blood vessel aneurysm from exostoses pressing on blood vessels or other vascular problems (Albokhari et al. 2023)
• Spinal cord compression issues: incontinence, nerve damage and nerve problems associated with spinal tumors (Bari et al. 2012, Burki et al. 2011, Zaijun et al. 2013, Montgomery et al. 2019, and Monroig-Rivera et al. 2025)

List of associated issues

Heparan Sulfate ProteoGlycan (HSPG) Deficiency Issues. MHE results from a mutation in the EXT1 and EXT2 genes.  MHE patients have defective HSPG biosynthesis--their bodies do not produce HSPG (cf Cueller et al. 2013, Jones et al,. 2014, and Pacifici et al. 2019).  HSPGs are part of every cell surface and regulate biological processes ( cf Zak et al. 2002, Meneghetti et al. 2015). HSPGs  play a vital role in cell adhesion, migration, growth, and communication (Bishop et al. 20017, Kempf et al 2017, Vicente et al. 2018). Whitlock and Iozzo (2005) have identified various diseases related to HSPG's absence (i.e., if a body process requires HSPG and there is not enough HSPG to complete that function, then these issues could occur).  MHErs reported symptoms such as:

• Severe and continuing fatigue (Berg et al. 1999, Bathen 2019)
• Neurological deficiencies: Autism Spectrum Disorder (Fumitoshi et al. 2012,  Irie et al, 2012, Yamaguchi 2012, Perez et al. 2015, Kambouris et al. 2016, Kim et al 2022); cognitive issues (Farhan et al. 2015); tremors (Aldunate et al. 2004).
• Sleep disorders (Clark 2022, Chen 2023)
• Vertigo and hyperacusis (Lundberg et al., 2014)
• Low bone mass (Nozawa et al. 2018 and Matsumoto et al. 2020)
• Severe gastric issues  (Huang et al. 2018, Rueda et al. 2025) , including non H. Pylori ulcers (Ascencio et al. 1993 and Chmiela et al. 1995), gastric cancer (Weihua et al. 2002) and Cyclic Vomiting Syndrome (Kucukesmen et al. 2007)
• Fronto-temporal dementia (Narvid et al. 2009) and ADHD (Mooney et al. 2016), brain function (Condomitti and Wit 2018). Also see video of MHE mice at https://www.youtube.com/watch?v=6-EXRt_YL6A.
• Eyesight/ocular diseases (Park and Shukla, 2013)
• Dental defects (Kucukesmen et al. 2007 and Wiweger et al. 2012)
• Prediabetes  (Heibert 2021)Diabetes and glucose difficulty (Matsuzawa 2021)
• Unusual drug reactions (many drugs act on heparan-binding domain [Boer and Gaillard 2007])
• Kidney stones and other problems (See Van den Born et al. 1993 and Farhan et al. 2015)
• Lung issues (Nackerts et al. 1997 and Haeger et al. 2016)
• Anemia (Poli et al. 2017), blood clots and coagulation (Stringer and Gallagher 1997 and Ho et al. 1997), psuedoaneurysms (Wiater and Farley 1996 and Harari et al. 2024)
• Extremely painful menstruation and pregnancy issues (Alphin et al. 1988, Yin et al. 2018)
• Inflammation (Parish 2005); slow wound healing (Zhongjun et al. 2004); scarring and keloids  (Hosalkar et al. 2007)
• Connective tissue issues (Forsberg and Kjellen, 2001 and Otsuka et al. 2020).
• Liver functions (Arnold et al. 2020 and Dituri et al. 2022)
• Cholesterol and lipid functions (Kolsett and Salmverta 1999)
• Deficient Vitamin D synthesis (Cooper 2021)

Children's Corner

Teach your child to live with MHE

You just got a diagnosis for your child and you are terrified for their life. Yeah, MHE sucks. And it is a life-long, untreatable disease. Sure you can have surgery, sure, physical therapy helps. But the underlying condition will be there every day for the rest of your life. So. How can you prepare your child to live successfully with MHE?

• Believe their pain. MHE can have some strange symptoms. Even the bones can subluxate (go in and out) within seconds, so the kid who could not walk two minutes ago is running now. Believe your child. Do not let the doctors gaslight you or your child into pretending that nothing is wrong.
• Let your child master their pain. Give your child as much control and autonomy as possible. Provide a "pain corner" with comfy pillows, their favorite toys, quiet activities, warmies or coolies. Let your child go to that pain area whenever they feel the need--when they are tired or in pain. This lets them regulate their own pain and functions.
• Teach your child to brainstorm and plan around problems. Pain and limited mobility may limit certain options, but life still goes on. So when your child can not do something, brainstorm with them. Use your imaginations. You can not climb these steps. Ok, how can you get into the room? Can you slide on your butt? Should we get a giraffe from next door to help out? (Throw in silly suggestions because that expands their imagination and puts a bit of humor into the situation.)

Advocate for your child with HME in schools

It is vital to advocate for your child so that they can work well in schools. Here are some suggested ways to ask for accommodations for this complex disease. Note that not every child will need all of these accommodations.

My child has MHE, which involves bony bumps on their bones that can vary in size, location, and number as well as some neurological and other physical symptoms.Accommodations are needed for my child’s symptoms, which include:

• Limited mobility. Allow my child to participate in sports and in activities to the best of their abilities. When starting something new, allow my child to go last and ask my child privately if they can perform that action. If not, quietly allow them to pursue a different prearranged activity. Note that mobility changes daily and sometimes hourly, depending on the bone growth stages, whether muscle has moved over a bone growth,  or other complications.
• Neurological symptoms. My child has Asperger-like and ADHD symptoms, so please engage all measures for children on the spectrum as well as ADHD. Bone tumors on the spine can also create neurological issues. Please understand that bright lights or sound may cause pain or other issues. Please report any behavioral issues so that we can determine if MHE may be underlying these problems and we can address the issues with reasonable accommodations and an Individual Education Plan.
• Frequent pain and fatigue. If my child is in pain or is tired, allow them to rest in preplanned area with preplanned quiet activities (reading, watching an educational video, etc.). This area should be equipped with a heating pad and medication should be dispensed as agreed upon by me and the school.
• Writing difficulties. My child may have extra bones on their wrists or hands, making writing painful. Please allow my child to use a computer.  Typing may be slow and please allow other software such as Dragon Naturally Speaking or Otter AI.
• Coordination difficulties. My child may have neurological difficulties and problems coordinating eyesight. Please allow more time for tests if needed. Administer tests that require filling in bubbles in an alternative method.
• Incontinence/Vomiting. Please allow my child free access to the restroom without requiring a pass for sudden issues. Keep a spare set of clothing at the school in case of accidents.
• Hall passes. Give my child access to the nurse and bathroom as they determine that they need to go. My child may have bathroom urgencies or need to get pain medication quickly. My child may also have a limb that has "gone out" or stopped working for a few seconds to a few days and will need to attend to that medical urgency.

Advocation Laws and Directives

In U.S. cite Section 504 of the Rehabilitation Act.

How to Respond to Doctors

There are suggested treatment protocols for MHE (see Rueda et al., 2025). However, MHE is a rare disease, and you will probably be the first patient that a medical practitioner has ever seen with this disease.  Try to be patient with the doctors and get doctors who work with you as a partner--you having lived with MHE do know a lot about your body! Ill-informed or too-busy doctors often rely on research that is outdated or inaccurate. Here are some common misconceptions that a doctor might tell you and how to respond. Before you go to the doctor, write out your questions. Take someone with you to take notes. Advocate for yourself!

1.I have never seen an MHE patient. Surely this is just a bone condition! The condition involves much more than bone growths. MHErs do not biosynthesize heparan sulfate proteoglycans (HSPG), in much the same way that diabetics do not biosynthesize insulin (see Cueller et al. 2013 and Jones et al. 2014). Those HSPGs play a vital role in pretty much every single cell and every system in a human body (Bishop et al. 2017). Therefore, since I do not have sufficient levels of HSPG, I can have many different problems. Let's rule out anything comorbid (in other words, any other disease I might have at the same time). IF we can not find something to explain the cause of my symptoms of {REPEAT YOUR SYMPTOMS HERE} then we can blame the MHE and treat the symptoms.

2. You do not feel pain. It is just stress.  Bone does not have nerves, therefore there is no pain.  Even if that were true (which it is not--see Nencini and Ivanusic 2016 for example ), then you wouldn't mind putting a stone in your shoe, right? Because the stone would not feel any pain. Oh, you wouldn't like that because it might hurt? Really? Ok. So I have an extra bone (LIKE A STONE) where there should only be muscle, nerve, and ligaments (LIKE A FOOT). For MHE-specific pain studies, see Darilek et al. 2005.

3. Your MHE did not cause x symptom.  I had one MHE patient (or read a case study) and they did not have x symptom, so therefore you do not have x symptom (or x symptom is unrelated). MHE is a rare and complex disease. Sometimes medical professionals will resort to explanations of hypochondria or Munchausens to explain away something that they do not understand. MHE is different for each patient, as there are different genetic mutations (EXT1, EXT2, EXT3 genes all play a role, as well as your other genetic profiles). There is not enough research to determine whether your symptoms are or are not caused by MHE. It is best to work with a doctor who will look for causes and accept that your MHE is not the same as anyone else's--including your own family members. Also, look at the list below for similar case studies on HME.

4. No one else has had that reaction to that drug. You are lying or mistaken. No. HSPG plays a role in nearly every body function and is assumed to be present. My body does not produce HSPG. Therefore my drug interactions may well differ!

5. The bones do not grow past puberty. If they have, then it is cancer. While studies have assumed this, it is not true. This has not been well researched, because it is difficult to have full xrays and to monitor over a lifetime, which would be required for absolute proof. But while there is a slight chance of chondrosarcoma, other MHE patients have reported bone growth past puberty. See the pictures of the 92- year old woman's skeleton with MHE. Bones grew back over her surgeries at age 70 and 80. If bones do not grow back, how do you explain the growths on her implants?

Questions to ask doctors if you are not being taken seriously

Scripts to Use When You Feel Dismissed

• This is affecting my daily life. I can not function well with this problem. Show pictures. Keep a diary of your pain and what you are not able to do. For example: When the tumor on my rib prevents me from raising my arm, I can not dress myself or brush my hair. When the fatigue is so bad, I can not go to class. When the pain is over a 5 (slamming your hand in a car door) continually, then I can not think well.

• Yes, the test results you got were normal, but I have problems. However, there are no tests for Heparan Sulfate Proteoglycans, which may play a role. Therefore, we need to look deeper. I still have these issues. Explain again that you have MHE and do not biosynthesize HSPG, which plays a role in every cell. Look for common problems--because of course you can still have those! But do not let the doctor gaslight you into thinking it is all in your head. If nothing else, look in Google Scholar with HSPG and your symptom.

• I’m still concerned. Can we talk about next steps? What can we do, and how long should we wait to see if that step works? Ask again about your specific symptom. There may be a medication to try, or physical therapy. Note what you have tried--keep a record!

Scripts for When Symptoms Are Minimized

• This may seem mild to you, but this is really affecting my life. Again, be specific. Use the analogy of a rock in your shoe or anything else that makes sense to you.

• I'm a zebra. I have a rare complex disease. What can we do? Again remind them that MHE is a complex systemic disease and the extra bones are only one symptom of a wider range of problems stemming from not biosynthesizing  HSPG.

• While this may seem mild, I think it is part of an overall pattern. This symptom is persistent and worsening, which is why I’m concerned. (Keep a diary. Keep images over time).

Scripts for Redirecting the Conversation

• I know my body is complex. But here is my main issue now--let's focus on that. Before your appointment, write out and send a list of your main symptoms. This is a complex disease and you will not get to everything.

• Can we go back to what I mentioned earlier? I know that everything is connected, but I am most concerned about ... so I can live my life. Keep that list. Have someone else in the room taking notes on that list of symptoms.

• Please send me a copy of my medical chart. I want to be sure my concern is documented in my chart. Always ask for a copy of your medical records, including doctors' notes.

Scripts for Asking for Clarification

• “Can you explain why you don’t think further evaluation is needed?” (MHE is a life long condition.)

• “What would be a red flag that should prompt me to follow up?” (Ask about red flags for chondrosarcoma)

• “If this doesn’t improve, what’s the next step?” (Get referrals.)

See also (MHE sites)

MHE Learning System a site for MHE patients to learn about the disease and to cope.

MHE Research Foundation a site to share MHE research.

Research and medical studies

Italics after a citation is a sentence directly from that work that summarizes the main points for HME patients and their doctors. Please go to the actual study cited.

HME Specific studies

Summary studies

Rueda-de-Eusebio, A., Gomez-Pena, S., Moreno-Casado, M.J. et al. Hereditary multiple exostoses: an educational review. Insights Imaging 16, 46 (2025). https://doi.org/10.1186/s13244-025-01899-6   This review summarises current knowledge on the clinical presentation, pathogenesis, imaging characteristics, complications, and treatment of HME.

Autism and neurological issues

Yamaguchi, Yu. Research on rare bone disorder reveals new insights into autism. https://www.eurekalert.org/news-releases/857331 March 2012, Sanford-Burnham researchers discover the molecular basis of autistic symptoms in children with a rare bone disorder -- findings that also provide new insights for the general autistic population.Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) used a mouse model of MHE to investigate cognitive function. They found that mice with a genetic defect that models human MHE show symptoms that meet the three defining characteristics of autism: social impairment, language deficits, and repetitive behavior.

See associated video presentations:

Yu Yamaguchi, M.D., Ph.D. - Consequences of Genetic Deficiency

'Heparan Sulfate, Hereditary Multiple Exostoses, and Autism: Insight from a Rare Disease for a Common Disease" at the Third Annual Rare Disease Day Symposium at Sanford-Burnham Medical Research Institute. The symposium took place at Sanford-Burnham's La Jolla campus on February 24, 2012 and the focus was Glycosylation-Based Disorders: Discovery, Patients, and Progress Toward Treatments.

Heparan Sulfate and Human Diseases, March 5, 2012.

Pain, disability, and fatigue

Amajjar I, Vergauwen K, Willigenburg NW, Huijnen IPJ, Smeets RJEM, Ham SJ, 2025, Scientific report. Physical activity level and health-related quality of life in adults with multiple osteochondromas: a Dutch cross-sectional study. 2045-2322, 2025 May 30, Vol. 15, Issue 1 Multiple Osteochondromas (MO) can significantly impact physical functioning,..These results underscore the need for targeted interventions focusing on pain management, psychological factors, and lifestyle changes to improve both PAL and HRQOL in MO patients.

Bathen T, Fredwall S, Steen U, 2019. Fatigue and pain in children and adults with multiple osteochondromas in Norway, a cross-sectional study. International journal of orthopaedic and trauma nursing [Int J Orthop Trauma Nurs] 2019 Aug; Vol. 34, pp. 28-35. Date of Electronic Publication: 2019 Feb 10.  ISSN: 18781241 Background: Multiple Osteochondromas (MO) is a rare skeletal disorder frequently needing orthopaedic surgery. High prevalence of pain has been reported, however fatigue has not previously been investigated. Results: Children with MO reported significantly higher fatigue than healthy children. Adults reported significantly higher fatigue than the general Norwegian population. Six of 11 children and 20 of 21 adults reported pain. Severe fatigue was more prevalent in persons with high age, high pain intensity and many pain locations; however none of these differences were significant.

Darilek, Sandra MS*; Wicklund, Catherine MS†; Novy, Diane PhD‡; Scott, Allison MD§; Gambello, Michael MD, PhD*; Johnston, Dennis PhD¶; Hecht, Jacqueline PhD*. Hereditary Multiple Exostosis and Pain. Journal of Pediatric Orthopaedics 25(3):p 369-376, May 2005. | DOI: 10.1097/01.bpo.0000150813.18673. This study was undertaken to characterize pain in individuals with hereditary multiple exostosis (HME). Eighty-four percent of participants reported having pain, indicating that pain is a real problem in HME.

Goud, A. L., de Lange, J., Scholtes, V. A. B., Bulstra, S. K., & Ham, S. J. (2012). Pain, Physical and Social Functioning, and Quality of Life in Individuals with Multiple Hereditary Exostoses in the Netherlands. Journal of Bone and Joint Surgery-American Volume, 94A(11), 1013-1020. https://doi.org/10.2106/JBJS.K.00406. Our study confirms that multiple hereditary exostoses is a chronic disease causing a profound impact on quality of life. The results suggest that pain is not the only problem associated with multiple hereditary exostoses, as it has an extensive influence on daily activities, as well as on social and psychological well-being, causing significant disability.

Tremosini, M., Morri, M., Forni, C., Pedrini, E., Mordenti, M., Gnoli, M., Di Cecco, A., Moroni, A., & Sangiorgi, L. (2025). Pain in patients with multiple inherited osteochondromas: Incidence and potential prognostic factors. Journal of Bone Oncology, 52, 100672. Purpose: the purpose of this study was to describe the baseline characteristics, presenting phenotype and treatment interventions for patients diagnosed with multiple osteochondromas who presented with severe pain symptoms. .Conclusion: from the early stages of multiple osteochondromas diagnosis, pain symptoms must be carefully assessed. An increase in age is associated with a worsening of pain; IOR classification of the multiple osteo-chondromas phenotype does not currently allow an association between the various classes and pain. A re-evaluation of the classification in this light could be an important new element for clinical practice.

Bone growth complications

Burki, Vincent, Alexander So, Bérengère Aubry-Rozier, 2011. Cervical myelopathy in hereditary multiple exostoses, Joint Bone Spine, Volume 78, Issue 4, https://doi.org/10.1016/j.jbspin.2011.02.021. Spinal cord compression due to cervical exostoses is a rare but recognized complication of hereditary multiple exostosis (HME), an autosomal dominant disorder. This disease, also called multiple osteochondromatosis, is characterised by osteocartilaginous exostoses, typically involving the juxtaepiphyseal regions of long bones. Complications such as transformation to sarcoma (1 to 5%) or neurological compression (of the spinal cord, 1 to 9%) can arise during the course of the disease.

Bukowska-Olech Ewelina, Trzebiatowska Wiktoria, Czech Wiktor, Drzymała Olga, Frąk Piotr, Klarowski Franciszek, Kłusek Piotr, Szwajkowska Anna, Jamsheer Aleksander, Hereditary Multiple Exostoses—A Review of the Molecular Background, Diagnostics, and Potential Therapeutic Strategies. https://www.frontiersin.org/article/10.3389/fgene.2021.759129   Hereditary multiple exostoses (HMEs) syndrome, also known as multiple osteochondromas, represents a rare and severe human skeletal disorder. The disease may severely affect the quality of patients’ life due to motion impairments, skeletal deformations, chronic pain, or growth retardation and possibility of malignant transformation of exostoses.

Matsumoto, K., Ogawa, H., Nozawa, S. et al. An analysis of osteoporosis in patients with hereditary multiple exostoses. Osteoporos Int 31, 2355–2361 (2020). https://doi.org/10.1007/s00198-020-05533-7 We analyzed osteoporosis in 20 HME patients. Our results indicate HME patients have low bone mass. They do not have abnormal bone metabolism.

Phan, A. Q., Pacifici, M., & Esko, J. D. (2017). Advances in the pathogenesis and possible treatments for multiple hereditary exostoses from the 2016 international MHE conference. Connective Tissue Research, 59(1), 85–98. https://doi.org/10.1080/03008207.2017.1394295.  MHE, also known as hereditary multiple exostoses (HME) or multiple osteochondromas (MO), is characterized by cartilage-capped outgrowths called osteochondromas that develop adjacent to the growth plates of skeletal elements in young patients. These benign tumors can affect growth plate function, leading to skeletal growth retardation, or deformations, and can encroach on nerves, tendons, muscles, and other surrounding tissues and cause motion impairment, chronic pain, and early onset osteoarthritis. In about 2–5% of patients, the osteochondromas can become malignant and life threatening.

Stiever, JR., and J.P. Dormans (2005). Manifestations of hereditary multiple exostoses. Journal of the American Academy of Orthopaedic Surgeons, 13: 110-120. https://pubmed.ncbi.nlm.nih.gov/15850368/ Hereditary multiple exostosis is an autosomal dominant disorder manifested by the presence of multiple osteochondromas. Linkage analysis has implicated mutations in the EXT gene family, resulting in an error in the regulation of normal chondrocyte proliferation and maturation that leads to abnormal bone growth. Although exostoses are benign lesions, they are often associated with characteristic progressive skeletal deformities and may cause clinical symptoms. Patients with hereditary multiple exostosis have a slight risk of sarcomatous transformation of the cartilaginous portion of the exostosis.

Screening and treatment

Fei, Li,  Clara Ngoh, Daniel E. Porter, Chondrosarcoma transformation in hereditary multiple exostoses: A systematic review and clinical and cost-effectiveness of a proposed screening model, Journal of Bone Oncology, Volume 13, 2018, Pages 114-122, ISSN 2212-1374, https://doi.org/10.1016/j.jbo.2018.09.011.  The most serious complication of hereditary multiple exostoses (HME) is chondrosarcoma transformation. Three HME screening strategies were then developed and compared using cost per life-year gained and incremental cost-effectiveness ratio (ICER).

Hosalkar, Harish MD, MBMS (Ortho), FCPS (Ortho), DNB (Ortho)*; Greenberg, Jared MD†; Gaugler, Rebecca L. BS‡; Garg, Sumeet MD§; Dormans, John P. MD∥, 2007. Abnormal Scarring With Keloid Formation After Osteochondroma Excision in Children With Multiple Hereditary Exostoses Journal of Pediatric Orthopaedics: May 2007 - Volume 27 - Issue 3 - p 333-337 doi: 10.1097/BPO.0b013e3180326732 Although this study has limited numbers, the results demonstrate a statistically significant correlation between keloid formation and MHE. The risk for abnormal scarring and keloid formation should be discussed with all patients before surgery.

Monroig-Rivera, Carlos MD1; Bockhorn, Lauren MD1,2; Thornberg, David BS1; Santillan, Brenda BS1,2; Rathjen, Karl E. MD1,2,a. Prevalence of Osteochondromas in the Spine in Patients with Multiple Hereditary Exostoses. JBJS Open Access 10(1):e24.00072, January-March 2025. | DOI: 10.2106/JBJS.OA.24.00072. Although nearly half of the patients had spinal osteochondromas, neural impingement was rare (4%). Neither age, gender, nor the presence of rib and pelvic osteochondromas were associated with spinal involvement, osteochondromas in the canal, or neural impingement. This information can be used to guide clinical decision-making regarding the use of MRI scans for patient screening.

Troxel, J., Fleury, I. G., & Buckwalter V, J. A. (2025). Revisiting Sex Differences in Multiple Hereditary Exostoses (MHE): A Comprehensive Retrospective Analysis of Patient Characteristics and Surgical Patterns. Journal of Pediatric Orthopaedics, 46(3), 180–185. We examined 103 MHE-diagnosed patients treated at the University of Iowa Hospitals and Clinics from June 2008 to March 2023. Our findings deviate from the commonly accepted male predominance in MHE, revealing an even male-female distribution.

Van der Woude HJ, Flipsen M, Welsink C, Van der Zwan AL, Ham SJ, 2025. Is total-body MRI useful as a screening tool to rule out malignant progression in patients with multiple osteochondromas? Results in a single-center cohort of 319 adult patients. By:  Skeletal radiology, 1432-2161, 2024 Jan, Vol. 53, Issue 1.To evaluate the results of total-body (TB) MRI used as a screening tool for assessment or exclusion of malignant transformation in patients with hereditary multiple osteochondromas (HMO). Conclusion: TB-MRI can identify malignant transformation of osteochondromas in HMO patients. All peripheral chondrosarcomas occurred in flat bones (ribs, scapula, pelvis) in our study. TB-MRI might assist in triage between higher risk patients with a high burden of OC, including the location of OC in main flat bones vs lower risk patients without OC of the flat bones.

Teeth

Wiweger, Malgorzata I. Wiweger, Zhe Zhao, Richard J. P. van Merkesteyn, Henry H. Roehl, and Pancras C. W. Hogendoorn, 2012. HSPG-Deficient Zebrafish Uncovers Dental Aspect of Multiple Osteochondromas. PLOS 1. https://doi.org/10.1371/journal.pone.0029734. Here we analyse dental defects present in ext2−/− fish. Histological analysis reveals that ext2−/− fish have very severe defects associated with the formation and the morphology of teeth. Our findings from zebrafish model were validated in a dental survey that was conducted with assistance of the MHE Research Foundation. The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the respondents indicating that MO might indeed be also associated with dental problems.

Genetic studies (EXT genes)

As HME is associated with genetic issues on the EXT genes, here is a list of genetic studies:

Benoist-Lasselina, Catherine Emmanuel de Margerieb, Linda Gibbsa, Sarah Cormierc, Caroline Silvec, Gisèle Nicolasd, Martine LeMerrera, Jean-Francois Mallete, Arno­­­­ld Munnicha, Jacky Bonaventurea, Louise Zylberbergb, Laurence Legeai-Malleta,  2006.  Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients. Bone, Volume 39, Issue 1, July 2006, Pages 17–26. . Multiple hereditary exostoses (MHE) is an autosomal dominant skeletal disorder caused by mutations in one of the two EXT genes and characterized by multiple osteochondromas that generally arise near the ends of growing long bones.

Busse-Wicher, Marta; Wicher, Krzysztof B.; Kusche-Gullberg, Marion (2014). "The extostosin family: Proteins with many functions". Matrix Biology. Elsevier BV. 35: 25–33. doi:10.1016/j.matbio.2013.10.001. hdl:1956/10590. ISSN 0945-053X. Mutations in either EXT1 or EXT2 cause hereditary multiple osteochondromas (HMO), an autosomal dominant disorder characterized by bone deformities and cartilage-capped bony outgrowths, called exostoses or osteochondromas, at the ends of the long bones (reviewed in (Jennes et al., 2009)). HMO is one of the most common inherited skeletal disorders with an estimated incidence of 1–2 per 100 000 live births.

Cuellar, A., Reddi, A.H. Cell biology of osteochondromas: Bone morphogenic protein signalling and heparan sulphates. International Orthopaedics (SICOT) 37, 1591–1596 (2013). https://doi.org/10.1007/s00264-013-1906-5. While factors for severity remain unknown, mutations in exostosin 1 and exostosin 2 genes, encoding glycosyltransferases involved in the biosynthesis of ubiquitously expressed heparan sulphate (HS) chains, are associated with MHE.

Nozawa S, Inubushi T, Irie F, et al. Osteoblastic heparan sulfate regulates osteoprotegerin function and bone mass. JCI Insight. 2018;3(3):e89624. Published 2018 Feb 8. doi:10.1172/jci.insight.89624. To determine the role of HS in bone homeostasis, we conditionally ablated Ext1, which encodes an essential glycosyltransferase for HS biosynthesis, in osteoblasts. Resultant conditional mutant mice developed severe osteopenia. Surprisingly, this phenotype is not due to impairment in bone formation but to enhancement of bone resorption. We also show that bone mineral density is reduced in patients with multiple hereditary exostoses, a genetic bone disorder caused by heterozygous mutations of Ext1, suggesting that the mechanism revealed in this study may be relevant to low bone mass conditions in humans.

Pacifici M. The pathogenic roles of heparan sulfate deficiency in hereditary multiple exostoses. Matrix Biol. 2018 Oct;71-72:28-39. doi: 10.1016/j.matbio.2017.12.011. Epub 2017 Dec 24. PMID: 29277722; PMCID: PMC6015767. Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan. Because of their unique structural features, the HS chains are able to specifically interact with signaling proteins–including bone morphogenetic proteins (BMPs)-via their HS-binding domain, regulating protein availability, distribution and action on target cells. Hereditary Multiple Exostoses (HME) is a rare pediatric disorder linked to germline heterozygous loss-of-function mutations in EXT1 or EXT2 that encode Golgi-resident glycosyltransferases responsible for HS synthesis, resulting in a systemic HS deficiency. HME is characterized by cartilaginous/bony tumors-called osteochondromas or exostoses- that form within perichondrium in long bones, ribs and other elements. This review examines most recent studies in HME, framing them in the context of classic studies. New findings show that the spectrum of EXT mutations is larger than previously realized and the clinical complications of HME extend beyond the skeleton.

Sefcik R, Earl D. Hereditary Multiple Osteochondromas. 2000 Aug 3 [Updated 2026 Jan 29]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1235. Each child of an individual with HMO has a 50% chance of inheriting an HMO-causing pathogenic variant.

Zak, B.M., B.E. Crawford, and J.D. Esko, 2002. Hereditary multiple exostoses and heparan sulfate polymerization Biochimica et Biophysica Acta (BBA) Volume 1573, Issue 3, 19 December 2002, Pages 346–355 http://www.sciencedirect.com/science/article/pii/S0304416502004026 Hereditary multiple exostoses (HME, OMIM 133700, 133701) results from mutations in EXT1 and EXT2, genes encoding the copolymerase responsible for heparan sulfate (HS) biosynthesis. Here, we provide an overview of HME, the EXT family of proteins, and possible models for the relationship of altered HS biosynthesis to the ectopic bone growth characteristic of the disease.

HSPG-Related studies

While HME is a rare disease and rarely studied, the connection between HME and HSPG is noted. Therefore, this list of research articles covers HME, HSPG, and the genetic issues associated with the EXT1, EXT2, and EXT3 genes.

Aldunate, Rebecca, Juan Carlos Casar, Enrique Brandan, Nibaldo C. Inestrosa, 2004. Structural and functional organization of synaptic acetylcholinesterase, Brain Research Reviews, Volume 47, Issues 1–3, "The presence of two heparin-binding domains in ColQ that interact with heparan sulfate proteoglycans (HSPGs) at the synaptic basal lamina; and second, a knockout mouse for perlecan, a HSPG concentrated in nerve–muscle contact, in which absence of asymmetric AChE at the NMJ is observed."

Aplin, J.D., Charlton, A.K. & Ayad, S.  1988. An immunohistochemical study of human endometrial extracellular matrix during the menstrual cycle and first trimester of pregnancy. Cell Tissue Res. 253: 231. https://doi.org/10.1007/BF00221758. Changes in the organisation and composition of extracellular matrix in human endometrium during the menstrual cycle and early pregnancy have been assessed by immunofluorescence.

Arnold, K. Y-E. Liao, and J. Liu, 2020. Potential Use of Anti-Inflammatory Synthetic Heparan Sulfate to Attenuate Liver Damage. Biomedicines 2020, 8(11), 503; Heparan sulfate (HS) is an essential glycan for liver function.

Ascencio, F. L. Å. Fransson and T. WadstrÖum, 1993. Affinity of the gastric pathogen Helicobacter pylori for the N-sulphated glycosaminoglycan heparan sulphate J Med Microbiol April 1993 vol. 38 no. 4 240-244 . Binding of 125I-heparan sulphate was a common property of Helicobacter pylori strains isolated from patients with gastroduodenal ulcer diseases.

Berg et al., 1999. Chronic fatigue syndrome and/or Fibromyalgia as a variation of Antiphospholipid antibody syndrome: an explanatory model and approach to laboratory  diagnosis Not in this paper, but the logic is that low levels of HSPG are found in patients with chronic fatigue, and there is probably a correlation with MHE fatigue and low levels of HSPG.

Bishop, J., Schuksz, M. & Esko, J. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446, 1030–1037 (2007). https://doi.org/10.1038/nature05817 Heparan sulphate proteoglycans reside on the plasma membrane of all animal cells studied so far and are a major component of extracellular matrices. . A recurrent theme is the electrostatic interaction of the heparan sulphate chains with protein ligands, which affects metabolism, transport, information transfer, support and regulation in all organ systems.

Boer and Gaillard, 2007. Drug Targeting to the Brain. Annual Review of Pharmacology and Toxicology. Volume 47, 2007. Pp 323-355.… For many diseases of the brain, such as Alzheimer's disease, Parkinson's disease, stroke, depression, schizophrenia, epilepsia and migraine headache, the drugs on the market … enter the cell following binding to heparan sulfate proteoglycan (HSPG) receptors …

Brown, Anissa Joy. Function of heparan sulfate proteoglycans (HSPGs) and heparanase (HPSE) in endochondral bone formation University of Delaware, ProQuest Dissertations Publishing, 2008. 3324491. Endochondral bone formation is a tightly regulated process involving coordination among cell-cell, cell-matrix and growth factor signaling that eventually results in the production of mineralized bone from a cartilage template. Chondrogenic and osteogenic differentiation occur in sequence during this process, and the temporospatial patterning clearly requires the activities of heparan sulfate proteoglycans (HSPGs), heparin binding growth factors (HBGFs) and their receptors.

O'Callaghan P, Zhang X, Li JP. 2018. Heparan Sulfate Proteoglycans as Relays of Neuroinflammation. J Histochem Cytochem. 2018 Apr;66(4):305-319. doi: 10.1369/0022155417742147. Epub 2018 Jan 1. PMID: 29290138; PMCID: PMC5958378. . We summarize some of the contrasting roles that HS and heparanase have been assigned in diseases associated with chronic inflammatory states, including Alzheimer's disease (AD).

Chen, Ming and Xiao, Xiao and Rui, Yimin and Jin, Yu, 2023. Relationship of Sleep Disorder with Neurodegenerative and Psychiatric Diseases: An Updated Review. Available at SSRN: https://ssrn.com/abstract=4484640 or http://dx.doi.org/10.2139/ssrn.4484640. "Another key factor in the circadian timing of Aβ42 phagocytosis is the presence of cell-surface heparan sulfate proteoglycans (HSPGs), which highlights a potential causative factor for increased Aβ42 accumulation in patients with clock/sleep disorders due to the apparent circadian rhythmicity of HSPGs levels and the inhibitory role of HSPGs in the phagocytosis of Aβ42(Clark et al., 2022)."

Chmiela, M. et al. 1995. The role of heparan sulphate-binding activity of Helicobacter pylori bacteria in their adhesion to murine macrophages. http://onlinelibrary.wiley.com/doi/10.1111/j.1699-0463.1995.tb01133.x/full The role of heparan sulphate (HS)-binding activity of Helicobacter pylori microbes in their adhesion to and ingestion by inflammatory peritoneal macrophages.

Clark, GT, Yu Y, Urban C et al. 2023. Circadian control of heparan sulfate levels times phagocytosis of amyloid beta aggregates. February 10, 202. PLOS Genetics. https://doi.org/10.1371/journal.pgen.1009994. PGs like heparan sulfate proteoglycans (HSPGs) and chondroitin sulfate proteoglycans (CSPGs) are involved in the clearance of Aβ42, associate with Aβ42 to foster the formation of plaques, and reduce Aβ plaque load upon the knockout of a key enzyme in the HSPG biosynthesis pathway... our findings suggest the disruption of the circadian timing of macrophage/microglia phagocytosis may be a vital component in Aβ42 metabolism, highlighting a potential causative factor in the increase in accumulation of Aβ42 in patients with clock/sleep disturbances [8,13,20,22,25,94,97].

Collins LE, Troeberg L. 2019. Heparan sulfate as a regulator of inflammation and immunity. J Leukoc Biol. 2019 Jan;105(1):81-92. doi: 10.1002/JLB.3RU0618-246R. Epub 2018 Oct 30. PMID: 30376187. In this review, we discuss the multiple roles for HS in regulating immune responses, and the evidence for inflammation-associated changes to HS structure.Keywords: chemokines; cytokines; heparan sulfate; inflammation; leukocyte.

Condomitti, G., & de Wit, J. (2018). Heparan Sulfate Proteoglycans as Emerging Players in Synaptic Specificity. Frontiers in molecular neuroscience, 11, 14. https://doi.org/10.3389/fnmol.2018.00014 The heparan sulfate proteoglycan (HSPG) family of cell-surface proteins is emerging as a key regulator of connectivity. HSPGs are expressed throughout brain development and play important roles in axon guidance, synapse development and synapse function.

Cooper, Isabella D.; Brookler, Kenneth H.; Crofts, Catherine A. P. (2021-09-06). "Rethinking Fragility Fractures in Type 2 Diabetes: The Link between Hyperinsulinaemia and Osteofragilitas" Biomedicines 9, no. 9: 1165. https://doi.org/10.3390/biomedicines9091165 Hyperinsulinaemia negatively impacts HSPG function and availability, via impairment of vitamin D regulation. Vitamin D regulates sulfate synthesis, required for heparan sulphate [145].

Dituri F, Gigante G, Scialpi R, Mancarella S, Fabregat I, Giannelli G. Proteoglycans in Cancer: Friends or Enemies? A Special Focus on Hepatocellular Carcinoma. Cancers. 2022; 14(8):1902. https://doi.org/10.3390/cancers14081902 Proteoglycans are a class of highly glycosylated proteins expressed in virtually all tissues, which are localized within membranes, but more often in the pericellular space and extracellular matrix (ECM), and are involved in tissue homeostasis and remodeling of the stromal microenvironment during physiological and pathological processes, such as tissue regeneration, angiogenesis, and cancer.

Farhan, S.M.K. , Wang J, Robinson JF, et al., 2015. Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses. Journal of Medical Genetics 2015;52:666-675.  Many genes are involved in modulating heparan sulfate synthesis, and when these genes are mutated, they can give rise to early-onset developmental disorders affecting multiple body systems.

Forsberg E. and L. Kjellen, 2001. Heparan sulfate: lessons from knockout mice. Journal of Clinical Investigation. https://www.jci.org/articles/view/13561. Kidney agenesis, “broken heart,” abnormal mast cells, somatic overgrowth, lung dysfunction, and chondrodysplasia are some phenotypes of mice where different genes important for heparan sulfate (HS) expression have been knocked out.The authors speculate that, during inflammation or wounding when fibronectin is degraded, syndecan-4 may be important for focal adhesion formation and actin fiber organization, which in turn contribute to cell migration.

Fumitoshi Irie, Hedieh Badie-Mahdavi, and Yu Yamaguchi, 2012. Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate. PNAS 2012 109 (13) 5052-5056;  March 27, 2012 vol. 109 no. 13 http://www.pnas.org/content/109/13/5052.short Heparan sulfate regulates diverse cell-surface signaling events, and its roles in the development of the nervous system recently have been increasingly uncovered by studies using genetic models carrying mutations of genes encoding enzymes for its synthesis. Our results demonstrate that heparan sulfate is critical for normal functioning of glutamatergic synapses and that its deficiency mediates socio-communicative deficits and stereotypes characteristic for autism.

Ge, Xiao Na, Bastan, Idil, Ha, Sung Gil, Greenberg, Yana G., Esko, Jeffrey D., Rao, Savita P., Sriramarao, P., 2018. Regulation of eosinophil recruitment and allergic airway inflammation by heparan sulfate proteoglycan (HSPG) modifying enzymes. Experimental Lung Research, 01902148, Mar2018, Vol. 44, Issue Our study demonstrates that allergen exposure reduces expression of Hs2st; loss of uronyl 2-O-sulfation in endothelial and leukocyte HSPG amplifies recruitment of eosinophils likely due to a compromised vascular endothelium resulting in persistent inflammation whereas loss of N-sulfation limits eosinophilia and attenuates inflammation underscoring the importance of site-specific sulfation in HSPG to their role in AAI.

Haeger SM, Yang Y, Schmidt EP. Heparan Sulfate in the Developing, Healthy, and Injured Lung. Am J Respir Cell Mol Biol. 2016;55(1):5-11. doi:10.1165/rcmb.2016-0043TR https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942210/ This Translational Review highlightsthe importance of athe glycosaminoglycan heparan sulfate (HS) on lung health and disease.

Hiebert, Linda M. 2021. Heparan Sulfate Proteoglycans in Diabetes. DOI: 10.1055/s-0041-1724118. Thieme E- Journals - Seminars in Thrombosis and Hemostasis / Abstract (thieme-connect.com). Understanding the role of HSPGs and how they are modified by diabetes may lead to new treatments as well as preventative measures to reduce the morbidity and mortality associated with this complex condition.

Ho, G., G Broze, A. Schwartz, 1997. Role of Heparan Sulfate Proteoglycans in the Uptake and Degradation of Tissue Factor Pathway Inhibitor-Coagulation Factor Xa Complexes. CELL BIOLOGY AND METABOLISM| VOLUME 272, ISSUE 27, P16838-16844, JULY 1997.https://www.jbc.org/article/S0021-9258(18)39299-8/fulltext These results suggest that heparan sulfate proteoglycans (HSPGs) are required for the uptake and degradation of 125I-TFPI·fXa complexes.

Huang M, He H, Belenkaya T, Lin X. Multiple roles of epithelial heparan sulfate in stomach morphogenesis. J Cell Sci. 2018 May 29;131(10):jcs210781. doi: 10.1242/jcs.210781. PMID: 29700203; PMCID: PMC6031332. In the posterior stomach, HS depletion disrupts glandular stomach patterning and cytodifferentiation via attenuation of Fgf signaling activity.

Irie, F.,  H. Badie-Mahdavi, Y. Yamaguchi, 2012. Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate Proc. Natl. Acad. Sci. U. S. A., 109 (2012), pp. 5052-5056. https://www.pnas.org/doi/pdf/10.1073/pnas.1117881109. Our results demonstrate that heparan sulfate is critical for normal functioning of glutamatergic synapses and that its deficiency mediates socio-communicative deficits and stereotypies characteristic for autism.

Jennes I, Pedrini E, Zuntini M, Mordenti M, Balkassmi S, Asteggiano CG, Casey B, Bakker B, Sangiorgi L, Wuyts W. Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum Mutat. 2009 Dec;30 (12):1620-7. doi: 10.1002/humu.21123. PMID: 19810120. MO is genetically heterogeneous, and is associated with mutations in Exostosin-1 (EXT1) or Exostosin-2 (EXT2), both tumor-suppressor genes of the EXT gene family. All members of this multigene family encode glycosyltransferases involved in the adhesion and/or polymerization of heparin sulfate (HS) chains at HS proteoglycans (HSPGs).

Jones, K. B., Pacifici, M., & Hilton, M. J. (2014). Multiple hereditary exostoses (MHE): elucidating the pathogenesis of a rare skeletal disorder through interdisciplinary research. Connective Tissue Research, 55(2), 80–88. https://doi.org/10.3109/03008207.2013.867957. MHE is largely caused by autosomal dominant mutations in EXT1 or EXT2, genes encoding Golgi-associated glycosyltransferases responsible for heparan sulfate (HS) synthesis. HS chains are key constituents of cell surface- and extracellular matrix-associated proteoglycans, which are known regulators of skeletal development. MHE affected individuals are HS-deficient, can display skeletal growth retardation and deformities, and consistently develop benign, cartilage-capped bony outgrowths (termed exostoses or osteochondromas) near the growth plates of many skeletal elements. Heparan sulfate proteoglycans (HSPGs) critically modulate adhesion-, growth-, and migration-related processes.

Kemp, Annissa et al. 2017. Control of Cell Shape, Neurite Outgrowth, and Migration by a Nogo-A/HSPG Interaction, Developmental Cell, Volume 43, Issue 1, 24 - 34.e5 https://www.cell.com/developmental-cell/fulltext/S1534-5807(17)30674-3 Heparan sulfate proteoglycans (HSPGs) critically modulate adhesion-, growth-, and migration-related processes. Here, we show that the transmembrane protein, Nogo-A, inhibits neurite outgrowth and cell spreading in neurons and Nogo-A-responsive cell lines via HSPGs. Finally, we show in explant cultures ex vivo that Nogo-A-?20 promotes the migration of neuroblasts via HSPGs but not S1PR2.

Kolset, S., Salmivirta, M. Cell surface heparan sulfate proteoglycans and lipoprotein metabolism. CMLS, Cell. Mol. Life Sci. 56, 857–870 (1999). https://doi.org/10.1007/s000180050031 https://link.springer.com/article/10.1007/s000180050031. Heparan sulfate has been further implicated in presentation and stabilization of lipoprotein lipase and hepatic lipase on cell surfaces and in the transport of lipoprotein lipase from extravascular cells to the luminal surface of the endothelia. In atherosclerosis, heparan sulfate is intimately involved in several events important to the pathophysiology of the disease.

Laabs, T.; Carulli, D.; Geller, H.M.; Fawcett, J.W. Chondroitin sulfate proteoglycans in neural development and regeneration. Curr. Opin. Neurobiol. 2005, 15, 116–120. [Google Scholar] [CrossRef] [PubMed] Proteoglycans are of two main types, chondroitin sulfate (CSPGs) and heparin sulfate (HSPGs). The CSPGs act mainly as barrier-forming molecules, whereas the HSPGs stabilise the interactions of receptors and ligands.

Lundberg, Y.W., Y. Xu, K.D. Theissen, and K.L. Framer, 2014. Mechanisms of otoconia and otolith development. Developmental Dynamics, 9/24/2014. Deletion of different HSPGs and CSPGs causes calcification deficiencies which exemplifies their critical role in bone and teeth formation.

Mansouri, R., Jouan, Y., Hay, E. et al. Osteoblastic heparan sulfate glycosaminoglycans control bone remodeling by regulating Wnt signaling and the crosstalk between bone surface and marrow cells. Cell Death Dis 8, e2902 (2017). https://doi.org/10.1038/cddis.2017.287 Syndecan-2 is a membrane heparan sulfate proteoglycan that is associated with osteoblastic differentiation. The osteogenic properties of matrix glycosaminoglycans (GAGs) have been explored; however, the functions of GAGs at the surface of bone-forming cells are less documented.

Matsuzawa, T. et al., 2021. Heparan sulfate promotes differentiation of white adipocytes to maintain insulin sensitivity and glucose homeostasis. Journal of Biological Chemistry. We observed that Ext1Δ/WT mice showed glucose intolerance because of insulin resistance. Our results demonstrate that HS plays a crucial role in the differentiation of white adipocytes through BMP4–FGF1 signaling pathways, thereby contributing to insulin sensitivity and glucose homeostasis.

Meneghetti, Maria C. Z.; Hughes, Ashley J.; Rudd, Timothy R.; Nader, Helena B.; Powell, Andrew K.; Yates, Edwin A.; Lima, Marcelo A. (2015-09-06). "Heparan sulfate and heparin interactions with proteins". Journal of the Royal Society, Interface. 12 (110): 0589. doi:10.1098/rsif.2015.0589. ISSN 1742-5662. PMC 4614469. PMID 26289657. Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissue-specific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro, ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them.

Mooney et al. 2016.Pathway analysis in attention deficit hyperactivity disorder: An ensemble approach. American Journal of Medical Genetics. Volume 171, Sept 2016. https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.b.32446 These results support previous hypotheses about the role of regulation of neurotransmitter release, neurite outgrowth and axon guidance in contributing to the ADHD phenotype and suggest the value of cross-method convergence in evaluating pathway analysis results.

Nackaerts, K. et al. 1997. Heparan Sulfate Proteoglycan Expression In Human Lung-Cancer Cells. Int. J. Cancer (Pred. Oncol.): 74, 335–345 (1997) r 1997 Wiley-Liss, Inc. https://www.researchgate.net/profile/Maurits_Demedts/publication/13997415_Heparan_sulfate_proteoglycan_expression_in_human_lung-cancer_cells/links/5600565108aeafc8ac8c7374.pdf Heparan sulfate (HS) functions as a co-factor in several signal-transduction systems that affect cellular growth, differentiation, adhesion and motility. HS, therefore, may also play a role in the malignant transformation of cells, tumor growth, cell invasiveness and the formation of tumor metastases. Our results suggest that poorly differentiated lung tumors have markedly altered patterns of HSPG expression, which may contribute to their invasive phenotype. Int. J. Cancer 74:335– 345, 1997.

Nencini Sara , Ivanusic Jason J. The Physiology of Bone Pain. How Much Do We Really Know? Frontiers in Physiology. Volume 7 - 2016. https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2016.00157. DOI=10.3389/fphys.2016.00157. ISSN=1664-042X Pain is associated with most bony pathologies. Clinical and experimental observations suggest that bone pain can be derived from noxious stimulation of the periosteum or bone marrow Whilst these provide some clues as to the way information about bone pain is centrally coded, they need to be expanded to further our understanding of other central territories involved.

Otsu, K.; Kato, S.; Ohtake, K.; Akamatsu, N. Alteration of rat liver proteoglycans during regeneration. Arch. Biochem. Biophys. 1992, 294, 544–549. Alteration of rat liver proteoglycans during regeneration - PubMed (nih.gov). Heparan sulfates (HS) are probably the major GAGs present on the surface of hepatocytes under normal conditions. Nevertheless, HSPGs expression increases during liver regeneration. Using [35S] sulfuric acid incorporation, Otsu et al. showed that, in the hepatic regeneration phase after hepatectomy, the synthesis of heparin sulfate proteoglycans, and to a lesser extent, of chondroitin/dermatan sulfate proteoglycans, increases up to 3–5 days and is temporally shifted compared to the stage of maximum mitosis that occurs 1–2 days following the surgical procedure [94].

Otsuka, T., Phan, A.Q., Laurencin, C.T. et al. Identification of Heparan-Sulfate Rich Cells in the Loose Connective Tissues of the Axolotl (Ambystoma mexicanum) with the Potential to Mediate Growth Factor Signaling during Regeneration. Regen. Eng. Transl. Med. 6, 7–17 (2020). https://doi.org/10.1007/s40883-019-00140-3 https://link.springer.com/article/10.1007/s40883-019-00140-3 . We hypothesized that there are cells in the axolotl that synthesize specific HSPGs that control growth factor signaling in time and space. Given their high level of HSPG expression, their stellate morphology, and their distribution throughout the loose connective tissues, we refer to these as the positional information GRID (Groups that are Regenerative, Interspersed and Dendritic) cells.

Parish, C., 2005. Heparan sulfate and inflammation. Nature Immunology 6(9):861-2 ·  October. https://www.researchgate.net/publication/7645220_Heparan_sulfate_and_inflammation. Entry of leukocytes into tissues is a key feature of inflammation. New data suggest the polysaccharide heparan sulfate is required for several stages of this entry process.

Park, P.J, and D. Shukla. Role of heparan sulfate in ocular diseases, Experimental Eye Research, Volume 110, 2013, Pages 1-9, ISSN 0014-4835, https://doi.org/10.1016/j.exer.2013.01.015. Abstract: Heparan sulfate (HS), a ubiquitous and structurally diverse cell surface polysaccharide and extracellular matrix component, is a factor common to several major eye pathologies. Its multitude of functions and variable distribution among the different ocular tissues makes it an important contributor to a variety of disease states. Although HS facilitates the pathogenesis of many disorders, its role in each varies. Unique functions of HS have been particularly noted in viral and bacterial keratitis and age-related macular degeneration.

Pérez, C., Sawmiller, D. & Tan, J. The role of heparan sulfate deficiency in autistic phenotype: potential involvement of Slit/Robo/srGAPs-mediated dendritic spine formation. Neural Dev 11, 11 (2016). https://doi.org/10.1186/s13064-016-0066-x Autism Spectrum Disorders (ASD) are the second most common developmental cause of disability in the United States. The brains of ASD patients have marked structural abnormalities, in the form of increased dendritic spines and decreased long distance connections. These structural differences may be due to deficiencies in Heparin Sulfate (HS), a proteoglycan involved in a variety of neurodevelopmental processes. Through interference with this pathway, HS deficiency can lead to excess spine formation.

Poli, Maura, Michela Asperti, Paola Ruzzenenti, Annamaria Naggi, and Paolo Arosio. 2017. "Non-Anticoagulant Heparins Are Hepcidin Antagonists for the Treatment of Anemia" Molecules 22, no. 4: 598. https://doi.org/10.3390/molecules22040598 This review summarizes recent findings on the anti-hepcidin activity of heparins and their possible use for the treatment of anemia caused by hepcidin excess, including the anemia of chronic diseases.

Russel A.L. and M.F.McCarty, 2000 Glucosamine for migraine prophylaxis?  Medical Hypotheses. Volume 55, Issue 3, September 2000, Pages 195-198. http://www.sciencedirect.com/science/article/pii/S0306987799910125 We postulate that supplemental glucosamine can boost mast cell heparin synthesis – perhaps correcting a functional heparin deficiency – thereby preventing or ameliorating the neurogenic inflammation that mediates pain in vascular headache. Whether or not this idea has validity, a controlled study of glucosamine for migraine prophylaxis appears to be warranted.

Stringer, S.E. and Gallagher. 1997. Molecules in focus. Heparan sulphate. The International Journal of Biochemistry & Cell Biology, Volume 29, Issue 5, 1997. Heparan sulphates, the N-sulphated polysaccharides components of proteoglycans, are common constituents of cell surfaces and the extracellular matrix. The diverse functions of heparan sulphate, which range from the control of blood coagulation to the regulation of cell growth and adhesion, depend on the capacity of the chains to activate protein ligands, such as antithrombin III and members of the fibroblast growth factor family. These properties are currently being exploited in the development of synthetic heparan sulphates as anticoagulants and promoters of wound healing. Conversely organic mimics of growth factor activating saccharides could possibly be designed to suppress tumour growth and prevent restenosis after coronary vessel angioplasty.

Theoharides TC et al.  1999. Stress-induced rat intestinal mast cell intragranular activation and inhibitory effect of sulfated proteoglycans.  Digestive Diseases and Sciences [1999, 44 (8 Suppl):87S-93S]. Pages 709-714. http://europepmc.org/abstract/med/10490045 Cyclic vomiting syndrome is characterized by sudden episodes of vomiting and abdominal pain. It occurs primarily in children, is exacerbated by stress, and is often considered a migraine equivalent. Migraines have been linked to mast cells, which are often found close to neurons where they are activated by neuropeptides. We investigated the ultrastructural appearance of rat ileal brush border and mast cells following acute stress by immobilization.These results suggest the possible usefulness of chondroitin sulfate in conditions such as cyclic vomiting syndrome.

Thompson, W.R. 2011. Perlecan modulates the function of the osteocyte lacuno-canalicular system. University of Delaware, ProQuest Dissertations Publishing, 2011. 3443246. In this study, along with my colleagues, I examined osteocyte lacunocanalicular morphology in mice deficient in the large heparan sulfate proteoglycan (HSPG) PLN in this tissue. . . Ultrastructural measurements using electron micrograph images of PLN deficient mice demonstrate a significant decrease in osteocyte canalicular pericellular area, resulting from a reduction in the total canalicular area, when compared to controls. Additionally, PLN deficient mice show significantly diminished canalicular density and a significant reduction in the number of transverse tethering elements per canaliculus.

van den Born J, van den Heuvel LP, Bakker MA, Veerkamp JH, Assmann KJ, Weening JJ, Berden JH., 1993. Distribution of GBM heparan sulfate proteoglycan core protein and side chains in human glomerular diseases. Kidney Int. 1993 Feb;43(2):454-63. http://www.ncbi.nlm.nih.gov/pubmed/8441243 Using monoclonal antibodies (mAbs) recognizing either the core protein or the heparan sulfate (HS) side chain of human GBM heparan sulfate proteoglycan (HSPG), we investigated their glomerular distribution on cryostat sections of human kidney tissues. In conclusion, major alterations were observed in the glomerular distribution of HS and HSPG-core in various human glomerulopathies. The mAbs can be useful to further delineate the significance of HSPG and HS for glomerular diseases.

Vicente, Carolina Meloni, da Silva, Daiana Aparecida, Sartorio, Priscila Veronica, Silva, Tiago Donizetti, Saad, Sarhan Sydney, Nader, Helena Bonciani, Forones, Nora Manoukian, Toma, Leny, Heparan Sulfate Proteoglycans in Human Colorectal Cancer, Analytical Cellular Pathology, 2018, 8389595, 10 pages, 2018. https://doi.org/10.1155/2018/8389595  https://www.hindawi.com/journals/acp/2018/8389595/ Heparan sulfate proteoglycans are complex molecules present in the cell membrane and extracellular matrix, which play vital roles in cell adhesion, migration, proliferation, and signaling pathways. Heparan sulfate proteoglycans are candidate molecules to clarify colorectal cancer tumorigenesis, as well as important targets to therapy and diagnosis.

Vlodavestky, I. et al. 2007. Heparanase: Structure, Biological Functions, and Inhibition by Heparin-Derived Mimetics of Heparan Sulfate. Current Pharmaceutical Design, Volume 13, Number 20, July 2007, pp. 2057-2073(17). http://www.ingentaconnect.com/content/ben/cpd/2007/00000013/00000020/art00004 Heparanase is an endoglycosidase which cleaves heparan sulfate (HS) and hence participates in degradation and remodeling of the extracellular matrix (ECM). Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype in experimental animals. These observations and the unexpected identification of a single functional heparanase, suggest that the enzyme is a promising target for anti-cancer and anti-inflammatory drug development.

Weihua T. et al. 2002. Heparanase: A Key Enzyme in Invasion and Metastasis of Gastric Carcinoma.Mod Pathol 2002;15(6):593–59. http://www.nature.com/modpathol/journal/v15/n6/abs/3880571a.html Previous reports have shown that the biochemical activity of heparanase is significantly correlated with the invasion and metastasis of malignant cells in vitro. It was concluded that heparanase might play an important role in the development of invasion and metastasis of the gastric cancer. It was indicated that patients with heparanase-positive gastric carcinoma would have a greater chance of metastasis with a poor prognosis.

Whitelock John M. and Renato V. Iozzo, 2005. Heparan Sulfate:  A Complex Polymer Charged with Biological Activity. Chem. Rev., 2005, 105 (7), pp 2745–2764. http://pubs.acs.org/doi/pdf/10.1021/cr0102   “HS is a complex and highly active biopolymer…” one section is on heparan sulfate therapies,

Yan Yin, Adam Wang, Li Feng, Yu Wang, Hong Zhang, Ivy Zhang, Brent M Bany, Liang Ma, Heparan Sulfate Proteoglycan Sulfation Regulates Uterine Differentiation and Signaling During Embryo Implantation, Endocrinology, Volume 159, Issue 6, June 2018, Pages 2459–2472, https://doi.org/10.1210/en.2018-00105 One important modulator of these signaling pathways is the cell surface and extracellular matrix macromolecules, heparan sulfate proteoglycans (HSPGs). HSPGs play crucial roles in signal transduction by regulating morphogen transport and ligand binding. In this study, we examine the role of HSPG sulfation in regulating uterine receptivity…

Zhongjun Zhou et al. 2004.  Impaired Angiogenesis, Delayed Wound Healing and Retarded Tumor Growth in Perlecan Heparan Sulfate-Deficient Mice. DOI: 10.1158/0008-5472.CAN-04-0810 Published July 2004. http://cancerres.aacrjournals.org/content/64/14/4699. Perlecan, a modular proteoglycan carrying primary heparan sulfate (HS) side chains, is a major component of blood vessel basement membranes.Perlecan HS-deficient (Hspg2Δ3/Δ3) mice survived embryonic development and were apparently healthy as adults. However, mutant mice exhibited significantly delayed wound healing, retarded FGF-2-induced tumor growth, and defective angiogenesis.

Zhu W, Li J, Liang G. How does cellular heparan sulfate function in viral pathogenicity? Biomed Environ Sci. 2011 Feb;24(1):81-7. doi: 10.3967/0895-3988.2011.01.011. PMID: 21440844. Heparan sulfate (HS) is ubiquitously expressed on the surfaces and in the extracellular matrix of virtually all cell types, making it an ideal receptor for viral infection. Understanding how heparan sulfate functions during virus infection in vivo may prove critical for elucidating the molecular mechanism of viral pathogenesis, and may contribute to the development of therapeutics targeting HS.

Case studies

Ahn, YS., Kim, S., Kim, WJ. et al. Characteristics of hip impingement syndrome in patients with multiple hereditary exostoses. BMC Musculoskelet Disord 22, 153 (2021). https://doi.org/10.1186/s12891-021-04021-1 Between 2001 and 2019, total 51 patients (102 hips) were evaluated in this study. Patients with MHE were classified to femoro-acetabular impingement (FAI) symptom group, ischio-femoral impingement (IFI) symptom group and non-impingement symptom group by comparing the symptoms, clinical signs and imaging studies.

Albokhari, Daniah, Christopher R. Bailey, Francis Hwang, Clifford R. Weiss, Jonathan Forsberg, Nara Sobreira.  2023. Venous malformation may be a feature of EXT1-related hereditary multiple exostoses: A report of two unrelated probands.  American Journal of Medical Genetics.   Report two unrelated probands that presented with a clinical and molecular diagnosis of HME with venous malformation, a clinical feature not previously reported in individuals with HME.

Anel-Quimpo, Joselynna, Mark Anthony Santiago Sandoval, Frances Lina Lantion-Ang, 2011. Hypercalcaemia from genitourinary tuberculosis in a female with multiple exostoses. BMJ Journals. https://casereports.bmj.com/content/2011/bcr.12.2010.3651. The authors present a puzzling case of nephrolithiasis, hypercalcaemia, amenorrhoea, short stature and gross skeletal deformities in a 30-year-old female. Multiple pituitary hormone deficiency and metabolic bone disease were initially considered but were eventually excluded. The final diagnosis is genitourinary tuberculosis (TB) which caused the hypercalcaemia, nephrolithiasis and amenorrhoea, and also found to have the syndrome of multiple exostoses which explained the gross skeletal deformities and the short stature. After treatment with anti-TB therapy, there was resolution of hypercalcaemia and return of regular menstruation. The short stature and gross skeletal deformities remain as part of the congenital syndrome.

Bari MS, Jahangir Alam MM, Chowdhury FR, Dhar PB, Begum A. 2012. Hereditary multiple exostoses causing cord compression. J Coll Physicians Surg Pak 22:797–799.  Neurological presentations are rare and usually happened due to direct compression of a peripheral nerve or nerve root or less often the spinal cord. This case is possibly the first case of HME described from Bangladesh, presented with dorsal cord compression. Decompression was done and the complaints of myelopathy were improved.

Caino, Silvia, Marisa Angelica Cubilla, Romina Alba, María Gabriela Obregón, Virginia Fano, Abel Gómez, Lorena Zecchini, Pablo Lapunzina, Miriam Aza-Carmona, Karen E. Heath, and et al. 2022. "Clinical and Genetic Analysis of Multiple Osteochondromas in a Cohort of Argentine Patients" Genes 13, no. 11: 2063. https://doi.org/10.3390/genes13112063 Multiple Osteochondromatosis (MO, MIM 133700 & 133701), an autosomal dominant O-glycosylation disorder (EXT1/EXT2-CDG), can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature and pathogenic variants in two tumor suppressor genes, EXT1 and EXT2. In this work, we report a cross-sectional study including 35 index patients and 20 affected family members. Clinical phenotyping of all 55 affected cases was obtained, but genetic studies were performed only in 35 indexes.

Hariri O, Al Laham O, Ibrahim Basha Z, Ghannam E, Ghannam M, Mohammad A. Multiple Hereditary Exostoses instigating a popliteal pseudoaneurysm in a young Middle Eastern male: A case report and literature review. Int J Surg Case Rep. 2024 Apr 12;118:109633. doi: 10.1016/j.ijscr.2024.109633. Epub ahead of print. PMID: 38626641; PMCID: PMC11035074. We present the case of a 37-year-old Middle Eastern male with Multiple Hereditary Exostoses who experienced sudden-onset left lower limb pain persisting for a month prior to admission. It was associated with coldness and paresthesia of the ipsilateral lower limb. The presurgical radiological workup uncovered a popliteal pseudoaneurysm subsequent to Multiple Hereditary Exostoses.

Kambouris, M., Fadda A, Al-Arraj, Y, et al., 2016. Putative Relation Between Autism Spectrum Disease & Hereditary Multiple Exostosis Investigated by Whole Genome Sequencing & Comparative Genome Analyses in a Family with ASD and HME with EXT-1 Mutations A family with two male children affected with ASD and HME as well as an unaffected female child, was studied to identify the Genetic basis of ASD in the family and the possible relation between ASD & HME. The HME unaffected parent [mother] contributed heterozygous variants in the Heparan Sulfate biosynthesis pathway that in synergy with the EXT-1 mutation could be the genetic causes of ASD in the family.

Kim, Min Jeong, Yunjin Lee, Sang Ook Nam, Young Mi Kim, 2021. An 8q24.11q24.13 Microdeletion Encompassing EXT1 in a Boy with Autistic Spectrum Disorder, Intellectual Disability, and Multiple Hereditary Exostoses. Annals of Child Neurology. Letter to the Editor, 11/9/2021. Here, we describe the case of a boy with a microdeletion (8q24.11q24.13 [118,625,768-124,169,620]×1), who presented with autism, intellectual disability, and MHE. the parents signed informed consent and approved the anonymous use of clinical and molecular data for the present diagnostic study.

Küçükesmen, Çiḡdem DDS, PhD, Buḡra Özen, DDS, PhD,b and Mustafa Akçam, DDS, PhDc, 1997. Multiple Hereditary Osteochondromatosis: A Case Report. Eur J Dent. 2007 Jul; 1(3): 183–187.https://www.ncbi.nlm.nih. Common carious lesions owing to vomiting are not widespread in children. In this case, we aimed to report an 11-years-old male patient with common carious lesions due to repeated vomitings, chewing and eating difficulty and retarded growth with Multiple Hereditary Osteochondromatosis (MHO).

Li H, Yamagata T, Mori M, Momoi MY. 2002.Association of autism in two patients with hereditary multiple exostoses caused by novel deletion mutations of EXT1. J Hum Genet 2002;47:262-5. https://pubmed.ncbi.nlm.nih.gov/12032595/.  Two boys from separate families presented with hereditary multiple exostoses (EXT) and autism associated with mental retardation.

Malagón, V., 2001.  Development of Hip Dysplasia in Hereditary Multiple Exostosis. Journal of Pediatric Orthopaedics, 21(2): 205-211.  https://journals.lww.com/pedorthopaedics/Abstract/2001/03000/Development_of_Hip_Dysplasia_in_Hereditary.14.aspx. In approximately 25% of patients with hereditary multiple exostosis, there is an abnormal osteochondral formation localized in the femoral proximal metaphysis. Although this entity is rather frequent and quite severe, it is rarely found in the medical literature. The author describes six private cases, taken from a total of 24,000 patients (0.25/1000) as examples of this entity, and provides a review of the literature.

Mazza, D., Fabbri, M., Calderaro, C., Iorio, C., Labianca, L., Poggi, C., Turturro, F., Montanaro, A., & Ferretti, A. (2017). Chest pain caused by multiple exostoses of the ribs: A case report and a review of literature. World journal of orthopedics, 8(5), 436–440. https://doi.org/10.5312/wjo.v8.i5.436. An exceptional case of multiple internal exostoses of the ribs in a young patient affected by multiple hereditary exostoses (MHE) coming to our observation for chest pain as the only symptom of an intra-thoracic localization. The computed tomography (CT) scan revealed the presence of three exostoses located on the left third, fourth and sixth ribs, all protruding into the thoracic cavity, directly in contact with visceral pleura. Moreover, the apex of the one located on the sixth rib revealed to be only 12 mm away from pericardium.

Montgomery BK, Cahan EM, Frick S. Spinal Screening MRI Trends in Patients with Multiple Hereditary Exostoses: National Survey- PubMed . Cureus. 2019 Dec 23;11(12):e6452. doi: 10.7759/cureus.6452. PMID: 32010535; PMCID: PMC6975245. Background Multiple hereditary exostoses (MHE) is a rare disease characterized by multiple osteochondromas. Osteochondromas growing into the spinal canal can produce devastating consequences, including permanent neurologic deficits and even death. This study presents a case of an intracanal osteochondroma at C1 identified by routine screening and a survey describing current practices of MHE experts.

Narvid, J., M. L. Gorno-Tempini, A. Slavotinek, S. J. DeArmond, Y. H. Cha, B. L. Miller & K. Rankin, 2009. Of brain and bone: The unusual case of Dr. A. Neurocase Vol. 15, Iss. 3, 2009. http://www.tandfonline.com/doi/full/10.1080/13554790802632967. Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive decline in social conduct and a focal pattern of frontal and temporal lobe damage. Its biological basis is still poorly understood but the focality of the brain degeneration provides a powerful model to study the cognitive and anatomical basis of social cognition. Here, we present Dr. A, a patient with a rare hereditary bone disease (hereditary multiple exostoses) and FTD (pathologically characterized as Pick's disease), This case provides new evidence regarding the neural basis of social cognition and suggests a possible genetic link between bone disease and FTD.

Puiu1, Maria , Iulia Simina-Jurca, Simona Dumitriu, Smaranda Arghirescu,  Adela Chirita-Emandi,  2012. . Multiple Hereditary Exostoses - Clinical Features and Management. We report two cases of skeletally immature patients who presented with multiple exostoses, bone deformation without bone pain; and growth and pubertal retardation. The cases need adequate counseling, long-term follow-up, and measures to improve the quality of life of patients with multiple hereditary exostoses.

Stitzman Wengrowicz, M.L., J  Pretell-Mazzini,  J.P. Dormans, R.S. Davidson, 2011.. Regression of a Sessile Osteochondroma: A Case Study and Review of the Literature. https://www.researchgate.net/publication/267426996_Regression_of_a_Sessile_Osteochondroma_A_Case_Study_and_Review_of_the_Literature . The most common benign bone tumor is osteochondroma.  Its natural history is poorly understood as a consequence of its benign symptomatology in most cases. It typically grows in childhood and growth during adulthood can be a sign of malignant  degeneration. We present  a case of  spontaneous regression of  a solitary osteochondroma.  A review of the  current  literature which  reveals 21  other cases of  spontaneous regression  of solitary  osteochondromas is also discussed. We believe that the possibility of regression of solitary osteochondromas should be taken into account when considering surgical excision.

Viala P, Vanel D, Larbi A, Cyteval C, Laredo JD. Bilateral ischiofemoral impingement in a patient with hereditary multiple exostoses. Skeletal Radiol. 2012;41:1637–40. [PubMed] https://pubmed.ncbi.nlm.nih.gov/22865159/. We report a case of bilateral ischiofemoral impingement in a patient with hereditary multiple exostoses. The association of exostoses and femoral metaphyseal widening resulted in the narrowing of the ischiofemoral spaces.

Wang YZ, Park KW, Oh CS, Ahn YS, Kang QL, Jung ST, Song HR. Developmental pattern of the hip in patients with hereditary multiple exostoses. BMC Musculoskelet Disord. 2015;16:54. https://pmc.ncbi.nlm.nih.gov/articles/PMC4429362/. Coxa valga is a common clinical feature of hereditary multiple exostoses (HME). The current study aimed to determine the unique developmental pattern of the hip in patients with HME and evaluate the factors that influence its progression.

Wiater JM, Farley FA. Popliteal pseudoaneurysm caused by an adjacent osteochondroma: a case report and review of the literature. Am J Orthop (Belle Mead NJ). 1999 Jul;28(7):412-6. PMID: 10426440. A male 17-year-old with multiple hereditary exostoses presented with a mass in the distal left thigh several days after lifting weights. An arteriogram showed a popliteal artery pseudoaneurysm adjacent to a femoral osteochondroma. The osteochondroma was excised and the artery was repaired with a saphenous vein interposition graft. A review of the literature identified 23 similar reports. The average age of the patients was 21.3 years. Seventy-eight percent were men and half of the patients had multiple hereditary exostoses. Ten patients were initially misdiagnosed. The clinician should consider the diagnosis of pseudoaneurysm in a young patient with an osteochondroma and a mass about the knee.

Zaijun L, Xinhai Y, Zhipeng W, Wending H, Quan H, Zhenhua Z, Dapeng F, Jisheng Z, Wei Z, Jianru X. 2013. Outcome and prognosis of myelopathy and radiculopathy from osteochondroma in the mobile spine: a report on 14 patients. J Spinal Disord Tech 26:194–199. Fourteen symptomatic spinal osteochondroma (OC)  cases, including 2 hereditary multiple exostoses, were treated surgically from 2001 to 2010.

People and books with HME:

Deena Larsen wrote about her mother at http://www.deenalarsen.net/firs

Irv Rosenfeld wrote about his experiences with medical marijuana from the U.S. government in My Medicine.

Spanish Translation

Problemas de deficiencia de proteoglicano de sulfato de heparán (HSPG). La MHE es el resultado de una mutación en los genes EXT1 y EXT2. Los pacientes con MHE tienen una biosíntesis de HSPG defectuosa: sus cuerpos no producen HSPG (cf Cueller et al. 2013 y Jones et al. 2014). Los HSPG son parte de cada superficie celular y regulan los procesos biológicos (cf Zak et al. 2002, Meneghetti et al. 2015). Desempeñan un papel vital en la adhesión, migración, crecimiento y comunicación celular (Vicente et al. 2018). Whitlock e Iozzo (2005) han identificado varias enfermedades relacionadas con la ausencia de HSPG (es decir, si un proceso corporal requiere HSPG y no hay suficiente HSPG para completar esa función, entonces podrían ocurrir estos problemas). Los pacientes con MHE han reportado síntomas como:

• Baja masa ósea (Nozawa et al. 2018 y Matsumoto et al. 2020)
• Deficiencias neurológicas: Trastorno del espectro autista (Li et al, 2002, Fumitoshi et al. 2012, Irie et al, 2012, Yamaguchi 2012, Perez et al. 2015, Kambouris et al. 2016, Kim et al 2022); y problemas cognitivos (Farhan et al. 2015)
• Demencia frontotemporal (Narvid et al. 2009) y TDAH (Mooney et al. 2016), función cerebral (Condomitti y Wit 2018). Vea también el vídeo de ratones MHE en https://www.youtube.com/watch?v=6-EXRt_YL6A.
• Enfermedades oculares (Park y Shukla, 2013)
• Defectos dentales (Kucukesmen et al. 2007 y Wiweger et al. 2012)
• Prediabetes (Heibert 2021)Diabetes y dificultad para controlar la glucosa (Matsuzawa 2021)
• Reacciones medicamentosas inusuales (muchos medicamentos actúan sobre el dominio de unión del heparán [Boer y Gaillard 2007])
• Fatiga severa y continua (Berg et al. 1999)
• Problemas gástricos graves, incluidas úlceras no causadas por H. pylori (Ascencio et al. 1993 y Chmiela et al. 1995), cáncer gástrico (Weihua et al. 2002) y síndrome de vómitos cíclicos (Kucukesmen et al. 2007 y Theoharides et al. 1999)
• Cálculos renales y otros problemas (véase Van den Born et al. 1993 y Farhan et al. 2015)
• Vértigo e hiperacusia (Lundberg et al., 2014) y migrañas
• Problemas pulmonares (Nackerts et al. 1997 y Haeger et al. 2016)
• Anemia (Poli et al. 2017), coágulos sanguíneos y coagulación (Stringer y Gallagher 1997 y Ho et al. 1997), pseudoaneurismas (Wiater y Farley 1996 y Harari et al. 2024)
• Problemas menstruales y de embarazo extremadamente dolorosos (Alphin et al. 1988, Yin et al. 2018)
• Inflamación (Parroquia 2005); cicatrización lenta de heridas (Zhongjun et al. 2004); cicatrices y queloides (Hosalkar et al. 2007, y problemas del tejido conectivo (Forsberg y Kjellen, 2001 y Otsuka et al. 2020).
• Funciones hepáticas (Arnold et al. 2020 y Dituri et al. 2022)
• Funciones del colesterol y los lípidos (Kolsett y Salmverta 1999) y Síntesis de vitamina D (Cooper 2021) Problemas de crecimiento óseo. En la MHE, la falta de HSPG hace que los pacientes desarrollen exostosis, que son tumores benignos en múltiples ubicaciones en todo el cuerpo (Brown 2008, Thompson 2011 y Mansouri et al. 2017). La gravedad (número y tamaño de los tumores y otras complicaciones) de la MHE varía de un paciente a otro. Las exostosis en sí mismas pueden causar numerosos problemas, incluidos: irritación de tendones y músculos que produce dolor y pérdida de movimiento, deformidad esquelética, baja estatura, discrepancia en la longitud de las extremidades, subluxaciones y deformidad angular. Los problemas directamente asociados con estas exostosis incluyen:

• Dolor crónico y problemas con la calidad de vida (Goud et al. 2012)
• Inflamación, respuestas inmunitarias (Callaghan et al. 2018 y Collins y Troeberg 2019)
• Formación de bursa y bursitis resultante, así como artritis de aparición temprana.
• Problemas respiratorios y pulmonares al estar sobre costillas que sobresalen hacia la cavidad torácica (Mazza et al. 2017)
• Irritación de un nervio cercano (dolor, debilidad, entumecimiento, hormigueo)
• Aneurisma de vasos sanguíneos por exostosis que presionan los vasos sanguíneos u otros problemas vasculares (Albokhari et al. 2023)
• Problemas de compresión de la médula espinal: incontinencia, daño nervRésumé de la MEM pour les médecins et les écoles