Palmoplantar keratoderma-esophageal carcinoma syndrome

Last updated on: 24.11.2022

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History
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Rhomboids were first named after a mutation in the fruit fly Drosophila, discovered in a famous genetic screen that won Christiane Nüsslein-Volhard and Eric Wieschaus the Nobel Prize. In this screening, they found a number of mutants with similar phenotypes: "pointed" embryonic head skeletons, one of which was rhomboid. Hence the name "rhomboid".

Definition
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Palmoplantar keratosis with esophageal cancer and mutation in RHBDF2, also known as TOC syndrome, is an autosomal dominant paraneoplastic syndrome characterized by ,callus-like palmoplantar keratosis localized to pressure points, oral leukoplakia, and a 95% lifetime risk of esophageal cancer.

Etiopathogenesis
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Palmoplantar keratosis with esophageal carcinoma is due to a mutation in the RHBDF2 gene. The enzyme encoded by this gene is a (inactive) Drosophila rhomboid protease. Drosophila rhomboid proteases are positive regulators of EGF receptor(EGFR) signaling. RHBDF2 belongs to a conserved family of inhibitory rhomboid-like pseudoproteases that lack essential catalytic residues and inhibit rhomboid-dependent EGF signaling.

Histology
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RHBDF2 is altered in tylotic skin compared to normal skin. Immortalized tylotic keratinocytes have lower levels of total epidermal growth factor receptor (EGFR) but show increased proliferation and migration potential compared to normal cells. It is likely that EGFR signaling is dysregulated in tylotic cells. Furthermore, the localization of RHBDF2 was shown to be disturbed in both tylotic and sporadic squamous cell tumors of the esophagus.

Note(s)
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The rhomboid proteases are a family of enzymes found in almost all species. They are proteases: they cut the polypeptide chain of other proteins. This proteolytic cleavage is irreversible in cells and is an important type of cellular regulation. Although proteases are one of the oldest and best studied classes of enzymes, rhomboids belong to a recently discovered type of proteases: the intramembrane proteases.

Intramembrane proteases are unique in that their active sites are hidden in the lipid bilayer of cell membranes and they cleave other transmembrane proteins within their transmembrane domains. Approximately 30% of all proteins have transmembrane domains, and their regulated processing often has significant biological consequences. Accordingly, rhomboids regulate many important cellular processes and may be involved in a variety of human diseases.

For example, the protease function of rhomboids was discovered by showing that they regulate EGF receptor signaling in Drosophila. Furthermore, rhomboid-1 was shown to regulate sleep in Drosophila. Meanwhile, there is some evidence that rhomboids are involved in growth factor signaling in mammals, including humans. Mammalian rhomboid proteases have also been linked to ephrin signaling, cleavage of the anticoagulant protein thrombomodulin, and wound healing.

Literature
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  1. Adrain C et al. (2012) Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science 335:225-228.
  2. Blaydon DC et al (2012) RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet 90:340-346.
  3. Ellis A et al (1994) Tylosis associated with carcinoma of the oesophagus and oral leukoplakia in a large Liverpool family-a review of six generations. Eur J Cancer B Oral Oncol 30B:102-112.
  4. Field EA et al (1997) Oral tylosis: A re-appraisal. Oral Oncol 33:55-57.
  5. Hennies HC et al (1995) Palmoplantar keratoderma in association with carcinoma of the esophagus maps to chromosome 17q distal to the keratin gene cluster. Genomics 29:537-540.
  6. Kelsell DP et al (1996) Close mapping of the focal non-epidermolytic palmoplantar keratoderma (PPK) locus associated with esophageal cancer (TOC) Hum Mol Genet 5:857-860.
  7. Langan JE et al. (2004) Novel microsatellite markers and single nucleotide polymorphisms refine the tylosis with oesophageal cancer (TOC) minimal region on 17q25 to 42.5 kb: Sequencing does not identify the causative gene. Hum Genet 114:534-540.
  8. Lohi O et al (2004) Diverse substrate recognition mechanisms for rhomboids; thrombomodulin is cleaved by Mammalian rhomboids. Curr Biol 14:236-241.
  9. Risk JM et al (1994) Tylosis oesophageal cancer mapped. Nat Genet 8:319-321.
  10. Risk JM et al. (1999) Envoplakin, a possible candidate gene for focal NEPPK/esophageal cancer (TOC): The integration of genetic and physical maps of the TOC region on 17q25. Genomics 59:234-242.
  11. Risk JM et al. (2002) Characterization of a 500 kb region on 17q25 and the exclusion of candidate genes as the familial Tylosis Esophageal Cancer (TOC) locus. Oncogene 21:6395-6402.
  12. Stevens HP et al. (1996) Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas. Arch. Dermatol132:640-651.
  13. Urban S et al. (2001) Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107:173-182.
  14. Wang L et al (2021) RHBDF2 gene functions are correlated to facilitated renal clear cell carcinoma progression. Cancer Cell Int 21:590.

Incoming links (1)

Familial cancer syndrome;

Outgoing links (2)

Egf receptors; RHBDF2 Gene;

Disclaimer

Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

Last updated on: 24.11.2022