Have you ever imagined with hands, feet or head similar to an elephant?

BELIEVE IT OR NOT!

There is a terrible and uncommon disease which causes the appearance of this animal. This disease is called the PROTEUS SYNDROME. It is also known vulgarly as ELEPHANTIASIS

A CURRENT CHALLENGE FOR SCIENCE: PROTEUS SYNDROME

What is it? 

Proteus syndrome (PS) is a congenital, rare, complex, progressive, and disfiguring disorder that manifests variably as asymmetric, disproportionate overgrowth of body tissues derived from any germline layer.

There are no external factors that cause the disease; it is just produced due to the somatic activating mutation in serine-threonine protein kinase AKT1, this mutation was discovered a few of years ago by a german scientis whose last name is Lindhurst.

 

 

How did Lindhurst 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.

Diagram of AKT1 gene mutation and its developing

What is the history of Proteus Syndrome? 

Proteus Syndrome was first described by Cohen and Hayden in 1979, but actually Wiedemann was who called to this disease as Proteus Syndrome in 1983. The syndrome was named in this way beacuse of the Greek god Proteus (the polymorphous), who could get such a lot of forms according to the legends.

It is believed that Joseph Merrick, the main character of the movie ¨The Elephant Man¨ was the first person who got this disease. His case was presented to the Pathological Society of London in 1884 by Sir Frederick Treves. A diagnosis of neurofibromatosis was suggested in 1909, but there is no evidence of spots or histological proof of neurofibromas. It is also clear that Joseph Merrick's manifestations were much more bizarre than those of neurofibromatosis. Evidence indicates that Merrick suffered from the Proteus syndrome. 

Joseph Merrick´s head

Joseph Merrick´s foot

How is Proteus syndrome diagnosed?

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 and that appeared unexpectedly.
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 and also that the disease never stops but it is constantly damaging to the patient. 

Overgrowth of fingers

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:

Category A

• Cerebriform connective tissue nevus

Category B

• Linear epidermal nevus
• Asymmetric, disproportionate overgrowth.
• Specific tumors before second decade.

Category C

• Dysregulated adipose tissue
• Vascular malformations 
•  Facial phenotype 

Deformation of the skull

Overgrowing of legs

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.

Pulmonary Embolism

Deep Vein Thrombosis

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. Although each patient should have a specific tratment, there are some affections which are commons due to the disease and teher are treatments for them:

Overgrowth is an ongoing issue for many patients with Proteus syndrome. For overgrowth of tubular bones, epiphysiostasis and epiphysiodesis should be the mainstays of management.  The skeletal overgrowth of PS can result in significant biomechanical and functional compromise, for that reason it is also important that the patient does physical therapy.

Deep vein thrombosis (DVT) and pulmonary embolism (PE). The most urgent and life-threatening complication of Proteus syndrome can be DVT and PE. 

The authors recommend emergent evaluation of patients who develop symptoms of DVT (e.g., palpable subcutaneous rope-like mass, swelling, erythema, pain, and distal venous congestion) or PE (e.g., shortness of breath, chest pain, and cough).   

Psychosocial issues. In addition to functional compromise, the skeletal and connective tissue overgrowth of PS can result in disfigurement for some patients, a significant concern for many families. This condition is progressive and the degree of severity varies widely among patients, creating uncertainty for both clinicians and families.For those reason, the patient must receive a psychological treatment with a professional to overcome these issues. 

Psychological help for Jordan

Physical Therapy for Martha

Is there any possibility that the relatives of a patient also get the disease?

Generally, there is no possibility that a relative of a person who has the disease, due to genetic links, get the disease, so:

• Parents of a proband: No parent of a child with bone fide Proteus syndrome has been demonstrated to have any significant, distinctive manifestations of the disorder. 
• Sibs of a proband: Given the somatic mutational mechanism of Proteus syndrome, the risk  for an affected sib would be expected to be the same as in the general population. 
• Offspring of a proband: The reproductive outcome data on adults with PS are very limited. 

Jordan and his parents

 

Sample Case Report

One of the most current and fatal cases of this syndrome was found in the USA, a boy of twelve years was examined at the Hospital of Massachusetts, his name was Peter. At admission he was found to have petechiae on buccal mucosa and fecal discoloration. Multiple abnormalities in his musculoskeletal system and skin were found. He had lymph edema in left leg, hemihypertrophy, macrodactyly in both foots and macrocephaly, including a hemorrhagic disorder. 

The skin abnormalities included thickening of skin and epidermal nevi over the trunk and lower extremities, with the largest one being 5×5 cm in diameter. Another prominent feature in this case was macrocephaly (head circumference=62 cm).

In popliteal area of both legs there were some enlarged lymph nodes with the largest one being 11×8 mm in diameter, it means a little more than the double of a the lynmph node of a normal human being.

His mother stated that she had an uneventful pregnancy and normal vaginal delivery, and also that here was no history of bleeding disorder in the family.

Peter´s  affections

Fun  Facts:

• This exceedingly rare syndrome affects less than one per million people and currently there are just  200 confirmed cases reported worldwide. 
• The most of the cases are presented in children from India and from the United States.
• The disease affects more boys than girls
• There is no cure for the disease yet.
• Proteus syndrome has minimal or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood. 

Two paradigms of the life:
Lok at them and their fortress to overcome the obstacles even though they have Proteus Syndrome

 

 
 
I hope you enjoy the blog and that the data is very useful!

Below there are several links in which I researched the information, icluding some papers. Check them if you would like extra data:

• http://hinari-gw.who.int/whalecomwww.ncbi.nlm.nih.gov/whalecom0/pmc/articles/PMC3758728/?report=reader#!po=7.14286. 
• http://hinari-gw.who.int/whalecomwww.ncbi.nlm.nih.gov/whalecom0/pmc/articles/PMC3446058/.http://hinari-gw.who.int/whalecomwww.ncbi.nlm.nih.gov/whalecom0/pmc/articles/PMC3179535/.
• http://www.nejm.org/doi/pdf/10.1056/NEJMoa1104017. 
• http://www.proteus-syndrome.org.
• http://hinari-gw.who.int/whalecomwww.ncbi.nlm.nih.gov/whalecom0/books/NBK99495/.
• http://www.bmj.com/content/293/6548/683.
• http://www.nejm.org/doi/pdf/10.1056/NEJMe1107384.
• http://www.dirjournal.org/text.php3?id=529. 
• https://www.google.com.ec/search?q=proteus+syndrome&source=lnms&tbm=isch&sa=X&ei=-0a_UrPxJdSPkAfRxoH4Bw&ved=0CAcQ_AUoAQ&biw=1366&bih=678#q=proteus+syndrome&tbm=isch&imgdii=_