Friday, October 25, 2013

Proteus syndrome

Proteus syndrome is a rare disorder that causes overgrowth - sometimes grotesque - of skin, bones, muscles, fatty tissues, and blood and lymphatic vessels. The incidence is less than 1 case per 1 million of the population. The symptoms of Proteus syndrome are very varied and include partial gigantism of hands, feet or both, benign tumors such as hemangiomas, lipomas and lymphangiomas, abnormally distended veins, nevi, macrocephaly (an enlarged skull) and asymmetry of the limbs because of long bone overgrowth. It is a progressive condition: children are usually born without obvious deformities, but develop abnormal skin and bone growths as they age. The location of these growths varies, but typically the skull and one or more limbs will be affected. 

The name of Proteus syndrome comes from the Greek god Proteus, who was able to assume many different shapes. This is because the deformations associated with this disorder can be so numerous and so varied.

People suffering from Proteus syndrome are at risk of premature death due to deep vein thrombosis and pulmonary embolism (i.e. blood clots that form in veins, become detached and travel to the lungs, where they block blood flow) 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 develop. Afflicted individuals also have an increased risk of developing certain tumors.

The intelligence of people suffering from Proteus syndrome is typically normal.

(a) Asymmetric finger overgrowth in a patient with Proteus syndrome; (b) X-ray of both hands showing bone overgrowth in the same patient.  
Image from: Angurana et al. (2013)

In 2011 researchers discovered which mutated gene may be responsible for 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 (i.e. a gene which is only present in a certain subset of cells in the body, not in all of them. Mosaicism can result from a mutation in one of the cells of a developing embryo; the faulty gene is later present in only those cells which are descended from the mutant cell.) From 1% to 50% of cells in the tissues and cell lines from patients with the Proteus syndrome carried the mutated gene, and mutant cell lines showed greater AKT activity than did control cell lines. AKT/PKB is a kinase (an enzyme responsible for transmitting signals within the cell - when activated, it reversibly modifies certain other proteins) that aids in cell survival and stimulates cell proliferation.

To put it plainly - Proteus syndrome is most probably caused by a faulty gene that is active in only some of the body's cells, because the mutation occurred in one of the cells of the developing embryo. The mutated gene codes a protein that enables these cells to have an increased lifespan and divide like crazy. In every sufferer, a different subset of cells is affected - hence the highly varied forms this disorder can take, from overgrown limbs to great lumpy tumors on skin. When present in all the body's cells (in a nonmosaic state), the mutation is lethal.

 Skull X-ray showing bone overgrowth on the top of the head of a girl with Proteus syndrome.
Image from: Angurana et al. (2013)

 It has been hypothesized that Joseph Merrick, the famous "Elephant Man" (1862 - 1890), an Englishman with severe deformities who was exhibited as a human curiosity and earned a measure of fame in the Victorian era, might have suffered from Proteus syndrome or from a combination of Proteus syndrome and another genetic disorder, neurofibromatosis type I. An autobiographical pamphlet about Merrick stated that his symptoms first began to appear when he was around 5 years old; he developed swellings on his face and head and thick, lumpy skin like that of an elephant. This was attributed to the fact that his mother had been knocked over and frightened by an elephant when she was pregnant with Joseph. Merrick died aged only 27; the certified cause of death was asphyxia, caused by the weight of his overgrown head when he lay down. He later became the subject of the play and film Elephant Man.

Joseph Merrick, the "Elephant Man", who possibly suffered from Proteus syndrome. Note the bony growths on the skull and the grotesquely enlarged right hand as compared with the left, which is completely normal.  
Image from: Wikipedia


Angurana SK, Angurana RS, Panigrahi I, Marwaha RK. (2013) Proteus syndrome: Clinical profile of six patients and review of literature. Indian J Hum Genet. 2013 Apr;19(2):202-6. doi: 10.4103/0971-6866.116117.

Lindhurst et al. (2011) A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 365(7):611-9. doi: 10.1056/NEJMoa1104017. Epub 2011 Jul 27. 

Proteus syndrome
John Merrick

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