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Proteus syndrome

NORD is very grateful to Leslie G. Biesecker, MD, Chief, Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.

Synonyms of Proteus syndrome

  • PS

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Proteus syndrome is a rare disorder characterized by overgrowth of various tissues of the body. The cause of the disorder is a mosaic mutation 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 cases, life-threatening conditions relating to abnormal blood clotting may develop including deep vein thrombosis and pulmonary embolism.

Symptoms

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 case to case. In some cases, affected individuals may exhibit only a few, mild symptoms of Proteus syndrome, making diagnosis extremely difficult.

In most cases, 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 affects 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 cases, 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 are 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 cases, 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 cases, mental retardation 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).

Causes

Proteus syndrome is caused by a mutation 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 cases of Proteus syndrome to the mutation of the PTEN gene located on chromosome 10. This has led to confusion for affected individuals. Other researchers believe that these cases, while similar to Proteus syndrome in some respects, do not fulfill the specific diagnostic criteria. These so-called Proteus syndrome cases represent a different, distinct disorder. No definitely confirmed case of Proteus syndrome has been linked to the PTEN gene mutation.

Affected Populations

Proteus syndrome is an extremely rare disorder. Approximately 200 cases 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 cases 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 cases may go undiagnosed, while other cases may be incorrectly labeled as Proteus syndrome. 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.

Related Disorders

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

Hemihyperplasia multiple lipomatosis (HHML) syndrome is a rare disorder characterized by the development of multiple benign tumors consisting of fatty tissue (lipomata) and the abnormal enlargement of one side or structure of the body (hemihyperplasia), resulting in unequal (asymmetric) growth. Hemihyperplasia may indicate asymmetry between just one limb and another or between one half of the body and the other. Hemihyperplasia may be mildly progressive. The exact cause of HHML is unknown.

Encephalocraniocutaneous lipomatosis (ECCL) is an extremely rare disorder characterized by eye abnormalities, skin abnormalities including tumors consisting of fatty tissue (lipomas) affecting the scalp and central nervous system, and skin lesions consisting of improperly developed connective tissue (connective tissue nevi). Specific symptoms vary greatly from case to case. Some individuals have normal intelligence while others may experience mental retardation. Seizures and porencephalic cysts have been reported in some cases. Additional symptoms may be present in some case. Although ECCL was previously thought to represent a form of Proteus syndrome limited to the head and neck, recently researchers have delineated more specific criteria for ECCL and it appears to be a distinct disorder from Proteus.

Klippel-Trenaunay syndrome, a rare disorder that is present at birth (congenital), is characterized by the presence of a capillary vascular malformation (port wine stain) on the skin of an arm or leg (cutaneous) occurring in association with excessive growth (hypertrophy) of the soft tissue and bone of that leg and/or arm (limb), and varicose veins (venous malformations). Some affected individuals will also have an underlying lymphatic malformation of the affected limb. In individuals with the disorder, such hypertrophy typically affects one limb or one side of the body (hemihypertrophy). The symptoms and findings associated with the disorder may vary in range and severity from case to case. (For more information on this disorder, choose "Klippel-Trenaunay" as your search term in the Rare Disease Database.)

Maffucci syndrome is a rare genetic disorder characterized by benign overgrowths of cartilage (enchondromas), skeletal deformities, and dark red irregularly shaped patches of skin, resulting from benign growths on the skin (cutaneous) consisting of masses of blood vessels (hemangiomas). Enchondromas are most often found in certain bones (phalanges) of the hands and feet. Skeletal malformations may include legs that are disproportionate in length and/or abnormal side-to-side curvature of the spine (scoliosis). In many cases, bones may tend to fracture easily. In most cases, hemangiomas appear at birth or during early childhood and may be progressive. Maffucci syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose "Maffucci" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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 alteration 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.

Treatment
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 may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Proteus syndrome

References

TEXTBOOKS
Biesecker LG. 2005. Proteus syndrome. In: Cassidy SB, Allanson JE, editors. Management of Genetic Syndromew. New York: Wiley. p 449-456.

Biesecker L. Proteus Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:239.

JOURNAL ARTICLES
Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff M, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC for the NISC Comparative Sequencing Program, Biesecker LG. A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome. New Engl J Med 2011;365:611-9

Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet. 2006;14:1151-7.

Turner JF, Cohen MM Jr., Biesecker LG. A reassessment of the Proteus syndrome literature: application of diagnostic criteria on published cases. Am J Med Genet. 2004;130A:111-22.

Cohen MM Jr. Proteus syndrome: an update. Am J Med Genet C Semin Med Genet. 2005;137:38-52.

Biesecker LG. The multifaceted challenges of Proteus syndrome. JAMA. 2001;285:2240-2243.

Biesecker LG, Happle R, Mulliken JB, et al. Proteus syndrome:diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999;84:389-395.

Biesecker LG, Peters, KF, Darling, TN, et al. Clinical differentiation between Proteus syndrome and hemihyperplasia: description of a distinct form of hemihyperplasia. Am J Med Genet. 1998;79:311-318.

Gordon PL, Wilroy RS, Lasater OE, et al. Neoplasms in Proteus syndrome. Am J Med Genet. 1995;57:74-78.

Slovotinek AM, Vacha SJ, Peters KF, et al. Sudden death caused by pulmonary thromboembolism in Proteus syndrome. Clin Genet. 2000;58:386-389.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/01/03 00:00:00 GMT+0

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