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Dermatologic Manifestations of Proteus Syndrome

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


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]



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]




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


Proteus syndrome has no predilection for any particular race.


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


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]



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]

Contributor Information and Disclosures

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

Disclosure: Nothing to disclose.


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.


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.

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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.
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