Sclerosteosis

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Sclerosteosis is an autosomal recessive disorder characterized by bone overgrowth. It was first described in 1958 [1] [2] but given the current name in 1967. [3] Excessive bone formation is most prominent in the skull, mandible and tubular bones. [1] It can cause facial distortion and syndactyly. [1] Increased intracranial pressure can cause sudden death in patients. [1] It is a rare disorder that is most prominent in the Afrikaner population in South Africa (40 patients), but there have also been cases of American and Brazilian families. [1]

Contents

Cause

Sclerosteosis is caused by mutations in the SOST gene that encodes the sclerostin protein. [4] The sclerostin protein is necessary in inhibiting the Wnt signaling pathway. Wnt signalling results in increased osteoblast activity and RANKL synthesis. Sclerostin therefore increases bone formation by indirectly inhibiting RANKL synthesis and thus osteoclast activation.

See also

Related Research Articles

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<span class="mw-page-title-main">Osteogenesis imperfecta</span> Group of genetic disorders resulting in fragile bones

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

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<span class="mw-page-title-main">Osteocyte</span> Mature osteoblasts which helps in communication between cells and also in molecular synthesis

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<span class="mw-page-title-main">Fraser syndrome</span> Recessive genetic disorder involving eye and genital abnormalities

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

Sclerostin is a protein that in humans is encoded by the SOST gene. It is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN family of bone morphogenetic protein (BMP) antagonists. Sclerostin is produced primarily by the osteocyte but is also expressed in other tissues, and has anti-anabolic effects on bone formation.

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

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

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<span class="mw-page-title-main">LRP5</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.

<span class="mw-page-title-main">DKK1</span> Protein-coding gene in the species Homo sapiens

Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene.

<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">LRP6</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

<span class="mw-page-title-main">ALX4</span> Protein-coding gene in the species Homo sapiens

Homeobox protein aristaless-like 4 is a protein that in humans is encoded by the ALX4 gene. Alx4 belongs to the group-1 aristaless-related genes, a majority of which are linked to the development of the craniofacial and/or appendicular skeleton, along with PRRX1, SHOX, ALX3, and CART1. The Alx4 protein acts as a transcriptional activator and is predominantly expressed in the mesenchyme of the developing embryonic limb buds. Transcripts of this gene are detectable in the lateral plate mesoderm just prior to limb induction. Alx4 expression plays a major role in the determination of spatial orientation of the growing limb bud by aiding in the establishment of anteroposterior polarity of the limb. It does this by working in conjunction with Gli3 and dHand to restrict the expression of Sonic Hedgehog (SHh) to the posterior mesenchyme, which will eventually give rise to the Zone of Polarizing Activity (ZPA). This gene has been proven to be allelic with mutations and deletions giving rise to a host of craniofacial dismorphologies and several forms of polydactyly in mammalian development. A mouse-model knockout of this gene, dubbed Strong's luxoid, was originally created by Forstheofel in the 1960s and has been extensively studied to understand the partial and complete loss-of-function properties of this gene.

<span class="mw-page-title-main">Camurati–Engelmann disease</span> Rare skeletal genetic disorder

Camurati–Engelmann disease (CED) is a very rare autosomal dominant genetic disorder that causes characteristic anomalies in the skeleton. It is also known as progressive diaphyseal dysplasia. It is a form of dysplasia. Patients typically have heavily thickened bones, especially along the shafts of the long bones. The skull bones may be thickened so that the passages through the skull that carry nerves and blood vessels become narrowed, possibly leading to sensory deficits, blindness, or deafness.

Van Buchem disease, or hyperostosis corticalis generalisata, is an autosomal recessive skeletal disease which is characterised by uninhibited bone growth, especially in the mandible, skull and ribs.

<span class="mw-page-title-main">Frans van Buchem</span> 20th century Dutch physician and professor

Franciscus Stephanus Petrus (Frans) van Buchem was a Dutch physician and professor, known for the discovery of Van Buchem disease, which was named after him. He married Elisabeth Euphemia Maria Christiana Nuijens in January, 1930, aged 32. His PhD thesis was supervised by Nobel prize winner Professor Willem Einthoven. Frans was, among other things, the Chief Physician in Internal Medicine of the St Elisabeth Hospital and after the end of World War Two, became a professor of Internal Medicine at the University of Groningen. In 1954, van Buchem diagnosed a patient with what he referred to as hyperosteosis corticales generalisata familiaris, later named Van Buchem disease. A year later, he published an article in Acta Radiologica on the disease.

References

  1. 1 2 3 4 5 Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (Mar 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Human Molecular Genetics. 10 (5): 537–43. doi: 10.1093/hmg/10.5.537 . PMID   11181578.
  2. Truswell AS (May 1958). "Osteopetrosis with syndactyly; a morphological variant of Albers-Schönberg's disease". The Journal of Bone and Joint Surgery. British Volume. 40-B (2): 209–18. PMID   13539104.
  3. Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (Feb 2002). "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease". Journal of Medical Genetics. 39 (2): 91–7. doi:10.1136/jmg.39.2.91. PMC   1735035 . PMID   11836356.
  4. Sebastian A, Loots GG (March 2018). "Genetics of Sost/SOST in sclerosteosis and van Buchem disease animal models". Metabolism. 80: 38–47. doi: 10.1016/j.metabol.2017.10.005 . PMID   29080811.