Proteus syndrome: what is it, causes, symptoms, treatment, prognosis

What is Proteus Syndrome?

Proteus syndrome - a rare disease characterized by the proliferation of various body tissues. The cause of the disease is a mosaic form of gene mutation AKT1. Disproportionate, asymmetric growth occurs in the form of a mosaic (ie, an occasional "patchy" pattern of affected and unaffected areas).

Affected individuals can experience a wide range of complications, which may include progressive skeletal malformations, benign and malignant tumors, blood vessel malformations, bullous lung disease and certain lesions skin. Some people can develop life-threatening conditions associated with bleeding disorders, including deep vein thrombosis and pulmonary embolism.

Signs and symptoms

Proteus syndrome can affect bones and connective tissue, adipose tissue, skin, central nervous system and internal organs. Specific symptoms and severity vary greatly from patient to patient. Some patients have only a few mild symptoms, making diagnosis difficult.

Most affected people are born without any noticeable symptoms. Brain overgrowth at birth may be evident in some patients. Overgrowth usually starts between 6-18 months. The specific areas of the body affected vary greatly from patient to patient. Bones, connective tissue and fat are the most commonly affected tissues in the body.

The overgrowth associated with Proteus syndrome is irregular, disproportionate, and may affect one side of the body, such as only one foot. Overgrowth of bones (hyperostosis) may occur, affecting the skull, the long bones of the arms and legs, and the feet and hands. Disease overgrowth is usually severe and deforms bones beyond recognition. The spine may be affected, resulting in scoliosis - a condition in which the spine is abnormally curved. The progressive overgrowth of bone eventually affects the joints, limiting the range of motion. Ultimately, the affected joint can significantly outgrow and become immobile.

During childhood, patients may develop abnormal skin conditions, including localized areas of severe excess fat growth, especially affecting the abdomen or arms and legs. In some cases, benign tumors consisting of adipose tissue (lipomas). In addition to excessive overgrowth of adipose tissue, some patients develop adipose tissue atrophy, especially in the chest area.

Affected children may also develop a raised, warty lesion (epidermal nevus), usually rough and dark brown or brownish black in color. An epidermal nevus may be present at birth. Another skin lesion known as connective tissue nevi of the meninges may occur. This slow-growing lesion is most common on the feet and less commonly on the hands. It is absent at birth and consists of a thickened abnormally dense subcutaneous tissue. Deep grooves may form on the skin.

In Proteus syndrome, various malformations of the blood vessels (vascular malformations) are common. Capillaries, veins, and lymphatic vessels may be affected. Capillaries are tiny blood vessels that connect arteries and veins. Veins are blood vessels that carry blood to the heart. Lymphatic vessels are part of the lymphatic system, the circulating network of vessels, ducts and nodes, which filter and distribute certain protein-rich fluid (lymph) and blood cells throughout body.

People with Proteus syndrome may be at risk for blood clots in their legs, a condition known as deep vein thrombosis of the lower extremities. The legs may become painful and swollen, and the blood vessels in the legs may become noticeably enlarged. In some cases, part of the blood clot may detach and travel up through the bloodstream to the lungs, where it can cause pulmonary embolism. Pulmonary embolism - a clot getting stuck inside the pulmonary artery that can potentially cause shortness of breath, sudden chest pain, wasting, or life-threatening complications such as high blood pressure in the pulmonary artery (pulmonary hypertension).

In Proteus syndrome, additional signs may be observed, including abnormal enlargement of certain internal organs, such as spleen, thymus, colon and other tissues.

Patients also have a predisposition to developing a wide variety of tumors, most of which are benign. Tumors most commonly associated with the disease are bilateral ovarian cystadenomas, a group of rare tumors of the salivary glands known as monomorphic adenomas and meningiomas.

Less common manifestations of the syndrome include malformations of the central nervous system, for example, overgrowth of half of the brain (hemimegalencephaly). Some patients may have mental retardation and have also been reported epilepsy. People with these abnormalities may also have distinct facial features, including an elongated face. photo above), downward sloping folds of the eyelids (eye slits), drooping eyelids (ptosis), a low bridge of the nose, wide nostrils and a long narrow head (dolichocephaly). The reason for the association of neurological and facial abnormalities is unknown.

Some people with Proteus syndrome may develop cystic lung disease, kidney or urinary tract diseaseas well as eye pathologies such as strabismus or benign cysts or tumors of the eyeballs (epibulbar cysts or dermoids).

Causes

Proteus syndrome is caused by a mutation in a growth-regulating gene called AKT1, which occurs after fertilization of the embryo (somatic mutation). Patients have some cells with a normal copy of this regulatory gene and some cells with an abnormal gene (mosaicism). The variety of symptoms associated with the disease is in part due to the ratio of healthy and abnormal (abnormal) cells. When all cells have a pathological gene, this condition is incompatible with life. Researchers believe that this somatic mutation occurs randomly for no apparent reason (sporadically).

Some researchers have attributed a subgroup of patients with Proteus syndrome to a gene mutation PTENlocated on chromosome 10. This led to the confusion of patients. Other researchers believe that these patients, although similar in some respects to patients with Proteus syndrome, do not meet certain diagnostic criteria. This so-called Proteus syndrome is a completely different disease. None of the patients with definite confirmed Proteus syndrome were found to have a gene mutation PTEN.

Affected populations

Proteus syndrome is an extremely rare disease. About 200 patients have been described in the medical literature and it appears that the disease affects people of all ethnic and racial groups. However, researchers with extensive experience in the treatment of Proteus' syndrome studied these patients and determined that only fewer than 100 people met the strict diagnostic criteria for the disease.

Because the diagnosis of the disease is so difficult, some people may not be diagnosed at the time. how others can be misdiagnosed when they have another condition instead of that disease. Therefore, it is extremely difficult to determine the true frequency of the disorder in the general population.

Proteus syndrome affects men more often than women. This was first reported in the medical literature in 1979. Researchers now believe that Joseph Merrick, whose life was filmed in the movie "The Elephant Man," suffered from Proteus syndrome, and not neurofibromatosis, as previously thought.

Symptom-related disorders

Symptoms of the following conditions may be similar to those of Proteus syndrome. Comparisons can be useful for differential diagnosis.

• Hemihyperplasia-multiple lipomatosis syndrome - a rare disease characterized by the development of multiple benign tumors consisting of adipose tissue (lipoma) and abnormal enlargement of one side or body structure (hemihyperplasia), resulting in uneven (asymmetric) growth. Hemihyperplasia may indicate asymmetry only between one limb and the other, or between one half of the body and the other. Hemihyperplasia can be moderately progressive. The cause of the disease is usually a somatic gene mutation PIK3CA.
• Encephalocranicutaneous lipomatosis - an extremely rare disease characterized by eye abnormalities, skin abnormalities, including tumors consisting of adipose tissue (lipomas), affecting the scalp and the central nervous system, and skin lesions consisting of improperly developed connective tissue (connective tissue nevi). Specific symptoms vary greatly from patient to patient. Some people have normal intelligence, others may have mental retardation. Some people have registered epilepsy and porencephalic cysts. Additional symptoms may also be present. Although it was previously thought that encephalocraniocutaneous lipomatosis is a form of Proteus syndrome limited to the head and neck, researchers have recently defined more specific criteria for the disease, and it seems that this disease is different from the syndrome Proteus. A number of patients with this disorder have mosaic mutations in a gene called FGFR1.
• Klippel-Trenone syndrome - a rare disease that is present at birth (congenital), characterized by the presence of capillary vascular malformation (port port wine stain or flaming nevus) on the skin arm or leg arising from excessive growth (hypertrophy) of the soft tissues and bones of this leg and / or arm (limbs) and varicose veins (venous malformation). Some affected people also have a lymphatic abnormality in the affected limb. In people with this condition, this hypertrophy usually affects one limb or one side of the body (hemihypertrophy). Symptoms and signs associated with the disorder can vary in range and severity from patient to patient. Klippel-Trenone syndrome is usually caused by a mosaic mutation PIK3CA and is part of the spectrum of excess growth associated with PIK3CA.
• Maffucci Syndrome - a rare genetic disorder characterized by benign growths of cartilage (enchondromas), skeletal deformities and dark red patches irregularly shaped skin resulting from benign neoplasms on the skin (skin), consisting of masses of blood vessels (hemangiomas). Enchondromas are most commonly found in certain bones (phalanges) of the hands and feet. Skeletal malformations can include disproportionate leg length and / or abnormal curvature of the spine from side to side (scoliosis). For many people, bones break easily. In most people, hemangiomas appear at birth or in early childhood and may progress. Maffucci syndrome is inherited in an autosomal dominant manner.

Diagnostics

Diagnosis of Proteus syndrome is made using published clinical diagnostic criteria and molecular tests. Confirming the diagnosis can be difficult and the interpretation of clinical diagnostic criteria is ambiguous. Identifying the Causal Gene Mutation AKT1 molecular diagnostics can allow, although this can also be challenging. The gene change is rarely present in the blood and therefore diagnostic DNA testing should usually be performed on biopsies of the affected tissue.

Other diagnostic methods that may be used in the assessment may include plain x-rays, computed tomography (CT) to detect skull lesions, high-resolution computed tomography for lung cysts and magnetic resonance imaging (MRI) of the brain, abdomen, pelvis and limbs. Ultrasonography is used to detect scrotal or ovarian growths and to evaluate deep vein thrombosis.

Standard treatments

Treatment for Proteus syndrome is aimed at eliminating the specific symptoms that appear in each person. Typically, numerous orthopedic procedures are needed to try to control the rapid outgrowth associated with Proteus syndrome. Surgery may be necessary when excess growth impairs joint function, scoliosis, or angular deformities. Surgery to reduce overgrown tissue or body parts may be indicated. Epiphysiosis (removal or ablation of growth plates in bones) can be especially helpful in preventing or treating skeletal overgrowth in the syndrome.

Patients with Proteus syndrome undergoing surgery should be closely monitored as surgery may predispose victims to deep vein thrombosis. With surgery, consideration should be given to preventing blood clots for preventing blood clots from forming (antithrombotic prophylaxis) or treating blood clots after they education.

Genetic counseling is recommended for patients and their families. Other treatments are symptomatic and supportive.

Forecast

The prognosis varies depending on the severity of the complications.