FaCD Online Syndrome Fact Sheet

Last updated: 02 Aug 2011

Name: Proteus syndrome

Synonym: Incl.: Encephalocraniocutaneous Lipomatosis, ECCL, Proteus-like s.

Mode of Inheritance: de novo mosaic

OMIM number: 176920  


ATK1, mapped to 14q32.32
PTEN, mapped to 10q23.3

Tumor features

cutaneous lipomateus hamartomas
intracranial lipomas
lymphatic hamartomas
ovarian serous cystadenoma
parotid gland, monomorphic adenoma of
sucutaneous lipomateus hamartomas

Tumor features (possible)

breast cancer
epididymis, cystadenoma of
fallopian tube cancer
mandibular odontoma
mesothelioma, pleural
odontoma, maxillar
optic glioma
pineal gland tumor
sacrococcygeal teratoma
thyroid hyperplasia / goitre
tunica vaginalis, mesothelioma of

Non-tumor features

developmental delay/mental deficiency/mental retardation
epidermal nevi, verrucous
feet, large
hands, large
hyperostosis, cranial
long-bone overgrowth
nasal bridge, depressed
palpebral fissures, downward slanting
plantar hyperplasia
porencephalic cyst


Clinical hallmarks are overgrowth (gigantism) of hand and feet, plantar hyperplasia, limb asymmetry, macrocephaly, cranial hyperostosis, overgrowth of the long bones, hemangioma, lipomas, lymphangiomas and verrucous epidermal nevi[1-3]. Vaughn et al argued that the vascular tumors in Proteus syndrome are best classified as lymphatic hamartomas[4]. The production of insulin-like growth factors appears to be generally disturbed in Proteus syndrome[5].

Patients with Proteus syndrome are possibly at an increased risk to develop malignant tumors. A wide range of uncommon types have been reported, including cases with multiple primary tumors[6-8, 21-24, 27,31]. Precise risk figures are unavailable.

Almost all cases are sporadic; a few possible familial cases have been reported. In most cases the disorder was considered to be caused by mosaicism for a somatic gene mutation[9;10]. The gene in question has now been identified as ATK1[30]. In a few cases germline PTEN mutations have been detected, so there is clinical overlap with Cowden syndrome[18,19].

Encephalocraniocutaneous Lipomatosis (ECCL) is a rare congenital hamartomatous disorder characterized by unilateral craniofacial hamartomatous-lipomatous skin lesions, and ipsilateral malformations of the central nervous system: lipomas, cortical atrophy, porencephalic cysts, neuronal migration defects, and spinal cord lipomas. The CNS defects are associated with mental retardation and seizures. Savage et al.[12] reported an ECCL patient with an ipsilateral mandibular ameloblastic fibro-odontoma and a maxillary odontoma. All reported cases of ECCL are sporadic. [13-15]. ECCL is thought to be part of the Proteus syndrome spectrum[16;17]. A germline NF 1 gene mutation was detected in one case[17].

Diagnostic Criteria Proteus syndrome[11]:

Diagnosis if 1 sign from category A or 2 signs from category B or 3 signs from category C are present:

  • -Connective tissue nevus

  • -Epidermal nevus
  • -Disproportionate overgrowth, including hyperostosis (one or more regions involved: limbs, skull, external auditory meatus, vertebrae, spleen/thymus)
  • -Specific tumors before age 30: bilateral ovarian cystadenomas or parotid monomorphic adenoma

  • -Dysregulated adipose tissue: lipomas or regional absence of fat
  • -Vascular malformation: capillary, venous or lymphatic
  • -Facial phenotype: dolichocephaly, long face, minor downslanting of palpebral fissures and/or minor ptosis, low nasal bridge, wide or anteverted nares, open mouth at rest.


Proteus Syndrome Foundation, USA 24 1 08


[1] Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E. The proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 1983; 140(1):5-12.
[2] Samlaska CP, Levin SW, James WD, Benson PM, Walker JC, Perlik PC. Proteus syndrome. Arch Dermatol 1989; 125(8):1109-1114.
[3] Cohen MM, Jr. Understanding proteus syndrome, unmasking the elephant man, and stemming Elephant fever. Neurofibromatosis 1988; 1:260-280.
[4] Vaughn RY, Lesher JL, Jr., Chandler FW, O'Quinn JL, Hobbs JL, Howell CG, Edgerton MT. Histogenesis of vascular tumors in the Proteus syndrome. South Med J 1994; 87(2):228-232.
[5] Rudolph G, Blum WF, Jenne EW, Schoning M, Enders H, Meitinger T, Murken JD, Kampik A. Growth hormone (GH),insulin-like growth factors (IGFs), and IGF-binding protein-3 (IGFBP-3) in a child with proteus syndrome. Am J Med Genet 1994; 50:204-210.
[6] Gordon PL, Wilroy RS, Lasater OE, Cohen MM, Jr. Neoplasms in Proteus syndrome. Am J Med Genet 1995; 57:74-78.
[7] Zachariou Z, Krug M, Benz G, Daum R. Proteus syndrome associated with a sacrococcygeal teratoma; a rare combination. Eur J Pediatr Surg 1996; 6(4):249-251.
[8] Hornstein L, Bove KE, Towbin RB. Linear nevi,hemihypertrophy,connective tissue hamartomas, and unusual neoplasms in children. J Pediat 1987; 110:404-408.
[9] Cohen MM, Jr. Proteus syndrome: clinical evidence for somatic mosaicism and selective review. Am J Med Genet 1993; 47:645-652.
[10] Smeets E, Fryns JP, Cohen MM, Jr. Regional Proteus syndrome and somatic mosaicism. Am J Med Genet 1994; 51(1):29-31.
[11] 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; 84:389-395.
[12] Savage MG, Heldt L, Dann JJ, Bump RL. Encephalocraniocutaneous lipomatosis ad mixed odontogenic tumors. J Oral Maxillofac Surg 1985; 43:617-620.
[13] Sanchez NP, Rhodes AR, Mandell F, Mihm MC. Encephalocraniocutaneous lipomatosis: a new neurocutaneous syndrome. Br J Dermatol 1981; 104:89-96.
[14] Grimalt R, Ermacora E, Mistura L, Russo G, Tadini GL, Triulzi F, Cavicchini S, Rondanini GF, Caputo R. Encephalocraniocutaneous lipomatosis: case report and review of the literature. Pediatr Dermatol 1993; 10(2):164-168.
[15] Nowaczyk MJM, Mernagh JR, Bourgeois JM, Thompson PJ, Jurriaans E. Brief clinical report: Antenatal and postnatal findings in encephalocraniocutaneous lipomatosis. Am J Med Genet 2000; 91:261-266.
[16] Wiedemann HR, Burgio GR. Encephalocraniocutaneous lipomatosis and Proteus syndrome. Am J Med Genet 1986; 25:403-404.
[17] Legius E, Wu R, Marynen P, Fryns JP, Cassiman JJ. Encephalocraniocutaneous lipomatosis with a mutation in the NF1 gene. J Med Genet 1995; 32:316-319.
[18] Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC, Parisi M, Winter RM, Eng C. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet 2001; 358(9277):210-1.
[19] Barker K, Martinez A, Wang R, Bevan S, Murday V, Shipley J, Houlston R, Harper J. PTEN mutations are uncommon in Proteus syndrome. Journal of medical genetics 2001; 38(7):480-1.
[20] Gustafson S, Zbuk KM, Scacheri C, Eng C. Cowden syndrome. Seminars in oncology 2007; 34(5):428-34.
[21] Iqbal J, He G, Biesecker LG, Rosen P, Duray PH, Schwartzentruber D, Beg M, Kahn E. Morphological characterization of the breast in Proteus syndrome complicated by ductal carcinoma in situ. Annals of clinical and laboratory science 2006; 36(4):469-74.
[22] Funk T, Frew P, Rodgers W, Troxell M. Unusual fallopian tube neoplasm in a 10-year-old patient with Proteus syndrome: a case report and review of the literature. Pediatric and developmental pathology 2006 Jul-Aug; 9(4):316-20.
[23] Farajzadeh S, Zahedi MJ, Moghaddam SD. A new gastrointestinal finding in Proteus syndrome: report of a case of multiple colonic hemangiomas. International journal of dermatology 2006; 45(2):135-8.
[24] Matsumoto S, Takahashi S, Goto T, Tomita K, Takeuchi T, Kitamura T. Proteus syndrome with giant myelolipoma in the pelvis. International journal of urology 2005; 12(11):1005-6.
[25] Cohen MM. Proteus syndrome: an update. American journal of medical genetics. Part C, Seminars in medical genetics 2005; 137(1):38-52.
[26] Turner JT, Cohen MM, Biesecker LG. Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases. American journal of medical genetics. Part A 2004; 130(2):111-22.
[27] Gong Y, Chao J, Bauer B, Sun X, Chou PM. Primary cutaneous alveolar rhabdomyosarcoma of the perineum. Archives of pathology & laboratory medicine 2002; 126(8):982-4.
[28] Hoey SE, Eastwood D, Monsell F, Kangesu L, Harper JI, Sebire NJ. Histopathological features of Proteus syndrome. Clin Exp Dermatol 2008 Jan 16 [Epub ahead of print]
[29] Biesecker L. The challenges of Proteus syndrome: diagnosis and management. European journal of human genetics : EJHG 2006; 14(11):1151-7.
[30] 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. A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome. N Engl J Med. 2011 Jul 27. [Epub ahead of print]
[31] Asahina A, Fujita H, Omori T, Kai H, Yamamoto M, Mii K. Proteus syndrome complicated by multiple spinal meningiomas. Clin Exp Dermatol. 2008 Nov;33(6):729-32.