Proteus Syndrome

Proteus syndrome is one of the world’s rarest genetic conditions, affecting fewer than 1 in 1 million people worldwide. This complex disorder causes some parts of the body to grow abnormally and out of proportion, leading to significant physical differences that worsen over time.

Table of contents

• What is Proteus syndrome?
• How common is the condition?
• What causes Proteus syndrome?
• Signs and symptoms
• Complications
• How is it diagnosed?
• Treatment and management
• Outlook and prognosis

What is Proteus syndrome?

Proteus syndrome is a rare genetic condition that causes excessive growth of bones, skin, organs and tissues. The disease causes parts of the body to grow out of proportion with the rest of it. The overgrowth is usually asymmetrical, meaning it affects the right and left sides of the body differently^[1].

Newborn babies with Proteus syndrome usually don’t show any signs of the condition. The unusual growth starts to appear between the ages of 6 months and 18 months. It rapidly develops within the first 10 years of life and gets more severe as a person ages^[1].

The condition is named after Proteus, the ancient Greek god of change. Scientists chose this name because Proteus syndrome can cause body structures to change shapes over time^[1].

How common is the condition?

Proteus syndrome is an extremely rare condition that affects fewer than 1 in 1 million people around the world. Only a few hundred cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition^[2][3].

It is difficult to diagnose the disease because it is so rare and other conditions also cause asymmetrical overgrowth. Researchers believe some people go undiagnosed, while others are misdiagnosed with the condition. Those most readily diagnosed are also the most severely affected^[1][3].

Some studies show the condition affects men slightly more often than women^[1].

What causes Proteus syndrome?

Proteus syndrome is caused by a mutation in a gene called AKT1. This gene helps regulate cell growth and division. A mutation in this gene disrupts a cell’s ability to control its own growth, allowing it to grow and divide abnormally^[2].

The genetic change is not inherited from a parent. It arises randomly in one cell during the early stages of development before birth. This means the condition occurs sporadically and is not passed on from one generation to the next^[2][6].

As cells continue to grow and divide during development, some cells will have the mutation and other cells will not. This mixture of cells with and without a genetic mutation is known as mosaicism. This helps explain why overgrowth affects only some parts of the body while other parts remain normal^[2][5].

Studies suggest that the AKT1 gene mutation is more common in groups of cells that experience overgrowth than in the parts of the body that grow normally^[2].

Signs and symptoms

The first signs of Proteus syndrome usually appear between 6 months and 18 months of age when asymmetrical overgrowth begins. The pattern and severity of overgrowth can vary greatly from person to person. It can affect almost any part of the body, including bones, skin, organs and tissues. The condition rapidly progresses during the first decade of life^[1][2].

The bones in the arms, legs, skull and spine may develop irregularly. Arms and legs may grow to significantly different lengths. A person may develop severe curvature of the spine, a condition called scoliosis. Overgrowth may eventually affect the mobility of joints^[1].

Proteus syndrome can cause abnormal skin growths. Thick, raised lesions called cerebriform connective tissue nevus often form. They are typically found on the soles of the feet but can also affect the hands. These have a deeply grooved appearance that resembles the surface of the brain. This kind of skin growth is rarely seen in any other condition and is considered almost pathognomonic, meaning it strongly indicates Proteus syndrome^[1][2][4].

Abnormal growth of blood vessels, including capillaries and veins, may occur. Overgrowth of fat tissue, called adipose tissue, can affect the stomach, arms and legs. Mostly benign (noncancerous) tumors consisting of fatty tissue, called lipomas, may develop^[1].

Some people with Proteus syndrome have neurological abnormalities as well. These may include intellectual disabilities, seizures, and vision loss^[1][2].

Proteus syndrome can cause distinctive facial features such as a long face, outside corners of the eyes that point downward, a flat nose bridge with wide nostrils, and an open-mouth expression^[1][2].

Complications

The most life-threatening complication of Proteus syndrome is a type of blood clot called a deep vein thrombosis (DVT). DVTs affect the deep veins of the legs. If these clots travel through the bloodstream, they can lodge in the lungs and cause a life-threatening complication called a pulmonary embolism. Pulmonary embolism is a common cause of death in people with Proteus syndrome^[1][2].

People with Proteus syndrome have an increased risk of developing various types of tumors. These include benign tumors such as unilateral ovarian cystadenomas in women, testicular tumors in men, meningiomas (tumors of the membranes covering the brain and spinal cord), and monomorphic adenomas of the parotid gland^[2][3].

Because of carrying excess weight and enlarged limbs, arthritis and muscle pain may also develop. The mass of extra tissue can create additional health problems^[3].

The visible deformity can affect the social experiences of people with the condition, causing emotional difficulties, social rejection and stigma^[3].

How is it diagnosed?

As Proteus syndrome is a rare condition, diagnosis will usually only be possible at a specialist center with input from a multidisciplinary team. Doctors use a checklist of features or characteristics present in a person to make a diagnosis of Proteus syndrome. This checklist is called the diagnostic criteria for Proteus syndrome^[6].

There are three general characteristics that must be present for doctors to consider a diagnosis of Proteus syndrome. These are mosaic distribution (areas of overgrowth are patchy and only some body parts show signs of overgrowth), sporadic occurrence (no one else in the affected person’s family has similar features), and progressive course (overgrowth has noticeably altered the appearance of the affected body parts over time)^[6].

The diagnosis is confirmed by identification of a mutation in the AKT1 gene in affected tissue. This requires DNA testing of tissue biopsied from an affected body part^[6].

Imaging studies such as plain x-rays are often important to assess and monitor areas of overgrowth. X-rays should demonstrate bony overgrowth seen in Proteus syndrome but usually not seen in other overgrowth conditions. MRIs of the chest and abdomen can reveal internal lesions such as lipomas or pulmonary cysts^[1].

Treatment and management

Proteus syndrome cannot be cured, but there is much that can be done to manage the symptoms. As Proteus syndrome can affect many areas of the body, treatment is usually managed by a multidisciplinary team. This may include dermatologists (skin specialists), orthopaedic surgeons (bone and joint specialists), plastic surgeons, radiologists (imaging specialists), and other specialists as needed. Regular review is advisable so that any symptoms can be monitored and managed promptly if problems occur^[6].

Surgery may be required for scoliosis or to address specific areas of overgrowth. Exceptionally large digits may require surgical reduction or even amputation in extreme circumstances so that a person can wear shoes or use their hand. Hemifacial overgrowth or tongue enlargement may require surgical intervention if airway obstruction, feeding difficulties, or severe malocclusion is present^[1].

Physiotherapy and occupational therapy can be helpful to improve movement, with adaptations to footwear where needed. Leg length discrepancy needs to be addressed by an experienced orthopedist, as it can create a host of secondary problems^[6].

Aggressive management of blood clots may be lifesaving in patients who present with calf or leg pain, a palpable cord, and shortness of breath or respiratory distress. Physicians who care for individuals with Proteus syndrome should be made aware of the potential thrombotic risks. Some clinicians have suggested serious consideration of prophylactic anticoagulation prior to elective surgery^[1].

A repurposed cancer drug called miransertib appears to reduce the severity of lesions and pain experienced by people with Proteus syndrome. The drug was well tolerated, even in children, according to research studies. The drug was originally developed for treating cancers that were activated by a variant of the gene AKT1, the same gene pathway affected in Proteus syndrome. Researchers have found encouraging results showing that a much lower dose of the medication than used in cancer trials is well tolerated and that there are some initial indications that the drug had a beneficial effect on symptoms of Proteus syndrome^[12][13].

Outlook and prognosis

Proteus syndrome is a progressive condition, meaning it worsens over time. The irregular overgrowth increases with age and increases susceptibility to tumors^[5].

By the time they reach their 23rd year, 25 percent of people with Proteus syndrome have died. The most common cause of death is pulmonary embolism^[12].

With appropriate multidisciplinary care and monitoring for complications, particularly blood clots, many people with Proteus syndrome can live into adulthood. Some individuals have lived into their 60s with the condition^[18].

Partial gigantism-nevi-hemihypertrophy-macrocephaly syndrome, Wiedemann syndrome

• Bones
• Skin
• Blood vessels
• Adipose tissue (fat)
• Connective tissue
• Brain
• Spinal cord
• Ovaries
• Testes
• Parotid gland
• Lungs