Proteus Syndrome

What Proteus syndrome is

Proteus syndrome is named after the Greek sea god Proteus, who could change his shape. It is a mosaic disorder: the genetic change is present in some of the body's cells but not others, so only certain areas overgrow. The overgrowth is disproportionate (out of proportion to the rest of the body), asymmetric (one side or area more than another), and progressive (it continues and often accelerates through childhood).

It is thought that Joseph Merrick, the "Elephant Man" of 19th-century London, had Proteus syndrome rather than neurofibromatosis, as was once believed.

Cause

In 2011, researchers at the US National Institutes of Health found that Proteus syndrome is caused by a specific change in the AKT1 gene. AKT1 helps control cell growth and survival. The variant switches the protein on permanently, so cells carrying it grow and divide too much.

The variant arises spontaneously in one cell early in embryonic development. Every cell descended from it carries the change. Because the change would likely be lethal if present in every cell, it only exists in mosaic form. It is not inherited from parents, and affected people are not known to pass it to their children.

Signs and symptoms

Overgrowth usually becomes noticeable between 6 and 18 months of age.

Bones and limbs

• Overgrowth of bones in the limbs, hands, feet, fingers, toes or skull, often on one side
• Leg length difference and joint problems
• Bony growths and stiffness of joints
• Scoliosis and overgrown vertebrae

Skin and soft tissue

• Cerebriform connective tissue nevus: thick, deeply grooved, brain-like skin, usually on the soles of the feet and sometimes palms. It is highly characteristic of Proteus syndrome
• Linear epidermal nevi: raised, rough, darker streaks of skin
• Vascular malformations of capillaries, veins or lymph vessels
• Areas of excess fat (lipoma-like lumps) or, in some areas, loss of fat

Other features

• Overgrowth of internal organs such as the spleen
• Certain tumors, including ovarian cystadenomas and parotid gland tumors
• Lung cysts (bullous changes)
• A long face, low nasal bridge and other facial differences in some
• Intellectual disability or seizures in a minority

Diagnosis

Diagnosis is based on clinical criteria (mosaic distribution, progressive course and specific features such as the cerebriform nevus) and confirmed by testing for the AKT1 variant in an affected tissue, such as a skin biopsy from an overgrown area. Blood tests are usually negative, because the variant is often absent from blood cells.

Doctors distinguish Proteus syndrome from other overgrowth disorders:

Imaging such as X-rays, MRI and CT assesses bones, soft tissue, vessels and lungs.

Treatment and management

There is no cure. Care involves a team of geneticists, orthopedic surgeons, dermatologists, vascular specialists, pulmonologists and therapists.

• Orthopedic care: surgery to slow growth in an overgrowing bone (epiphysiodesis), correct leg length differences, straighten the spine or remove overgrown tissue. Timing is critical in growing children.
• Clot prevention: people with Proteus syndrome have a high risk of deep vein thrombosis and pulmonary embolism, especially around surgery. Blood thinners are often used before and after operations.
• Skin and footwear: custom shoes and orthotics for overgrown or nevus-covered feet.
• Monitoring for tumors, lung changes and organ enlargement.
• Physical and occupational therapy to maintain mobility and independence.
• Psychological support for the child and family.
• Targeted therapy: miransertib, a drug that blocks AKT, has been studied in clinical trials and has shown benefit in some patients. It is not yet a standard approved treatment.

Outlook

The course varies widely. Some people have mild, limited overgrowth, while others have severe, disabling changes. Life expectancy can be shortened, mainly by pulmonary embolism, lung complications and surgical risks. With careful clot prevention and specialist care, many people live into adulthood.

Frequently asked questions

What causes Proteus syndrome?

It is caused by a specific change in the AKT1 gene that happens by chance in one cell during early development. Only the cells descended from that cell carry it, so overgrowth affects some parts of the body and not others. It is not caused by anything parents did and is not inherited.

How rare is Proteus syndrome?

Extremely rare. It is estimated to affect fewer than 1 in a million people, and only a few hundred confirmed cases have been described worldwide. Many people once thought to have it actually have other overgrowth conditions, which is why genetic confirmation in affected tissue is important.

Is Proteus syndrome inherited?

No. The gene change arises spontaneously after conception and exists only in some cells. Parents of an affected child have no increased chance of having another affected child, and there are no reports of people with Proteus syndrome passing it on.

What is the life expectancy with Proteus syndrome?

It varies with severity. Some people live well into adulthood, while others have shortened lives, mostly due to blood clots in the lungs, lung disease or surgical complications. Preventing blood clots and specialist monitoring are the most important ways to improve survival.

Did the Elephant Man have Proteus syndrome?

Most experts believe Joseph Merrick, known as the Elephant Man, had Proteus syndrome rather than neurofibromatosis, based on descriptions and his skeleton. Some have suggested he may have had both. Without DNA confirmation, it remains a well-supported but unproven theory.