Osteogenesis Imperfecta: Bruck Syndrome (Brittle Bone Disease)
Brief Summary of Disease
Bruck syndrome (BS) is a rare disease in which bone fragility is associated with congenital joint contractures, permanent tightening of the tissues. It has been regarded as an autosomal recessive form of osteogenesis imperfecta (OI), or imperfect bone formation 3, 7, 9 . Therefore, people experiencing this disease will have bones that break (fracture) easily, often with little to no physical activity. There also exists a chance of multiple fractures occurring at the same time, and sometimes even before or during birth 7 . This disease affects 1 in 10,000 to 20,000 people worldwide, and researchers have discovered 19 different forms of OI 2,5 . OI type II is the most severe type in which infants often experience life-threatening complications at, or shortly after, birth. Studies have also illustrated that the median survival time for males with OI being 72.4 years, compared to 81.9 in the reference population. The median survival time for females with OI was 77.4 years, compared to 84.5 years in the reference population 4 . Patients with OI display a multitude of skeletal characteristics ranging from low bone mass (OI Type I) to increasing bone deformities (OI Type II/III) and death before birth (OI Type IV) 1,4 .
“The most frequent cause of OI is the glycine substitutions in the helical domain of type I collagen, which can significantly affect helical assembly.”
Etiology and Pathology
OI is predominantly onset by autosomal dominant mutations in the two genes that encode type I collagen (COL1A1 and COL1A2) as these cause approximately 90 percent of all cases
5
. Being the most abundant protein in the bones, collagen functions to provide structure and support to the body. It is particularly important in bone, skin, and connective tissue
3
. The most frequent cause of OI is the glycine substitutions in the helical domain of type I collagen, which can significantly affect helical assembly. As a result, the body may respond by hydrolyzing the improper collagen structure. If the body does not destroy the improper collagen, the ability of collagen fibrils crystals to form bone is altered, causing brittleness
5,8
. Furthermore, recessive forms of OI also relate heavily to the defects in the collagen chaperones responsible for production of pro-collagen and the assembly of the related proteins
10
. Examples of collagen chaperones that are defective in OI patients include chaperone HSP47 (Cole-Carpenter syndrome) and FKBP65. Mutations in these chaperones result in an improper folding pattern in the collagen 1 proteins which then cause the recessive form of the disorder. Defects in these proteins lead to defective bone mineralization which aids in the formation of the brittle bone symptom of OI
7
.
“ Individuals suffering from OI may also display a discoloration of the sclera (whites of the eyes), usually giving them a blue-gray color.”
Symptoms
Adults with “mild” OI (Type I) may have significant musculoskeletal symptoms, that might begin with arthritis, and back pain but can later lead to scoliosis, tendon rupture, and even numerous fractures
6
. With that being said, the clinical characteristics vary broadly from osteoporosis in adulthood to lethality in children. Individuals suffering from OI may also display a discoloration of the sclera (whites of the eyes), usually giving them a blue-gray color
1,4
. The blue-gray color of the sclera is due to the underlying choroidal veins which show through. This is due to the sclera being thinner than normal due to the improper formation of Type I collagen
8,9
. Other extraskeletal manifestations can occur down the road such as hearing loss, increased bruising and bleeding, and hypercalciuria (excessive calcium in the urine). In more severe cases (OI Type 2), in which collagen is not of sufficient quality or quantity, can result in death within the first year of life due to respiratory failure or intracerebral hemorrhage
4
.
Diagnosis
“ An OI diagnosis can be confirmed through DNA or collagen testing, but in many cases, the occurrence of bone fractures with little trauma and the presence of other clinical features such as blue sclera are sufficient for a diagnosis. ”
Diagnosis for OI is typically based on symptoms or medical imaging, such as X-rays. Signs on medical imaging include abnormalities in all extremities and the spine. An OI diagnosis can be confirmed through DNA or collagen testing, but in many cases, the occurrence of bone fractures with little trauma and the presence of other clinical features such as blue sclera are sufficient for a diagnosis 10 . Furthermore, a skin biopsy can be performed to determine the structure and quantity of type I collagen. DNA testing can confirm the diagnosis, however, it cannot exclude it because not all mutations causing OI are known and/or tested for 7 . OI type II is often diagnosed by ultrasound during pregnancy, where already multiple fractures and other characteristic features may be present 5,10 . Relative to control, OI cortical bones in studies show increased porosity, canal diameter, and connectivity in micro-computed tomography. Lastly, severe types of OI can usually be detected before birth by using an in-vitro genetic testing technique 9 .
Prognosis
The life expectancy for OI is 72.4 years for males and 77.4 for females respectively. To date, there exists no known treatment, medication, or surgery that can cure OI. Healthcare professionals and physicians often work to prevent deformities occuring in the first place or correcting symptoms once diagnosed with the disease 1 . Some of the approaches include dental procedures, physical therapy, providing assistive devices such as wheelchairs and braces. A type of surgery that puts metal rods through long bones may also be performed to strengthen them 3,5 . Furthermore, sometimes bisphosphonates (drugs used to treat osteoporosis) are used. Despite not building new bone mass, bisphosphonates slow the loss of existing bones. In patients with severe OI, these drugs were shown to reduce bone pain, prevent new vertebral fractures, reshape previously fractured vertebral bodies, and reduce the number of long-bone fractures 8 . Lastly, physiotherapy is used to strengthen muscles and improve motility in a gentle manner, while minimizing the risk of fracture. This often involves hydrotherapy, light resistance exercises, and the use of support cushions to improve posture. Individuals suffering from this syndrome are encouraged to change positions regularly throughout the day to balance the muscles being used and the bones under pressure 6,9 .
Ayush Suri
Relevant Resources
Brittle Bone Society seeks a world in which the needs of people living with OI are better understood, respected and fully met. They work towards improving the quality of life for people diagnosed with OI by providing emotional support, signposting and information, financial help for wheelchairs and equipment, and raising awareness of the condition. They also support and work with healthcare professionals and offer an advocacy role when required at a policy level 2 .
Works Cited
1. Berg C, Geipel A, Noack F et al. Prenatal diagnosis of Bruck syndrome. Prenat Diagn. 2005;25(7):535-538. doi:10.1002/pd.801
2. Brittle Bone Society UK & ROI. Brittle Bone Society. https://brittlebone.org. Published 2020. Accessed October 15, 2020. https://brittlebone.org/
3. Caparrós-Martin J, Valencia M, Pulido V et al. Clinical and molecular analysis in families with autosomal recessive osteogenesis imperfecta identifies mutations in five genes and suggests genotype-phenotype correlations. American Journal of Medical Genetics Part A. 2013;161(6):1354-1369. doi:10.1002/ajmg.a.35938
4. Datta V, Sinha A, Saili A, Nangia S. Bruck syndrome. The Indian Journal of Pediatrics. 2005;72(5):441-442. doi:10.1007/bf02731745
5. Ha-Vinh R, Alanay Y, Bank R et al. Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation inPLOD2. American Journal of Medical Genetics Part A. 2004;131A(2):115-120. doi:10.1002/ajmg.a.30231
6. Horwitz E, Gordon P, Koo W et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proceedings of the National Academy of Sciences. 2002;99(13):8932-8937. doi:10.1073/pnas.132252399
7. McPherson E, Clemens M. Bruck syndrome (osteogenesis imperfecta with congenital joint contractures): Review and report on the first North American case. Am J Med Genet. 1997;70(1):28-31.
doi:10.1002/(sici)1096-8628(19970502)70:1<28::aid data-preserve-html-node="true"-ajmg6>3.0.co;2-n
8. Mokete L, Robertson A, Viljoen D, Beighton P. Bruck syndrome: congenital joint contractures with bone fragility. Journal of Orthopaedic Science. 2005;10(6):641-646. doi:10.1007/s00776-005-0958-9
9. Zack P, Franck L, Devile C, Clark C. Fracture and non-fracture pain in children with osteogenesis imperfecta. Acta Paediatr. 2007;94(9):1238-1242. doi:10.1111/j.1651-2227.2005.tb02082.x
10. Zhou P, Liu Y, Lv F et al. Novel Mutations in FKBP10 and PLOD2 Cause Rare Bruck Syndrome in Chinese Patients. PLoS One. 2014;9(9):e107594. doi:10.1371/journal.pone.0107594
Cite This Article:
Suri A., Mughal R., Wong V. Osteogenesis Imperfecta: Bruck Syndrome (Brittle Bone Disease).Illustrated by S. Chen. Rare Disease Review. February 2021.
DOI: 10.13140/RG.2.2.16599.60325
