Proteus syndrome is a rare disorder with a genetic background[1] that can cause tissue overgrowth involving all three
embryonic lineages. Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development.[2] The clinical and
radiographic symptoms of Proteus syndrome are highly variable, as are its orthopedic manifestations.[3][4]
Only a few more than 200 cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition.[5] 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.[6][7] American pathologist
Michael Cohen described it in 1979.[8]
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 typically in early childhood. The musculoskeletal manifestations are cardinal for the diagnosis of Proteus syndrome.[3] 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.[citation needed]
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.[9] In addition, the presence of visible deformity have a negative effect on the social experiences of the affected individual, causing cognitive,
social rejection and stigma.[citation needed]
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.[3] 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.[3]
Genetics
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
AKT1kinase in a mosaic state.[11]
Previous research had suggested the condition linked to PTEN on
chromosome 10,[12] while other research pointed to
chromosome 16.[13] 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.[14][15]
Many sources classify Proteus syndrome to be a type of
nevus syndrome. The
lesions appear to be distributed in a mosaic manner.[20] It has been confirmed that the disorder is an example of genetic
mosaicism.[11]
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.[21] However, the diagnosis of Proteus syndrome in this patient has been questioned by others.[22]
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.[23] The Phase 0 trial opened in November 2015.[24] This trial is based on
in vitro data showing inhibition of AKT1 in
cell lines from patients with Proteus syndrome.[25]
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.[26][27]
Mandy Sellars has been diagnosed by some doctors as having this condition.[5] 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.[citation needed]
^Temtamy SA, Rogers JG (December 1976). "Macrodactyly, hemihypertrophy, and connective tissue nevi: Report of a new syndrome and review of the literature". The Journal of Pediatrics. 89 (6): 924–927.
doi:
10.1016/S0022-3476(76)80597-5.
PMID993918.
^Opitz JM, Jorde LB (July 27, 2011). "Hamartoma Syndromes, Exome Sequencing, and a Protean Puzzle". The New England Journal of Medicine. 365 (7): 661–3.
doi:
10.1056/NEJMe1107384.
PMID21793737.
^Cohen MM, Hayden PW (1979). "A newly recognized hamartomatous syndrome". Birth Defects Orig. Artic. Ser. 15 (5B): 291–6.
PMID118782.
^Thiffault I, Schwartz CE, Der Kaloustian V, Foulkes WD (October 2004). "Mutation analysis of the tumor suppressor PTEN and the glypican 3 (GPC3) gene in patients diagnosed with Proteus syndrome". Am. J. Med. Genet. A. 130A (2): 123–7.
doi:
10.1002/ajmg.a.30335.
PMID15372512.
S2CID32014732.
^Marsh DJ, Trahair TN, Martin JL, Chee WY, Walker J, Kirk EP, Baxter RC, Marshall GM (April 22, 2008). "Rapamycin treatment for a child with germline PTEN mutation". Nature Clinical Practice Oncology. 5 (6): 357–361.
doi:
10.1038/ncponc1112.
PMID18431376.
S2CID2870300.
^Cohen MM, Turner JT, Biesecker LG (November 1, 2003). "Proteus Syndrome: Misdiagnosis with PTEN Mutations". American Journal of Medical Genetics. 122A (4): 323–324.
doi:
10.1002/ajmg.a.20474.
PMID14518070.
S2CID26811086.