Dermatologic Manifestations of Proteus Syndrome

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

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