NORD is very grateful to Leslie G. Biesecker, MD, Chief, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report. The opinions here are his own and do not necessarily reflect the policy or assessment of the National Institutes of Health.
Proteus syndrome is a rare disorder characterized by overgrowth of various tissues of the body. The cause of the disorder is a mosaic variant in a gene called AKT1. Disproportionate, asymmetric overgrowth occurs in a mosaic pattern (i.e., a random "patchy" pattern of affected and unaffected areas). Affected individuals may experience a wide variety of complications that may include progressive skeletal malformations, benign and malignant tumors, malformations of blood vessels (vascular malformations), bullous pulmonary disease, and certain skin lesions. In some people, life-threatening conditions relating to abnormal blood clotting may develop including deep vein thrombosis and pulmonary embolism.
Proteus syndrome may affect bone and connective tissue, fatty tissues, skin, central nervous system and internal organs (viscera). The specific symptoms and severity varies greatly from patient to patient. In some patients, affected individuals may exhibit only a few, mild symptoms of Proteus syndrome, making diagnosis challenging.
Proteus syndrome may affect bone and connective tissue, fatty tissues, skin, central nervous system and internal organs (viscera). The specific symptoms and severity varies greatly from person to person. Some affected individuals may exhibit only a few, mild symptoms of Proteus syndrome, making diagnosis extremely difficult.
Most affected individuals are born without any noticeable symptoms. Some patients can have brain overgrowth apparent at birth. Overgrowth usually begins between 6-18 months. The specific affected areas of the body vary greatly from patient to patient. Bone, connective tissue and fat are the most commonly affected tissues in the body.
Overgrowth associated with Proteus syndrome is irregular, disproportionate, and may affect one side of the body such as only one foot and not the other (asymmetric). Overgrowth of bone (hyperostosis) may occur affecting the skull, the long bones of the arms and legs, and the feet and hands. Overgrowth in Proteus syndrome is usually severe and typically deforms bones to the point that they are unrecognizable. The spine may be affected, resulting in scoliosis – a condition in which the spine is abnormally curved. Progressive, bony overgrowth eventually affects the joints limiting range of motion. Ultimately, an affected joint may become significantly overgrown and locked in place (immobilized).
In childhood, affected individuals may develop abnormal skin conditions including localized areas of severe fatty overgrowth especially affecting the stomach or the arms and legs. In some, benign tumors consisting of fatty tissue (lipomas) may develop. In addition to fatty tissue overgrowth, some affected individuals may develop areas of fatty tissue loss (atrophy) especially in the chest.
Affected children may also develop a raised, rough (verrucous) lesion (epidermal nevus) that is usually rough and dark brown or brownish-black. An epidermal nevus may be present at birth. Another skin lesion known cerebriform connective tissue nevus may occur. This slow-growing lesion is most often found on the feet and less commonly on the hands. It is not present at birth and is made up of thickened, abnormally firm subcutaneous tissue. The skin may develop deep grooves or furrows.
Malformations of various blood vessels (vascular malformations) are common in Proteus syndrome. The capillaries, veins, and lymph vessels can be affected. The capillaries are tiny blood vessels that connect arteries and veins. Veins are blood vessels that take blood to the heart. Lymph vessels are part of the lymphatic system, the circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body.
Individuals with Proteus syndrome may be at risk for developing blood clots in the legs a condition known as deep vein thrombosis (DVT). The legs may become painful and swollen and blood vessels in the legs may be visibly enlarged. In some, a piece of a DVT may break off and travel up the bloodstream toward the lungs, where it may cause a pulmonary embolism. A pulmonary embolism is the lodging of a clot within the pulmonary artery, which can potentially cause breathlessness, a sudden pain the chest, exhaustion, or life-threatening complications such as high blood pressure of the pulmonary artery.
Additional findings can occur in Proteus syndrome including abnormal enlargement of certain internal organs such as the spleen, thymus, colon, and other tissues.
Affected individuals also have a predisposition of developing a wide variety of tumors, most of which are benign. The tumors most often associated with Proteus syndrome are bilateral ovarian cystadenomas, a group of rare salivary gland tumors known as monomorphic adenomas, and meningiomas.
Less common findings in Proteus syndrome include malformations of the central nervous system such as overgrowth of half of the brain (hemimegalencephaly). In some patients, intellectual disability may be present and seizures have been reported as well. Individuals with these abnormalities may also have distinct facial features including a long face, downward slanting eyelid folds (palpebral fissures), droopy eyelids (ptosis), low bridge of the nose, wide nostrils (nares), and a long narrow head (dolichocephaly). The reason for the association of neurological and facial abnormalities is unknown.
Some individuals with Proteus syndrome may develop cystic lung disease, kidney or urinary abnormalities, and eye abnormalities such as crossed eyes (strabismus) or benign cysts or tumors of the eyeballs (epibulbar cysts or dermoids).
Proteus syndrome is caused by a variant in a growth regulatory gene called AKT1 that occurs after fertilization of the embryo (somatic mutation). Affected persons have some cells with a normal copy of this regulatory gene and some cells with the abnormal gene (mosaic). The variability of symptoms associated with Proteus is due in part to the ratio of healthy cells to abnormal cells. When all cells have the abnormal gene, the condition is not compatible with life. Researchers believe that this somatic mutation occurs randomly for no apparent reason (sporadically).
Some researchers have attributed a subset of patients of Proteus syndrome to variants in the PTEN gene located on chromosome 10. This has led to confusion for affected individuals. Other researchers believe that these patients, while similar to Proteus syndrome in some respects, do not fulfill the specific diagnostic criteria. This so-called Proteus syndrome represents a different, distinct disorder. No one definitely confirmed to have Proteus syndrome has been found to have the PTEN gene variant.
Proteus syndrome is an extremely rare disorder. Approximately 200 patients have been reported in the medical literature and it seems to affect people of all ethnic and racial groups. However, researchers with extensive experience in Proteus syndrome reviewed these patients and determined that just fewer than 100 met the stringent diagnostic criteria for Proteus syndrome.
Because the diagnosis of Proteus syndrome is so difficult some people may go undiagnosed, while others may be incorrectly diagnosed with Proteus syndrome when they instead have a different condition. Therefore, it is extremely difficult to determine the true frequency of this disorder in the general population.
Proteus syndrome affects males slightly more often than females. It was first reported in the medical literature in 1979. Researchers now believe that Joseph Merrick, whose life was the subject of the movie The Elephant Man, had Proteus syndrome and not neurofibromatosis, as previously thought.
Diagnosis of Proteus syndrome is made using published clinical diagnostic criteria and molecular testing. Confirming a diagnosis of Proteus syndrome can be difficult and the interpretation of the clinical diagnostic criteria is controversial. The identification of the causative gene variant in AKT1 can allow molecular diagnosis, although this too can be challenging. The gene alteration is uncommonly present in the blood and therefore DNA diagnostic testing must generally be performed on biopsies of affected tissues. Other diagnostic techniques that may be used in evaluation may include plain x-rays (radiography), computed tomography (CT) scans for skull lesions, high resolution CT scan of the lungs for pulmonary cysts and magnetic resonance imaging (MRI) of the brain, abdomen, pelvis and limbs. Ultrasound is used to detect scrotal or ovarian masses and can be used to evaluate deep vein thromboses.
The treatment of Proteus is directed toward the specific symptoms that are apparent in each individual. Multiple orthopedic procedures are usually necessary to try and control the rapid overgrowth associated with Proteus syndrome. Surgery may be necessary when overgrowth interferes with joint function or causes scoliosis or angular deformities. Surgery to reduce overgrown tissues or body parts may be indicated. Epiphysiodesis (removal or ablation of growth plates in bones) may be especially useful to prevent or treat the skeletal overgrowth of Proteus syndrome.
Patients with Proteus syndrome undergoing surgical procedures must be closely monitored because surgery may predispose affected individuals to deep vein thrombosis. When undergoing surgery, affected individuals should be considered for prophylaxis to prevent blood clots (antithrombotic prophylaxis) or treatment for blood clots once they develop.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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