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Disease Profile

Proteus syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

Q87.3

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Hemihypertrophy and macrocephaly; Partial gigantism of hands and feet, nevi, hemihypertrophy, macrocephaly; Partial gigantism-nevi-hemihypertrophy-macrocephaly syndrome

Categories

Blood Diseases; Congenital and Genetic Diseases; Ear, Nose, and Throat Diseases;

Summary

Proteus syndrome is characterized by excessive growth of a part or portion of the body. The overgrowth is usually asymmetric, which means it affects the right and left sides of the body differently. Newborns with Proteus syndrome have few or no signs of the disorder. Overgrowth becomes apparent between the ages of 6 and 18 months and becomes more severe with age. It may result in differences in appearance and with time, an increased risk for blood clots and tumors. Some people with Proteus syndrome have neurological abnormalities, including intellectual disability, seizures, and vision loss, as well as distinctive facial features.[1] Proteus syndrome is caused by a change (mutation) in the AKT1 gene. It is not inherited, but occurs as a random mutation in a body cell in a developing baby (fetus) early in pregnancy. The AKT1 gene mutation affects only a portion of the body cells.[2] This is why only a portion of the body is affected and why individuals with Proteus syndrome can be very differently affected. Management of the condition often requires a team of specialists with knowledge of the wide array of features and complications of this condition.[3][4]

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal form of the vertebral bodies
0003312
Abnormal subcutaneous fat tissue distribution
Abnormal fat tissue distribution below the skin
0007552
Arteriovenous malformation
0100026
Asymmetry of the thorax
Asymmetric chest
0001555
Cachexia
Wasting syndrome
0004326
Capillary hemangioma
Strawberry birthmark
0005306
Decreased muscle mass
0003199
Disproportionate tall stature
0001519
Epidermal nevus
0010816
Irregular hyperpigmentation
0007400
Kyphosis
Hunched back
Round back

[ more ]

0002808
Lipoma
Fatty lump
Noncancerous fatty lump

[ more ]

0012032
Lower limb asymmetry
Left and right leg differ in length or width
0100559
Lymphangioma
0100764
Macrodactyly
Finger overgrowth
0004099
Melanocytic nevus
Beauty mark
0000995
Scoliosis
0002650
Skeletal dysplasia
0002652
Subcutaneous nodule
Firm lump under the skin
Growth of abnormal tissue under the skin

[ more ]

0001482
Upper limb asymmetry
Unequal size of arms
0100560
Vascular skin abnormality
0011276
30%-79% of people have these symptoms
Abnormal lung lobation
0002101
Bronchogenic cyst
0100730
Calvarial hyperostosis
Overgrowth of skullcap
0004490
Dolichocephaly
Long, narrow head
Tall and narrow skull

[ more ]

0000268
Finger syndactyly
0006101
Generalized hyperkeratosis
0005595
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Lymphedema
Swelling caused by excess lymph fluid under skin
0001004
Macrotia
Large ears
0000400
Multiple cafe-au-lait spots
0007565
Pulmonary embolism
Blood clot in artery of lung
0002204
Round face
Circular face
Round facial appearance
Round facial shape

[ more ]

0000311
Thrombophlebitis
0004418
Visceral angiomatosis
0100761
5%-29% of people have these symptoms
Abnormality of dental enamel
Abnormal tooth enamel
Enamel abnormalities
Enamel abnormality

[ more ]

0000682
Abnormality of retinal pigmentation
0007703
Abnormality of the metacarpal bones
Abnormality of the long bone of hand
0001163
Abnormality of the nail
0001597
Abnormality of the neck
0000464
Abnormality of the wrist
Abnormalities of the wrists
0003019
Anteverted nares
Nasal tip, upturned
Upturned nasal tip
Upturned nose
Upturned nostrils

[ more ]

0000463
Arterial thrombosis
Blood clot in artery
0004420
Buphthalmos
Enlarged eyeball
0000557
Carious teeth
Dental cavities
Tooth cavities
Tooth decay

[ more ]

0000670
Cataract
Clouding of the lens of the eye
Cloudy lens

[ more ]

0000518
Central heterochromia
0007818
Chorioretinal coloboma
Birth defect that causes a hole in the innermost layer at the back of the eye
0000567
Clinodactyly of the 5th finger
Permanent curving of the pinkie finger
0004209
Craniosynostosis
0001363
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root

[ more ]

0005280
Diabetes insipidus
0000873
Downslanted palpebral fissures
Downward slanting of the opening between the eyelids
0000494
Enlarged polycystic ovaries
Enlarged ovaries with cysts
0008675
Exostoses
Formation of new noncancerous bone on top of existing bone
0100777
Facial asymmetry
Asymmetry of face
Crooked face
Unsymmetrical face

[ more ]

0000324
Generalized hirsutism
Excessive hairiness over body
0002230
Generalized hyperpigmentation
0007440
Gray matter heterotopia
0002282
Hallux valgus
Bunion
0001822
Hip dislocation
Dislocated hips
Dislocation of hip

[ more ]

0002827
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Joint stiffness
Stiff joint
Stiff joints

[ more

Cause

Proteus syndrome is caused by mutations in the AKT1 gene. These mutations are not inherited from a parent, but arise randomly in one cell during the early stages of development before birth. As cells continue to grow and divide, some cells will have the mutation and others will not. Therefore, people with Proteus syndrome have an altered AKT1 gene only in some of their cells. This mixture of cells with and without a genetic mutation is known as mosaicism.[1] The AKT1 gene codes a protein that helps regulate cell growth and division (proliferation) and cell death. A mutation in this gene disrupts a cell's ability to regulate its own growth, allowing it to grow and divide abnormally. The mutated gene makes an abnormal protein. The mutation in the AKT1 gene is known as “c. 49G>A, p.Glu17Lys,” and it is a type of an “activating mutation.” This means that the AKT1 gene has a “spelling error” that causes an abnormally active protein to be made in the body. This active protein is thought to increase rates of cell growth and may prevent cells from dying off when they naturally would. Increased cell proliferation in various tissues and organs leads to the abnormal growth characteristics and to an increased risk to develop tumors.[1][2][4]

Diagnosis

The diagnosis of Proteus syndrome is based on clinical criteria that include three general characteristics and a specific symptom checklist. A mutation in the AKT1 gene can be identified in more than 90% of people meeting the diagnostic criteria.

There are three general characteristics or features that must be present for doctors to consider a diagnosis of Proteus syndrome:[2]

  1. Mosaic distribution: This means that the areas of overgrowth are patchy and that only some body parts show signs of overgrowth while others are unaffected.
  2. Sporadic occurrence: This means that no one else in the affected person’s family has similar features of overgrowth.
  3. Progressive course: This means that the overgrowth has noticeably altered the appearance of the affected body parts over time or that new areas of overgrowth have appeared over time.

If a person has all three of these general characteristics in addition to some specific characteristics, doctors may consider a diagnosis of Proteus syndrome.

The specific characteristics are grouped into three categories: A, B, and C. A diagnosis of Proteus syndrome requires all three general features to be present and either one feature from Category A, or two features from Category B, or three features from Category C:[2][4][5] 

Category A: Cerebriform connective tissue nevus, which are skin lesion characterized by deep grooves and gyrations as seen on the surface of the brain.

Category B:

  • Patches of skin caused by an overgrowth of cells in the outermost layer of skin (Linear epidermal nevus)

  • Asymmetric, disproportionate overgrowth (at least one of the following):
    • Limbs
    • Hyperostosis of the skull
    • Hyperostosis of the external auditory canal
    • Megaspondylodysplasia
    • Viscera: spleen/thymus
  • Specific tumors before being 20 years old of age
    • Bilateral ovarian cystadenoma (a type of benign tumor in the ovary)
    • Parotid monomorphic adenoma (a benign tumor in s salivary gland)

Category C

  • Abnormal growth and/or distribution of fat (dysregulated fatty tissue overgrowth) (either of the following):
    • Fatty tumours (lipomas)
    • Lack of fat under the skin (regional lipohypoplasia)
  • Vascular malformations (differences in the blood vessels, veins, or capillaries or vessels of the immune system called the lymphatic vessels) including one of the following:
    • Capillary malformation
    • Venous malformation
    • Lymphatic malformation
    • Lung bullae
  • Facial features (all of the following):
    • A long and narrow head (dolichocephaly)
    • Long face
    • Down slanting palpebral fissures and/or minor dropping of the eyelids (ptosis)
    • Depressed nasal bridge
    • Wide or opening nares
    • Open mouth at rest

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    Each person with Proteus syndrome will have different medical needs that require individualized treatment. Many patients with Proteus syndrome are followed by several specialists such as a geneticist, a pediatrician, a dermatologist, and others.[2]

    Treatment of the overgrowth include orthopedic procedures to delay or stop linear bone growth and correction of skeletal deformities such as scoliosis. Developmental intervention or special education is suggested for developmental delays. Because any organ or tissue can be affected, the affected person should be monitored for any possible complication. The following are recommended: monitoring for and treating vascular problems, such as blood clot (thrombus) that forms within a vein (vein thrombosis) and blockage of an artery in the lungs by a blood clot (pulmonary embolism); monitoring and treating the lung disease; and routine monitoring for evidence of tumor development with management of the skin problems, especially for the lesions known as cerebriform connective tissue nevi.[5] 

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Social Networking Websites

      • RareConnect is an online social network for patients and families to connect with one another and share their experience living with a rare disease. The project is a joint collaboration between EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders). Click on the link above to view the community for limb differences.

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • The American Society for Surgery of the Hand provides information on congenital differences of the hand. Click on American Society for Surgery of the Hand to view the information page.
        • The Children’s Hospital Boston has a information page on congenital limb defects. Click on the link above to view this information page.
        • Contact a Family is a UK-wide charity providing advice, information and support to individuals affected by various health conditions. They enable parents, families, and individuals to get in contact with others, on a local, national, and international basis. Each year they reach at least 275,000 families. Click on Contact a Family to view their information on Proteus syndrome.
        • The New Zealand Dermatolgical Society's Web site has information on Proteus syndrome. Click on the link above to view this information page.
        • Genetics Home Reference (GHR) contains information on Proteus syndrome. This website is maintained by the National Library of Medicine.
        • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
        • The Proteus Syndrome Foundation Web site provides information on this syndrome. Click on the link to view the information page.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
          • MeSH® (Medical Subject Headings) is a terminology tool used by the National Library of Medicine. Click on the link to view information on this topic.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Proteus syndrome. Click on the link to view a sample search on this topic.

            Selected Full-Text Journal Articles

              References

              1. Proteus syndrome. Genetics Home Reference (GHR). June 2012; https://ghr.nlm.nih.gov/condition/proteus-syndrome. Accessed 5/12/2014.
              2. Newly Diagnosed. Proteus Syndrome Foundation. https://www.proteus-syndrome.org/newly-diagnosed.html.
              3. Biesecker L. The challenges of Proteus syndrome: diagnosis and management. European Journal of Human Genetics. 2006; 14:1151-1157. https://www.nature.com/ejhg/journal/v14/n11/pdf/5201638a.pdf. Accessed 9/28/2011.
              4. Barry M. Proteus syndrome. Medscape Reference. February, 2016; https://emedicine.medscape.com/article/948174.
              5. Biesecker LG & Sapp JC.. Proteus syndrome. GeneReviews. August 9, 2012; https://www.ncbi.nlm.nih.gov/books/NBK99495/.

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