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Proteus Syndrome

, MD and , ScM, CGC.

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Initial Posting: .


Clinical characteristics.

Proteus syndrome is characterized by progressive, segmental or patchy overgrowth of diverse tissues of all germ layers, most commonly affecting the skeleton, skin, and adipose and central nervous systems. In most individuals Proteus syndrome has minimal or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism.


The diagnosis of Proteus syndrome is based on clinical criteria that include three general characteristics and a specific symptom checklist. A mosaic somatic pathogenic variant in AKT1 has been identified in more than 90% of individuals meeting diagnostic criteria.


Treatment of manifestations: Management of overgrowth is the chief concern; the approaches are diverse and include various orthopedic procedures to delay or halt linear bone growth; correction of skeletal deformities such as scoliosis; monitoring for and treating deep vein thrombosis and pulmonary embolism; monitoring and treating the parenchymal and restrictive pulmonary disease; management of the skin manifestations, especially the cerebriform connective tissue nevi; developmental intervention or special education for developmental delays.

Prevention of secondary complications: Any organ or tissue can be affected and, thus, the secondary complications are highly variable.

Surveillance: Monitoring should be tailored to individual patients’ presentations; routine monitoring for evidence of tumor development is by medical history and physical examination; periodic imaging is not indicated.

Genetic counseling.

All individuals with clinically confirmed Proteus syndrome known to these authors have been simplex cases caused by somatic mosaicism for the specific de novo pathogenic variant c.49G>A (p.Glu17Lys). It is hypothesized that a non-mosaic (i.e., germline) AKT1 c.49G>A pathogenic variant would be lethal in early development. There is no known risk to offspring of an affected individual; however, the number of affected individuals who have reproduced is very small. Thus, the risks to the parents of an affected child and to affected persons who do reproduce are not increased compared to the general population. Because Proteus syndrome is not inherited, prenatal testing is not indicated.


Proteus syndrome (PS) can be diagnosed based on clinical findings in individuals with classic signs. Molecular genetic testing may be useful to confirm the diagnosis in these individuals and is used to establish the diagnosis in individuals in whom the clinical findings are ambiguous or mild.

Clinical Diagnosis

Major findings are the following:

  • Distorting, progressive overgrowth, a characteristic finding of PS is quite distinct from that of most overgrowth syndromes. The skeletal overgrowth of PS does not typically manifest until age six to 18 months and has had its onset as late as age 12 years (if the skeletal overgrowth is prenatal, it is unlikely to be PS). Whereas most other overgrowth syndromes have proportionate overgrowth (preservation of the general skeletal architecture), a key finding in PS is distortion of the skeletal architecture. This can be so severe that in isolation, a bone affected by PS can be unrecognizable in its shape. It is not uncommon for the overgrowth to accelerate rapidly in childhood, with leg length discrepancies of 20 cm being reported. Scoliotic curves of more than 90° are not uncommon. Any bone can be affected.
  • Cerebriform connective tissue nevi (CCTN), present in most individuals with PS, is nearly pathognomonic. The CCTN is a specific type of the more common connective tissue nevus and is most commonly found (from most to least common location) on the plantar foot, hand, alae, ear, and lacrimal puncta, and on others less commonly. True CCTNs are firm and have a distinct pattern resembling the brain’s sulci (hence the term “cerebriform”). They should not be confused with prominent plantar or palmar wrinkling seen in other forms of overgrowth.
  • Linear verrucous epidermal nevus (LVEN) is a streaky, pigmented, rough nevus that often follows the lines of Blaschko. They can be present anywhere on the body.
  • Adipose dysregulation, most commonly manifest as “lipomatous” overgrowth, is frequently seen in persons with PS. Paradoxically in other areas of the body, the affected person can also have lipoatrophy. Note: Persons with PS do not have the typical, ovoid, encapsulated lipomas common in the elderly and so the term “lipoma” is technically incorrect, but in wide usage.
  • Other findings include vascular malformations (most commonly capillary and lymphatic), overgrowth of other tissues (most commonly spleen, liver, thymus, gut), tumors (most commonly ovarian cystadenomas and meningiomas), bullous pulmonary degeneration, and facial dysmorphic features.

The diagnosis is established in individuals with:

  • All the following general criteria:
    • Mosaic distribution of lesions
    • Sporadic occurrence
    • Progressive course
  • Specific criteria from categories A-C; either:
    • One from category A
    • Two from category B
    • Three from category C

Categories of Specific Criteria to Establish the Diagnosis of Proteus Syndrome

Category A

  • Cerebriform connective tissue nevus
    Note: Cerebriform connective tissue nevi are skin lesions characterized by deep grooves and gyrations as seen on the surface of the brain.

Category B

  • Linear epidermal nevus
  • Asymmetric, disproportionate overgrowth (at least one of the following):
    Note: Asymmetric, disproportionate overgrowth should be carefully distinguished from asymmetric, proportionate, or ballooning overgrowth.
    • Limbs
    • Hyperostosis of the skull
    • Hyperostosis of the external auditory canal
    • Megaspondylodysplasia
    • Viscera: spleen/thymus
  • Specific tumors before second decade
    • Bilateral ovarian cystadenoma
    • Parotid monomorphic adenoma

Category C

  • Dysregulated adipose tissue (either of the following):
    • Lipomatous overgrowth
    • Regional lipohypoplasia
  • Vascular malformations (one of the following):
    • Capillary malformation
    • Venous malformation
    • Lymphatic malformation
    • Lung bullae
  • Facial phenotype (all of the following):
    • Dolichocephaly
    • Long face
    • Down slanting palpebral fissures and/or minor ptosis
    • Depressed nasal bridge
    • Wide or anteverted nares
    • Open mouth at rest

Of note, substantial clinical diagnostic confusion regarding PS exists [Turner et al 2004]. It is now clear that PS is but one type, and in fact an uncommon type, of segmental overgrowth associated with cutaneous and subcutaneous manifestations such as linear nevi, fatty tissue overgrowth, and vascular malformations. See Differential Diagnosis.

The disambiguation of these entities was challenging, but it is now widely accepted: the above clinical diagnostic criteria have proven to be very useful for segregating affected individuals into distinct categories for management and clinical research. More than 90% of those who meet the clinical criteria for Proteus syndrome have a somatic mosaic pathogenic variant in AKT1. Persons who do not meet these criteria do not have pathogenic variants in AKT1. That the clinical criteria have been so highly predictive of molecular testing is a robust validation of their predictive power and utility.

Molecular Genetic Testing

Gene. AKT1 is the only gene in which pathogenic variants are known to cause Proteus syndrome.

Table 1.

Summary of Molecular Genetic Testing Used in Proteus Syndrome

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method 3
AKT1Targeted analysis for pathogenic variantsc.49G>A (p.Glu17Lys)>90% (33/34) 4

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Somatic mosaicism for the c.49G>A AKT1 variant is the only pathogenic variant identified to date in individuals with clinically confirmed PS [Lindhurst et al 2011].

Interpretation of test results. Detection of low-level mosaicism depends on test sensitivity and the tissue specimens chosen for analysis.

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing may be useful to confirm the diagnosis in individuals who meet clinical criteria and to establish the diagnosis in individuals in whom the clinical findings are ambiguous or mild.

Because all AKT1 c.49G>A pathogenic variants reported to date are somatic and mosaic, more than one tissue may need to be studied. Reliable diagnosis generally requires DNA be analyzed from a biopsy of affected tissues, typically a punch biopsy of an affected area of skin.

It is important to recognize that in only a minority of affected individuals (2/31 cases in a recent report [Lindhurst et al 2011] with the AKT1 c.49G>A variant present in one or more tissues was the variant also present in a sample of peripheral blood. Therefore, the absence of a pathogenic variant in a peripheral blood sample is a poor test to exclude the diagnosis.

Prenatal diagnosis is not indicated as PS is not inherited.

Clinical Characteristics

Clinical Description

Proteus syndrome (PS) displays a wide range of severity. Most affected individuals have little or no manifestations at birth. The one exception is that a few (probably <5%) first manifest PS with hemimegencephaly, often associated with CNS migration defects and later intellectual disability. This manifestation is prenatal. In most other affected individuals, the congenital manifestations are so subtle as to be discounted or missed. These include subtle degrees of asymmetry or faint linear nevi.

Most typically, the first manifestations of the disorder occur between age six and 18 months with the onset of asymmetric overgrowth; it is most commonly of the feet or hands but may occur anywhere.

The prognosis for an individual with PS is based on the location and degree of the overgrowth present in the individual and the presence or absence of significant complications such as bullous pulmonary disease, hemimegencephaly, and pulmonary embolism. The disorder is highly variable. Literature surveys are not useful for the purpose of establishing the prognosis because reported cases tend to show bias of ascertainment to more severe involvement and many of those reported to have “Proteus syndrome” do not meet clinical diagnostic criteria for the disorder.

While it is difficult to calculate life expectancy, it is clear that there are many more children with PS than adults. With appropriate management, mildly affected individuals have an excellent prognosis.

Overgrowth. The overgrowth in PS can be startling in its severity and rapidity of progression. Most segmental overgrowth disorders are congenital and proportional. That is, these other disorders manifest at birth with a limb, hand, or finger that is, for example, 30% larger than the contralateral body part, and this overgrown body part will continue to be approximately 30% larger than the contralateral body part at one year of age and three years of age. (See Differential Diagnosis for discussion of specific disorders.) In contrast, the overgrowth of PS is, for most parts of the skeleton (see above for exception re hemimegencephaly), absent at birth, possibly 15% larger at age one year, 30% larger at three years, and 100% larger at age six years (hypothetic examples). Once a clinician observes this phenomenon in a patient with bone fide PS, the distinction is evident.

As well, plain radiographs clearly distinguish PS overgrowth from non-PS overgrowth. The bones affected by PS, especially the tubular bones of the limbs and the vertebral bodies and skull, develop distorting, bizarre, irregular calcified overgrowth that can render the bone unrecognizable with time. Such progressive and irregular bony changes are rare in non-PS overgrowth.

The rapid and severe nature of the overgrowth poses a challenge to orthopedic management.

Dermatologic findings. The CCTN lesion is rarely present in infancy, typically developing in childhood and progressing through adolescence. It rarely progresses in adulthood [Beachkofsky et al 2010]. The sulci of the CCTN lesions commonly get deep enough in late adolescence to pose challenges with cleanliness and malodor.

The linear epidermal nevi and vascular malformations are most commonly recognized in the first months of life and are generally stable over time [Twede et al 2005].

Overgrowth of lipomatous tissue/lipoatrophy. It is common for individuals to manifest overgrowth of adipose tissue, most commonly in infancy. Overgrowth of adipose tissue can continue to appear in novel locations throughout childhood and into young adulthood.

Similarly, many individuals with PS experience marked regional lipoatrophy, and many manifest both regional lipomatous overgrowth and lipoatrophy.

Vascular malformations. Many individuals with PS have cutaneous capillary malformations and prominent venous patterning or varicosities; large and complex vascular malformations affect some individuals. Those with PS manifest skeletal and other overgrowth in areas where no vascular malformations are present (unlike other overgrowth conditions).

Importantly, arteriovenous malformation (AVM) is uncommon in PS.

Genotype-Phenotype Correlations

Proteus syndrome is known to be caused by only a single, mosaic pathogenic variant (p.Glu17Lys) in AKT1. Unpublished data suggest that the severity of the disorder is correlated with the cell type and degree of mosaicism of the pathogenic variant in the affected tissues.


Incomplete penetrance cannot be assessed in a mosaic genetic disorder that is not inherited.


Other descriptors used include elephant man disease. This descriptor is derived from the fact that Mr. Joseph Carey Merrick, who held this unfortunate descriptor, is now thought to have had Proteus syndrome [Cohen 1987]. The use of this descriptor for other than historical purposes is discouraged.


Proteus syndrome is very rare. The prevalence is difficult to measure but approximately 100 cases are known to the author [Biesecker, personal observation]. A very rough estimate is that PS affects 1:1,000,000 – 1:10,000,000 persons. Other, less specifically delineated forms of segmental overgrowth are more common than is PS.

Proteus syndrome is pan ethnic.

Differential Diagnosis

As mentioned in Diagnosis and Clinical Description, significant diagnostic confusion regarding PS exists. Although the following disorders share some features with PS, both the natural history (i.e., almost always post-natal onset) and manifestations (e.g., disproportionate and progressive distorting skeletal overgrowth, CCTN) of PS are important distinctions that can aid in clinical diagnosis.

PTEN hamartoma tumor syndrome (PHTS) is a heterogeneous disorder that manifests asymmetric overgrowth, macrocephaly, cutaneous vascular malformations, and tumor susceptibility. The full spectrum of this interesting and distinctive disorder is not known but it can be readily distinguished from PS. A phenotypic subtype, described as type II segmental Cowden syndrome [Happle 2007] or SOLAMEN syndrome [Caux et al 2007] is the consequence of a germline pathogenic variant in PTEN with a somatic, mosaic second PTEN variant that gives the phenotype its segmental attributes.

PTHS includes growth abnormalities with linear nevi and vascular malformations that are clinically and molecularly distinct from those of PS.

PTHS is inherited in an autosomal dominant manner; Proteus syndrome is not inherited. Thus, the genetic implications in the two disorders are quite distinct, providing further argument for a clear distinction between individuals affected with Proteus syndrome and those with the PTEN hamartoma tumor syndrome.

CLOVE(S) syndrome. CLOVE is an acronym for congenital lipomatous overgrowth, vascular anomalies, and epidermal nevi. It was delineated in 2007, one of several now-distinct entities previously included in the heterogeneous designation of PS [Sapp et al 2007]. It manifests prenatal asymmetric overgrowth that is primarily proportionate in nature. Affected persons commonly have splayed feet and toes. The vascular malformations are most commonly combined lymphatico-venous anomalies with cutaneous blebbing and weeping. The lipomatous nature of the overgrowth is characterized by overgrowth of fat within normal fatty fascial planes and linear verrucous epidermal nevi. Some persons can have CNS abnormalities. See PIK3CA-Related Segmental Overgrowth.

Hemihyperplasia, either as an isolated finding or associated with one of a variety of other manifestations (for review, see Cohen et al [2002]) should be considered. One of the more specific types of hemihyperplasia is the hemihyperplasia with multiple lipomatosis syndrome [Biesecker et al 1998]. This congenital, primarily non-progressive form of hemihyperplasia is sometimes confused with Proteus syndrome.

Klippel-Trenaunay syndrome is a disorder that manifests both overgrowth and vascular malformations. However, in this disorder the overgrowth is generally ipsilateral and overlapping with the vascular malformations, the typical vascular malformation is the lateral venous anomaly, and the skeletal overgrowth is entirely lacking in the distortion and progressivity seen in persons with Proteus syndrome [Cohen 2000].


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Proteus syndrome, the following evaluations are recommended [Tosi et al 2011]:

  • Detailed and comprehensive (general, spine, and hand) orthopedic evaluation
  • Skeletal survey as a baseline study of the extent and severity of overgrowth
  • CT imaging, possibly with three-dimensional reconstruction for patients with significant scoliosis. As the vertebral bodies are commonly progressively deformed, this study can be very helpful for surgical planning.
  • Pulmonology consultation, pulmonary function testing, and high-resolution computed tomography of the chest for patients with signs or symptoms compatible with bullous pulmonary disease

Other imaging techniques are highly useful and should be determined by manifestations on examination and by the medical history. Computed tomography, magnetic resonance imaging, and ultrasound have been extremely useful in the characterization of this disorder [Jamis-Dow et al 2004].

Treatment of Manifestations

As with any complex and multisystem disorder, patients with PS benefit from a coordinated and multidisciplinary clinical approach tailored to the individual’s specific needs and manifestations.

Overgrowth is an ongoing issue for many patients with Proteus syndrome. The management is complex and highly dependent on the nature of the overgrowth, which can vary substantially among patients.

For overgrowth of tubular bones, epiphysiostasis and epiphysiodesis should be the mainstays of management. One intervention that the authors have found to be detrimental to patients with Proteus syndrome is distraction osteotomy (so-called Ilizarov procedure) performed on the normal (shorter) limbs. Readers are referred to a recent review and conference report for more details on this complex issue [Tosi et al 2011].

The skeletal overgrowth of PS can result in significant biomechanical and functional compromise. Because of this, ongoing and comprehensive Rehabilitation Medicine care, including physical and occupational therapy, is important for many patients. In addition, many patients with PS develop substantial needs for custom-designed footwear or orthotics due to leg-length inequality or plantar CCTNs.

Patients with PS who develop large plantar CCTNs should receive regular dermatologic care and attention to manage malodor (a potential complication of difficulty with cleanliness of the deepening of the sulci in late adolescence) and other concerns, such as pressure ulcerations. Large plantar CCTNs can also contribute to problems with shoe fit and often warrant pedorthic intervention as mentioned above.

Management of the overgrowth of adipose tissue is challenging because the areas of adipose overgrowth are not encapsulated and discrete (in contrast to lipomas) and, therefore, can be difficult to resect and commonly regrow after surgical debulking. The authors generally recommend open surgical approaches over liposuction because the highly vascularized lipomatous overgrowth in some patients can result in hemorrhaging that is difficult to control and/or chronically weeping lymphatics.

Deep vein thrombosis (DVT) and pulmonary embolism (PE). The most urgent and life-threatening complication of Proteus syndrome can be DVT and PE [Slavotinek et al 2000]. The rarity of this problem in the general pediatric population can result in a delay in diagnosis.

The authors recommend emergent evaluation of patients who develop symptoms of DVT (e.g., palpable subcutaneous rope-like mass, swelling, erythema, pain, and distal venous congestion) or PE (e.g., shortness of breath, chest pain, and cough which may include hemoptysis). Because patients with PE can be asymptomatic, it is recommended that a patient with a DVT be evaluated for PE regardless of symptoms.

  • Evaluation for DVTs. In the absence of cardiopulmonary compromise, consider the d-dimer assay and/or ultrasonographic evaluation.
  • Evaluation of PE. High-resolution chest CT (so called spiral CT) with contrast is recommended. Ventilation-perfusion nuclear medicine scanning may be appropriate in some cases.

Treatment of DVT and PE should follow recommended anticoagulation guidelines for these disorders. The authors recommend hematologic evaluation and consultation for consideration of anticoagulant prophylaxis for patients undergoing surgery or other procedures that may predispose to DVT/PE.

Bullous pulmonary disease. Although uncommon, bullous pulmonary disease does affect some patients with Proteus syndrome, and, as with other disease manifestations, this can progress with startling rapidity. Pulmonary evaluation is recommended for these patients and resection of large bullous lesions may be indicated in some cases. Bullous disease in the context of scoliosis can pose significant and complex challenges for appropriate management.

Psychosocial issues. In addition to functional compromise, the skeletal and connective tissue overgrowth of PS can result in disfigurement for some patients, a significant concern for many families [Turner et al 2007]. This condition is progressive and the degree of severity varies widely among patients, creating uncertainty for both clinicians and families. Coping with an ultra-rare and chronic condition like PS poses challenges for many patients and families, and genetic and psychosocial counseling is certainly warranted in most instances.

Although PS is exceedingly rare, a robust support group infrastructure exists and many families find this very helpful (see Resources).


Individualized surveillance plans for the skeletal, pulmonary, soft-tissue, and other manifestations of PS should be developed according to patients’ specific needs.

Because of the predisposition to a range of tumors (most of which are benign) patients should be monitored by their primary care provider with regular evaluations including a directed medical history and examination.

Evaluation of Relatives at Risk

Because PS is not inherited, relatives are not at increased risk and do not require evaluation.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Proteus syndrome (PS) is not inherited.

  • There are no confirmed cases with vertical transmission or sib recurrence.
  • The molecular data show that all affected persons are mosaic for the same AKT1 pathogenic variant (c.49G>A), suggesting that the variant occurred post-fertilization in one cell of the multicellular embryo.

Risk to Family Members

Parents of a proband. No parent of a child with bone fide Proteus syndrome has been demonstrated to have any significant, distinctive manifestations of the disorder, nor would such a finding be expected, given the somatic mutational mechanism of the disease.

Sibs of a proband. Given the somatic mutational mechanism of Proteus syndrome, the risk for an affected sib would be expected to be the same as in the general population.

Offspring of a proband. The reproductive outcome data on adults with PS are very limited. There are no instances of vertical transmission of PS.

Other family members of a proband. The risk to other family members is the same as that in the general population.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mosaic pathogenic variant. This is a relatively new area for clinical genetics as there are only a small (although growing) number of disorders known to be caused by this genetic mechanism.

Counseling for recurrence risks in Proteus syndrome should emphasize that, while no pregnancy is at zero risk, all evidence suggests that the risk of recurrence for this disorder is not increased, compared to the general population.

Family planning

  • The optimal time for determination of genetic risk is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Ultrasound examination. Atypical Proteus syndrome (i.e., the uncommon prenatal form with hemimegencephaly) may be detectable using prenatal ultrasound, but no cases are known to the authors.

Molecular genetic testing. As PS is typically not prenatal in onset, and is not inherited, prenatal testing is not indicated.

One theoretic (and speculative) exception may be consideration of prenatal testing for the AKT1 p.Glu17Lys pathogenic variant in a simplex case of prenatal onset hemimegencephaly. Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Preimplantation genetic diagnosis (PGD). The authors recognize no potential role for PGD in Proteus syndrome.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Proteus Foundation
    4915 Dry Stone Drive
    Colorado Springs CO 80918
    Phone: 719-660-1346
  • Proteus Foundation UK
    2 Watermill Close
    Bexhill-on-Sea East Sussex TN39 5EJ
    United Kingdom
    Phone: 01424 736640

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Proteus Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Proteus Syndrome (View All in OMIM)


Molecular Genetic Pathogenesis

The PI3KCA/AKT pathway includes a number of other genes that have been implicated in oncogenesis and/or overgrowth. This pathway is a key mediator of signal transduction from receptor tyrosine kinase growth-promoting and apoptosis-inhibiting factors.

Gene structure. AKT1 extends over approximately 26 kb and includes 14 exons. The mRNA is approximately 3 kb, the reference cDNA is 3,008 bp (NM_005163.2), and the open reading frame is 1,443 bp. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. A number of putative normal variants exist in AKT1 (see Most of the variants have been seen in multiple unrelated persons and are not believed to be associated with any phenotypic effects; however, they have not been rigorously analyzed for subtle effects.

Pathogenic variants. Only the single c.49G>A (p.Glu17Lys) variant in AKT1 has been associated with Proteus syndrome.

Of note, this variant has also been identified as being somatically mutated in a number of tumors (see COSMIC). A synonymous variant in AKT1 has been associated with schizophrenia [Tan et al 2008].

Normal gene product. The gene encodes a protein of 480 amino acids (NP_005154.2).

Abnormal gene product. It has been shown that the p.Glu17Lys pathogenic variant causes constitutive activation of the AKT1 kinase by means of pathologic localization to the plasma membrane and activation of the PI3KCA/AKT pathway [Carpten et al 2007].


Literature Cited

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  17. Slavotinek AM, Vacha SJ, Peters KF, Biesecker LG. Sudden death caused by pulmonary thromboembolism in Proteus syndrome. Clin Genet. 2000;58:386–9. [PubMed: 11140839]
  18. Tan HY, Nicodemus KK, Chen Q, Li Z, Brooke JK, Honea R, Kolachana BS, Straub RE, Meyer-Lindenberg A, Sei Y, Mattay VS, Callicott JH, Weinberger DR. Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. J Clin Invest. 2008;118:2200–8. [PMC free article: PMC2391279] [PubMed: 18497887]
  19. Tosi LL, Sapp JC, Allen ES, O'Keefe RJ, Biesecker LG. Assessment and management of the orthopedic and other complications of Proteus syndrome. J Child Orthop. 2011;5:319–27. [PMC free article: PMC3179535] [PubMed: 23024722]
  20. Turner J, Biesecker B, Leib J, Biesecker L, Peters KF. Parenting children with Proteus syndrome: Experiences with, and adaptation to, courtesy stigma. Am J Med Genet A. 2007;143A:2089–97. [PubMed: 17702022]
  21. Turner JT, Cohen MM Jr, Biesecker LG. Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases. Am J Med Genet A. 2004;130A:111–22. [PubMed: 15372514]
  22. Twede JV, Turner JT, Biesecker LG, Darling TN. Evolution of skin lesions in Proteus syndrome. J Am Acad Dermatol. 2005;52:834–8. [PubMed: 15858474]

Suggested Reading

  1. Biesecker L. The challenges of Proteus syndrome: Diagnosis and management. Eur J Hum Genet. 2006;14:1151–7. [PubMed: 16883308]
  2. Biesecker LG. The multifaceted challenges of Proteus syndrome. JAMA. 2001;285:2240–3. [PubMed: 11325326]
  3. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, Cohen MM Jr. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999;84:389–95. [PubMed: 10360391]

Chapter Notes

Author Notes

Leslie G Biesecker, MD is a board-certified clinical geneticist and pediatrician. He performs clinical and molecular research on Proteus syndrome and related disorders at the NIH.

Revision History

  • 9 August 2012 (me) Review posted live
  • 19 April 2012 (lgb) Original submission

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