proteus syndrome proteus syndrome proteus syndrome is a rare disorder with a genetic background that can cause tissue overgrowth involving all three embryonic lineages. patients with proteus syndrome tend to have an increased risk of embryonic tumor development. the clinical and radiographic symptoms of proteus syndrome are highly variable, as are its orthopedic manifestations. proteus syndromeother namespartial gigantism-nevi-hemihypertrophy-macrocephaly syndrome, wiedemann syndromealex green, a 7-year-old boy with proteus syndrome, confirmed to have the akt1 p.e17k somatic variant. alex died at the age of 9.specialtymedical genetics 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. the syndrome 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 samia temtamy and john rogers in 1976. american pathologist michael cohen described it in 1979. signs and symptoms portuguese illustration of a foreign woman with likely proteus syndrome, 1695 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 typically in early childhood. the musculoskeletal manifestations are cardinal for the diagnosis of proteus syndrome. 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. 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 those with 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 affected individual, causing cognitive and social deficits. affected individuals are at increased risk for developing certain tumors including unilateral ovarian cystadenomas, testicular tumors, meningiomas, and monomorphic adenomas of the parotid gland. hemimegalencephaly is often found to be associated. orthopaedic features the musculoskeletal manifestations of proteus syndrome are frequent and recognizable. patients tend to demonstrate a unique pattern of skeletal abnormalities. the orthopaedic features are usually bilateral, asymmetrical, progressive and involving all four limbs and spine. affected patients usually have localized periarticular limb distortions, limb length discrepancy, and spine deformity. patients with proteus syndrome can have regular bone configuration and contours despite the bone enlargement. patients can also exhibit deformation of the skull in the form of dolichocephaly or elongated skull and facial abnormalities. because of the rarity of the syndrome and the variability of signs, the orthopaedic management should be individualized. 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. 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. diagnosis differential diagnosis macrodystrophia lipomatosa fibrolipomatous hamartoma neurofibromatosis type 1 klippel–trénaunay syndrome parkes weber syndrome sotos syndrome hemangiomas 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. 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. in earlier tests on tissue and cell samples obtained from patients, arq 092 reduced phosphorylation of akt and downstream targets of akt in as little as two hours. the phase 0 trial opened in november 2015. this trial is based on in vitro data showing inhibition of akt1 in cell lines from patients with proteus syndrome. 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 (an englishman known as the "elephant man") had proteus syndrome. however, the exact condition had by joseph merrick is still not known with certainty. mandy sellars has been diagnosed by some doctors as having 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 the often-misdiagnosed pik3ca-related overgrowth spectrum, a syndrome caused by a pik3ca gene mutation.