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Proteus Syndrome

  • Author: Megan Barry, MD; Chief Editor: Luis O Rohena, MD  more...
 
Updated: Feb 04, 2016
 

Background

Proteus syndrome is a rare condition that can be loosely categorized as a hamartomatous disorder. It is a complex disorder with multisystem involvement and great clinical variability. Once thought to have neurofibromatosis, Joseph Merrick (also known as "the elephant man" and studied by Treves in the 1800s) is now, in retrospect, thought by clinical experts to actually have had Proteus syndrome.

This condition is characterized by various cutaneous and subcutaneous lesions, including vascular malformations, lipomas, hyperpigmentation, and several types of nevi. Cerebriform nevi are thought to be characteristic of the disorder. Progressive, asymmetrical limb overgrowth is pathognomonic, and patients have an unusual body habitus. Because cutaneous lesions tend to appear over time, the diagnosis may be delayed until late infancy, childhood, or even adulthood. Orthopedic complications often pose the most challenging medical problems, although vascular complications also contribute to overall morbidity. Severe disfigurement and social stigmatization are additional challenges that must be addressed.

Examples of various malformations and physical symptoms in Proteus syndrome are shown in the images below.

Macroglossia and hemifacial overgrowth associated Macroglossia and hemifacial overgrowth associated with hyperpigmentation.
Port wine stain on the trunk with small epidermal Port wine stain on the trunk with small epidermal nevus.
Macrodactyly with splaying of toes after toe reduc Macrodactyly with splaying of toes after toe reduction procedure.
Ear enlargement associated with cutaneous hyperpig Ear enlargement associated with cutaneous hyperpigmentation and hemifacial macrosomia.
Scoliosis with scar resulting from prior surgical Scoliosis with scar resulting from prior surgical resection of a large subcutaneous lipoma.
Evidence of proximal muscle wasting of the upper e Evidence of proximal muscle wasting of the upper extremities.
Hypertrophy of the thighs and calves. Hypertrophy of the thighs and calves.
Profile demonstrating retrognathia. Profile demonstrating retrognathia.

Patient education

Patients and their families can be referred to the Proteus Syndrome Foundation.

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Pathophysiology

A study by Lindhurst et al demonstrated that a somatic mutation in the AKT1 gene is causative for Proteus syndrome. The researchers performed exome sequencing of DNA from biopsies of affected tissues and compared this with DNA from normal tissues in these patients. AKT1 mutations were found in the affected tissues but not in the normal tissues.[1]

Proteus syndrome is caused by a somatic mutation rather than a germline one, meaning that only cells descended from the affected cell will display symptoms. This means that individuals with mutations later in development will generally have a less severe phenotype. The random nature of the somatic mutation explains the variability of presentation in patients with Proteus syndrome.

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Epidemiology

Frequency

International

Proteus syndrome is believed to be exceedingly rare, with less than 100 confirmed affected individuals reported worldwide.[2] This suggests that prevalence is less than 1 case per 1,000,000 live births. However, this condition is also often misdiagnosed.

Mortality/Morbidity

The following is noted in patients with Proteus syndrome:

  • Hemihyperplasia (asymmetrical overgrowth of the head, face, and digits) and soft tissue overgrowth are among the more significant medical complications. Some scientists have suggested that the bony overgrowth in Proteus syndrome is secondary to mesenchymal changes beginning during embryonic life, with formation of extra-large cartilage precursors. [3]
  • Soft tissue and bone overgrowth may slow after puberty.
  • Absent or decreased subcutaneous fat (lipohypoplasia) of the trunk or limbs may also be seen in patients with Proteus syndrome, contributing to the gracile appearance and well-recognized body habitus in severely affected individuals. [4]
  • Facial involvement may be associated with not only asymmetric mandibular growth, maxillary growth, or both, but also with premature dental eruption and idiopathic root resorption.
  • Eye findings may include strabismus as well as epibulbar dermoids or cysts; ocular findings are reported in more than 40% of affected individuals. [5]
  • Scoliosis or kyphoscoliosis may be severe and progressive, leading to respiratory compromise in some cases. Neck and trunk elongation with upper body wasting and leg muscle hypertrophy may contribute to overall abnormal body habitus and concomitant functional abnormalities.
  • Although less common, kidney or bladder problems may be identified in slightly less than 10% of affected individuals. Genitourinary problems described include hydronephrosis, renal cysts, asymmetry of the kidneys or bladder, and nephrogenic diabetes. [5]
  • Cutaneous and subcutaneous lesions can create significant cosmetic and functional problems. Benign growths, such as lipomas, connective tissue nevi, epidermal nevi, and vascular malformations, may be locally invasive and contribute greatly to morbidity.
  • Individuals with a larger number of skin manifestations are also more likely to have more severe involvement of other tissues.
  • Whereas ovarian cystadenomas are frequent enough in women with Proteus syndrome to be included as part of the diagnostic criteria, other fairly rare neoplasms have been identified in affected individuals. Meningiomas, various testicular tumors, and parotid monomorphic adenomas have been described. [2] More recently, a patient with Proteus syndrome was shown to have multiple spinal cord meningiomas. [6]
  • Cystic lung malformations are reported in slightly less than 10% of patients and are especially common in younger female patients. [5]
  • Intrathoracic or intra-abdominal lipomas occur and should be screened for because of the particularly aggressive nature of these lesions. [2, 7]
  • Increased risk for thrombotic events such as deep vein thrombosis (DVT) or pulmonary embolism (PE) contribute to the overall morbidity and mortality, even in young children, and is reported to be one of the most common causes of death in affected individuals. [8]
  • Learning disabilities or mental retardation occurs in a subset of patients. A particular facial phenotype often is associated with mental impairment with or without CNS malformations and seizures. Infantile seizures, specifically Ohtahara syndrome, have been described in several patients with Proteus syndrome in association with hemimegalencephaly. [9]

Race

Race-, sex-, and age-related demographics

No racial or ethnic differences in disease occurrence are apparent. Classically, males have been thought to be more commonly affected than females, but new studies with genetically confirmed cases have not yet been published.[5]

The genetic mutation that causes Proteus Syndrome is a somatic mutation that occurs after conception and is propagated in one or more subsets of embryonic cells. The classic progressive, asymmetrical overgrowth may not be obvious at birth, which can delay diagnosis.

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Contributor Information and Disclosures
Author

Megan Barry, MD Resident Physician, Department of Dermatology, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

William G Wilson, MD Genentech Professor of Pediatrics, Associate Chair for Education, Department of Pediatrics, University of Virginia School of Medicine; Chief, Division of Medical Genetics, Department of Pediatrics, University of Virginia Health System

William G Wilson, MD is a member of the following medical societies: Academic Pediatric Association, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Medical Society of Virginia, Society for Inherited Metabolic Disorders, Council on Medical Student Education in Pediatrics, Society for the Study of Inborn Errors of Metabolism

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Elaine H Zackai, MD Professor of Pediatrics, Professor of Obstetrics and Gynecology, Professor of Pediatrics in Human Genetics, University of Pennsylvania School of Medicine; Director, Clinical Genetics Center, University of Pennsylvania; Senior Physician and Director of Clinical Genetics, The Children's Hospital of Philadelphia

Elaine H Zackai, MD is a member of the following medical societies: American Cleft Palate-Craniofacial Association, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Acknowledgements

The authors of editors of Medscape Drugs & Diseases wish to thank Beth A Pletcher, MD, Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey, for her previous contributions to this article.

References
  1. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011 Aug 18. 365(7):611-9. [Medline]. [Full Text].

  2. Cohen MM Jr. Proteus syndrome: an update. Am J Med Genet C Semin Med Genet. 2005 Aug 15. 137C(1):38-52. [Medline].

  3. Pazzaglia UE, Beluffi G, Bonaspetti G, et al. Bone malformations in Proteus syndrome: an analysis of bone structural changes and their evolution during growth. Pediatr Radiol. 2007 Aug. 37(8):829-35. [Medline].

  4. Happle R. Lipomatosis and partial lipohypoplasia in Proteus syndrome: a clinical clue for twin spotting?. Am J Med Genet. 1995 Apr 10. 56(3):332-3. [Medline].

  5. 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 Oct 1. 130A(2):111-22. [Medline].

  6. 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. [Medline].

  7. Furquim I, Honjo R, Bae R, Andrade W, Santos M, Tannuri U. Proteus syndrome: report of a case with recurrent abdominal lipomatosis. J Pediatr Surg. 2009 Apr. 44(4):E1-3. [Medline].

  8. Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet. 2006 Nov. 14(11):1151-7. [Medline].

  9. Bastos H, da Silva PF, de Albuquerque MA, Mattos A, Riesgo RS, Ohlweiler L. Proteus syndrome associated with hemimegalencephaly and Ohtahara syndrome: report of two cases. Seizure. 2008 Jun. 17(4):378-82. [Medline].

  10. Lacerda Lda S, Alves UD, Zanier JF, et al. Differential diagnoses of overgrowth syndromes: the most important clinical and radiological disease manifestations. Radiol Res Pract. 2014. 2014:947451. [Medline]. [Full Text].

  11. Wieland I, Tinschert S, Zenker M. High-level somatic mosaicism of AKT1 c.49G>A mutation in skin scrapings from epidermal nevi enables non-invasive molecular diagnosis in patients with Proteus syndrome. Am J Med Genet A. 2013 Apr. 161A(4):889-91. [Medline].

  12. Elsayes KM, Menias CO, Dillman JR, et al. Vascular malformation and hemangiomatosis syndromes: spectrum of imaging manifestations. AJR Am J Roentgenol. 2008 May. 190(5):1291-9. [Medline].

  13. Irion KL, Hocchegger B, Marchiori E, et al. Proteus syndrome: high-resolution CT and CT pulmonary densitovolumetry findings. J Thorac Imaging. 2009 Feb. 24(1):45-8. [Medline].

  14. Hoey SE, Eastwood D, Monsell F, Kangesu L, Harper JI, Sebire NJ. Histopathological features of Proteus syndrome. Clin Exp Dermatol. 2008 May. 33(3):234-8. [Medline].

  15. Sugarman JL. Epidermal nevus syndromes. Semin Cutan Med Surg. 2007 Dec. 26(4):221-30. [Medline].

  16. Buis J, Enjolras O, Soupre V, Roman S, Vazquez MP, Picard A. 980-nm laser diode and treatment of subcutaneous mass in Proteus-like syndrome. J Eur Acad Dermatol Venereol. 2010 Jan. 24(1):109-11. [Medline].

  17. Turner J, Biesecker B, Leib J, et al. Parenting children with Proteus syndrome: experiences with, and adaptation to, courtesy stigma. Am J Med Genet A. 2007 Sep 15. 143A(18):2089-97. [Medline].

  18. Lindhurst MJ, Yourick MR, Yu Y, Savage RE, Ferrari D, Biesecker LG. Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome. Sci Rep. 2015 Dec 11. 5:17162. [Medline]. [Full Text].

  19. Biesecker LG, Happle R, Mulliken JB, et al. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999 Jun 11. 84(5):389-95. [Medline].

  20. Brockmann K, Happle R, Oeffner F, König A. Monozygotic twins discordant for Proteus syndrome. Am J Med Genet A. 2008 Aug 15. 146A(16):2122-5. [Medline].

  21. Cohen MM Jr. Mental deficiency, alterations in performance, and CNS abnormalities in overgrowth syndromes. Am J Med Genet C Semin Med Genet. 2003 Feb 15. 117C(1):49-56. [Medline].

  22. Franc-Guimond J, Houle AM, Barrieras D. The Proteus syndrome associated with life threatening hematuria. J Urol. 2003 Dec. 170(6 Pt 1):2418-9. [Medline].

  23. Hoeger PH, Martinez A, Maerker J, et al. Vascular anomalies in Proteus syndrome. Clin Exp Dermatol. 2004 May. 29(3):222-30. [Medline].

  24. Nguyen D, Turner JT, Olsen C, et al. Cutaneous manifestations of Proteus syndrome: correlations with general clinical severity. Arch Dermatol. 2004 Aug. 140(8):947-53. [Medline].

  25. Sigaudy S, Fredouille C, Gambarelli D, et al. Prenatal ultrasonographic findings in Proteus syndrome. Prenat Diagn. 1998 Oct. 18(10):1091-4. [Medline].

  26. Twede JV, Turner JT, Biesecker LG, et al. Evolution of skin lesions in Proteus syndrome. J Am Acad Dermatol. 2005 May. 52(5):834-8. [Medline].

 
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Macroglossia and hemifacial overgrowth associated with hyperpigmentation.
Port wine stain on the trunk with small epidermal nevus.
Macrodactyly with splaying of toes after toe reduction procedure.
Ear enlargement associated with cutaneous hyperpigmentation and hemifacial macrosomia.
Scoliosis with scar resulting from prior surgical resection of a large subcutaneous lipoma.
Evidence of proximal muscle wasting of the upper extremities.
Hypertrophy of the thighs and calves.
Profile demonstrating retrognathia.
 
 
 
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