Proteus syndrome

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Proteus syndrome
Other namesPartial gigantism-nevi-hemihypertrophy-macrocephaly syndrome, Wiedemann syndrome
NIH Proteus Patient.jpg
Alex Green, a 7-year-old boy with Proteus syndrome, confirmed to have the AKT1 p.E17K somatic variant. Alex died at the age of 9.
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg

Proteus syndrome is a rare disorder with a genetic background [1] that can cause tissue overgrowth involving all three embryonic lineages. Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development. [2] The clinical and radiographic symptoms of Proteus syndrome are highly variable, as are its orthopedic manifestations. [3] [4]

Contents

Only a few more than 200 cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition. [5] As attenuated forms of the disease may exist, there could be many people with Proteus syndrome who remain undiagnosed. Those most readily diagnosed are also the most severely disfigured.

The syndrome is named after the Greek sea-god Proteus, who could change his shape. The condition appears to have been first described in the American medical literature by Samia Temtamy and John Rogers in 1976. [6] [7] American pathologist Michael Cohen described it in 1979. [8]

Signs and symptoms

Portuguese illustration of a foreign woman with deformities indicative of Proteus syndrome, 1695 A woman with scales on her upper body and grossly enlarged l Wellcome V0007397.jpg
Portuguese illustration of a foreign woman with deformities indicative of Proteus syndrome, 1695

Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and lymphatic vessels. Proteus syndrome is a progressive condition wherein children are usually born without any obvious deformities. Tumors of skin and bone growths appear as they age typically in early childhood. The musculoskeletal manifestations are cardinal for the diagnosis of Proteus syndrome. [3] The severity and locations of these various asymmetrical growths vary greatly but typically the skull, one or more limbs, and soles of the feet will be affected. There is a risk of premature death in affected individuals due to deep vein thrombosis and pulmonary embolism caused by the vessel malformations that are associated with this disorder. Because of carrying excess weight and enlarged limbs, arthritis and muscle pain may also be symptoms. Further risks may occur due to the mass of extra tissue.[ citation needed ]

The disorder itself does not uniformly cause learning impairments: the distribution of intelligence deficits among those with Proteus syndrome appears higher than that of the general population, although this is difficult to determine with statistical significance. [9] In addition, the presence of visible deformity have a negative effect on the social experiences of the affected individual, causing emotional difficulties, social rejection and stigma.[ citation needed ]

Affected individuals are at increased risk for developing certain tumors including unilateral ovarian cystadenomas, testicular tumors, meningiomas, and monomorphic adenomas of the parotid gland.[ citation needed ]

Hemimegalencephaly is often found to be associated. [10]

Orthopaedic features

The musculoskeletal manifestations of Proteus syndrome are frequent and recognizable. Patients tend to demonstrate a unique pattern of skeletal abnormalities. The orthopaedic features are usually bilateral, asymmetrical, progressive and involving all four limbs and spine. Affected patients usually have localized periarticular limb distortions, limb length discrepancy, and spine deformity. Patients with Proteus syndrome can have regular bone configuration and contours despite the bone enlargement. [3] Patients can also exhibit deformation of the skull in the form of dolichocephaly or elongated skull and facial abnormalities. Because of the rarity of the syndrome and the variability of signs, the orthopaedic management should be individualized. [3]

Genetics

Proteus syndrome is an overgrowth disorder caused by a rare genetic mosaicism. A genetic mutation during embryonic development gives rise to overgrowth in a subset of the individual's cells. Proteus Syndrome - NHGRI - NHI.jpg
Proteus syndrome is an overgrowth disorder caused by a rare genetic mosaicism. A genetic mutation during embryonic development gives rise to overgrowth in a subset of the individual's cells.

In 2011 researchers determined the cause of Proteus syndrome. In 26 of 29 patients who met strict clinical criteria for the disorder, Lindhurst et al. identified an activating mutation in AKT1 kinase in a mosaic state. [11]

Previous research had suggested the condition linked to PTEN on chromosome 10, [12] while other research pointed to chromosome 16. [13] Prior to the findings regarding AKT1 in 2011, other researchers expressed doubt regarding the involvement of PTEN or GPC3 , which codes for glypican 3 and may play a role in regulating cell division and growth regulation. [14] [15]

Diagnosis

Differential diagnosis

Classification

Many sources classify Proteus syndrome to be a type of nevus syndrome. The lesions appear to be distributed in a mosaic manner. [20] It has been confirmed that the disorder is an example of genetic mosaicism. [11]

Treatment

A team of doctors in Australia have trial-tested the drug rapamycin in the treatment of a patient said to have Proteus syndrome and have found it to be an effective remedy. [21] However, the diagnosis of Proteus syndrome in this patient has been questioned by others. [22]

The Proteus syndrome research team in the National Human Genome Research Institute at the United States National Institutes of Health have initiated a Phase 0 dose finding trial with the AKT1 inhibitor ARQ 092, which is being developed by the Arqule Corporation. In earlier tests on tissue and cell samples obtained from patients, ARQ 092 reduced phosphorylation of AKT and downstream targets of AKT in as little as two hours. [23] The Phase 0 trial opened in November 2015. [24] This trial is based on in vitro data showing inhibition of AKT1 in cell lines from patients with Proteus syndrome. [25]

Notable cases

In a 1986 article in the British Medical Journal , Michael Cohen and J.A.R. Tibbles proposed the idea that Joseph Merrick (an Englishman known as the "Elephant Man") had Proteus syndrome. However, the exact condition that Joseph Merrick had is still not known with certainty. [26] [27]

Mandy Sellars has been diagnosed by some doctors as having this condition. [5] Her legs and feet have grown at a disproportionate rate since birth. However, in 2013, Sellars's case was profiled on British television in a special called Shrinking My 17 Stone Legs, in which it was determined that Sellars's condition was not, in fact, Proteus syndrome, but rather the often-misdiagnosed PIK3CA-related overgrowth spectrum, a syndrome caused by a PIK3CA gene mutation.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Benign tumor</span> Mass of cells which cannot spread throughout the body

A benign tumor is a mass of cells (tumor) that does not invade neighboring tissue or metastasize. Compared to malignant (cancerous) tumors, benign tumors generally have a slower growth rate. Benign tumors have relatively well differentiated cells. They are often surrounded by an outer surface or stay contained within the epithelium. Common examples of benign tumors include moles and uterine fibroids.

<span class="mw-page-title-main">Protein kinase B</span> Set of three serine threonine-specific protein kinases

Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

<span class="mw-page-title-main">Hamartoma</span> Tumour-like overgrowth due to a systemic genetic condition

A hamartoma is a mostly benign, local malformation of cells that resembles a neoplasm of local tissue but is usually due to an overgrowth of multiple aberrant cells, with a basis in a systemic genetic condition, rather than a growth descended from a single mutated cell (monoclonality), as would typically define a benign neoplasm/tumor. Despite this, many hamartomas are found to have clonal chromosomal aberrations that are acquired through somatic mutations, and on this basis the term hamartoma is sometimes considered synonymous with neoplasm. Hamartomas are by definition benign, slow-growing or self-limiting, though the underlying condition may still predispose the individual towards malignancies.

<span class="mw-page-title-main">Cowden syndrome</span> Medical condition

Cowden syndrome is an autosomal dominant inherited condition characterized by benign overgrowths called hamartomas as well as an increased lifetime risk of breast, thyroid, uterine, and other cancers. It is often underdiagnosed due to variability in disease presentation, but 99% of patients report mucocutaneous symptoms by age 20–29. Despite some considering it a primarily dermatologic condition, Cowden's syndrome is a multi-system disorder that also includes neurodevelopmental disorders such as macrocephaly.

<i>PTEN</i> (gene) Tumor suppressor gene

Phosphatase and tensin homolog (PTEN) is a phosphatase in humans and is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers, specifically glioblastoma, lung cancer, breast cancer, and prostate cancer. Genes corresponding to PTEN (orthologs) have been identified in most mammals for which complete genome data are available.

<span class="mw-page-title-main">Bannayan–Riley–Ruvalcaba syndrome</span> Medical condition

Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare overgrowth syndrome and hamartomatous disorder with occurrence of multiple subcutaneous lipomas, macrocephaly and hemangiomas. The disease is inherited in an autosomal dominant manner. The disease belongs to a family of hamartomatous polyposis syndromes, which also includes Peutz–Jeghers syndrome, juvenile polyposis and Cowden syndrome. Mutation of the PTEN gene underlies this syndrome, as well as Cowden syndrome, Proteus syndrome, and Proteus-like syndrome, these four syndromes are referred to as PTEN Hamartoma-Tumor Syndromes.

<span class="mw-page-title-main">Simpson–Golabi–Behmel syndrome</span> Congenital disorder

Simpson–Golabi–Behmel syndrome (SGBS) is a rare inherited congenital disorder that can cause craniofacial, skeletal, vascular, cardiac, and renal abnormalities. There is a high prevalence of cancer associated in those with SGBS which includes wilms tumors, neuroblastoma, tumors of the adrenal gland, liver, lungs and abdominal organs. The syndrome is inherited in an X-linked recessive manner. Females that possess one copy of the mutation are considered to be carriers of the syndrome but may still express varying degrees of the phenotype, suffering mild to severe malady. Males experience a higher likelihood of fetal death.

<span class="mw-page-title-main">Papillary hidradenoma</span> Medical condition

A papillary hidradenoma, also termed hidradenoma papilliferum or mammary-like gland adenoma of the vulva, is a rare, but nonetheless most common benign tumor that occurs in and between anal and genital regions of females. These hidradenomas are sharply circumscribed, nodular tumors that usually develop in women's anogenital area but uncommonly occur in other sites in women and men. Papillary hidradenomas that develop outside of the anogenital region are termed ecctopic papillary hidradenomas or ectopic hidradenoma papilliferums.

<span class="mw-page-title-main">Glypican</span>

Glypicans constitute one of the two major families of heparan sulfate proteoglycans, with the other major family being syndecans. Six glypicans have been identified in mammals, and are referred to as GPC1 through GPC6. In Drosophila two glypicans have been identified, and these are referred to as dally and dally-like. One glypican has been identified in C. elegans. Glypicans seem to play a vital role in developmental morphogenesis, and have been suggested as regulators for the Wnt and Hedgehog cell signaling pathways. They have additionally been suggested as regulators for fibroblast growth factor and bone morphogenic protein signaling.

<span class="mw-page-title-main">AKT1</span> Protein-coding gene in the species Homo sapiens

RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 protein domains. It is commonly referred to as PKB, or by both names as "Akt/PKB".

<span class="mw-page-title-main">Glypican 3</span> Protein-coding gene in the species Homo sapiens

Glypican-3 is a protein that, in humans, is encoded by the GPC3 gene. The GPC3 gene is located on human X chromosome (Xq26) where the most common gene encodes a 70-kDa core protein with 580 amino acids. Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).

<span class="mw-page-title-main">Lhermitte–Duclos disease</span> Medical condition

Lhermitte–Duclos disease (LDD), also called dysplastic gangliocytoma of the cerebellum (DGC), is a rare, slowly growing tumor of the cerebellum, a gangliocytoma sometimes considered to be a hamartoma, characterized by diffuse hypertrophy of the granular layer of the cerebellum. It is often associated with Cowden syndrome. It was described by Jacques Jean Lhermitte and P. Duclos in 1920.

Overgrowth syndromes in children constitute a group of rare disorders that are characterised by tissue hypertrophy. Individual overgrowth syndromes have been shown to overlap with regard to clinical and radiologic features. The details of the genetic bases of these syndromes are unfolding. Any of the three embryonic tissue layers may be involved. The syndromes may manifest in localized or generalized tissue overgrowth. Latitudinal and longitudinal growth may be affected. Nevertheless, the musculoskeletal features are central to the diagnosis of some syndromes such as Proteus syndrome.

<span class="mw-page-title-main">PI3K/AKT/mTOR pathway</span> Cell cycle regulation pathway

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and calmodulin. Both leptin and insulin recruit PI3K signalling for metabolic regulation. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9.

<span class="mw-page-title-main">Proteus-like syndrome</span> Medical condition

Proteus-like syndrome (PLS) is a condition similar to Proteus syndrome, but with an uncertain cause. It's characterized by skeletal and hamartous overgrowth of multiple tissues, nevi in cerebriform connective tissue, blood vessel malformations and linear epidermal nevi.

<span class="mw-page-title-main">Macrocephaly-capillary malformation</span> Medical condition

Macrocephaly-capillary malformation (M-CM) is a multiple malformation syndrome causing abnormal body and head overgrowth and cutaneous, vascular, neurologic, and limb abnormalities. Though not every patient has all features, commonly found signs include macrocephaly, congenital macrosomia, extensive cutaneous capillary malformation, body asymmetry, polydactyly or syndactyly of the hands and feet, lax joints, doughy skin, variable developmental delay and other neurologic problems such as seizures and low muscle tone.

<span class="mw-page-title-main">CLOVES syndrome</span> Medical condition

CLOVES syndrome is a rare overgrowth syndrome with complex vascular anomalies. CLOVES syndrome affects people with various symptoms, ranging from mild fatty soft-tissue tumors to vascular malformations encompassing the spine or internal organs.

<span class="mw-page-title-main">Facial infiltrating lipomatosis</span> Medical condition

Facial infiltrating lipomatosis (FIL), also referred to as congenital infiltrating lipomatosis of the face or facial infused lipomatosis, is an ultra-rare craniofacial overgrowth condition caused by a genetic mutation of the PIK3CA gene. The condition is a part of the PIK3CA related overgrowth spectrum (PROS). The disease is congenital and non-hereditary. First described by Slavin and colleagues in 1983.

Papillomatosis of the breast (PB) is a rare, benign, epitheliosis-like lesion, i.e. an overgrowth of the cells lining the ducts of glands that resembles a papilla or nipple-like nodule/tumor. PB tumors develop in the apocrine glands of the breast. PB is also termed juvenile papillomatosis because of its frequent occurrence in younger women and Swiss cheese disease because of its microscopic appearance. Rarely, PB has also been diagnosed in very young, adolescent, and adult males.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term for rare syndromes characterized by malformations and tissue overgrowth caused by somatic mutations in PIK3CA gene. In PROS diseases individuals malformations are seen in several different tissues such as skin, vasculature, bones, fat and brain tissue depending on the specific disease.

References

  1. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 554. ISBN   978-0-7216-2921-6.
  2. ↑ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN   0-07-138076-0.
  3. 1 2 3 4 El-Sobky, Tamer Ahmed; Elsayed, Solaf M.; El Mikkawy, Dalia M.E. (2015). "Orthopaedic manifestations of Proteus syndrome in a child with literature update". Bone Reports. 3: 104–108. doi:10.1016/j.bonr.2015.09.004. PMC   5365241 . PMID   28377973.
  4. ↑ Jamis-Dow CA, Turner J, Biesecker LG, Choyke PL (2004). "Radiologic manifestations of Proteus syndrome". Radiographics. 24 (4): 1051–68. doi: 10.1148/rg.244035726 . PMID   15256628.
  5. 1 2 Woman's 11-stone legs may be lost at BBC
  6. ↑ Temtamy SA, Rogers JG (December 1976). "Macrodactyly, hemihypertrophy, and connective tissue nevi: Report of a new syndrome and review of the literature". The Journal of Pediatrics. 89 (6): 924–927. doi:10.1016/S0022-3476(76)80597-5. PMID   993918.
  7. ↑ Opitz JM, Jorde LB (July 27, 2011). "Hamartoma Syndromes, Exome Sequencing, and a Protean Puzzle". The New England Journal of Medicine. 365 (7): 661–3. doi:10.1056/NEJMe1107384. PMID   21793737.
  8. ↑ Cohen MM, Hayden PW (1979). "A newly recognized hamartomatous syndrome". Birth Defects Orig. Artic. Ser. 15 (5B): 291–6. PMID   118782.
  9. ↑ Turner JT, Cohen MM, Biesecker LG (Oct 1, 2004). "Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases". American Journal of Medical Genetics. 130A (2): 111–122. doi:10.1002/ajmg.a.30327. PMID   15372514. S2CID   41588085.
  10. ↑ Bastos, Halisson; da Silva, Paula Fabiana Sobral; de Albuquerque, Marco Antônio Veloso; Mattos, Adriana; Riesgo, Rudimar Santos; Ohlweiler, Lygia; Winckler, Maria Isabel Bragatti; Bragatti, José Augusto; Duarte, Rodrigo Dias; Zandoná, Denise Isabel (June 2008). "Proteus syndrome associated with hemimegalencephaly and Ohtahara syndrome: Report of two cases". Seizure. 17 (4): 378–382. doi: 10.1016/j.seizure.2007.11.001 . PMID   18082431. S2CID   13492116.
  11. 1 2 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 (Aug 18, 2011). "A mosaic activating mutation in AKT1 associated with the Proteus syndrome". N Engl J Med. 365 (7): 611–9. doi:10.1056/NEJMoa1104017. PMC   3170413 . PMID   21793738.
  12. ↑ Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ (2002). "Germline mutation of the tumour suppressor PTEN in Proteus syndrome". J. Med. Genet. 39 (12): 937–40. doi:10.1136/jmg.39.12.937. PMC   1757209 . PMID   12471211.
  13. ↑ Cardoso MT, de Carvalho TB, Casulari LA, Ferrari I (2003). "Proteus syndrome and somatic mosaicism of the chromosome 16". Panminerva Medica. 45 (4): 267–71. PMID   15206168.
  14. ↑ Thiffault I, Schwartz CE, Der Kaloustian V, Foulkes WD (October 2004). "Mutation analysis of the tumor suppressor PTEN and the glypican 3 (GPC3) gene in patients diagnosed with Proteus syndrome". Am. J. Med. Genet. A. 130A (2): 123–7. doi:10.1002/ajmg.a.30335. PMID   15372512. S2CID   32014732.
  15. ↑ "Entrez Gene: GPC3 glypican 3".
  16. ↑ Abdulhady, H; El-Sobky, TA; Elsayed, NS; Sakr, HM (11 June 2018). "Clinical and imaging features of pedal macrodystrophia lipomatosa in two children with differential diagnosis review". Journal of Musculoskeletal Surgery and Research. 2 (3): 130. doi: 10.4103/jmsr.jmsr_8_18 . S2CID   80970016.
  17. ↑ Friedman, JM (11 January 2018). Neurofibromatosis 1. University of Washington, Seattle. PMID   20301288 . Retrieved 30 April 2018.{{cite book}}: |work= ignored (help)
  18. ↑ Sung, HM; Chung, HY; Lee, SJ; et, al (2015). "Clinical experience of the Klippel-Trenaunay syndrome". Arch Plast Surg. 42 (5): 552–8. doi:10.5999/aps.2015.42.5.552. PMC   4579165 . PMID   26430625.
  19. ↑ Nguyen, TA; Krakowski, AC; Naheedy, JH; Kruk, PG; Friedlander, SF (2015). "Imaging Pediatric Vascular Lesions". Clin Aesthet Dermatol. 8 (12): 27–41. PMC   4689509 . PMID   26705446.
  20. ↑ Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM, Viljoen DL, Cohen MM (1999). "Proteus syndrome: differential diagnosis, and patient evaluation". Am J Med Genet. 84 (5): 389–95. doi:10.1002/(SICI)1096-8628(19990611)84:5<389::AID-AJMG1>3.0.CO;2-O. PMID   10360391.
  21. ↑ Marsh DJ, Trahair TN, Martin JL, Chee WY, Walker J, Kirk EP, Baxter RC, Marshall GM (April 22, 2008). "Rapamycin treatment for a child with germline PTEN mutation". Nature Clinical Practice Oncology. 5 (6): 357–361. doi:10.1038/ncponc1112. PMID   18431376. S2CID   2870300.
  22. ↑ Cohen MM, Turner JT, Biesecker LG (November 1, 2003). "Proteus Syndrome: Misdiagnosis with PTEN Mutations". American Journal of Medical Genetics. 122A (4): 323–324. doi:10.1002/ajmg.a.20474. PMID   14518070. S2CID   26811086.
  23. ↑ Lindhurst, Marjorie J.; Yourick, Miranda R.; Yu, Yi; Savage, Ronald E.; Ferrari, Dora; Biesecker, Leslie G. (2015-12-11). "Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome". Scientific Reports. 5: 17162. Bibcode:2015NatSR...517162L. doi:10.1038/srep17162. ISSN   2045-2322. PMC   4675973 . PMID   26657992.
  24. ↑ "Dose Finding Trial of ARQ 092 in Children and Adults With Proteus Syndrome". ClinicalTrials.gov . National Human Genome Research Institute (NHGRI). Oct 31, 2015. NCT02594215.
  25. ↑ Lindhurst, Marjorie J.; Yourick, Miranda R.; Yu, Yi; Savage, Ronald E.; Ferrari, Dora; Biesecker, Leslie G. (2015). "Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome". Scientific Reports. 5: 17162. Bibcode:2015NatSR...517162L. doi:10.1038/srep17162. PMC   4675973 . PMID   26657992. 17162.
  26. ↑ Tibbles JA, Cohen MM (1986). "The Proteus syndrome: the Elephant Man diagnosed". Br Med J (Clin Res Ed). 293 (6548): 683–5. doi:10.1136/bmj.293.6548.683. PMC   1341524 . PMID   3092979.
  27. ↑ – Spiring P (2001). "The Improbable Elephant Man". Biologist (London) 48(3) 104., Article in The Sunday Telegraph, – BBC News, [http://www.eurekalert.org/pub_releases/2003-07/dhc-ada071803.php – Eurekalert!, Article in The Daily Telegraph
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