Protein Syndrome by A.Griguolo

Generality

Proteus syndrome is a very rare genetic disease, characterized by the uncontrolled growth of different types of tissues (bone, skin, fat, etc.) and of different internal organs (blood vessels, spleen, brain, etc.).

Due to a specific mutation in the AKT1 gene, Proteus syndrome is never a hereditary condition; this means that at its origin there is always an acquired mutational event, taking place after conception, in the very early stages of embryonic development.

Diagnosing a disease like Proteus syndrome is not easy, because the symptomatology varies from patient to patient (so there is no reference symptom picture) and because a genetic test is needed on a sample of cells taken from a tissue or organ victim of uncontrolled growth.

Currently, those suffering from Proteus syndrome can only rely on symptomatic treatments, ie aimed at alleviating the symptoms.

What is Proteus Syndrome?

Proteus syndrome is a genetic disease, whose main characteristic is causing, in its carriers, the uncontrolled, disharmonic and completely random growth of bones, skin, muscles, adipose tissue, blood and lymphatic vessels, internal organs of the trunk and organs of the central nervous system.

As a result of the aforementioned uncontrolled growth process, Proteus syndrome can deeply disfigure the physical appearance of those affected, making it, in some circumstances, very different from any healthy human being.

Curiosity

The syndrome of Proteus is the disease of which Joseph Merrick, the man of British origin who had gone down in history with the elephant-man epithet, suffered, probably due to some deformities of the body that made him look like an elephant.

Meaning of disharmonic growth

In describing the most important feature of Proteus syndrome, the previous definition reported the expression "uncontrolled growth, disharmonic and completely random".

Since some readers may wonder what the aforementioned expression means, it is necessary to give a brief explanation of the individual terms, anticipating some information relating to the causes and symptoms:

Uncontrolled growth - Because Proteus syndrome induces unregulated proliferation of cells constituting target tissues and organs.
Disharmonic growth - Because Proteus syndrome can induce the uncontrolled growth of an internal trunk organ, without altering the size of the others; this leads to a lack of proportion between the body concerned and the other organs.
Furthermore, in attacking the bone tissues, Proteus syndrome acts in a completely asymmetric way, in the sense that it determines the abnormal growth of a bone of half of the body, but not of its contralateral (eg: it increases abnormally the humerus right, but not the left humerus).
Random growth - Because Proteus syndrome affects tissues and organs totally randomly, without any criteria. In fact, in the chapter dedicated to causes, it will emerge that the affected tissues and organs are those in which the mutation of the gene responsible for Proteus syndrome resides.
The completely random way in which Proteus syndrome works is the reason why every patient represents a case in itself.

Epidemiology: how common is Proteus syndrome?

According to statistics, Proteus syndrome would have an incidence of less than one in a million. Thus, it is a very rare genetic disease.

However, it is necessary to point out, for many experts in the field, the condition in question would be underdiagnosed; in other words, more people would be born with Proteus syndrome than reported by the epidemiological statistical studies.

Did you know that ...

Currently, there are about 120 cases in the world of Proteus syndrome, while the total cases recorded in so-called medical literature are slightly over 200.

Origin of the name

Proteus is a marine god of Greek mythology, who possesses the extraordinary ability to transform his physical appearance whenever he considers it necessary.

Who gave the name to the Proteus syndrome has chosen to refer to the god Proteus probably because the manifestations of the genetic disease in question vary from patient to patient, in a completely random way.

Causes

Proteus syndrome is due to a specific AKT1 gene mutation, located on chromosome 14 .

In the human being, the aforementioned mutation is always acquired spontaneously, from nothing and without precise reasons, during the course of embryonic development - that is, after the sperm has fertilized the egg and embryogenesis has begun.

What causes the mutation of the protein associated with Proteus syndrome?

Premise: the genes present on human chromosomes are DNA sequences that have the task of producing fundamental proteins in biologic processes indispensable to life, including cell growth and replication.

In the absence of mutations against him, the AKT1 gene produces a protein responsible for regulating the processes of growth, division and cell death; in other words, it gives life to a protein regulating the life cycle of cells, avoiding the phenomena of cellular hyperproliferation.

In the presence instead of the mutation responsible for Proteus syndrome, the AKT1 gene loses all its regulatory properties (it is no longer an effective regulator of the life cycle of cells) and this means that the cells involved are the object of uncontrolled growth and division.

The lack of effective regulation of the life cycle of cells in people with Proteus syndrome is the reason why some parts of the body are the protagonists of excessive growth.

Curiosity

In the past, before discovering that the AKT1 gene was responsible for Proteus syndrome, geneticists and molecular biologists believed that the aforementioned genetic disease depended on mutations in the PTEN gene, located on chromosome 10.

Proteus syndrome is an example of genetic mosaicism

In subjects with Proteus syndrome, the cellular heritage includes healthy cells, whose DNA is devoid of the mutation in AKT1, and diseased cells, carriers on the DNA of the mutation in AKT1.

In genetics, this particular circumstance - ie the presence, in a multicellular individual, of two cell lines with different DNA - is called mosaicism (or genetic mosaicism ).

Mosaicism is the explanation for several features of Proteus syndrome:

It is because of the mosaicism that, in individuals with Proteus syndrome, only certain parts of the body are subject to uncontrolled growth. Specifically, those tissues whose cells are diseased, or carriers of the mutation in the AKT1 gene, undergo uncontrolled growth;
The severity of the symptomatology depends on the extent of the mosaicism: the more the number of diseased cells is high, compared to the number of healthy cells, the more parts of the body (bones, muscles, skin, internal organs, etc.) are object of uncontrolled growth.

In genetics, the term mosaicism indicates the presence, in a multicellular individual, of two or more different genetic lines that all find expression (ie they are visible).

Symptoms and Complications

The symptoms and signs of Proteus syndrome vary from patient to patient, depending on the tissues and organs subject to overgrowth (or, in any case, subjected to the AKT1 gene mutation).

Having clarified this aspect, in the presence of Proteus syndrome a typical symptomatological picture includes:

Excessive development of some bones (example of hyperostosis ). Proteus syndrome has a predilection for the bones of the upper limbs, lower extremities, skull and spine.
The presence of benign skin growths. Among these benign skin growths are the verrucous epidermal nevi and the cerebriform nevi of connective tissue; in the Proteus syndrome, the second type of skin growths is mainly located on the feet.
Excessive development of some blood vessels (both arteries and veins) and some lymphatic vessels.
The excessive development of some adipose areas and the formation of lipomas (benign tumors of adipose tissue).
The immense growth of internal organs of the trunk, including, in particular, the spleen, thymus and colon.
The formation of usually benign tumors, such as bilateral ovarian cystadenoma (a benign ovarian tumor), monomorphic adenoma of the salivary glands, monomorphic adenoma of the parathyroid gland, testicular cancer (exclusively in male patients) and meningioma (benign brain tumor originating from the meninges).

Less common symptoms and signs of Proteus syndrome

At the typical clinical manifestations described above, Proteus syndrome can sometimes add another series of symptoms and signs, a series that includes:

The excessive development of one half of the brain ( hemimegalencephaly ) and other brain malformations. These abnormalities can lead to intellectual deficits, epilepsy and vision problems;
Ptosis (waning eyelid) and eyelid fissures facing downwards;

A lipoma

Dolicocefalia (long and narrow head);
Nasal bridge in lower than normal position;
Abnormalities of the kidneys and / or urinary tract;
Strabismus;
Dermoid ocular cyst;
Emphysematous cysts or bubbles in the lungs.

Did you know that ...

When Proteus syndrome affects the brain, it is very often associated with facial abnormalities and the aforementioned eye problems.

The reasons behind this association are currently a mystery.

When does the symptomatology appear?

Most people with Proteus syndrome do not have any symptoms and signs of the disease at birth. In fact, Proteus syndrome tends to give the first manifestations of itself between 6 and 18 months of life of the patient, becoming ever more serious from that moment on.

Complications

Over time, Proteus syndrome can give rise to several complications. These complications are substantially what results from the inexorable deterioration of the symptomatological picture; indeed:

Bone malformations in the lower limbs tend to lead to deformities which, in addition to making the affected bones unrecognizable, more or less seriously compromise the motility of neighboring joints and predispose to sprains and joint dislocations ;
Abnormalities of the spine favor the onset of scoliosis ;
The abnormal growth of blood vessels is a promoter of the phenomenon of deep vein thrombosis, from which, in turn, the dangerous medical condition known as pulmonary embolism can derive. Characterized by the presence of an embolus in the pulmonary arteries, pulmonary embolism can have fatal consequences for the patient;
Brain malformations tend to affect the patient's intellectual development, to the point that he has difficulty in providing for himself, in everyday life.

Diagnosis

The diagnosis of Proteus syndrome is quite difficult, even for a long-experienced doctor.

The main reasons for the diagnostic difficulties are due to the wide spectrum of all possible symptoms and to the fact that the mutation in the AKT1 gene is not easily detectable.

What is the most effective diagnostic procedure?

To be able to identify Proteus syndrome, doctors believe it is essential to conduct a thorough physical examination, compare the data that emerged from the latter with the diagnostic criteria established by the medical community for the disease in question and, finally, carry out a genetic test on a sample of cells from a tissue or organ victim of an anomaly.

IS A GENETIC TEST ON A BLOOD SAMPLE EFFECTIVE?

The genetic analysis carried out on a blood sample almost never allows to diagnose Proteus syndrome, as in the blood cells the mutation of AKT1 is generally absent.

This is why doctors, when they are dealing with a suspected case of Proteus syndrome, resort to a genetic test on a sample of cells belonging to a tissue or organ with an abnormal appearance.

What other exams can be supportive?

The information coming from:

Simple X-ray radiographs of abnormal body parts;
A CT scan or MRI scan of the brain (to assess brain malformations);
A CT scan of the lungs (to assess the presence of cysts or abnormal blisters in the lungs);
An MRI at the pelvis, trunk and upper and lower limbs (to assess the presence of bones and / or internal organs with unusual anatomy).

Therapy

The treatment of Proteus syndrome is purely symptomatic - that is aimed at controlling the symptomatology and avoiding / delaying complications - as there is still no cure capable of canceling the mutation responsible for the condition in question before birth.

Symptomatic therapy: what does it consist of?

Generally, the symptomatic therapy of Proteo syndrome includes:

A series of orthopedic surgical interventions against excessive bone growth and the complications to which the latter may give rise (bone deformities, scoliosis, joint stiffness, etc.);
These surgical procedures are usually followed by physiotherapy treatments ;
A pharmacological treatment plan aimed at preventing the phenomenon of deep vein thrombosis (antithrombotic therapy);
A series of surgical operations aimed at eliminating skin growths and adipose tissues subject to excessive growth.

What medical figures involve the symptomatic therapy of Proteus syndrome?

The symptomatic treatment of Proteus syndrome requires the coordinated intervention of several medical specialists, including: dermatologists, cardiologists, pulmonologists, orthopedists and physiotherapists.

Furthermore, it is important that patients and patients' families receive the support of an expert in the field of psychology, in order to adequately address the current pathological condition.