Proteus syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Synonyms and keywords:PS

Overview

Proteus syndrome is an exceedingly rare disorder which falls under the category of hamartomatous disorder. Proteus syndrome is a very complex disorder which involves multiple organ systems in the body. In The United States of America in order to say a condition is a rare disease it should affect fewer than 200,000 people. Rare diseases also called as orphan diseases. Orphan Drug Act was passed on 1983 by congress for the rare diseases. Today an average of 25-30 million americans have been reported with rare diseases. The number of people with individual rare disease may be less but overall the number of people with rare diseases are large in number.

Historical Perspective

Discovery

• Proteus syndrome was first discovered by Frederick Treves, a British surgeon, in 1884.
• Frederick Treves showed the proteus syndrome on Joseph Merrick, who used to be called as the famous Elephant Man, to the Pathological Society of London.

Classification

• Proteus syndrome is one of the syndromes which falls under PTEN hamartoma tumor syndromes (PHTS). PHTS are due to germline mutations in PTEN gene.
• PTEN hamartoma tumor syndromes (PHTS) which include the following:
  • Proteus syndrome
  • Cowden syndrome
  • Bannayan-Riley-Ruvalcaba syndrome
  • Lhermitte-Duclos disease
  • Autism spectrum disorders
  • https://selly.gg/@brandon122

Pathophysiology

• Genes involved in the pathogenesis of proteus syndrome include: Mutations in the AKT1 and PTEN gene leads to oncogenesis
• Phosphatase and tensin homolog (PTEN) gene plays an important role in the following:
  • Phosphoinositide-3-kinase (PI3K)-AKT pathway and
  • Rapamycin (mTOR) signaling pathways
• PTEN track backs to 10q23 which encodes and plays a significant role in the following:
  • Effects G1 cell cycle arrest and apoptosis
  • Cellular proliferation and
  • Migration
  • Apoptosis

Causes

• The most common cause of proteus syndrome is a mutation which has mosaic variant in a gene called AKT1 and phosphatase and tensin homolog (PTEN) mutations in some patients.

Differentiating Proteus syndrome from other Diseases

Proteus syndrome must be differentiated from the following rare disorders:

• Encephalocraniocutaneous lipomatosis
• Hemihyperplasia lipomatosis syndrome
• Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) syndrome
• Klippel-Trenaunay-Weber syndrome
• Ollier disease
• Macrodactyly
• Maffucci syndrome
• Neurofibromatosis type 1
• Bannayan-Riley-Ruvalcaba syndrome
• Cowden syndrome
• Lhermitte-Duclos disease

Epidemiology and Demographics

Incidence

• The incidence of proteus syndrome is approximately 1 per 1,000,000-1:10,000,000 individuals worldwide.
• There are few than 100 cases of proteus syndrome have been reported worldwide.

Race

• There is no racial predilection to proteus syndrome.

Gender

• Males are more commonly affected by proteus syndrome than females.

Risk Factors

• There are no established risk factors for proteus syndrome.

Screening

• There is insufficient evidence to recommend routine screening for proteus syndrome.

Natural History, Complications, and Prognosis

Natural History

• The symptoms of proteus syndrome usually develop in the first decade of life, most commonly begin in toddler period, and start with symptoms such as segmental or patchy overgrowth which effects skeleton, skin, adipose, and central nervous system(CNS).

Complications

• Common complications of proteus syndrome include:
  • Hemihyperplasia
  • Bullous pulmonary disease
  • Hemimegalencephaly
  • Scoliosis
  • Macrocephaly
  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE)
  • Strabismus
  • Learning disabilities or mental retardation

Prognosis

• Prognosis is generally excellent in mildly affected children with proteus syndrome.
• Depending on the location of the gene and the degree of the overgrowth at the time of diagnosis, the prognosis may vary.

Diagnosis

Diagnostic study of choice

• Punch biopsy of an affected area of skin and identification of AKT1 gene at chromosome 14q32.33, gene testing is the gold standard test for the diagnosis of proteus syndrome.
• On AKT1 gene testing methods used to find the mutation are targeted analysis, sequence analysis, deletion/duplication analysis, other non-sequencing-based tests, exome sequencing and genome sequencing.

X-Ray Findings

• An x-ray may be helpful in the diagnosis of proteus syndrome. Findings on an x-ray suggestive of proteus syndrome include:
  • Scoliosis or kyphosis
  • Macrodactyly(Large digits)
  • Periarticular bony overgrowth
  • Soft tissue overgrowth in tibiocalcaneal joint

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    X-ray in Proteus Syndrome- Asymmetric and disproportionate over growth of right hand fingers with macrodactyly. Case courtesy -Suresh Kumar Angurana Et Al

Case Studies

Case #1