Osteochondrodysplasia

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Osteochondrodysplasia
Other namesSkeletal dysplasia
SpecialtyOrthopedic

An osteochondrodysplasia,[note 1] or skeletal dysplasia, is a disorder of the development of bone and cartilage.[1] Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia.[2] Nonetheless, if taken collectively, genetic skeletal dysplasias or osteochondrodysplasias comprise a recognizable group of genetically determined disorders with generalized skeletal affection. These disorders lead to disproportionate short stature and bone abnormalities, particularly in the arms, legs, and spine.[3] Skeletal dysplasia can result in marked functional limitation and even mortality.

Osteochondrodysplasias or skeletal dysplasia subtypes can overlap in clinical aspects, therefore plain radiography is absolutely necessary to establish an accurate diagnosis.[4] Magnetic resonance imaging can provide further diagnostic insights and guide treatment strategies especially in cases of spinal involvement. As some disorders that cause skeletal dysplasia have treatments available, early diagnosis is particularly important, but may be challenging due to overlapping features and symptoms[5] that may also be common in unaffected children.

Types[edit]

Achondroplasia[edit]

Main article: Achondroplasia

Achondroplasia is a type of autosomal dominant genetic disorder that is the most common cause of dwarfism. It is also the most common type of non-lethal osteochondrodysplasia or skeletal dysplasia. The prevalence is approximately 1 in 25,000 births.[6] Achondroplastic dwarfs have short stature, with an average adult height of 131 cm (4 feet, 3 inches) for males and 123 cm (4 feet, 0 inches) for females. In achondroplasia the dwarfism is readily apparent at birth. likewise, craniofacial abnormalities in the form of macrocephaly and mid-face hypoplasia are present at birth. The previous clinical findings differentiate between achondroplasia and pseudoachondroplasia in which dwarfism is not recognizable at birth and craniofacial abnormalities are not considered a disease feature. Plain radiography plays an additional and important role in the differential diagnosis of achondroplasia.[4]

Pseudoachondroplasia[edit]

Pseudoachondroplasia is an osteochondrodysplasia made distinctive by disproportionate short stature, hip and knee deformities, brachydactyly (short fingers) and ligamentous laxity. It affects at least 1 in 20,000 individuals. Pseudoachondroplasia is inherited in an autosomal dominant manner and is caused solely by mutations in the cartilage oligomeric matrix protein COMP gene.[7] It’s distinguished by a moderate to severe form of disproportionate short-limb short stature. The limb shortening is fundamentally confined to the proximal limb segments i.e., Femurs and humeri. A known presenting feature is a waddling gait, noticed at the onset of walking. A prompt diagnosis of a skeletal dysplasia in general and Pseudoachondroplasia in specific is still based upon a comprehensive clinical and radiographic correlation.[4] A detailed radiographic examination of the axial and appendicular skeleton is invaluable for the differential diagnosis of Pseudoachondroplasia. Coxa vara (reduced neck shaft angle), broad femoral necks, short femurs and humeri, and bullet-shaped vertebrae are noticeable radiographic features. Additionally, the presence of metaphyseal broadening, cupping and dense line of ossification about the knee can simulate rachitic changes. These radiographic features are collectively known as rachitic-like changes. The presence of epiphyseal changes serves as an important differentiating feature from achondroplasia.[4]

Osteogenesis imperfecta[edit]

Main article: Osteogenesis imperfecta

COL1A1/2-related osteogenesis imperfecta is inherited in an autosomal dominant manner. The proportion of cases caused by a De novo COL1A1 or COL1A2 mutations are the cause of osteogenesis imperfecta in the vast majority of perinatally lethal osteogenesis imperfecta, and progressively deforming osteogenesis imperfecta. In classic non-deforming osteogenesis imperfecta with blue sclerae or common variable osteogenesis imperfecta with normal sclerae, nearly 60% of cases are de novo. COL1A1/2-related osteogenesis imperfecta is identified by repeated fractures with trivial trauma, defective dentinogenesis imperfecta (DI), and hearing loss. The clinical features of COL1A1/2-related osteogenesis imperfecta can be highly variable ranging from severe and lethal perinatal fractures to individuals with minimal tendency to repeated fractures and skeletal deformities and with a normal stature and life span. In between the clinical spectrum may include individuals with various degrees of disabling skeletal deformities and short stature.[8] The radiographic findings of osteogenesis imperfecta include; long bone deformations such as bowing of the tibias and femurs, pencil-like deformity and tapering of bones, cortical thinning and rarefaction, pathologic fractures at various degrees of healing, bone shortening and vertebral wedging.[4] Accordingly, COL1A1/2-related osteogenesis imperfecta has been classified into four sub-types (I, II, III, and IV) built upon the diversity of the radioclinical features.[9]

Mucopolysaccharidosis[edit]

Mucopolysaccharidoses (MPS) constitute a commonly seen group of osteochondrodysplasias. Mucopolysaccharidosis can cause a wide spectrum of clinical and radiologic manifestations ranging from mild skeletal and systemic involvement to severe life-threatening manifestations. It is caused by a contiguous gene duplication or deletion syndrome in which multiple genes are involved. All forms of MPS are inherited in an autosomal recessive pattern, except fir of MPS II; Hunter syndrome which is X-linked.[10] They are caused by an abnormal function of the lysosomal enzymes, which blocks degradation of mucopolysaccharides and leads to accumulation of harmful byproducts, namely, heparan sulfate, dermatan sulfate, and keratan sulfate.[10] The resulting cellular malfunction can lead to a diverse array of skeletal and visceral manifestations. MPS have been subcategorized according to the type of enzyme inadequacy and glycoprotein accumulated.[11]

Cleidocranial dysostosis[edit]

Main article: Cleidocranial dysostosis

Cleidocranial dysostosis is a general skeletal condition named for the collarbone (cleido-) and cranium deformities which people with it often have. Common features include:[12]

Fibrous dysplasia[edit]

Main article: Fibrous dysplasia

Fibrous dysplasia causes bone thinning[13] and growths or lesions in one or more bones of the human body.

These lesions are tumor-like growths that consist of replacement of the medullary bone with fibrous tissue, causing the expansion and weakening of the areas of bone involved. Especially when involving the skull or facial bones, the lesions can cause externally visible deformities. The skull is often, but not necessarily, affected, and any other bones can be involved.[14]

Langer–Giedion syndrome[edit]

Main article: Langer–Giedion syndrome

Langer–Giedion syndrome is a very rare genetic disorder caused by a deletion of chromosomal material. Diagnosis is usually made at birth or in early childhood. The features associated with this condition include mild to moderate learning difficulties, short stature, unique facial features, small head and skeletal abnormalities including bony growths projecting from the surfaces of bones.[15]

Maffucci syndrome[edit]

Main article: Maffucci syndrome

Maffucci syndrome is a sporadic disease characterized by the presence of multiple enchondromas associated with multiple simple or cavernous soft tissue hemangiomas. Also lymphangiomas may be apparent.[16]

Patients are normal at birth and the syndrome manifests during childhood and puberty. The enchondromas affect the extremities and their distribution is asymmetrical.[17]

Osteosclerosis[edit]

Main article: Osteosclerosis

Osteosclerosis, an elevation in bone density,[18] is normally detected on an X-ray as an area of whiteness and is where the bone density has significantly increased.

Other[edit]

Diagnosis[edit]

The diagnosis is mainly based upon delineating the specific clinical and radiographic pattern of skeletal involvement. However, the different types of skeletal dysplasia can overlap considerably in their clinical presentation. Molecular or genetic analysis may be required to resolve diagnostic difficulties.

Differential diagnosis[edit]

Juvenile idiopathic arthritis may closely resemble the clinical presentation of some osteochondrodysplasias or genetic skeletal dysplsias. In that, both conditions can present with swollen, stiff and deformed joints.[20][21]

Type II collagen disorders are caused by variants in the COL2A1 gene. Type II collagen disorders can result in mild disease or severe which can cause death within weeks of birth. Infants with the severe form of the disease would be born with clear indications of the disease, such as disproportionate short stature, skeletal dysplasia, distinctive eye abnormalities, cleft palate, and others. However, infants with mild disease may only experience arthritis at birth, but may progress to more severe disease later in life. Early diagnosis can be challenging. Furthermore, type II collagenopathies have significant phenotypic overlap with conditions such as MPS. Guidelines are available to ensure healthcare professional are aware of the conditions and the symptoms of disease to support efficient diagnosis.[22]

Treatment[edit]

Emerging therapies for genetic skeletal dysplasias include enzyme replacement therapy,[23] small molecule therapy,[24] hematopoietic stem cell transplantation[25][26] and gene therapy. These therapies aim at preventing disease progression and thus improving quality of life. Enzyme replacement therapies are some of the mucopolysaccharidoses[23] and Gaucher disease.[27] Results have shown effectivity of enzyme replacement therapy. Hematopoietic stem cell transplantation can be lifesaving for some disorders, such as with malignant infantile osteopetrosis.[25][26]

Even with treatments such as enzyme replacement therapy and stem cell transplantation, people with skeletal dysplasia often require orthopedic surgery and other disease management interventions. There is a lack of information available to support these patients as most physicians may only see one or two skeletal dysplasia patients in their lifetime. Guidelines are available to support best practices for managing several areas of skeletal dysplasia, such as the craniofacial aspects of skeletal dysplasia,[28] spinal disorders,[5] diagnosis and management of type II collagen disorders,[22] pregnancy of people with skeletal dysplasia,[29] peri-operative management,[30] and foramen magnum stenosis in achondroplasia.[31] Written and video resources for patients with skeletal dysplasia and caregivers are also available.

Management[edit]

Timely management of skeletal dysplasia is important to combat functional deterioration.[4] Due to rarity of the individual disorders that cause skeletal dysplasia, management can be challenging if a patient does not have access to a facility that has physicians who specialize in skeletal dysplasia. Guidelines have been developed for the management different aspects of skeletal dysplasia,[32] including best practices for managing craniofacial[28] and spinal manifestations,[5] diagnosis and management of type II collagen disorders,[22] pregnancy of people with skeletal dysplasia,[29] peri-operative management,[30] and foramen magnum stenosis in achondroplasia.[31] Written and video resources to support patients with skeletal dysplasia and caregivers are also available.

Footnotes[edit]

Notes[edit]

  1. ^ Etymology: from Ancient Greek ὀστέο(ν) (ostéo(n)) 'bone', χόνδρο(ς) (khóndro(s)) 'cartiledge', δυσ (dus) 'badly', and -πλασίᾱ (-plasíā) 'formed'.

References[edit]

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  2. ^ Geister, Krista A.; Camper, Sally A. (2015-01-01). "Advances in Skeletal Dysplasia Genetics". Annual Review of Genomics and Human Genetics. 16 (1): 199–227. doi:10.1146/annurev-genom-090314-045904. PMC 5507692. PMID 25939055.
  3. ^ Mortier, Geert R.; Cohn, Daniel H.; Cormier-Daire, Valerie; Hall, Christine; Krakow, Deborah; Mundlos, Stefan; Nishimura, Gen; Robertson, Stephen; Sangiorgi, Luca; Savarirayan, Ravi; Sillence, David; Superti-Furga, Andrea; Unger, Sheila; Warman, Matthew L. (2019-10-21). "Nosology and classification of genetic skeletal disorders: 2019 revision". American Journal of Medical Genetics Part A. 179 (12): 2393–2419. doi:10.1002/ajmg.a.61366. hdl:11343/286524. ISSN 1552-4825. PMID 31633310. S2CID 204813822.
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  5. ^ a b c White, Klane; Bober, Michael B; Cho, Tae-Joon; Goldberg, Michael J; Hoover-Fong, Julie; Irving, Melita; Kamps, Shawn; Mackenzie, William G; Raggio, Cathleen (2020-02-18). "Best practice guidelines for management of spinal disorders in skeletal dysplasia". dx.doi.org. doi:10.21203/rs.2.23876/v1. hdl:11343/245301. PMID 32580780. Retrieved 2023-12-13.
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  8. ^ Steiner, RD; Adsit, J; Basel, D (14 February 2013). "COL1A1/2 Osteogenesis Imperfecta". COL1A1/2-Related Osteogenesis Imperfecta. University of Washington, Seattle. PMID 20301472. Retrieved 16 April 2018.
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  10. ^ a b "Mucopolysaccharidoses". NORD (National Organization for Rare Disorders). Retrieved 2022-11-18.
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  13. ^ "fibrous dysplasia of bone" at Dorland's Medical Dictionary
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  15. ^ Devidayal, null; Marwaha, Ram Kumar (2006-02-01). "Langer-Giedion Syndrome". Indian Pediatrics. 43 (2): 174–175. ISSN 0019-6061. PMID 16528117 – via PubMed.
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  18. ^ "Medcyclopaedia - Osteosclerosis". Retrieved 2007-12-23.
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  22. ^ a b c Savarirayan, Ravi; Bompadre, Viviana; Bober, Michael B.; Cho, Tae-Joon; Goldberg, Michael J.; Hoover-Fong, Julie; Irving, Melita; Kamps, Shawn E.; Mackenzie, William G.; Raggio, Cathleen; Spencer, Samantha S.; White, Klane K. (September 2019). "Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders". Genetics in Medicine. 21 (9): 2070–2080. doi:10.1038/s41436-019-0446-9. ISSN 1098-3600. PMID 30696995.
  23. ^ a b Jameson, Elisabeth; Jones, Simon; Remmington, Tracey (18 June 2019). "Enzyme replacement therapy with laronidase (Aldurazyme®) for treating mucopolysaccharidosis type I". Cochrane Database of Systematic Reviews. 6 (4): CD009354. doi:10.1002/14651858.CD009354.pub5. PMC 6581069. PMID 31211405.
  24. ^ Savarirayan, Ravi; Tofts, Louise; Irving, Melita; Wilcox, William R.; Bacino, Carlos A.; Hoover-Fong, Julie; Font, Rosendo Ullot; Harmatz, Paul; Rutsch, Frank; Bober, Michael B.; Polgreen, Lynda E.; Ginebreda, Ignacio; Mohnike, Klaus; Charrow, Joel; Hoernschemeyer, Daniel (December 2021). "Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study". Genetics in Medicine. 23 (12): 2443–2447. doi:10.1038/s41436-021-01287-7. PMC 8327889. PMID 34341520.
  25. ^ a b Hashemi Taheri, Amir Pejman; Radmard, Amir Reza; Kooraki, Soheil; Behfar, Maryam; Pak, Neda; Hamidieh, Amir Ali; Ghavamzadeh, Ardeshir (September 2015). "Radiologic resolution of malignant infantile osteopetrosis skeletal changes following hematopoietic stem cell transplantation: Radiologic Resolution of MIOP After HSCT". Pediatric Blood & Cancer. 62 (9): 1645–1649. doi:10.1002/pbc.25524. PMID 25820806. S2CID 11287381.
  26. ^ a b El-Sobky, Tamer; El-Haddad, Alaa; Elsobky, Ezzat; Elsayed, Solaf; Sakr, Hossam (1 March 2017). "Reversal of skeletal radiographic pathology in a case of malignant infantile osteopetrosis following hematopoietic stem cell transplantation". The Egyptian Journal of Radiology and Nuclear Medicine. 48 (1): 237–243. doi:10.1016/j.ejrnm.2016.12.013.
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  28. ^ a b Savarirayan, Ravi; Tunkel, David E.; Sterni, Laura M.; Bober, Michael B.; Cho, Tae-Joon; Goldberg, Michael J; Hoover-Fong, Julie; Irving, Melita; Kamps, Shawn E. (2021-01-05). "Best practice guidelines in managing the craniofacial aspects of skeletal dysplasia". dx.doi.org. doi:10.21203/rs.3.rs-61766/v2. hdl:11343/272597. PMID 33446226. Retrieved 2023-12-13.
  29. ^ a b Savarirayan, Ravi; Rossiter, Judith P.; Hoover-Fong, Julie E.; Irving, Melita; Bompadre, Viviana; Goldberg, Michael J.; Bober, Michael B.; Cho, Tae-Joon; Kamps, Shawn E.; Mackenzie, William G.; Raggio, Cathleen; Spencer, Samantha S.; White, Klane K. (December 2018). "Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia". American Journal of Obstetrics and Gynecology. 219 (6): 545–562. doi:10.1016/j.ajog.2018.07.017. ISSN 0002-9378. PMID 30048634.
  30. ^ a b White, Klane K.; Bompadre, Viviana; Goldberg, Michael J.; Bober, Michael B.; Cho, Tae-Joon; Hoover-Fong, Julie E.; Irving, Melita; Mackenzie, William G.; Kamps, Shawn E.; Raggio, Cathleen; Redding, Gregory J.; Spencer, Samantha S.; Savarirayan, Ravi; Theroux, Mary C. (August 2017). "Best practices in peri-operative management of patients with skeletal dysplasias". American Journal of Medical Genetics Part A. 173 (10): 2584–2595. doi:10.1002/ajmg.a.38357. hdl:11343/293252. ISSN 1552-4825. PMID 28763154. S2CID 22251966.
  31. ^ a b White, Klane K.; Savarirayan, Ravi; Goldberg, Michael J.; MacKenzie, William; Bompadre, Viviana; Bober, Michael B.; Cho, Tae-Joon; Hoover-Fong, Julie; Parnell, Shawn E.; Raggio, Cathleen; Spencer, Samantha A.; Campbell, Jeffery W.; Rapoport, David M.; Kifle, Yemiserach; Blackledge, Marcella (2016-01-11). "Response: "Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy" and "is there a correlation between sleep disordered breathing and foramen magnum stenosis in children with achondroplasia?"". American Journal of Medical Genetics Part A. 170 (4): 1101–1103. doi:10.1002/ajmg.a.37546. hdl:11343/290811. ISSN 1552-4825. PMID 26754314. S2CID 35361558.
  32. ^ "Publications". Skeletal Displasia Management Consortium. 27 February 2023. Retrieved 14 December 2023.

External links[edit]

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