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Proteus syndrome

Orpha number ORPHA744
Synonym(s) Partial gigantism - nevi - hemihypertrophy - macrocephaly
Prevalence <1 / 1 000 000
Inheritance Not applicable
Age of onset Infancy
ICD-10
  • Q87.3
ICD-O -
OMIM
UMLS
  • C0085261
MeSH
  • D016715
MedDRA -
SNOMED CT
  • 23150001

Summary

Proteus syndrome (PS) is a very rare and complex hamartomatous overgrowth disorder characterized by progressive overgrowth of the skeleton, skin, adipose, and central nervous systems.

Approximately 120 cases of PS have been reported to date. The prevalence is estimated to be less than 1/1,000,000 live births.

Neonates usually appear normal at birth. Onset usually occurs from 6-18 months of age with asymmetric overgrowth seen mainly in the hands or feet. Macrodactyly is the most common presenting symptom, along with hemihypertrophy. Skeletal overgrowth can be severe and rapidly progressive with the development of bizarre, distorting, irregular calcified overgrowth in the tubular bones of the limbs and the skull's vertebral bodies. Cerebriform connective tissue nevi (CCTN) can occur anywhere on the body and usually develop later in childhood. Vascular malformations and linear epidermal nevi occur in the first months of life and generally stabilize with time. Adipose dysregulation and vascular malformations are noted in infancy. Neurological manifestations include intellectual deficit, sinus thrombosis and intracranial lesions. Complications include hemimegencephaly, bullous pulmonary disease, pulmonary embolism (PE) and deep vein thrombosis (DVT). Tumors are mainly benign but rarely malignant tumours (such as papillary adenocarcinoma of the testis, meningioma and cystadenoma of the ovaries) have been reported.

Causal mutations of PS have been reported in two components of the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway: PTEN, which make PS a part of the PTEN Hamartoma Tumor Syndrome (PTHS; see this term) and AKT1. The AKT1 mutation is a somatic mosaic, reported to occur in 1-47% of cases. PTEN mutations have been reported both in the consititutive DNA and as somatic mosaic mutations in PS patients.

Diagnosis is based on a specific set of clinical criteria. The general criteria (mosaic distribution of lesions, sporadic occurrence, progressive course) must be met along with either specific category A criteria (CCTN) or 2 category B criteria (asymmetric disproportionate overgrowth, linear epidermal nevus, specific tumors before the 2nd decade) or 3 category C criteria (vascular malformations, dysregulated adipose tissue, distinct facial phenotype). If these criteria are not met then a patient may be diagnosed with Proteus-like syndrome (see this term). Molecular genetic testing may confirm diagnosis.

Differential diagnoses include Klippel-Trenaunay-Weber syndrome, hemihypertrophy, Ollier disease, macrodactyly, Maffucci syndrome, CLOVE syndrome, neurofibromatosis type 1 and other PHTS disorders (see these terms).

Prenatal testing is not performed as most cases of PS are not inherited.

PS is not inherited in those with a somatic AKT1 de novo mutation so there is no risk to family members. As PTEN mutations are inherited autosomal dominantly genetic counseling is possible. Although theoretically possible, there is no report of patients reproducing.

Treatment requires a multidisciplinary approach. The interventions used to control overgrowth of tubular bones are epiphysiostasis, epiphysiodesis and amputation in extreme cases. Physical and occupational therapy is very important. Custom designed orthotics or footwear may be necessary. Dermatological care along with management of malodor (if present) is needed for those with CCTNs. Lesions should only be surgically removed if malignancy is suspected or if deformity and/or pain are significant. If DVT or PE occurs, anticoagulation guidelines should be followed promptly. Patients should be examined regularly for the presence of tumors, due to predisposition, and if present should follow standard treatment protocols. Psychosocial counseling can be beneficial for patients and their families. Annual physical examination and radiography is also recommended.

Prognosis varies depending on the severity of complications.

Expert reviewer(s)

  • Dr Deborah MARSH

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Detailed information

Summary information
Diagnostic criteria
  • EN (2006,pdf)
Practical genetics
  • EN (2006,pdf)
Clinical genetics review
  • EN (2012)
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