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Proteus syndrome

MedGen UID:
39008
Concept ID:
C0085261
Neoplastic Process
Synonyms: Elattoproteus syndrome; Gigantism, partial, of hands and feet, nevi, hemihypertrophy, and macrocephaly; Hemihypertrophy and macrocephaly; Macrocephaly mesodermal hamartoma spectrum; Partial gigantism of hands and feet, nevi, hemihypertrophy, macrocephaly; PROTEUS SYNDROME, SOMATIC
SNOMED CT: Proteus syndrome (23150001)
Modes of inheritance:
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Gene (location): AKT1 (14q32.33)
 
Monarch Initiative: MONDO:0008318
OMIM®: 176920
Orphanet: ORPHA744

Disease characteristics

Excerpted from the GeneReview: Proteus Syndrome
Proteus syndrome (PS) is characterized by progressive segmental or patchy overgrowth most commonly affecting the skeleton, skin, adipose, and central nervous systems. In most individuals PS has modest 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. [from GeneReviews]
Authors:
Leslie G Biesecker  |  Julie C Sapp   view full author information

Additional descriptions

From OMIM
Proteus syndrome is a highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Specific features include cerebriform connective tissue nevus, thin limbs, lipomas, and lung cysts. Some patients may have intellectual disability with dysmorphic facies. Deep venous thrombosis is common and constitutes a significant risk factor. Many features of Proteus syndrome overlap with other overgrowth syndromes (Turner et al., 2004; review by Cohen, 2014). Cohen (2014) provided a detailed review of the clinical features, diagnosis, and management issues of Proteus syndrome. Some authors (Zhou et al., 2000, 2001; Smith et al., 2002) have reported a 'Proteus-like' syndrome associated with germline and tissue-specific somatic mutations in the PTEN gene (601728), which is mutated in Cowden syndrome (CWS1); see 158350 for a discussion of these patients.  http://www.omim.org/entry/176920
From MedlinePlus Genetics
Proteus syndrome is a rare condition characterized by overgrowth of the bones, skin, and other tissues. Organs and tissues affected by the disease grow out of proportion to the rest 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 condition. Overgrowth becomes apparent between the ages of 6 and 18 months and gets more severe with age.

In people with Proteus syndrome, the pattern of overgrowth varies greatly but can affect almost any part of the body. Bones in the limbs, skull, and spine are often affected. The condition can also cause a variety of skin growths, particularly a thick, raised, and deeply grooved lesion known as a cerebriform connective tissue nevus. This type of skin growth usually occurs on the soles of the feet and is hardly ever seen in conditions other than Proteus syndrome. Blood vessels (vascular tissue) and fat (adipose tissue) can also grow abnormally in Proteus syndrome.

Some people with Proteus syndrome have neurological abnormalities, including intellectual disability, seizures, and vision loss. Affected individuals may also have distinctive facial features such as a long face, outside corners of the eyes that point downward (down-slanting palpebral fissures), a low nasal bridge with wide nostrils, and an open-mouth expression. For reasons that are unclear, affected people with neurological symptoms are more likely to have distinctive facial features than those without neurological symptoms. It is unclear how these signs and symptoms are related to abnormal growth.

Other potential complications of Proteus syndrome include an increased risk of developing various types of noncancerous (benign) tumors and a type of blood clot called a deep venous thrombosis (DVT). DVTs occur most often in the deep veins of the legs or arms. If these clots travel through the bloodstream, they can lodge in the lungs and cause a life-threatening complication called a pulmonary embolism. Pulmonary embolism is a common cause of death in people with Proteus syndrome.  https://medlineplus.gov/genetics/condition/proteus-syndrome

Clinical features

From HPO
Hemangioma
MedGen UID:
5477
Concept ID:
C0018916
Neoplastic Process
A hemangioma is a benign tumor characterized by blood-filled spaces lined by benign endothelial cells. A hemangioma characterized by large endothelial spaces (caverns) is called a cavernous hemangioma (in contrast to a hemangioma with small endothelial spaces, which is called capillary hemangioma).
Lipoma
MedGen UID:
44173
Concept ID:
C0023798
Neoplastic Process
Benign neoplasia derived from lipoblasts or lipocytes of white or brown fat. May be angiomatous or hibernomatous.
Multiple lipomas
MedGen UID:
677074
Concept ID:
C0745730
Finding
The presence of multiple lipomas (a type of benign tissue made of fatty tissue).
Venous malformation
MedGen UID:
754284
Concept ID:
C2937220
Congenital Abnormality
A vascular malformation resulting from a developmental error of venous tissue composed of dysmorphic channels lined by flattened endothelium and exhibiting slow turnover. A venous malformation may present as a blue patch on the skin ranging to a soft blue mass. Venous malformations are easily compressible and usually swell in thewhen venous pressure increases (e.g., when held in a dependent position or when a child cries). They may be relatively localized or quite extensive within an anatomic region.
Hemihypertrophy
MedGen UID:
90701
Concept ID:
C0332890
Congenital Abnormality
Overgrowth of only one side of the body.
Intellectual disability, moderate
MedGen UID:
7680
Concept ID:
C0026351
Mental or Behavioral Dysfunction
Moderate mental retardation is defined as an intelligence quotient (IQ) in the range of 35-49.
Spinal cord compression
MedGen UID:
11549
Concept ID:
C0037926
Disease or Syndrome
External mechanical compression of the spinal cord.
Deep venous thrombosis
MedGen UID:
57448
Concept ID:
C0149871
Disease or Syndrome
Formation of a blot clot in a deep vein. The clot often blocks blood flow, causing swelling and pain. The deep veins of the leg are most often affected.
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Thin bony cortex
MedGen UID:
318844
Concept ID:
C1833325
Finding
Abnormal thinning of the cortical region of bones.
Facial hyperostosis
MedGen UID:
347471
Concept ID:
C1857501
Finding
Excessive growth (overgrowth) of the facial bones, that is of the facial skeleton.
Spinal canal stenosis
MedGen UID:
396107
Concept ID:
C1861329
Anatomical Abnormality
An abnormal narrowing of the spinal canal.
Calvarial hyperostosis
MedGen UID:
350147
Concept ID:
C1863351
Finding
Excessive growth of the calvaria.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Cerebriform connective tissue nevus
MedGen UID:
860278
Concept ID:
C4011841
Finding
The cerebriform connective tissue nevus (CCTN) is one of the most characteristic skin findings. It commonly occurs on the soles of the feet, and frequently causes problems because of pain, pruritus, infection, bleeding,exudation, odor, and walking impairment.
Mandibular hyperostosis
MedGen UID:
870861
Concept ID:
C4025321
Anatomical Abnormality
Hyperostosis (bony overgrowth) of the mandible.
Lymphangioma
MedGen UID:
6153
Concept ID:
C0024221
Neoplastic Process
Lymphangiomas are rare congenital malformations consisting of focal proliferations of well-differentiated lymphatic tissue in multi cystic or sponge like structures. Lymphangioma is usually asymptomatic due to its soft consistency but compression of adjacent structures can be seen due to the mass effect of a large tumor.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Open mouth
MedGen UID:
116104
Concept ID:
C0240379
Finding
A facial appearance characterized by a permanently or nearly permanently opened mouth.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Nevus
MedGen UID:
45074
Concept ID:
C0027960
Neoplastic Process
A nevus is a type of hamartoma that is a circumscribed stable malformation of the skin.
Epidermal acanthosis
MedGen UID:
65136
Concept ID:
C0221270
Finding
Diffuse hypertrophy or thickening of the stratum spinosum of the epidermis (prickle cell layer of the skin).
Epidermal nevus
MedGen UID:
83106
Concept ID:
C0334082
Disease or Syndrome
PIK3CA-related overgrowth spectrum (PROS) encompasses a range of clinical findings in which the core features are congenital or early-childhood onset of segmental/focal overgrowth with or without cellular dysplasia. Prior to the identification of PIK3CA as the causative gene, PROS was separated into distinct clinical syndromes based on the tissues and/or organs involved (e.g., MCAP [megalencephaly-capillary malformation] syndrome and CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome). The predominant areas of overgrowth include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues, including swelling, pain, and occasionally localized bleeding secondary to trauma. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus. Many children have feeding difficulties that are often multifactorial in nature. Endocrine issues affect a small number of individuals and most commonly include hypoglycemia (largely hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and growth hormone deficiency.
Hyperkeratosis
MedGen UID:
209030
Concept ID:
C0870082
Disease or Syndrome
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
Hypertrophy of skin of soles
MedGen UID:
358029
Concept ID:
C1867617
Finding
Depigmentation/hyperpigmentation of skin
MedGen UID:
870419
Concept ID:
C4024864
Anatomical Abnormality
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Limbal dermoid
MedGen UID:
401267
Concept ID:
C1867616
Neoplastic Process
A benign tumor typically found at the junction of the cornea and sclera (limbal epibullar dermoid).

Professional guidelines

PubMed

Sapp JC, Buser A, Burton-Akright J, Keppler-Noreuil KM, Biesecker LG
Am J Med Genet C Semin Med Genet 2019 Dec;181(4):565-570. Epub 2019 Nov 6 doi: 10.1002/ajmg.c.31744. PMID: 31692258Free PMC Article
Biesecker L
Eur J Hum Genet 2006 Nov;14(11):1151-7. Epub 2006 Aug 2 doi: 10.1038/sj.ejhg.5201638. PMID: 16883308
Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, Cohen MM Jr
Am J Med Genet 1999 Jun 11;84(5):389-95. doi: 10.1002/(sici)1096-8628(19990611)84:5<389::aid-ajmg1>3.0.co;2-o. PMID: 10360391

Suggested Reading

PubMed

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 MA, 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, Biesecker LG
N Engl J Med 2011 Aug 18;365(7):611-9. Epub 2011 Jul 27 doi: 10.1056/NEJMoa1104017. PMID: 21793738Free PMC Article
Turner JT, Cohen MM Jr, Biesecker LG
Am J Med Genet A 2004 Oct 1;130A(2):111-22. doi: 10.1002/ajmg.a.30327. PMID: 15372514
Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, Cohen MM Jr
Am J Med Genet 1999 Jun 11;84(5):389-95. doi: 10.1002/(sici)1096-8628(19990611)84:5<389::aid-ajmg1>3.0.co;2-o. PMID: 10360391

Recent clinical studies

Etiology

Martinez-Lopez A, Salvador-Rodriguez L, Montero-Vilchez T, Molina-Leyva A, Tercedor-Sanchez J, Arias-Santiago S
Curr Opin Pediatr 2019 Dec;31(6):747-753. doi: 10.1097/MOP.0000000000000812. PMID: 31693582
Hill CR, Theos A
Dermatol Clin 2019 Apr;37(2):229-239. doi: 10.1016/j.det.2018.11.004. PMID: 30850045
Asch S, Sugarman JL
Handb Clin Neurol 2015;132:291-316. doi: 10.1016/B978-0-444-62702-5.00022-6. PMID: 26564089
Gustafson S, Zbuk KM, Scacheri C, Eng C
Semin Oncol 2007 Oct;34(5):428-34. doi: 10.1053/j.seminoncol.2007.07.009. PMID: 17920899
Dalal AB, Phadke SR, Pradhan M, Sharda S
Indian J Pediatr 2006 Jul;73(7):609-15. doi: 10.1007/BF02759927. PMID: 16877856

Diagnosis

Lindhurst MJ, Brinster LR, Kondolf HC, Shwetar JJ, Yourick MR, Shiferaw H, Keppler-Noreuil KM, Elliot G, Rivas C, Garrett L, Gomez-Rodriguez J, Sebire NJ, Hewitt SM, Schwartzberg PL, Biesecker LG
Hum Mol Genet 2019 Sep 1;28(17):2920-2936. doi: 10.1093/hmg/ddz116. PMID: 31194862Free PMC Article
Rocha RCC, Estrella MPS, Amaral DMD, Barbosa AM, Abreu MAMM
An Bras Dermatol 2017 Sep-Oct;92(5):717-720. doi: 10.1590/abd1806-4841.20174496. PMID: 29166516Free PMC Article
Rawal S, Sharma B, Dabla S, Singh J, Goyal S
J Assoc Physicians India 2016 May;64(5):69-71S. PMID: 27735155
Neylon OM, Werther GA, Sabin MA
Curr Opin Pediatr 2012 Aug;24(4):505-11. doi: 10.1097/MOP.0b013e3283558995. PMID: 22705997
Moog U
J Med Genet 2009 Nov;46(11):721-9. Epub 2009 Jul 1 doi: 10.1136/jmg.2009.066068. PMID: 19574261

Therapy

Keppler-Noreuil KM, Burton-Akright J, Kleiner DE, Sapp JC, Lindhurst MJ, Han CG, Biesecker LG, Gochuico BR
Ann Am Thorac Soc 2022 Nov;19(11):1871-1880. doi: 10.1513/AnnalsATS.202111-1214OC. PMID: 35839129Free PMC Article
Martinez-Lopez A, Salvador-Rodriguez L, Montero-Vilchez T, Molina-Leyva A, Tercedor-Sanchez J, Arias-Santiago S
Curr Opin Pediatr 2019 Dec;31(6):747-753. doi: 10.1097/MOP.0000000000000812. PMID: 31693582
Hill CR, Theos A
Dermatol Clin 2019 Apr;37(2):229-239. doi: 10.1016/j.det.2018.11.004. PMID: 30850045
Hoeger PH, Martinez A, Maerker J, Harper JI
Clin Exp Dermatol 2004 May;29(3):222-30. doi: 10.1111/j.1365-2230.2004.01513.x. PMID: 15115498
Pearson H
Nature 2002 May 2;417(6884):10-1. doi: 10.1038/417010a. PMID: 11986637

Prognosis

Flores-Sarnat L, Sarnat HB
Handb Clin Neurol 2015;132:9-25. doi: 10.1016/B978-0-444-62702-5.00002-0. PMID: 26564069
Geister KA, Camper SA
Annu Rev Genomics Hum Genet 2015;16:199-227. Epub 2015 Apr 22 doi: 10.1146/annurev-genom-090314-045904. PMID: 25939055Free PMC Article
Neylon OM, Werther GA, Sabin MA
Curr Opin Pediatr 2012 Aug;24(4):505-11. doi: 10.1097/MOP.0b013e3283558995. PMID: 22705997
Biesecker L
Eur J Hum Genet 2006 Nov;14(11):1151-7. Epub 2006 Aug 2 doi: 10.1038/sj.ejhg.5201638. PMID: 16883308
Bilkay U, Tokat C, Ozek C, Gundogan H, Erdem O, Gurler T, Cagdas A
Scand J Plast Reconstr Surg Hand Surg 2003;37(5):307-10. doi: 10.1080/02844310310000446. PMID: 14649692

Clinical prediction guides

Lindhurst MJ, Brinster LR, Kondolf HC, Shwetar JJ, Yourick MR, Shiferaw H, Keppler-Noreuil KM, Elliot G, Rivas C, Garrett L, Gomez-Rodriguez J, Sebire NJ, Hewitt SM, Schwartzberg PL, Biesecker LG
Hum Mol Genet 2019 Sep 1;28(17):2920-2936. doi: 10.1093/hmg/ddz116. PMID: 31194862Free PMC Article
Nathan N, Keppler-Noreuil KM, Biesecker LG, Moss J, Darling TN
Dermatol Clin 2017 Jan;35(1):51-60. doi: 10.1016/j.det.2016.07.001. PMID: 27890237Free PMC Article
Flores-Sarnat L, Sarnat HB
Handb Clin Neurol 2015;132:9-25. doi: 10.1016/B978-0-444-62702-5.00002-0. PMID: 26564069
Geister KA, Camper SA
Annu Rev Genomics Hum Genet 2015;16:199-227. Epub 2015 Apr 22 doi: 10.1146/annurev-genom-090314-045904. PMID: 25939055Free PMC Article
Cohen MM Jr
Clin Genet 2014 Feb;85(2):111-9. Epub 2013 Oct 23 doi: 10.1111/cge.12266. PMID: 23992099

Recent systematic reviews

Jia RB, Wang YF, Jia RB
Eur Rev Med Pharmacol Sci 2023 Nov;27(21):10313-10321. doi: 10.26355/eurrev_202311_34306. PMID: 37975355
Munhoz L, Arita ES, Nishimura DA, Watanabe PCA
Oral Radiol 2021 Jan;37(1):2-12. Epub 2019 Nov 16 doi: 10.1007/s11282-019-00416-y. PMID: 31734933

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