Genetics of Proteus Syndrome Clinical Presentation

  • Author: Beth A Pletcher, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 18, 2010
 

History

In cases of suspected Proteus syndrome, clinicians must carefully use the standard diagnostic criteria (as listed below) to preclude misdiagnosis. A literature review suggests that less than half of reported cases have clearly defined Proteus syndrome.[4] This has led to speculation that a subset of patients with presumed Proteus syndrome have PTEN gene mutations, when, in fact, these individuals do not have enough diagnostic features warrant a diagnosis of Proteus syndrome.[3] The following are the 3 general criteria necessary for clinical diagnosis without regard to specific clinical features:

  • Lesions follow a mosaic distribution or pattern.
  • Problems follow a progressive course.
  • The disorder appears to be sporadic (ie, not inherited).

Diagnostic confirmation also requires the presence of manifestations listed under the following categories:

  • Category A (1 required) - Connective tissue nevus
  • Category B (2 required)
    • Epidermal nevus
    • Disproportionate overgrowth of one or more of the following: limbs, digits, cranium, vertebrae, external auditory meatus, spleen, or thymus
    • Bilateral ovarian cystadenomas or a parotid monomorphic adenoma in a patient younger than 20 years
  • Category C (all 3 required)
    • Lipomas or focal atrophy of adipose tissue
    • Capillary, venous, or lymphatic malformation
    • Facial features including dolichocephaly, a long face, down-slanting palpebrae, ptosis, depressed nasal bridge, anteverted nares, and open mouth position while at rest
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Physical

  • When present at birth, asymmetric limb, digital, or cranial overgrowth may be a major diagnostic finding.
  • Digital, limb, or cranial overgrowth usually involves both soft tissue and bone.
  • Cranial or external auditory canal hyperostosis may be seen.
  • Scoliosis associated with disproportionate vertebral growth is common.
  • The combination of disproportionate overgrowth and focal atrophy can lead to a unique habitus characterized by wasting of upper arm muscles, an elongated thorax, an extremely gracile neck, and muscular hypertrophy of the thighs.
  • Cystic lung malformations that lead to cystic pulmonary emphysema and restrictive lung disease secondary to severe scoliosis are relatively common. Recurrent pneumonias, shortness of breath, or reduced exercise tolerance may point to significant respiratory compromise.
  • Organomegaly is less common but can also occur with splenomegaly or occasional thymus enlargement.
  • The 6 most common skin findings include (from most to least frequent) lipomas, vascular malformations, connective tissue nevi, epidermal nevi, partial lipohypoplasia, and patchy dermal hypoplasia.
    • Connective tissue nevi are virtually pathognomonic and typically have a cerebriform contour. They often occur on the soles of the feet but can also be found on other areas.
    • Epidermal nevi tend to be the flat, soft variety.
    • Lipomas may be well demarcated or locally invasive with large intra-abdominal or intrathoracic lesions presenting serious medical concerns.
    • Vascular lesions may include capillaries, lymphatics, venules, or combinations of these. They tend to grow gradually over time and, unlike the more common capillary hemangiomas seen in the general population, rarely regress. Port wine stains or patchy hyperpigmentation may also be seen.
  • Learning difficulties or mental retardation are seen in about 1 in 5 individuals with Proteus syndrome.
  • Facial features that often coincide with poor mental development include a prominent occiput, ptosis with or without down-slanting palpebrae, upturned nose, and a long, narrow face.
  • Seizures are reported in more than 10% of affected individuals.
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Contributor Information and Disclosures
Author

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

Beth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

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 American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Robert Anthony Saul, MD  Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center

Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives

Disclosure: Nothing to disclose.

Daniel Rauch, MD, FAAP  Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine

Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine

Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Cohen MM Jr. "Proteus syndrome". In: Cohen MM Jr., Neri G, Weksberg R eds. Overgrowth Syndromes, Chapter 9. 170(6 Pt 1). New York: Oxford University Press; 2002:pp75-110.

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

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

  4. 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. Oct 1 2004;130A(2):111-22. [Medline].

  5. 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. Aug 2007;37(8):829-35. [Medline].

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

  7. Asahina A, Fujita H, Omori T, Kai H, Yamamoto M, Mii K. Proteus syndrome complicated by multiple spinal meningiomas. Clin Exp Dermatol. Nov 2008;33(6):729-32. [Medline].

  8. 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. Apr 2009;44(4):E1-3. [Medline].

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

  10. 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. Jun 2008;17(4):378-82. [Medline].

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

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

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

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

  15. 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. Jan 2010;24(1):109-11. [Medline].

  16. 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. Sep 15 2007;143A(18):2089-97. [Medline].

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

  18. Becktor KB, Becktor JP, Karnes PS, Keller EE. Craniofacial and dental manifestations of Proteus syndrome: a case report. Cleft Palate Craniofac J. Mar 2002;39(2):233-45. [Medline].

  19. Biesecker LG, Peters KF, Darling TN, et al. Clinical differentiation between Proteus syndrome and hemihyperplasia: description of a distinct form of hemihyperplasia. Am J Med Genet. Oct 2 1998;79(4):311-8. [Medline].

  20. Cohen MM Jr. Further diagnostic thoughts about the Elephant Man. Am J Med Genet. Apr 1988;29(4):777-82. [Medline].

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

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

  23. Goodship J, Redfearn A, Milligan D, et al. Transmission of Proteus syndrome from father to son?. J Med Genet. Nov 1991;28(11):781-5. [Medline].

  24. Hamm H. Cutaneous mosaicism of lethal mutations. Am J Med Genet. Aug 6 1999;85(4):342-5. [Medline].

  25. Happle R. Elattoproteus syndrome: delineation of an inverse form of Proteus syndrome. Am J Med Genet. May 7 1999;84(1):25-8. [Medline].

  26. Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol. Apr 1987;16(4):899-906. [Medline].

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

  28. Krüger G, Pelz L, Wiedemann HR. Transmission of Proteus syndrome from mother to son?. Am J Med Genet. Jan 1 1993;45(1):117-8. [Medline].

  29. Nazzaro V, Cambiaghi S, Montagnani A, et al. Proteus syndrome. Ultrastructural study of linear verrucous and depigmented nevi. J Am Acad Dermatol. Aug 1991;25(2 Pt 2):377-83. [Medline].

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

  31. Plötz SG, Abeck D, Plotz W, et al. Proteus syndrome with widespread portwine stain naevus. Br J Dermatol. Dec 1998;139(6):1060-3. [Medline].

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

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

  34. Wiedemann HR, Burgio GR, Aldenhoff P, et al. 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. Mar 1983;140(1):5-12. [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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