Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Dermatologic Manifestations of Proteus Syndrome

  • Author: Megan Barry, MD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Jul 15, 2016
 

Background

Proteus syndrome (PS) is a sporadically occurring hamartomatous disorder associated with irregular asymmetric overgrowth of multiple body tissues and cell lineages. Most malformations in patients with Proteus syndrome have a mesodermal origin. Characteristic plurifocal overgrowths (partial or regional gigantism) can involve any structure of the body but most commonly involve the bone, connective tissue, and fat. Although some evidence of this syndrome was published in the medical literature as early as 1907, the modern medical description of the disease is attributed to Cohen and Hayden, who identified the syndrome in 1979.[1] In 1983, to stress the polymorphic nature of the clinical manifestations of the disorder, Wiedermann named it "Proteus syndrome" after the Greek god Proteus, who could change his shape at will to avoid capture.[2]

Perhaps the most famous case of Proteus syndrome is that of Joseph Merrick, the "Elephant Man" described by Sir Frederick Treves in 1884, who was made famous by a stage play and movie of the same name. Although first thought to have neurofibromatosis, Merrick is now believed to have had Proteus syndrome. Preserved castings of his soles show cerebriform cutaneous hyperplasia, a characteristic finding in persons with Proteus syndrome.[3]

Next

Pathophysiology

Proteus syndrome is a rare, sporadic disease with patchy or mosaic manifestations.[4] In 2011, the New England Journal of Medicine published a paper by Lindhurst et al naming a mutation in AKT1 as the cause of Proteus syndrome.[5] Twenty-nine patients with Proteus syndrome were studied, and 26 were found to have activation of AKT protein in the affected tissues. All unaffected patients were negative for the activating mutation.

Patients with Proteus syndrome have a somatic mutation, meaning that the mutation arises randomly during development of the fetus after fertilization. Only tissues that descend from the mutated cell have the AKT activation and, therefore, have phenotypic abnormalities. Patients who have mutation at an earlier stage of development will then have more severe clinical symptoms.

The mutated AKT1 is constitutively activated as a result of phosphorylation. AKT is part of the PI3K/AKT/MTOR pathway, which regulates apoptosis of tissues. Activation of AKT leads to lack of apoptosis and overgrowth of tissues.

While PTEN was previously thought to be implicated in this disorder, this is no longer thought to be the case. Patients with PTEN mutation are now thought to have Proteus-like syndrome.[6, 7]

Previous
Next

Epidemiology

Frequency

Around 100 cases have been reported in the literature.[8]

Race

Proteus syndrome has no predilection for any particular race.

Sex

The male-to-female ratio is 1.9:1 (n = 96).[9]

Age

At least some of the abnormalities associated with Proteus syndrome can be present at birth or appear in the first years of life. Frank asymmetry or overgrowth is present in less than 18%. Symptoms usually progress until puberty, when there seems to be a plateau.[10] Notably, the cerebriform nevi typically do not manifest until age 2 years, on average, often delaying the correct diagnosis of Proteus syndrome.[11]

Previous
Next

Prognosis

Patients with Proteus syndrome have difficulty ambulating because of toe macrodactyly, scoliosis, and joint instability, with frequent hip dislocations, expansive subcutaneous tumors, and compression neuropathies due to intraneural hamartomas. Some patients may have persistent atelectasis, pneumonia, or symptoms of pulmonary insufficiency. Mental retardation is present in approximately 30% of patients. Premature death has been reported in 20% of Proteus syndrome patients, most often related to deep venous thrombosis leading to pulmonary embolus, postoperative complications, or pneumonia.[9]

The disease is progressive but somewhat variable in prognosis. With appropriate medical and surgical care, patients with Proteus syndrome may age normally.[12] However, despite treatment efforts, Proteus syndrome may result in extreme musculoskeletal, cutaneous, and visceral deformities.[13]

Previous
 
 
Contributor Information and Disclosures
Author

Megan Barry, MD Resident Physician, Department of Dermatology, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Barbara B Wilson, MD Edward P Cawley Associate Professor, Department of Dermatology, University of Virginia School of Medicine

Barbara B Wilson, MD is a member of the following medical societies: Alpha Omega Alpha, Medical Society of Virginia, Sigma Xi, American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey J Miller, MD Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center

Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Society for Investigative Dermatology, Association of Professors of Dermatology, North American Hair Research Society

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Albert C Yan, MD Section Chief, Associate Professor, Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine

Albert C Yan, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology, Society for Pediatric Dermatology, American Academy of Pediatrics

Disclosure: Nothing to disclose.

Acknowledgements

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Mina Yassaee Kingsbery, MD Co-Chief Resident, Department of Dermatology, New York Presbyterian Hospital, Columbia University College of Physicians and Surgeons

Mina Yassaee Kingsbery, MD is a member of the following medical societies: American Academy of Dermatology, Society for Pediatric Dermatology, and Women's Dermatologic Society

Disclosure: Nothing to disclose.

Matthew J Mahlberg, MD Fellow in Mohs Micrographic Surgery and Procedural Dermatology, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Matthew J Mahlberg is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Eleonora Ruocco, MD Staff Physician, Assistant Professor, Department of Dermatology and Venereology, University of Naples Medical School, Italy

Disclosure: Nothing to disclose.

Carlo Tolone, MD Department of Pediatrics, Second University of Naples, Italy

Disclosure: Nothing to disclose.

Antonio Vozza, MD Associate Chairman, Assistant Professor, Department of Dermatology, Second University of Naples, Italy

Disclosure: Nothing to disclose.

References
  1. Cohen MM Jr, Hayden PW. A newly recognized hamartomatous syndrome. Birth Defects Orig Artic Ser. 1979. 15(5B):291-6. [Medline].

  2. Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E. The proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr. 1983 Mar. 140(1):5-12. [Medline].

  3. Braun-Falco O, Plewig G, Wolff HH, et al. Dermatology. 2nd ed. Berlin: Springer; 2000: 849-50.

  4. Rodenbeck DL, Greyling LA, Anderson JH, Davis LS. Early Recognition of Proteus Syndrome. Pediatr Dermatol. 2016 Jul 4. [Medline].

  5. Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011 Aug 18. 365(7):611-9. [Medline]. [Full Text].

  6. Happle R. The manifold faces of proteus syndrome. Arch Dermatol. 2004 Aug. 140(8):1001-2. [Medline].

  7. Romano C, Schepis C. PTEN gene: a model for genetic diseases in dermatology. ScientificWorldJournal. 2012. 2012:252457. [Medline]. [Full Text].

  8. Cohen MM Jr. Proteus syndrome: an update. Am J Med Genet C Semin Med Genet. 2005 Aug 15. 137(1):38-52. [Medline].

  9. Turner JT, Cohen MM Jr, Biesecker LG. Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases. Am J Med Genet A. 2004 Oct 1. 130(2):111-22. [Medline].

  10. Nazzaro V, Cambiaghi S, Montagnani A, Brusasco A, Cerri A, Caputo R. Proteus syndrome. Ultrastructural study of linear verrucous and depigmented nevi. J Am Acad Dermatol. 1991 Aug. 25(2 Pt 2):377-83. [Medline].

  11. Twede JV, Turner JT, Biesecker LG, Darling TN. Evolution of skin lesions in Proteus syndrome. J Am Acad Dermatol. 2005 May. 52(5):834-8. [Medline].

  12. Choi ML, Wey PD, Borah GL. Pediatric peripheral neuropathy in proteus syndrome. Ann Plast Surg. 1998 May. 40(5):528-32. [Medline].

  13. Atherton DJ. Naevi and other developmental defects. Champion RH, Burton JL, Burns DA, eds. Rook/Wilkinson/Ebling's Textbook of Dermatology. 6th ed. Oxford, England: Blackwell Science; 1998. 519-616.

  14. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, et al. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999 Jun 11. 84(5):389-95. [Medline].

  15. Nguyen D, Turner JT, Olsen C, Biesecker LG, Darling TN. Cutaneous manifestations of proteus syndrome: correlations with general clinical severity. Arch Dermatol. 2004 Aug. 140(8):947-53. [Medline].

  16. del Rosario Barona-Mazuera M, Hidalgo-Galván LR, de la Luz Orozco-Covarrubias, Durán-McKinster C, Tamayo-Sánchez L, Ruiz-Maldonado R. Proteus syndrome: new findings in seven patients. Pediatr Dermatol. 1997 Jan-Feb. 14(1):1-5. [Medline].

  17. Cohen MM Jr. Proteus syndrome. Cohen MM Jr, Neri G, Weksberg R, eds. Overgrowth Syndromes. New York, NY: Oxford University Press; 2002. 75-110.

  18. Samlaska CP, Levin SW, James WD, Benson PM, Walker JC, Perlik PC. Proteus syndrome. Arch Dermatol. 1989 Aug. 125(8):1109-14. [Medline].

  19. Cohen MM Jr. Proteus syndrome: clinical evidence for somatic mosaicism and selective review. Am J Med Genet. 1993 Oct 1. 47(5):645-52. [Medline].

  20. Jamis-Dow CA, Turner J, Biesecker LG, Choyke PL. Radiologic manifestations of Proteus syndrome. Radiographics. 2004 Jul-Aug. 24(4):1051-68. [Medline].

  21. Asahina A, Fujita H, Omori T, Kai H, Yamamoto M, Mii K. Proteus syndrome complicated by multiple spinal meningiomas. Clin Exp Dermatol. 2008 Nov. 33(6):729-32. [Medline].

  22. Newman B, Urbach AH, Orenstein D, Dickman PS. Proteus syndrome: emphasis on the pulmonary manifestations. Pediatr Radiol. 1994. 24(3):189-93. [Medline].

  23. Franc-Guimond J, Houle AM, Barrieras D. The Proteus syndrome associated with life threatening hematuria. J Urol. 2003 Dec. 170(6 Pt 1):2418-9. [Medline].

  24. Macedo A Jr, Ottoni SL, Barroso U Jr, Ortiz V. Bladder hemangiomas and Proteus syndrome: A rare clinical association. J Pediatr Urol. 2009 Dec 29. [Medline].

  25. De Becker I, Gajda DJ, Gilbert-Barness E, Cohen MM Jr. Ocular manifestations in Proteus syndrome. Am J Med Genet. 2000 Jun 19. 92(5):350-2. [Medline].

  26. Hodge D, Misbah SA, Mueller RF, Glass EJ, Chetcuti PA. Proteus syndrome and immunodeficiency. Arch Dis Child. 2000 Mar. 82(3):234-5. [Medline].

  27. Biesecker LG, Peters KF, Darling TN, Choyke P, Hill S, Schimke N, et al. Clinical differentiation between Proteus syndrome and hemihyperplasia: description of a distinct form of hemihyperplasia. Am J Med Genet. 1998 Oct 2. 79(4):311-8. [Medline].

  28. Hagari Y, Aso M, Shimao S, Okano T, Kurimasa A, Takeshita K. Proteus syndrome: report of the first Japanese case with special reference to differentiation from Klippel-Trenaunay-Weber syndrome. J Dermatol. 1992 Aug. 19(8):477-80. [Medline].

  29. McCall S, Ramzy MI, Curé JK, Pai GS. Encephalocraniocutaneous lipomatosis and the Proteus syndrome: distinct entities with overlapping manifestations. Am J Med Genet. 1992 Jul 1. 43(4):662-8. [Medline].

  30. Biesecker LG. Proteus Syndrome. Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 2nd ed. New York, NY: Wiley-Liss; 2005. 437-44.

  31. Cohen MM Jr. Causes of premature death in Proteus syndrome. Am J Med Genet. 2001 Jun 1. 101(1):1-3. [Medline].

  32. Marsh DJ, Trahair TN, Martin JL, Chee WY, Walker J, Kirk EP, et al. Rapamycin treatment for a child with germline PTEN mutation. Nat Clin Pract Oncol. 2008 Jun. 5(6):357-61. [Medline].

  33. Lublin M, Schwartzentruber DJ, Lukish J, Chester C, Biesecker LG, Newman KD. Principles for the surgical management of patients with Proteus syndrome and patients with overgrowth not meeting Proteus criteria. J Pediatr Surg. 2002 Jul. 37(7):1013-20. [Medline].

  34. Vaughn RY, Selinger AD, Howell CG, Parrish RA, Edgerton MT. Proteus syndrome: diagnosis and surgical management. J Pediatr Surg. 1993 Jan. 28(1):5-10. [Medline].

  35. Peters KF, Biesecker LG. An opportunity for genetic counseling intervention: Depression in parents of individuals with proteus syndrome. J Genet Couns. 2000. 9:161-70.

 
Previous
Next
 
Epidermal nevus of the trunk follows the Blaschko lines.
Cerebriform connective-tissue nevus on the plantar surface.
Overall clinical aspect.
Proteus syndrome with hemihypertrophy of the limbs.
Proteus syndrome with gigantism of the feet and macrodactyly.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.