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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
Modes of inheritance:
Somatic mutation
MedGen UID:
107465
Concept ID:
C0544886
Cell or Molecular Dysfunction
Sources: HPO, OMIM
Any mutation with an origin in cells that are not destined to become gametes. As a consequence, such mutations are not transmitted to progeny, though they will be transmitted during any mitosis within the individual. Somatic mutations may contribute to a broad variety of pathologies including cancer.
Sporadic
MedGen UID:
342827
Concept ID:
C1853237
Finding
Sources: HPO, OMIM
Cases of the disease in question occur without a previous family history, i.e., as isolated cases without being transmitted from a parent and without other siblings being affected.
not inherited
MedGen UID:
832438
Concept ID:
CN227390
Intellectual Product
Source: Orphanet
Describes a disorder that is not inherited.
Somatic mutation (HPO, OMIM)
Sporadic (HPO, OMIM)
not inherited (Orphanet)
SNOMED CT: Proteus syndrome (23150001)
 
Gene (location): AKT1 (14q32.33)
OMIM®: 176920
Orphanet: ORPHA744

Disease characteristics

Excerpted from the GeneReview: Proteus Syndrome
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. [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 (158350) and Bannayan-Riley-Ruvalcaba syndrome (BRRS; 153480). See 158350 for a discussion of these patients.  http://www.omim.org/entry/176920
From GHR
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://ghr.nlm.nih.gov/condition/proteus-syndrome

Clinical features

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).
Epibulbar dermoid
MedGen UID:
99224
Concept ID:
C0496897
Neoplastic Process
An epibulbar dermoid is a benign tumor typically found at the junction of the cornea and sclera (limbal epibullar dermoid).
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.
Lymphangioma
MedGen UID:
6153
Concept ID:
C0024221
Neoplastic Process
A benign tumor resulting from a congenital malformation of the lymphatic system. Lymphangioendothelioma is a type of lymphangioma in which endothelial cells are the dominant component.
Multiple lipomas
MedGen UID:
677074
Concept ID:
C0745730
Finding
The presence of multiple lipomas (a type of benign tissue made of fatty tissue).
Hemihypertrophy
MedGen UID:
90701
Concept ID:
C0332890
Congenital Abnormality
Overgrowth of only one side of the body.
Hypertrophy of skin of soles
MedGen UID:
358029
Concept ID:
C1867617
Finding
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).
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.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.
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
Deep vein thrombosis, or DVT, is a blood clot that forms in a vein deep in the body. Most deep vein clots occur in the lower leg or thigh. If the vein swells, the condition is called thrombophlebitis. A deep vein thrombosis can break loose and cause a serious problem in the lung, called a pulmonary embolism. Sitting still for a long time can make you more likely to get a DVT. Some medicines and disorders that increase your risk for blood clots can also lead to DVTs. Common symptoms are . - Warmth and tenderness over the vein . - Pain or swelling in the part of the body affected . - Skin redness . Treatment includes medicines to ease pain and inflammation, break up clots and keep new clots from forming. Keeping the affected area raised and applying moist heat can also help. If you are taking a long car or plane trip, take a break, walk or stretch your legs and drink plenty of liquids.
Lymphangioma
MedGen UID:
6153
Concept ID:
C0024221
Neoplastic Process
A benign tumor resulting from a congenital malformation of the lymphatic system. Lymphangioendothelioma is a type of lymphangioma in which endothelial cells are the dominant component.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.
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
Macrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by Olney, 2007 and Williams et al., 2008). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by Alfaiz et al., 2014).
Mandibular hyperostosis
MedGen UID:
500975
Concept ID:
CN003966
Finding
Hyperostosis (bony overgrowth) of the mandible.
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.
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.
Epibulbar dermoid
MedGen UID:
99224
Concept ID:
C0496897
Neoplastic Process
An epibulbar dermoid is a benign tumor typically found at the junction of the cornea and sclera (limbal epibullar dermoid).
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.
Facial hyperostosis
MedGen UID:
347471
Concept ID:
C1857501
Finding
Excessive growth (overgrowth) of the facial bones, that is of the facial skeleton.
Calvarial hyperostosis
MedGen UID:
350147
Concept ID:
C1863351
Finding
Excessive growth of the calvaria.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Macrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by Olney, 2007 and Williams et al., 2008). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by Alfaiz et al., 2014).
Mandibular hyperostosis
MedGen UID:
500975
Concept ID:
CN003966
Finding
Hyperostosis (bony overgrowth) of the mandible.
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).
Nevus
MedGen UID:
45074
Concept ID:
C0027960
Neoplastic Process
Moles are growths on the skin. They happen when pigment cells in the skin, called melanocytes, grow in clusters. Moles are very common. Most people have between 10 and 40 moles. A person may develop new moles from time to time, usually until about age 40. In older people, they tend to fade away. Moles are usually pink, tan or brown. They can be flat or raised. They are usually round or oval and no larger than a pencil eraser. About one out of every ten people has at least one unusual (or atypical) mole that looks different from an ordinary mole. They are called dysplastic nevi. They may be more likely than ordinary moles to develop into melanoma, a type of skin cancer. You should have a health care professional check your moles if they look unusual, grow larger, change in color or outline, or in any other way. NIH: National Cancer Institute.
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

Suggested Reading

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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. PMID: 10360391

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