• Disease Overview
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
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Proteus Syndrome

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Last updated: 8/4/2023
Years published: 1988, 1989, 1995, 2003, 2007, 2008, 2012, 2015, 2018, 2023


Acknowledgment

NORD gratefully acknowledges Christopher A. Ours, MD, Assistant Research Physician, Center for Precision Health Research, 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.


Disease Overview

Summary


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), cystic 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.

Introduction


Proteus syndrome was first reported in the medical literature in 1979. Researchers now believe that Joseph Merrick, whose life was the subject of the play and movie The Elephant Man, had Proteus syndrome and not neurofibromatosis, as previously thought.

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Signs & Symptoms

Proteus syndrome may affect bone and connective tissue, fatty tissues, skin, central nervous system and internal organs (viscera). Bone, connective tissue and fat are the most commonly affected tissues in the body. The specific symptoms and severity vary greatly from person to person. Some individuals may exhibit only a few, mild symptoms of Proteus syndrome, making diagnosis challenging.

Most affected individuals are born without any noticeable symptoms. Some patients can have brain overgrowth at birth. Overgrowth usually begins between 6-18 months.

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 may affect the skull, the long bones of the arms and legs, and the feet and hands. Overgrowth of long bones of the legs can often cause one leg to be longer than the other. The spine may be affected, resulting in an abnormally curved spine (scoliosis). Progressive, bony overgrowth can affect joints in the fingers or larger joints such as the knee limiting movement and range of motion. Ultimately, joints 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 on the trunk 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 as cerebriform connective tissue nevus (CCTN) 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 that look like the surface of a brain.

Malformations of various blood vessels (vascular malformations) are common in Proteus syndrome. 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 to the lungs. This blood clot in the lung, pulmonary embolism, can be life threatening. It can cause breathlessness, sudden pain in the chest, exhaustion or 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 liver, spleen, kidney, and others. Eye abnormalities such as crossed eyes (strabismus) or benign tumors on the white part of the eye (epibulbar dermoid) may be present. Some individuals with Proteus syndrome may develop cystic lung disease that can lead to worsening breathing problems and require surgery.

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 ovarian and testicular cystadenoma, a rare salivary gland tumor known as monomorphic adenoma and meningioma.

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.

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Causes

Proteus syndrome is caused by a variant in a growth regulatory gene called AKT1 that occurs after fertilization (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 syndrome is due in part to the ratio of cells with and without the gene variant. When all cells have the AKT1 gene variant, the condition is not compatible with life. Proteus syndrome is not inherited but is caused by a mutation that occurs during development. Researchers believe that this somatic mutation occurs randomly for no apparent reason (sporadically).

Some researchers have attributed a subset of individuals with 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 or Proteus-like syndrome represents a different, distinct disorder. There have not been any patients confirmed to have Proteus syndrome who were found to have a PTEN gene variant.

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Affected populations

Proteus syndrome is an extremely rare disorder. It affects males slightly more than females. 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 reports 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.

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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 variant in AKT1 can allow molecular diagnosis, although this too can be challenging. The gene change is not present in the blood and therefore DNA testing must be performed on biopsies of affected tissue, most often skin. Other diagnostic techniques that may be used in an evaluation include plain x-rays (radiography), computed tomography (CT) scans for skull lesions or lung 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.

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Standard Therapies

Treatment
The treatment of Proteus is directed toward the specific symptoms 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 skeletal overgrowth in Proteus syndrome.

Surgery can increase the risk of developing a blood clot. When undergoing surgery, close monitoring for blood clots and consideration of blood thinners to prevent blood clots (antithrombotic prophylaxis) is recommended.

There is no approved medication treatment for Proteus syndrome. However, there are clinical trials to determine if AKT inhibitors can delay or slow overgrowth.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

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: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/

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

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

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

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

JOURNAL ARTICLESs
Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Pharmacodynamic study of miransertib in individuals with Proteus syndrome. Am J Hum Genet. 2019;104(3):484-491. doi:10.1016/j.ajhg.2019.01.015

Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011;365(7):611-619. doi:10.1056/NEJMoa1104017

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

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

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.

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

Sapp JC, Buser A, Burton-Akright J, Keppler-Noreuil KM, Biesecker LG. A dyadic genotype-phenotype approach to diagnostic criteria for Proteus syndrome. Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):565-570.

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.

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Programs & Resources

RareCare® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations


More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

View report
Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

View report
National Organization for Rare Disorders