Diagnostic Criteria & FAQs

What is Proteus syndrome?
Proteus syndrome is a rare overgrowth condition. The overgrowth in Proteus syndrome can cause differences in the appearance and growth rate of various body parts. This overgrowth is also typically asymmetric, that is, it does not affect corresponding body parts similarly. The word “Proteus” comes from the name of the ancient Greek god of change; this name was chosen because the overgrowth in Proteus syndrome can cause changes in the shapes of body structures over time.

What causes Proteus syndrome?

Proteus syndrome is NOT caused by anything either parent does (or does not) do before or during pregnancy.  Proteus syndrome is not caused by any environmental exposures before or during pregnancy. Researchers at NIH have recently learned that Proteus syndrome is caused by a mosaic alteration, or mutation, in a gene called “AKT1.” The NIH research group, led by Dr. Leslie Biesecker, recently published their findings in a journal article in the New England Journal of Medicine. The following sections may answer some questions people might have about this discovery.

What is a “mosaic” genetic alteration?

Our bodies are made up of millions of different cells.  Each cell has its own copy of the genetic code in it that serves as the cells’ instruction manual. A mosaic gene alteration is a change in the genetic code that is present in some of the body’s cells but not others. Scientists studying Proteus syndrome have previously hypothesized, or guessed, that the genetic alteration responsible for causing the condition would be mosaic.  This is because of the way that Proteus syndrome affects people — some parts of the body appear to be affected with the condition while other body parts appear normal.  Also, no two people with Proteus syndrome are affected in exactly the same way.

How did researchers find this gene alteration?

The NIH team, with financial support from the Proteus Syndrome Foundations of the US and the UK, used new genetic sequencing technologies to look at all of the genes of a few patients with Proteus syndrome and some of their relatives.  By reading through, or “sequencing,” all of these individuals’ genes, they found that one gene, AKT1, was altered in patients with Proteus syndrome but normal in unaffected relatives.

The NIH researchers tested the AKT1 gene in 29 patients with Proteus syndrome and they found an AKT1mutation in 26 patients.  The source of the sample, that is, where the DNA used for the test came from, turned out to be very important in this study. When the NIH researchers tested the AKT1 gene in cells that came from clearly affected parts of the body, such as an abnormal skin biopsy, they found an AKT1 mutation in about 75 percent of the samples.  When the cells of clearly unaffected parts of the body were tested, they found the mutation in only about 30 percent of the samples. Only very specialized testing was able to detect this mutation in blood cells, and only two patients’ blood cells were positive using this specialized technique.

These results match what scientists have believed about Proteus syndrome:  the genetic alteration that causes the condition is not present in all of the cells of the body.  This makes genetic testing for AKT1 mutations in people with Proteus syndrome complicated because the sample that used for testing may not actually have the gene change in it or it may be present in such low levels that is not able to be detected.

What is the AKT1 gene and how is it altered in people with Proteus syndrome?

Genes are the body’s instructions for growth and development because they provide the blueprint to make proteins, chemicals that are responsible for all the body’s important functions. AKT1 is a gene that makes a protein that acts like a switch that controls cell growth. The AKT1 protein interacts with dozens of other proteins to control when the body’s cells should grow or divide, rest and die off.  Most of what we understand about the AKT1 protein and the other proteins it works with as part of a larger “pathway” comes from cancer research, since cancer is a disease that causes increased cell growth.

People with Proteus syndrome have an altered AKT1 gene in some of their cells.  This altered gene makes an abnormal protein.  The official name for this alteration is “c. 49G>A, p.Glu17Lys,” and it is called an “activating mutation.”  This means that the AKT1 gene has a “spelling error” that causes an abnormally active protein to be made in the body.  This active protein is thought to increase rates of cell growth and may prevent cells from dying off when they naturally would. Researchers think that this helps to explain why patients with Proteus syndrome experience overgrowth and are at an increased risk to develop tumors.

What does this discovery mean for people with Proteus syndrome?

Understanding the genetic cause of Proteus syndrome could lead to significant advances in diagnosing and treating this rare condition, and there is reason for patients and their families to be excited and hopeful about this discovery.  For researchers, this discovery will help focus efforts to develop animal models of Proteus syndrome, test new drugs and other therapies and gain a better understanding of the complications seen in many patients.

How common is Proteus syndrome?
Proteus syndrome is very rare. Only a few hundred people are thought to be affected with this condition worldwide. Because it is so rare, it can be difficult for doctors to accurately diagnose Proteus syndrome.

How is Proteus syndrome diagnosed?
(Please not this is changing to a degree due to the discovery of AKTI)

Doctors use a checklist of features or characteristics present in a person to make a diagnosis of Proteus syndrome. This kind of checklist is called the “diagnostic criteria” for Proteus syndrome and helps doctors to accurately diagnose the condition.

There are three general characteristics or features that must be present for doctors to consider a diagnosis of Proteus syndrome:

  1. Mosaic distribution: this means that the areas of overgrowth are patchy and that only some body parts show signs of overgrowth while others are unaffected
  2. Sporadic occurrence: this means that no one else in the affected person’s family has similar features of overgrowth
  3. Progressive course: this means that the overgrowth has noticeably altered the appearance of the affected body parts over time or that new areas of overgrowth have appeared over time

If a person has all three of these general characteristics in addition to some specific characteristics, doctors may consider a diagnosis of Proteus syndrome.

The specific characteristics are grouped into three categories: A, B, and C. A diagnosis of Proteus syndrome requires all three general features to be present and either one feature from Category A, or two features from Category B, or three features from Category C. These features are listed in the table below. Definitions for the terms are listed below. (Definitions can be found at the bottom of the page)

General Criteria

We have a child with Proteus syndrome.  What are the chances our next child will also have Proteus syndrome?

It is very important to talk about questions like this with a geneticist or genetic counselor, because having the right diagnosis for your child is very important in answering this question.  The chances for a person with Proteus syndrome to have an affected sibling are low, much less than 1/100 or 1 percent.  Adults with Proteus syndrome have never had any affected children.

What medical problems can Proteus syndrome cause?
Proteus syndrome can affect any part of the body but commonly affects the bones and skin. Overgrowth of a bone can cause orthopedic problems, and overgrowth of the skin can cause cosmetic and other concerns. Less commonly, individuals with Proteus syndrome have lung problems that require monitoring. Many children and adults with Proteus syndrome have normal intelligence and have good general health. Children and adults with Proteus syndrome are at risk to get a type of blood clot called a “DVT,” or deep vein thrombosis, which can cause a serious problem called a pulmonary embolism. It is important for doctors caring for people with Proteus syndrome to be aware of this risk.

It is important to realize that every person with Proteus syndrome is different and that no two people with this condition will have the same medical concerns.

How is Proteus syndrome treated?
Each person with Proteus syndrome will have different medical needs that need individualized treatment. Many patients with Proteus syndrome are followed by a geneticist or another doctor, such as a pediatrician (for children) or internist (for adults) who coordinates their medical care. Many manifestations of Proteus syndrome (for example, skin changes and fatty overgrowth) rarely require aggressive or frequent treatment. In other cases, a particular feature may be monitored over a period of time before a treatment decision is made. Many patients with Proteus syndrome are followed by an orthopedic surgeon for their bone problems and there are a number of treatments available to reduce the overgrowth in the limbs or digits. Other specialists who might be involved in the care of a person with Proteus syndrome include a dermatologist (skin doctor), physiatrist (rehabilitation medicine doctor), pulmonologist (lung doctor), physical/occupational therapists, and a pedorthist (a person who makes shoe and other orthotics). People with Proteus syndrome should also be seen by a hematologist (blood doctor) for an evaluation a few weeks before having surgery so doctors can consider the risk for blood clots and possible ways to reduce the chances for blood clots.

How can I help my child or my family cope with this condition?
Proteus syndrome is a rare condition that can cause physical differences and changes over time. Many parents and families are frustrated by how long it can take to get a diagnosis and how hard it can be to find a doctor with experience treating this condition. Even after a family has a diagnosis, it can be very difficult to explain this condition to others or answer rude and unwelcome questions, and some children struggle to adapt to physical challenges or differences.

Every family of a child with a rare condition faces unique challenges and has a unique set of strengths. Learning more about the condition and talking with other parents are two things that many families say are helpful. Older children and teens can find connecting with other children with similar concerns to be very helpful, and many children with chronic illnesses say that sharing their thoughts about their condition with another young person their age makes them feel less alone and more understood. Sibilngs of children with health concerns have their own unique emotional needs, and there are a growing number of resources, such as Sibshops [http://www.siblingsupport.org/sibshops], available to them.

Definitions of terms from table:

Cerebriform connective tissue nevus – this is a very distinct type of skin overgrowth seen almost exclusively in people with Proteus syndrome. Abbreviated as “CCTN,” this skin growth can have deep grooves and wrinkles.

Linear epidermal nevus – streaky skin pigmentation that is often brown. This skin change sometimes has a rough or velvety texture.

Asymmetric disproportionate overgrowth – growth of a body structure or structure that is different from the overall growth rate of the child and is not the same from structure to structure.

Bilateral ovarian cystadenomas – an abnormal growth of ovarian tissue

Monomorphic partotid adenomas – an abnormal growth of the parotid gland, one of the glands that makes saliva

Dysregulated adipose tissue – this means abnormal growth and/or distribution of fat and includes benign (not cancerous) fatty tumors (often called “lipomas”) or a lack of fat under the skin

Vascular malformations – differences in the blood vessels (capillaries and veins) or vessels of the immune system (the lymphatic vessels) are formed

Lung bullae – when the tiny air sacs that make up the lung from large, hollow areas. These hollow areas (“bullae”) don’t function as well as normal lung tissue.

Phenotype – a distinct and observable physical characteristic (often described using medical terminology)