Proteus syndrome

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

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

Proteus syndrome is highly variable, 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. Dr. Michael Cohen described it in 1979. Only a few more than 200 cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition. 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 living with a form of Proteus syndrome (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. 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. 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, while other research pointed to chromosome 16. 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.

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. However, the diagnosis of Proteus syndrome in this patient has been questioned by others. 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 of 2015 and is currently recruiting patients in a study titled "Dose Finding Trial of ARQ 092 in Children and Adults With Proteus Syndrome", ClinicalTrials.gov Identifier: NCT02594215| url = https://clinicaltrials.gov/ct2/show/NCT02594215. This trial is based on in vitro data showing inhibition of AKT1 in cell lines from patients with Proteus syndrome| url = http://www.nature.com/articles/srep17162

Classification

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

Notable cases

In 1971, Ashley Montagu suggested in his book The Elephant Man: A Study in Human Dignity that Joseph Merrick suffered from neurofibromatosis type 1 (NF1), and this has continued to be reported. Newer research has suggested that Merrick's deformities were actually caused by Proteus syndrome (PS), or possibly by a combination of NF1 with PS. However, the exact condition suffered by Joseph Merrick is still not known with certainty.

Mandy Sellars has been diagnosed by some doctors as suffering from this condition. 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.

See also

• Epidermal nevus syndrome
• Mosaic (genetics)
• List of radiographic findings associated with cutaneous conditions

External links

• GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS)
• The Proteus Family Network UK
• The Proteus Syndrome Foundation