Bruck syndrome

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Bruck syndrome
Other namesOsteogenesis imperfecta-congenital joint contractures syndrome
Autosomal recessive - en.svg
Bruck syndrome is inherited in an autosomal recessive manner
Specialty Rheumatology   OOjs UI icon edit-ltr-progressive.svg

Bruck syndrome is characterized as the combination of arthrogryposis multiplex congenita and osteogenesis imperfecta. Both diseases are uncommon, but concurrence is extremely rare which makes Bruck syndrome very difficult to research. [1] Bruck syndrome is thought to be an atypical variant of osteogenesis imperfecta most resembling type III, if not its own disease. [2] [3] Multiple gene mutations associated with osteogenesis imperfecta are not seen in Bruck syndrome. Many affected individuals are within the same family, and pedigree data supports that the disease is acquired through autosomal recessive inheritance. [4] Bruck syndrome has features of congenital contractures, bone fragility, recurring bone fractures, flexion joint and limb deformities, pterygia, short body height, and progressive kyphoscoliosis. Individuals encounter restricted mobility and pulmonary function. A reduction in bone mineral content and larger hydroxyapatite crystals are also detectable [5] Joint contractures are primarily bilateral and symmetrical, and most prone to ankles. [3] Bruck syndrome has no effect on intelligence, vision, or hearing. [4]

Contents

Genetics

The genetics of Bruck syndrome differs from osteogenesis imperfecta. Osteogenesis imperfecta involves autosomal dominant mutations to Col 1A2 or Col 1A2 which encode type 1 procollagen. [6] Bruck syndrome is linked to mutations in two genes, and therefore is divided in two types. Bruck syndrome type 1 is caused by a homozygous mutation in the FKBP10 gene. Type 2 is caused by a homozygous mutation in the PLOD2 gene. [6]

Mechanism

Type 1 encodes FKBP65, an endoplasmic reticulum associated peptidyl-prolyl cis/trans isomerase (PPIase) that functions as a chaperone in collagen biosynthesis. Osteoblasts deficient in FKBP65 have a buildup of procollagen aggregates in the endoplasmic reticulum which reduces their ability to form bone. [7] Furthermore, Bruck syndrome type 1 patients have under-hydroxylated lysine residues in the collagen telopeptide and as a result show diminished hydroxylysylpyridinoline cross-links. [6]

Type 2 encodes the enzyme, lysyl hydroxylase 2, which catalyzes hydroxylation of lysine residues in collagen cross-links. PLOD2 is most expressed in active osteoblasts since collagen cross-linking is tissue-specific. Mutation in PLOD2 alters the structure of telopeptide lysyl hydroxylase and prevents fibril formation of collagen type 1. Bone analysis shows the lysine residues of telopeptides in collagen type 1 are under-hydroxylated. [6]

Diagnosis

Diagnosis of Bruck syndrome must distinguish the association of contractures and skeletal fragility. Ultrasound is used for prenatal diagnosis. The diagnosis of a neonate bears resemblance to arthrogryposis multiplex congenital, and later in childhood to osteogenesis imperfecta. [1]

Management

Until more molecular and clinical studies are performed there will be no way to prevent the disease. Treatments are directed towards alleviating the symptoms. To treat the disease it is crucial to diagnose it properly. [6] Orthopedic therapy and fracture management are necessary to reduce the severity of symptoms. Bisphosphonate drugs are also an effective treatment. [4]

History

The first case was in 1897 of a male who was described by Bruck as having bone fragility and bone contractures. [4] Bruck was credited with the first description and the disease's eponym. [1]

Related Research Articles

Collagen is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole-body protein content. Collagen consists of amino acids bound together to form a triple helix of elongated fibril known as a collagen helix. It is mostly found in connective tissue such as cartilage, bones, tendons, ligaments, and skin.

<span class="mw-page-title-main">Ehlers–Danlos syndromes</span> Group of genetic connective tissues disorders

Ehlers–Danlos syndromes (EDS) are a group of 13 genetic connective-tissue disorders in the current classification, with the latest type discovered in 2018. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis.

<span class="mw-page-title-main">Osteogenesis imperfecta</span> Group of genetic disorders that mainly affect the bones

Osteogenesis imperfecta, colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be mild to severe. Symptoms found in various types of OI include whites of the eye (sclerae) that are blue instead, short stature, loose joints, hearing loss, breathing problems and problems with the teeth. Potentially life-threatening complications, all of which become more common in more severe OI, include: tearing (dissection) of the major arteries, such as the aorta; pulmonary valve insufficiency secondary to distortion of the ribcage; and basilar invagination.

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

Arthrogryposis (AMC) describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning 'curving of joints'.

A connective tissue disease (collagenosis) is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds together, and protects organs. These tissues form a framework, or matrix, for the body, and are composed of two major structural protein molecules: collagen and elastin. There are many different types of collagen protein in each of the body's tissues. Elastin has the capability of stretching and returning to its original length—like a spring or rubber band. Elastin is the major component of ligaments and skin. In patients with connective tissue disease, it is common for collagen and elastin to become injured by inflammation (ICT). Many connective tissue diseases feature abnormal immune system activity with inflammation in tissues as a result of an immune system that is directed against one's own body tissues (autoimmunity).

<span class="mw-page-title-main">Collagen, type I, alpha 1</span> Mammalian protein found in Homo sapiens

Collagen, type I, alpha 1, also known as alpha-1 type I collagen, is a protein that in humans is encoded by the COL1A1 gene. COL1A1 encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including cartilage.

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

Dentinogenesis imperfecta (DI) is a genetic disorder of tooth development. It is inherited in an autosomal dominant pattern, as a result of mutations on chromosome 4q21, in the dentine sialophosphoprotein gene (DSPP). It is one of the most frequently occurring autosomal dominant features in humans. Dentinogenesis imperfecta affects an estimated 1 in 6,000-8,000 people.

Osteochondrodysplasia is a general term for a disorder of the development (dysplasia) of bone ("osteo") and cartilage ("chondro"). Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Nonetheless, if taken collectively, genetic skeletal dysplasias or osteochondrodysplasias comprise a recognizable group of genetically determined disorders with generalized skeletal affection. Osteochondrodysplasias can result in marked functional limitation and even mortality.

Lysyl hydroxylases are alpha-ketoglutarate-dependent hydroxylases enzymes that catalyze the hydroxylation of lysine to hydroxylysine. Lysyl hydroxylases require iron and vitamin C as cofactors for their oxidation activity. It takes place following collagen synthesis in the cisternae (lumen) of the rough endoplasmic reticulum (ER). There are three lysyl hydroxylases (LH1-3) encoded in the human genome, namely: PLOD1, PLOD2 and PLOD3. From PLOD2 two splice variant can be expressed, where LH2b differs from LH2a by incorporating the small exon 13A. LH1 and LH3 hydroxylate lysyl residues in the collagen triple helix, whereas LH2b hydroxylates lysyl residues in the telopeptides of collagen. In addition to its hydroxylation activity, LH3 has glycosylation activity that produces either monosaccharide (Gal) or disaccharide (Glc-Gal) attached to collagen hydroxylysines.

<span class="mw-page-title-main">Collagen, type III, alpha 1</span>

Type III Collagen is a homotrimer, or a protein composed of three identical peptide chains (monomers), each called an alpha 1 chain of type III collagen. Formally, the monomers are called collagen type III, alpha-1 chain and in humans are encoded by the COL3A1 gene. Type III collagen is one of the fibrillar collagens whose proteins have a long, inflexible, triple-helical domain.

<span class="mw-page-title-main">Lysyl oxidase</span> Mammalian protein found in Homo sapiens

Lysyl oxidase (LOX), also known as protein-lysine 6-oxidase, is an enzyme that, in humans, is encoded by the LOX gene. It catalyzes the conversion of lysine molecules into highly reactive aldehydes that form cross-links in extracellular matrix proteins. Its inhibition can cause osteolathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.

Collagen IV is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, collagen IV lacks the regular glycine in every third residue necessary for the tight, collagen helix. This makes the overall arrangement more sloppy with kinks. These two features cause the collagen to form in a sheet, the form of the basal lamina. Collagen IV is the more common usage, as opposed to the older terminology of "type-IV collagen". Collagen IV exists in all metazoan phyla, to whom they served as an evolutionary stepping stone to multicellularity.

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

Bethlem myopathy is predominantly an autosomal dominant myopathy, classified as a congenital form of muscular dystrophy. There are two forms of Bethlem myopathy.

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

Cartilage associated protein is a protein that in humans is encoded by the CRTAP gene.

Leprecan is a protein associated with osteogenesis imperfecta type VIII.

<span class="mw-page-title-main">Collagen, type I, alpha 2</span>

Collagen alpha-2(I) chain is a protein that in humans is encoded by the COL1A2 gene.

<span class="mw-page-title-main">PLOD3</span> Protein-coding gene in the species Homo sapiens

Procollagen-lysine,2-oxoglutarate 5-dioxygenase 3 is an enzyme that in humans is encoded by the PLOD3 gene.

<span class="mw-page-title-main">Ullrich congenital muscular dystrophy</span> Medical condition

Ullrich congenital muscular dystrophy (UCMD) is a form of congenital muscular dystrophy. There are two forms: UCMD1 and UCMD2.

<span class="mw-page-title-main">Lethal congenital contracture syndrome</span> Medical condition

Lethal congenital contracture syndrome 1 (LCCS1), also called Multiple contracture syndrome, Finnish type, is an autosomal recessive genetic disorder characterized by total immobility of a fetus, detectable at around the 13th week of pregnancy. LCCS1 invariably leads to prenatal death before the 32nd gestational week. LCCS1 is one of 40 Finnish heritage diseases. It was first described in 1985 and since then, approximately 70 cases have been diagnosed.

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

Cole–Carpenter syndrome is an extremely rare autosomal recessive medical condition in humans. The condition effects less than 10 people worldwide. It is characterised by dysmorphic features and a tendency to fractures.

References

  1. 1 2 3 Mokete, L.; Robertson, A.; Viljoen, D.; Beighton, Peter (2005). "Bruck syndrome: congenital joint contractures with bone fragility". Journal of Orthopaedic Science. 10 (6): 641–646. doi:10.1007/s00776-005-0958-9. PMID   16307191. S2CID   46110203.
  2. ↑ Berg, C.; Geipel, A.; Noack, F; et al. (2005). "Mutations in FKBP10 cause recessive osteogenesis imperfecta and bruck syndrome". Prenatal Diagnosis. 25 (3): 545–548. doi:10.1002/jbmr.250. PMC   3179293 . PMID   20839288.
  3. 1 2 Blacksin, M.; Pletcher, B.; David, Miriam; et al. (1998). "Osteogenesis imperfecta with joint contractures: Bruck syndrome". Pediatric Radiology. 28 (2): 117–119. doi:10.1007/s002470050309. PMID   9472060. S2CID   12863084.
  4. 1 2 3 4 Datta, V.; Sinha, A.; Saili, A.; et al. (2005). "Osteogenesis Imperfecta". Journal of Pediatrics. 72 (5): 441–442. doi:10.1007/BF02731745. PMID   15973030. S2CID   24986309.
  5. ↑ Banks, R.; Robins, S.; Wijmenga; et al. (1999). "Defective collagen crosslinking in bone, but not in ligament or cartilage, in Bruck syndrome: Indications for a bone-specific telopeptide lysyl hydroxylase on chromosome 17". Proceedings of the National Academy of Sciences. 96 (3): 1054–1058. Bibcode:1999PNAS...96.1054B. doi: 10.1073/pnas.96.3.1054 . PMC   15349 . PMID   9927692.
  6. 1 2 3 4 5 Yapicioglu, H.; Ozcan, K.; Arikan, O.; et al. (2009). "Bruck syndrome: osteogenesis imperfecta and arthrogryposis multiplex congenital". Annals of Tropical Paediatrics. 29 (2): 159–1662. doi:10.1179/146532809x440798. PMID   19460271. S2CID   206847487.
  7. ↑ Shaheen, Ranad; Al-Owain, Mohammed; Faqeih, Eissa; Al-Hashmi, Nadia; Awaji, Ali; Al-Zayed, Zayed; Alkuraya, Fowzan S (2011). "Mutations in FKBP10 cause both Bruck syndrome and isolated osteogenesis imperfecta in humans". American Journal of Medical Genetics Part A. 155 (6): 1448–1452. doi:10.1002/ajmg.a.34025. PMID   21567934. S2CID   40133519.

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