Look to the root of the overgrowth to understand

PROS(PIK3CA-Related

Overgrowth Spectrum)

PROS is a broad-ranging spectrum of overgrowth disorders caused by PIK3CA mutations1

The classification “PROS” was established by the National Institutes of Health in 2015 to unite a group of overgrowth disorders based on their shared genomic cause.1

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Do your patients have any of the following disorders associated with PROS?1,3,4

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.1

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.2

KTS (Klippel-Trenaunay Syndrome)

CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal)

ILM (Isolated Lymphatic Malformation)

MCAP or MCM (Megalencephaly-Capillary Malformation)

HME (HemiMegalEncephaly)/DMEG (Dysplastic MEGalencephaly)/Focal cortical dysplasia type II

HHML (HemiHyperplasia-Multiple Lipomatosis)

FIL (Facial Infiltrating Lipomatosis)

FAVA (FibroAdipose Vascular Anomaly)

Macrodactyly

Muscular HH (HemiHyperplasia)

FAO (FibroAdipose hyperplasia or Overgrowth)

CLAPO syndrome (Capillary malformation of the lower lip, Lymphatic malformation of the face and neck, Asymmetry of the face and limbs, and Partial or generalized Overgrowth)

Epidermal nevus, benign lichenoid keratosis, or seborrheic keratosis

Other disorders may be identified and characterized as PROS.

Patients with PROS can suffer disfiguring or function-limiting effects1

Select complications of PROS1-3,5-7

Diagnosing PROS early is important for ongoing assessment and care1,8

Proper diagnosis of PROS can help guide assessment and care by the appropriate specialists. A multidisciplinary health care team is often necessary to manage all affected organs and potential complications.6

DIAGNOSIS OF PROS MAY CONSIST OF MULTIPLE METHODS:

Prenatal sonograms may reveal overgrowths, but PIK3CA mutation is not always detectable via amniocentesis.8-10

CLINICAL IMAGING OBSERVATION GENOMIC ASSESSMENT OF ONSET TIMING TESTING

Current management approaches are limited and may not address the underlying cause of diseaseSurgical and radiologic embolization procedures are currently the most common approaches to managing PROS. These procedures, however, may be unsuitable for some patients based on the risk-benefit profile.2,11-13

Patients may experience recurrence following surgery, and repeat surgeries are frequently required.2,11,14

To date, there are no approved therapies for PROS that aim to affect its root cause—PIK3CA mutation.

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. 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. 3. 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. 4. Limaye N, Kangas J, Mendola A, et al. Somatic activating PIK3CA mutations cause venous malformation. Am J Hum Genet. 2015;97(6):914-921. 5. Parker VER, Keppler-Noreuil KM, Faivre L, et al. Genet Med. 2019;21(5):1189-1198. 6. Mirzaa G, Conway R, Graham JM Jr, Dobyns WB. PIK3CA-related segmental overgrowth. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2019. 7. National Institutes of Health. Genetics home reference. Klippel-Trenaunay syndrome. https://ghr.nlm.nih.gov/condition/klippel-trenaunay-syndrome. Accessed March 20, 2020. 8. Quinlan-Jones E, Williams D, Bell C, Miller C, Gokhale C, Kilby MD. Prenatal detection of PIK3CA-related overgrowth spectrum in cultured amniocytes using long-range PCR and next-generation sequencing. Pediatr Dev Pathol. 2017;20(1):54-57. 9. Emrick LT, Murphy L, Shamshirsaz AA, et al. Prenatal diagnosis of CLOVES syndrome confirmed by detection of a mosaic PIK3CA mutation in cultured amniocytes. Am J Med Genet A. 2014;164A(10):2633-2637. 10. Lalonde E, Ebrahimzadeh J, Rafferty K, et al. Molecular diagnosis of somatic overgrowth conditions: a single-center experience. Mol Genet Genomic Med. 2019;7(3):e536. 11. Madsen RR, Vanhaesebroeck B, Semple RK. Cancer-associated PIK3CA mutations in overgrowth disorders. Trends Mol Med. 2018;24(10):856-870. 12. Bessis D, Vernhet H, Bigorre M, Quere I, Rossler J. Life-threatening cutaneous bleeding in childhood Klippel-Trenaunay syndrome treated with oral sirolimus. JAMA Dermatol. 2016;152(9):1058-1059. 13. Keppler-Noreuil KM, Lozier J, Oden N, et al. Thrombosis risk factors in PIK3CA-related overgrowth spectrum and Proteus syndrome. Am J Med Genet C Semin Med Genet. 2019;181(4):571-581. 14. Crunkhorn S. Nat Rev Drug Discov. 2018;17(8):545.

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ABNORMAL GROWTH can cause:• Pain• Reduced mobility• Scoliosis• Spinal compression

VASCULAR MALFORMATIONS can cause:• Internal bleeding• Blood clots (eg, DVT or PE)• Varicose veins

LYMPHATIC MALFORMATIONS can cause:• Cellulitis

OTHER COMPLICATIONS include:• Urinary incontinence• Abnormal kidneys • Seizures• Intellectual disability

DVT, deep vein thrombosis; PE, pulmonary embolism.

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