PROS (PIK3CA-Related Overgrowth Spectrum) is a broad-ranging spectrum of disorders caused by PIK3CA mutations1

 

“Overgrowth disorders” refers to the broad range of medical conditions characterized by excess tissue growth.2 A number of these overgrowth disorders are now understood to share a single cause: somatic mutations of the PIK3CA gene.1,3

The PIK3CA gene codes for the alpha isoform of PI3K, which is known to be involved in cell development and growth. When mutated, the PIK3CA gene can drive unchecked cellular growth and proliferation.1,3 In the case of PROS, the mutation occurs during embryonic development, resulting in a mosaic overgrowth pattern (ie, patches of affected and unaffected areas).


The classification "PROS"—PIK3CA-Related Overgrowth Spectrum—was established by the National Institutes of Health in 2015 to unite this group of overgrowth disorders with one term that reflects their shared genomic cause.1


Clinical Presentation of PROS

In addition to the presence of a PIK3CA mutation, PROS disorders have clinical commonalities.

Clinical hallmarks of PROS Clinical hallmarks of PROS

However, the clinical presentation of PROS is highly variable with respect to the extent, tissue specificity or pleiotropism, tissue types, affected organs, and anatomical locations of the overgrowths.

 

PROS features broadly include1:

  • OVERGROWTH of adipose, muscle, nerve, or skeletal tissue

  • VASCULAR MALFORMATION, including capillary, venous, arteriovenous, or lymphatic effects

  • SKIN LESIONS

Overgrowths are not always overt. Vascular malformations, for example, may not be externally apparent. Nonetheless, they represent a significant medical concern.3

 

Specific disorders associated with PROS include:

KTS is characterized by overgrowth and vascular malformations.1,4,5

CLOVES syndrome is characterized by congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis, and spinal abnormalities. Overlap with symptoms of hemihyperplasia-multiple lipomatosis and fibroadipose hyperplasia may also occur.1

ILM is a mass that contains fluid, which often affects the head and neck.1,6

MCAP syndrome is characterized by a core set of brain features that include megalencephaly and ventriculomegaly, which may progress to hydrocephalus or cerebellar tonsillar ectopia. Further progression to Chiari malformation and cortical brain abnormalities may also occur.1

Brain enlargement on one side or both sides of the brain is called HME or DMEG, respectively. Focal cortical dysplasia type II is a malformation of cortical development that involves dysmorphic neurons and changes outside the temporal lobe.1,7-9

HHML is characterized by moderate abnormalities of asymmetry and overgrowth with multiple subcutaneous lipomata, and static or mildly progressive hemihyperplasia.1

FIL is characterized by hemifacial soft-tissue and skeletal overgrowth, precocious dental development, macrodontia, hemimacroglossia, and mucosal neuromas.1

FAVA is a type of vascular malformation characterized by intramuscular venous malformations.1,10,11

Macrodactyly is a fibrofatty enlargement of a limb or part of a limb.12

Muscular HH is an overgrowth on one side of the body and may also be referred to as muscular hemihypertrophy.1,13

FAO is characterized by segmental and progressive overgrowth of subcutaneous and visceral fibroadipose tissue. It may also be associated with skeletal and muscular overgrowth.1

The hallmark feature of CLAPO syndrome is 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.1,14

An epidermal nevus is a benign skin abnormality caused by an overgrowth of cells that can result in a flat or raised, discolored patch of skin. Benign lichenoid keratosis is a skin lesion that presents as raised plaque or as a papule. Seborrheic keratosis is a skin lesion that is often pigmented and appears wart-like or as a smooth papule.1,15-17

Other disorders may be identified and characterized as PROS.

 

Prevalence of PROS

Although reported rates of individual PROS disorders are low or unknown, the spectrum collectively could represent a more significant patient number, with an estimated prevalence of 14 people per million.18*

*The estimated prevalence is based on available information for the following five disorders: KTS, CLOVES syndrome, MCAP or MCM, HHML, and FAO.

 

References:
  1. Keppler-Noreuil KM, Rios JJ, Parker VER, et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015;167A(2):287-295.
  2. Ko JM. Genetic syndromes associated with overgrowth in childhood. Ann Pediatr Endocrinol Metab. 2013;18(3):101-105.
  3. Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014;164A(7):1713-1733.
  4. National Institutes of Health. Klippel-Trenaunay syndrome. Genetics home reference. https://ghr.nlm.nih.gov/condition/klippel-trenaunay-syndrome. Accessed March 20, 2020.
  5. National Organization for Rare Disorders. Klippel-Trenaunay syndrome. Rare disease database. https://rarediseases.org/rare-diseases/klippel-trenaunay-syndrome/. Accessed March 24, 2020.
  6. National Organization for Rare Disorders. Lymphatic malformations. Rare disease database. https://rarediseases.org/rare-diseases/lymphatic-malformations/. Accessed March 25, 2020.
  7. National Organization for Rare Disorders. Hemimegalencephaly. Rare disease database. https://rarediseases.org/rare-diseases/hemimegalencephaly/. Accessed March 25, 2020.
  8. Del Campos Braojos F, Guimaraes CVA. Dysplastic megalencephaly phenotype presenting with prenatal high-output cardiac failure. Pediatr Radiol. 2018;48(8):1172-1177.
  9. Kabat J, Krol P. Focal cortical dysplasia – review. Pol J Radiol. 2012;77(2):35-43.
  10. Limaye N, Kangas J, Mendola A, et al. Somatic activating PIK3CA mutations cause venous malformation. Am J Hum Genet. 2015;97(6):914-921.
  11. Fernandez-Pineda I, David Marcilla D, Downey-Carmona FJ, et al. Lower extremity fibro-adipose vascular anomaly (FAVA): a new case of a newly delineated disorder. Ann Vasc Dis. 2014;7(3):316-319.
  12. Ezaki M. Insights into the pathogenesis of macrodactyly. J Hand Surg Eur Vol. 2019;44(1):25-31.
  13. Children’s Hospital of Philadelphia. Hemihyperplasia. https://www.chop.edu/conditions-diseases/hemihyperplasia#. Reviewed March 2014. Accessed March 25, 2020.
  14. Rodriguez-Laguna L, Ibanez K, Gordo G, et al. CLAPO syndrome: identification of somatic activating PIK3CA mutations and delineation of the natural history and phenotype. Genet Med. 2018;20(8):882-889.
  15. National Institutes of Health. Epidermal nevus. Genetics home reference. https://ghr.nlm.nih.gov/condition/epidermal-nevus. Reviewed August 2016. Accessed March 25, 2020.
  16. Mhatre A, Nadkarni N, Patil S, Agarwal S. A case of benign lichenoid keratosis. Indian J Dermapathol Diagn Dermatol. 2015;2:49-51.
  17. Aaron DM. Sehorrheic keratoses. Merck Manual Professional Version. https://www.merckmanuals.com/professional/dermatologic-disorders/benign-skin-tumors,-growths,-and-vascular-lesions/seborrheic-keratoses. Revised May 2019. Accessed March 25, 2020.
  18. Data on file. Novartis Pharmaceuticals Corp; 2020.

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