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Internal Medicine

Proteus syndrome (PS)

Disorder of patchy/mosaic postnatal growth dysregulation (primarily involving overgrowth) of unknown aetiology.


Pathophysiology

Somatic genetic activation mutation of the AKT1 gene 


Clinical features

Disorder primarily manifests as postnatal overgrowth, with irregular, distorting and progressive overgrowth that can include many tissues in a patchy/mosaic pattern.

  • Typically asymmetric and location varies remarkably
  • Commonly involved tissue:
    • Connective tissue and bone
    • Skin
    • Fat
  • Other tissue:
    • Central nervous system & eye
    • Spleen
    • Thymus
    • Colon
    • Other tissues
  • Most cases born without significant asymmetry and asymmetric overgrowth starts in the 6–18 months age range
  • Rapidly progressive growth (rate of overgrowth rapidly becomes disproportionate between body parts)
41431_2006_article_bf5201638_fig1_html
The distinction of overgrowth in a patient with PS (a–c) from that of a patient with hemihyperplasia (d, e). Panel a shows an early CCTN. Note that the appearance of this lesion is distinct from that of wrinkling of normal sole tissue. Panels b and c are from a patient with more advanced PS demonstrates several features of the disorder. Panel b shows distorting overgrowth of the first and fifth digits (arrows) with loss of the normal architecture of the digits. The overgrowth in the patient with PS is associated with calcified tissue around the epiphyses that restricts movement at the affected joints. The overgrowth in the patient with hemihyperplasia (d, e) is described by as ‘ballooning’ overgrowth as it is not associated with distortion. | Biesecker, L. (2006). The challenges of Proteus syndrome: diagnosis and management. European Journal of Human Genetics, 14(11), 1151–1157. https://doi.org/10.1038/sj.ejhg.5201638

Complications

  • Common:
    • Deep venous thrombosis (DVT)
    • Pulmonary embolism
  • affected bones can become unrecognizably distorted.
41431_2006_article_bf5201638_fig2_html
The progressive nature and severity of overgrowth in PS. Panel a shows a teenager with valgus deformity of the knee, fixation of the knee joint due to bony overgrowth surrounding the joint and external rotation of lower leg of more than 90°. Panel b shows the same patient a few years later with continued external rotation of the leg that now exceeds 135° with onset of bowing of the tibia. The surgical correction of such deformities is challenging. | Biesecker, L. (2006). The challenges of Proteus syndrome: diagnosis and management. European Journal of Human Genetics, 14(11), 1151–1157. https://doi.org/10.1038/sj.ejhg.5201638

Diagnosis

Revised PS diagnostic criteria

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A Somatic Activating. (2019) Recurrent Cerebriform Connective Tissue Nevus on the Foot of a Patient With Proteus Syndrome | MDedge Dermatology. Retrieved June 13, 2019, from https://www.mdedge.com/dermatology/article/115831/pediatrics/recurrent-cerebriform-connective-tissue-nevus-foot-patient/page/0/1

Differential diagnosis

  • Fibrolipomatous hamartoma
  • Macrodystrophia lipomatosa (ML)
    • Rare congenital disorder characterized by localised overgrowth of a part of an extremity or less commonly a whole extremity
  • Neurofibromatosis type 1 (NF1)
    • NF1 symptoms include light brown spots on the skin, freckles in the armpit and groin, small bumps within nerves, and scoliosis. NF tumors are generally non-cancerous.
  • Klippel–Trénaunay syndrome or angioosteohypertrophy syndrome or hemangiectatic hypertrophy
    • Rare congenital medical condition in which blood vessels and/or lymph vessels fail to form properly
    • 3 main features:
      • Nevus flammeus
      • Venous and lymphatic malformations
      • Soft-tissue hypertrophy of the affected limb
  • Parkes Weber syndrome (PWS)
    • Extremely rare congenital disorder of the vascular system, named after British dermatologist Frederick Parkes Weber, who first described the syndrome in 1907.
  • Hemangiomas
    • Usually benign tumours derived from blood vessel cells and can occur anywhere on the body, but most commonly appears on the face, scalp, chest or back.
    • M/C form: Infantile hemangioma “strawberry mark”
      • Seen on the skin at birth or in the first weeks of life

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