Other names: PROS

PIK3CA-Related Overgrowth Spectrum (PROS) is a spectrum of rare conditions and is characterized by atypical overgrowths and anomalies in blood vessels, the lymphatic system and other tissues. Specific conditions associated with PROS include:

• Klippel-Trenaunay syndrome (KTS) - characterized by overgrowth and vascular malformations.
• CLOVES syndrome - characterized by congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis, and spinal abnormalities.
• Isolated Lymphatic Malformation (ILM) - mass that contains fluid, which often affects the head and neck.
• Megalencephaly-Capillary Malformation (MCAP or M-CM) - characterized by a core set of brain features that include megalencephaly and ventriculomegaly, which may progress to hydrocephalus or cerebellar tonsillar ectopia.
• HemiMegal​Encephaly (HME) - brain enlargement on one side of the brain.
• HemiHyperplasia-Multiple Lipomatosis (HHML) - characterized by moderate abnormalities of asymmetry and overgrowth with multiple subcutaneous lipomata, and static or mildly progressive hemihyperplasia.
• Facial Infiltrating Lipomatosis (FIL) - characterized by hemifacial soft-tissue and skeletal overgrowth, precocious dental development, macrodontia, hemimacroglossia, and mucosal neuromas.
• FibroAdipose Vascular Anomaly (FAVA) - type of vascular malformation characterized by intramuscular venous malformations.
• Macrodactyly - fibrofatty enlargement of a limb or part of a limb.
• Muscular HemiHyperplasia (HH) - overgrowth on one side of the body and may also be referred to as muscular hemihypertrophy.
• FibroAdipose hyperplasia or Overgrowth (FAO) - characterized by segmental and progressive overgrowth of subcutaneous and visceral fibroadipose tissue. It may also be associated with skeletal and muscular overgrowth.
• CLAPO syndrome - characterized by capillary malformation of the lower lip, which is congenital, always present in the midline, symmetrical, and well defined. Other features include lymphatic malformations, which often involve the face and/or neck. Overgrowth may be identified; however, it is not always evident.
• Epidermal nevus - benign skin abnormality caused by an overgrowth of cells that can result in a flat or raised, discolored patch of skin.
• Benign lichenoid keratosis - skin lesion that presents as raised plaque or as a papule.
• Seborrheic keratosis - skin lesion that is often pigmented and appears wart-like or as a smooth papule.

The estimated prevalence of PROS conditions is approximately 14 people per million.

PROS is usually caused by somatic mutations in the PIK3CA gene. These changes typically are only present in some cells or some areas of the body, and are not known to be inherited. Rarely, PROS is caused by a de novo germline mutation, which is present in all cells of the body.

The diagnosis of a PROS disorder may include clinical assessment, imaging, observation of onset timing, and genomic testing of the PIK3CA gene. 

Patients with PROS (PIK3CA-Related Overgrowth Spectrum) can experience disfiguring, function-limiting, and life-threatening effects.

• Abnormal growth can cause:
  • pain
  • reduced mobility
  • scoliosis
  • spinal compression.
• Lymphatic malformations can cause:
  • cellulitis.
• Vascular malformations can cause:
  • internal bleeding
  • blood clots (DVT or PE)
  • varicose veins.
• Other complications include:
  • urinary incontinence
  • abnormal kidneys
  • seizures
  • intellectual disability.

Treatment for a PROS disorder may involve surgical interventions, special education, and speech and physical therapies.

Vijoice (alpelisib) is the first FDA-approved treatment for PROS conditions. Vijoice works by inhibiting the PI3K pathway, predominantly the PI3K-alpha isoform, to treat the conditions caused by the effects of PIK3CA mutations in adults and children.

Drugs used to treat PIK3CA-Related Overgrowth Spectrum