Hereditary multiple exostoses

Last updated
Hereditary multiple osteochondromas
Other namesHereditary multiple exostoses
EXT4.jpg
Photograph of the legs of a 26-year-old male showing multiple lumps leading to deformity.
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg

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

Contents

Presentation

A noticeable lump in relation to an extremity may be the first presenting symptom. Multiple deformities can arise, namely coronal plane deformities around the knees, ankles, shoulders, elbows, and wrists. For example, genu valgum (knock knees), ankle valgus, ulnar bowing and shortening, and radial head subluxation are encountered. The majority of affected individuals have clinically manifest osteochondromas around the knee. Forearm involvement in HMO is considerable. [1] [4] Furthermore, short stature may occur and is generally disproportionate. Such manifestations usually result from disruption of physeal growth especially that osteochondromas typically arise at the metaphyseal ends of long bones in close proximity to the physis. [1] [4] Intra-articular osteochondromas of the hip can induce limitation of range of motion, joint pain and acetabular dysplasia. [2] Likewise joint pain at other locations and neurovascular compression can occur. Furthermore, functional disability in regard to activities of daily living can be a presenting feature. Spinal deformity pain or neurological compromise should arouse suspicion of involvement of the vertebrae. [3]

Pain

According to self-reports, a far majority of patients experience pain, and about half experience generalized pain. Individuals who had HME-related complications were five times more likely to have pain, while those who had surgery were 3.8 more likely to have pain. No differences were found between males and females with respect to pain, surgery, or HME-related complications. [5]

Possible connection to autism

Some parents of children with HME have observed autism-like social problems in their children. To explore those observations more deeply, a 2012 study by the Sanford-Burnham Medical Research Institute used a mouse model of HME to observe cognitive function. The findings indicated that the mutant mice endorsed three autistic characteristics: social impairment, impairments in ultrasonic vocalization, and repetitive behavior. [6]

Genetics

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

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

Mutations in these genes typically lead to the synthesis of a truncated EXT protein which does not function normally. It is known that EXT proteins are important enzymes in the synthesis of heparan sulfate proteoglycans; however, the exact mechanism by which altered synthesis of heparan sulfate that could lead to the abnormal bone growth associated with HME is unclear. It is thought that normal chondrocyte proliferation and differentiation may be affected, leading to abnormal bone growth. [10] [11] 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. [12]

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. [13] Other studies have observed both incomplete and variable penetrance but without calculating the % penetrance, e.g. [14] 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 boys/men 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. [15] It is also possible for females to be severely affected. Severity of symptoms varies between individuals, even in the same family.[ citation needed ]

Symptoms are more likely to be severe if the mutation is on the ext1 gene rather than ext2 or ext3; ext1 is also the most commonly affected gene in patients of this disorder. [15]

Pathophysiology

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

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

. Most common locations are: [16]

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 [17] 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. [17] Problems may be had in later life and these could include weak bones and nerve damage. [18] [19] [20] The reported rate of transformation ranges from as low as 0.57% [13] to as high as 8.3% of people with HME. [21] Some authors have described an association between HME and the presence of popliteal pseudoaneurysms. [22]

Diagnosis

The diagnosis of HMO is based upon establishing an accurate correlation between the above-mentioned clinical features and the characteristic radiographic features. Family history can provide an important clue to the diagnosis. This is supplemented by testing for the two genes in which pathogenic variants are known to cause HMO namely EXT1 and EXT2. A combination of sequence analysis and deletion analysis of the entire coding regions of both EXT1 and EXT2 detects pathogenic variants in 70–95% of affected individuals. [3] [4] The hallmark of radiographic diagnosis is the presence of osteochondromas at the metaphyseal ends of long bones in which the cortex and medulla of the osteochondroma represent a continuous extension of the host bone. This is readily demonstrable in radiographs of the knees. [3] [1]

Treatment

The indications for surgical intervention in individuals with HMO remain unclear and vary greatly across the medical literature. In general surgical treatment of HMO includes one or more of the following procedures: ostechondroma excision, gradual or acute bone lengthening such as the ulna lengthening, corrective osteotomies, temporary hemiepiphysiodesis to correct angular joint deformities such as distal radius hemiepiphysiodesis and medial distal tibial hemiepiphysiodesis. [1] [3] Nevertheless, there is little evidence to support the ongoing pediatric orthopedic practice in hereditary multiple osteochondromas. Recent systematic reviews found insufficient evidence to prove that the ongoing surgical treatment of HMO improves function considerably or to prove that it impacts the quality of life of affected children. [1] [2] To enhance the amount of evidence in the medical literature certain recommendations have been put forward. The construction of well-designed prospective studies that can provide a more clear relationship between surgical procedures, patient characteristics and outcomes is on high demand. Otherwise, following the current study designs will continue to raise more questions than answers. [1] [2] Total hip arthroplasty has been used to remedy severe and painful HMO of the hip joint. Total hip arthroplasty in individuals with HMO is challenging because of distortion of anatomy and repeated surgeries performed to address complaints related to exostosis. [23]

Epidemiology

HME is estimated to occur in 1 in 50,000 people. [16] [20]

Additional images

Related Research Articles

<span class="mw-page-title-main">Langer–Giedion syndrome</span> Medical condition

Langer–Giedion syndrome (LGS) is a very uncommon autosomal dominant genetic disorder caused by a deletion of a small section of material on chromosome 8. It is named after the two doctors who undertook the main research into the condition in the 1960s. Diagnosis is usually made at birth or in early childhood.

<span class="mw-page-title-main">Treacher Collins syndrome</span> Human genetic disorder

Treacher Collins syndrome (TCS) is a genetic disorder characterized by deformities of the ears, eyes, cheekbones, and chin. The degree to which a person is affected, however, may vary from mild to severe. Complications may include breathing problems, problems seeing, cleft palate, and hearing loss. Those affected generally have normal intelligence.

<span class="mw-page-title-main">Exostosis</span> Formation of new bone on the surface of a bone

An exostosis, also known as a bone spur, is the formation of new bone on the surface of a bone. Exostoses can cause chronic pain ranging from mild to debilitatingly severe, depending on the shape, size, and location of the lesion. It is most commonly found in places like the ribs, where small bone growths form, but sometimes larger growths can grow on places like the ankles, knees, shoulders, elbows and hips. Very rarely are they on the skull.

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

Osteochondromas are the most common benign tumors of the bones. The tumors take the form of cartilage-capped bony projections or outgrowth on the surface of bones exostoses. It is characterized as a type of overgrowth that can occur in any bone where cartilage forms bone. Tumors most commonly affect long bones about the knee and in the forearm. Additionally, flat bones such as the pelvis and scapula may be affected. Hereditary multiple exostoses usually present during childhood. Yet, the vast majority of affected individuals become clinically manifest by the time they reach adolescence. Osteochondromas occur in 3% of the general population and represent 35% of all benign tumors and 8% of all bone tumors. The majority of these tumors are solitary non-hereditary lesions and approximately 15% of osteochondromas occur as hereditary multiple exostoses preferably known as hereditary multiple osteochondromas (HMOs). Osteochondromas do not result from injury and the exact cause remains unknown. Recent research has indicated that multiple osteochondromas is an autosomal dominant inherited disease. Germ line mutations in EXT1 and EXT2 genes located on chromosomes 8 and 11 have been associated with the cause of the disease. The treatment choice for osteochondroma is surgical removal of solitary lesion or partial excision of the outgrowth, when symptoms cause motion limitations or nerve and blood vessel impingements. In hereditary multiple exostoses the indications of surgery are based upon multiple factors that are taken collectively, namely: patient's age, tumor location and number, accompanying symptomatology, esthetic concerns, family history and underlying gene mutation. A variety of surgical procedures have been employed to remedy hereditary multiple exostoses such as osteochondroma excision, bone lengthening, corrective osteotomy and hemiepiphysiodesis. Sometimes a combination of the previous procedures is used. The indicators of surgical success in regard to disease and patient characteristics are greatly disputable. Because most studies of hereditary multiple exostoses are retrospective and of limited sample size with missing data, the best evidence for each of the currently practiced surgical procedures is lacking.

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

Metachondromatosis is an autosomal dominant, incompletely penetrant genetic disease affecting the growth of bones, leading to exostoses primarily in the hands and feet as well as enchondromas of long bone metaphyses and iliac crests. This syndrome affects mainly tubular bones, though it can also involve the vertebrae, small joints, and flat bones. The disease is thought to affect exon 4 of the PTPN11 gene. Metachondromatosis is believed to be caused by an 11 base pair deletion resulting in a frameshift and nonsense mutation. The disease was discovered and named in 1971 by Pierre Maroteaux, a French physician, when he observed two families with skeletal radiologic features with exostoses and Ollier disease. The observation of one family with five affected people led to the identification of the disease as autosomal dominant. There have been less than 40 cases of the disease reported to date.

<span class="mw-page-title-main">Heparan sulfate</span> Macromolecule

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

<span class="mw-page-title-main">Nail–patella syndrome</span> Medical condition

Nail–patella syndrome is a genetic disorder that results in small, poorly developed nails and kneecaps, but can also affect many other areas of the body, such as the elbows, chest, and hips. The name "nail–patella" can be very misleading because the syndrome often affects many other areas of the body, including even the production of certain proteins. The severity of these effects varies depending on the individual. It is also referred to as iliac horn syndrome, hereditary onychoosteodysplasia, Fong disease or Turner–Kieser syndrome.

<span class="mw-page-title-main">Epiphyseal plate</span> Cartilage plate in the neck of a long bone

The epiphyseal plate, epiphysial plate, physis, or growth plate is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, with maintenance remodeling throughout its existing bone tissue, but the growth plate is the place where the long bone grows longer.

<span class="mw-page-title-main">Multiple epiphyseal dysplasia</span> Rare genetic disorder

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

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

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

In enzymology, a N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">EXT1</span> Protein-coding gene in the species Homo sapiens

Exostosin-1 is a protein that in humans is encoded by the EXT1 gene.

<span class="mw-page-title-main">EXT2 (gene)</span> Protein-coding gene in the species Homo sapiens

Exostosin glycosyltransferase-2 is a protein that in humans is encoded by the EXT2 gene.

<span class="mw-page-title-main">EXTL3</span> Protein-coding gene in the species Homo sapiens

Exostosin-like 3 is a protein that in humans is encoded by the EXTL3 gene.

<span class="mw-page-title-main">EXTL1</span> Protein-coding gene in the species Homo sapiens

Exostosin-like 1 is a protein that in humans is encoded by the EXTL1 gene.

<span class="mw-page-title-main">Winchester syndrome</span> Rare hereditary connective tissue disease

Winchester syndrome is a rare hereditary connective tissue disease described in 1969, of which the main characteristics are short stature, marked contractures of joints, opacities in the cornea, coarse facial features, dissolution of the carpal and tarsal bones, and osteoporosis. Winchester syndrome was once considered to be related to a similar condition, multicentric osteolysis, nodulosis, and arthropathy (MONA). However, it was discovered that the two are caused by mutations found in different genes; however they mostly produce the same phenotype or clinical picture. Appearances resemble rheumatoid arthritis. Increased uronic acid is demonstrated in cultured fibroblasts from the skin and to a lesser degree in both parents. Despite initial tests not showing increased mucopolysaccharide excretion, the disease was regarded as a mucopolysaccharidosis. Winchester syndrome is thought to be inherited as an autosomal recessive trait.

<span class="mw-page-title-main">EXTL2</span> Protein-coding gene in the species Homo sapiens

Exostosin-like 2 is a protein that in humans is encoded by the EXTL2 gene. EXTL2 Glycosyltransferase is required for the biosynthesis of heparan-sulfate and responsible for the alternating addition of beta-1-4-linked glucuronic acid (GlcA) and alpha-1-4-linked N-acetylglucosamine (GlcNAc) units to nascent heparan sulfate chains.

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

Trevor disease, also known as dysplasia epiphysealis hemimelica and Trevor's disease, is a congenital bone developmental disorder. There is 1 case per million population. The condition is three times more common in males than in females.

Potocki–Shaffer syndrome (PSS), also known as DEFECT11 syndrome or chromosome 11p11.2 deletion syndrome, is a rare contiguous gene syndrome that results from the microdeletion of section 11.2 on the short arm of chromosome 11 (11p11.2). The syndrome has its name from Dr. Lorraine (Lori) Potocki and Dr. Lisa Shaffer who discovered the deletion on the 11th chromosome and studied the impacts.

Glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase is an enzyme with systematic name UDP-N-acetyl-D-glucosamine:beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase. This enzyme catalyses the following chemical reaction

References

  1. 1 2 3 4 5 6 7 EL-Sobky, TA; Samir, S; Atiyya, AN; Mahmoud, S; Aly, AS; Soliman, R (21 March 2018). "Current paediatric orthopaedic practice in hereditary multiple osteochondromas of the forearm: a systematic review". Sicot-J. 4: 10. doi:10.1051/sicotj/2018002. PMC   5863686 . PMID   29565244.
  2. 1 2 3 4 Makhdom, AM; Jiang, F; Hamdy, RC; Benaroch, TE; Lavigne, M; Saran, N (20 May 2014). "Hip joint osteochondroma: systematic review of the literature and report of three further cases". Advances in Orthopedics. 2014: 180254. doi: 10.1155/2014/180254 . PMC   4054980 . PMID   24963411.
  3. 1 2 3 4 5 Wuyts, W; Schmale, GA; Chansky, HA; et al. (21 November 2013). "Hereditary Multiple Osteochondromas". GeneReviews. University of Washington, Seattle. PMID   20301413 . Retrieved 24 March 2018.
  4. 1 2 3 Alvarez, CM; De Vera, MA; Heslip, TR; Casey, B (September 2007). "Evaluation of the anatomic burden of patients with hereditary multiple exostoses". Clin Orthop Relat Res. 462: 73–79. doi:10.1097/BLO.0b013e3181334b51. PMID   17589361. S2CID   39999620.
  5. ↑ Darilek S, Wicklund C, Novy D, Scott A, Gambello M, Johnston D, Hecht J (May 2005). "Hereditary multiple exostosis and pain". Journal of Pediatric Orthopaedics. 25 (3): 369–76. doi:10.1097/01.bpo.0000150813.18673.ad. PMID   15832158. S2CID   27884079.
  6. ↑ Irie F, Badie-Mahdavi H, Yamaguchi Y (March 2012). "Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate". Proceedings of the National Academy of Sciences of the United States of America. 109 (13): 5052–6. Bibcode:2012PNAS..109.5052I. doi: 10.1073/pnas.1117881109 . PMC   3323986 . PMID   22411800.
  7. ↑ Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G (1993). "Genetic heterogeneity in families with hereditary multiple exostoses". American Journal of Human Genetics. 53 (1): 71–9. PMC   1682231 . PMID   8317501.
  8. ↑ Wu YQ, Heutink P, de Vries BB, Sandkuijl LA, van den Ouweland AM, Niermeijer MF, Galjaard H, Reyniers E, Willems PJ, Halley DJ (1994). "Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11". Human Molecular Genetics. 3 (1): 167–71. doi:10.1093/hmg/3.1.167. PMID   8162019.
  9. ↑ Le Merrer M, Legeai-Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H, Toutain A, Achard F, Munnich A, Maroteaux P (1994). "A gene for hereditary multiple exostoses maps to chromosome 19p". Human Molecular Genetics. 3 (5): 717–22. CiteSeerX   10.1.1.1028.5356 . doi:10.1093/hmg/3.5.717. PMID   8081357.
  10. ↑ Zak BM, Crawford BE, Esko JD (2002). "Hereditary multiple exostoses and heparan sulfate polymerization". Biochimica et Biophysica Acta (BBA) - General Subjects. 1573 (3): 346–55. doi:10.1016/S0304-4165(02)00402-6. PMID   12417417.
  11. ↑ Stieber JR, Dormans JP (2005). "Manifestations of hereditary multiple exostoses". The Journal of the American Academy of Orthopaedic Surgeons. 13 (2): 110–20. doi:10.5435/00124635-200503000-00004. PMID   15850368. S2CID   29077708.
  12. ↑ Jaeken J, Hennet T, Matthijs G, Freeze HH (2009). "CDG nomenclature: time for a change!". Biochim. Biophys. Acta. 1792 (9): 825–6. doi:10.1016/j.bbadis.2009.08.005. PMC   3917312 . PMID   19765534.
  13. 1 2 Legeai-Mallet L, Munnich A, Maroteaux P, Le Merrer M (July 1997). "Incomplete penetrance and expressivity skewing in hereditary multiple exostoses". Clinical Genetics. 52 (1): 12–6. doi:10.1111/j.1399-0004.1997.tb02508.x. PMID   9272707. S2CID   44423092.
  14. ↑ Faiyaz-Ul-Haque M, Ahmad W, Zaidi SH, et al. (August 2004). "Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis)". Clinical Genetics. 66 (2): 144–51. doi:10.1111/j.1399-0004.2004.00275.x. PMID   15253765. S2CID   10431219.
  15. 1 2 Porter DE, Lonie L, Fraser M, et al. (September 2004). "Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study". The Journal of Bone and Joint Surgery. British Volume. 86 (7): 1041–6. doi:10.1302/0301-620x.86b7.14815. hdl: 20.500.11820/8754788e-ceea-4613-8e65-60d34fcf9edc . PMID   15446535. S2CID   7129239.
  16. 1 2 Turek's orthopaedics principles and their application (6th ed.). Philadelphia: Lippincott Williams & Wilkins. 2005. p. 263. ISBN   9780781742986.
  17. 1 2 Davies, A. Mark; Pettersson, Holger (2002). Pettersson, Holger; Ostensen, Harald (eds.). Radiography of the Musculoskeletal System (PDF). Geneva: World Health Organization. pp. 177, 189. ISBN   978-92-4-154555-6.
  18. ↑ CANNON JF (1954). "Hereditary multiple exostoses". American Journal of Human Genetics. 6 (4): 419–25. PMC   1716573 . PMID   14349947.
  19. ↑ McBride WZ (September 1988). "Hereditary multiple exostoses". American Family Physician. 38 (3): 191–2. PMID   3046271.
  20. 1 2 Schmale GA, Conrad EU, Raskind WH (July 1994). "The natural history of hereditary multiple exostoses". The Journal of Bone and Joint Surgery. American Volume. 76 (7): 986–92. doi:10.2106/00004623-199407000-00005. PMID   8027127. Archived from the original on 2014-09-20.
  21. ↑ Kivioja A, Ervasti H, Kinnunen J, Kaitila I, Wolf M, Böhling T (March 2000). "Chondrosarcoma in a family with multiple hereditary exostoses". The Journal of Bone and Joint Surgery. British Volume. 82 (2): 261–6. doi: 10.1302/0301-620X.82B2.0820261 . PMID   10755438.
  22. ↑ Parada Duarte O, Arambula Neira J, Castillo Herazo V, Oviedo Lara M, López Polanco A, Durán Omaña A, Herrera Ortiz AF. Popliteal artery pseudoaneurysm caused by non–penetrating trauma in a patient with hereditary multiple osteochondromatosis. Radiology Case Reports.2021;17(1):185-189. https://doi.org/10.1016/j.radcr.2021.10.025
  23. ↑ Vaishya, R; Swami, S; Vijay, V; Vaish, A (5 Jan 2015). "Bilateral total hip arthroplasty in a young man with hereditary multiple exostoses". BMJ Case Rep. 2015: bcr2014207853. doi:10.1136/bcr-2014-207853. PMC   4289752 . PMID   25564594.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.