Proteus syndrome

Proteus syndrome
Classification and external resources
Specialty medical genetics
OMIM 176920
DiseasesDB 30070
eMedicine derm/721 ped/1912
MeSH D016715

Proteus syndrome, also known as Wiedemann syndrome (named after the German pediatrician Hans-Rudolf Wiedemann), is a rare congenital disorder[1] that causes skin overgrowth and atypical bone development, often accompanied by tumors over half the body.[2]:776

Proteus syndrome is highly variable,[3] and is named after the Greek sea-god Proteus, who could change his shape.

The condition appears to have been first described in the American medical literature by Drs. Samia Temtamy and John Rogers in 1976.[4][5] Dr. Michael Cohen described it in 1979.[6] Only a few more than 200 cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition.[7] As attenuated forms of the disease may exist, there could be many people with Proteus syndrome who remain undiagnosed. Those most readily diagnosed are also the most severely disfigured.

Signs and symptoms

Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and lymphatic vessels.

Proteus syndrome is a progressive condition wherein children are usually born without any obvious deformities. Tumors of skin and bone growths appear as they age. The severity and locations of these various asymmetrical growths vary greatly but typically the skull, one or more limbs, and soles of the feet will be affected. There is a risk of premature death in affected individuals due to deep vein thrombosis and pulmonary embolism caused by the vessel malformations that are associated with this disorder. Because of carrying excess weight and enlarged limbs, arthritis and muscle pain may also be symptoms — as is the case for Mandy Sellars, a woman who has been diagnosed with a form of Proteus syndrome[8] (but see "Notable Cases" below). Further risks may occur due to the mass of extra tissue.

The disorder itself does not uniformly cause learning impairments: the distribution of intelligence deficits among sufferers of Proteus syndrome appears higher than that of the general population, although this is difficult to determine with statistical significance.[9] In addition, the presence of visible deformity may have a negative effect on the social experiences of the sufferer, causing cognitive and social deficits.

Afflicted individuals are at increased risk for developing certain tumors including unilateral Ovarian cystadenomas, testicular tumors, meningiomas, and monomorphic adenomas of the parotid gland.

Genetics

Proteus syndrome is an overgrowth disorder caused by a rare genetic mosaicism. A genetic mutation during embryonic development gives rise to overgrowth in a subset of the individual's cells

In 2011 researchers determined the cause of Proteus syndrome. In 26 of 29 patients who met strict clinical criteria for the disorder, Lindhurst et al. identified an activating mutation in AKT1 kinase in a mosaic state gene.[10] This mutation in the AKT1 gene was present in all 26 affected patients.

Previous research had suggested the condition linked to PTEN on chromosome 10,[11] while other research pointed to chromosome 16.[12] Prior to the findings regarding AKT1 in 2011, other researchers expressed doubt regarding the involvement of PTEN or GPC3, which codes for glypican 3 and may play a role in regulating cell division and growth regulation.[13][14]

Treatment

A team of doctors in Australia have trial tested the drug rapamycin in the treatment of a patient said to have Proteus syndrome and have found it to be an effective remedy.[15] However, the diagnosis of Proteus syndrome in this patient has been questioned by others.[16] The Proteus syndrome research team in the National Human Genome Research Institute at the United States National Institutes of Health have initiated a Phase 0 dose finding trial with the AKT1 inhibitor ARQ 092, which is being developed by the Arqule Corporation. This trial opened in November 2015 and recruited patients in a study titled "Dose Finding Trial of ARQ 092 in Children and Adults With Proteus Syndrome"[17] This trial is based on in vitro data showing inhibition of AKT1 in cell lines from patients with Proteus syndrome.[18]

Classification

Many sources classify Proteus syndrome to be a type of nevus syndrome. The lesions appear to be distributed in a mosaic manner.[19] It has been confirmed that the disorder is an example of genetic mosaicism.[20]

Notable cases

In a 1986 article in the British Medical Journal, Michael Cohen and J.A.R. Tibbles put forward the theory that Joseph Merrick had suffered from Proteus syndrome, a very rare congenital disorder which had been identified by Cohen only in 1979. However, the exact condition suffered by Joseph Merrick is still not known with certainty.[21][22]

Mandy Sellars has been diagnosed by some doctors as suffering from this condition.[7] Her legs and feet have grown at a disproportionate rate since birth. However, in 2013, Sellars' case was profiled on British television in a special called Shrinking My 17 Stone Legs, in which it was determined that Sellars' condition was not, in fact, Proteus syndrome, but rather a PIK3CA gene mutation.[23]

See also

References

  1. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 554. ISBN 0-7216-2921-0.
  2. ↑ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0.
  3. ↑ Jamis-Dow CA, Turner J, Biesecker LG, Choyke PL (2004). "Radiologic manifestations of Proteus syndrome". Radiographics. 24 (4): 1051–68. doi:10.1148/rg.244035726. PMID 15256628.
  4. ↑ Temtamy SA, Rogers JG (December 1976). "Macrodactyly, hemihypertrophy, and connective tissue nevi: Report of a new syndrome and review of the literature". The Journal of Pediatrics. 89 (6): 924–927. doi:10.1016/S0022-3476(76)80597-5. PMID 993918.
  5. ↑ Opitz JM, Jorde LB (July 27, 2011). "Hamartoma Syndromes, Exome Sequencing, and a Protean Puzzle". The New England Journal of Medicine. 365 (7): 661–3. doi:10.1056/NEJMe1107384. PMID 21793737.
  6. ↑ Cohen MM, Hayden PW (1979). "A newly recognized hamartomatous syndrome". Birth Defects Orig. Artic. Ser. 15 (5B): 291–6. PMID 118782.
  7. 1 2 Woman's 11-stone legs may be lost at BBC
  8. ↑ Neglia, Ashley (May 2009). "Living With Proteus syndrome". AOL Health. Retrieved June 2009. Check date values in: |access-date= (help)
  9. ↑ Turner JT, Cohen MM, Biesecker LG (Oct 1, 2004). "Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases". American Journal of Medical Genetics. 130A (2): 111–122. doi:10.1002/ajmg.a.30327. PMID 15372514.
  10. ↑ Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG (Aug 18, 2011). "A mosaic activating mutation in AKT1 associated with the Proteus syndrome.". N Engl J Med. 365 (7): 611–9. doi:10.1056/NEJMoa1104017. PMC 3170413Freely accessible. PMID 21793738.
  11. ↑ Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ (2002). "Germline mutation of the tumour suppressor PTEN in Proteus syndrome". J. Med. Genet. 39 (12): 937–40. doi:10.1136/jmg.39.12.937. PMC 1757209Freely accessible. PMID 12471211.
  12. ↑ Cardoso MT, de Carvalho TB, Casulari LA, Ferrari I (2003). "Proteus syndrome and somatic mosaicism of the chromosome 16". Panminerva medica. 45 (4): 267–71. PMID 15206168.
  13. ↑ Thiffault I, Schwartz CE, Der Kaloustian V, Foulkes WD (October 2004). "Mutation analysis of the tumor suppressor PTEN and the glypican 3 (GPC3) gene in patients diagnosed with Proteus syndrome". Am. J. Med. Genet. A. 130A (2): 123–7. doi:10.1002/ajmg.a.30335. PMID 15372512.
  14. ↑ "Entrez Gene: GPC3 glypican 3".
  15. ↑ Marsh DJ, Trahair TN, Martin JL, Chee WY, Walker J, Kirk EP, Baxter RC, Marshall GM (April 22, 2008). "Rapamycin treatment for a child with germline PTEN mutation". Nature Clinical Practice Oncology. 5 (6): 357–361. doi:10.1038/ncponc1112. PMID 18431376.
  16. ↑ Cohen MM, Turner JT, Biesecker LG (November 1, 2003). "Proteus Syndrome: Misdiagnosis with PTEN Mutations". American Journal of Medical Genetics. 122A (4): 323–324. doi:10.1002/ajmg.a.20474. PMID 14518070.
  17. ↑ "Dose Finding Trial of ARQ 092 in Children and Adults With Proteus Syndrome". ClinicalTrials.gov. National Human Genome Research Institute (NHGRI). Oct 31, 2015. NCT02594215.
  18. ↑ Lindhurst, Marjorie J.; Yourick, Miranda R.; Yu, Yi; Savage, Ronald E.; Ferrari, Dora; Biesecker, Leslie G. (2015). "Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome". Scientific Reports. Nature. 5. doi:10.1038/srep17162. 17162.
  19. ↑ Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM, Viljoen DL, Cohen MM (1999). "Proteus syndrome: differential diagnosis, and patient evaluation". Am J Med Genet. 84 (5): 389–95. doi:10.1002/(SICI)1096-8628(19990611)84:5<389::AID-AJMG1>3.0.CO;2-O. PMID 10360391.
  20. ↑ Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG (August 2011). "A mosaic activating mutation in AKT1 associated with the Proteus syndrome". N. Engl. J. Med. 365 (7): 611–9. doi:10.1056/NEJMoa1104017. PMC 3170413Freely accessible. PMID 21793738.
  21. ↑ Tibbles JA, Cohen MM (1986). "The Proteus syndrome: the Elephant Man diagnosed". Br Med J (Clin Res Ed). 293 (6548): 683–5. doi:10.1136/bmj.293.6548.683. PMC 1341524Freely accessible. PMID 3092979.
  22. ↑ – Spiring P (2001). "The Improbable Elephant Man". Biologist (London) 48(3) 104., – The Sunday Telegraph, – BBC News, – Eurekalert!, – The Daily Telegraph
  23. ↑ Steve Corbett "Help! My leg weighs 17-stone!", Sun+, 15 February 2013, retrieved 16 December 2014
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