PROS Disorders

PROS (PIK3CA-Related Overgrowth Spectrum) disorders are diverse, despite their shared genomic cause

As a result, patients diagnosed with the same PROS disorder may experience differences in manifestations, symptoms, and severity. Take an in-depth look at these different PROS disorders, below.1-4

 

Specific disorders associated with PROS include:

KTS (Klippel-Trenaunay Syndrome)

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

  • KTS can affect the development of bones, organs, and soft tissue, such as skin and muscles
  • Many patients develop port-wine stains

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

CLOVES syndrome is characterized by congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis, and spinal abnormalities.5,6

  • Lipomatous overgrowth often affects the front and back of the torso, as well as limbs, fingers, and toes
  • Bone abnormalities, including scoliosis and macrodactyly
  • Many people with CLOVES syndrome experience worsening symptoms over time
  • Overlap with symptoms of hemihyperplasia-multiple lipomatosis and fibroadipose hyperplasia may also occur

ILM (Isolated Lymphatic Malformation)

ILM is a mass that contains fluid, which often affects the head and neck.5,7,8

  • Frequently occurs in the neck and face, but it can be anywhere in the body, including the lower half of the body, arm, or torso

MCAP or M-CM (Megalencephaly-Capillary Malformation)

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.5

  • Further progression to Chiari malformation and cortical brain abnormalities may also occur
  • May involve capillary malformations that affect the skin

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

Brain enlargement on one side or both sides of the brain is called HME or DMEG, respectively.5,9

Focal cortical dysplasia type II is a malformation of cortical development that involves dysmorphic neurons and changes outside the temporal lobe.5,9

HHML (HemiHyperplasia-Multiple Lipomatosis)

HHML is characterized by moderate abnormalities of asymmetry and overgrowth with multiple subcutaneous lipomata, and static or mildly progressive hemihyperplasia.5

FIL (Facial Infiltrating Lipomatosis)

FIL is characterized by hemifacial soft-tissue and skeletal overgrowth, precocious dental development, macrodontia, hemimacroglossia, and mucosal neuromas.5

FAVA (FibroAdipose Vascular Anomaly)

FAVA is a type of vascular malformation characterized by intramuscular venous malformations.7,10

Macrodactyly

Macrodactyly is a fibrofatty enlargement of a limb or part of a limb.11

Muscular HH (HemiHyperplasia)

Muscular HH is an overgrowth on one side of the body and may also be referred to as muscular hemihypertrophy.5,12

FAO (FibroAdipose hyperplasia or Overgrowth)

FAO is characterized by segmental and progressive overgrowth of subcutaneous and visceral fibroadipose tissue. It may also be associated with skeletal and muscular overgrowth.5

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)

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. Overgrowth may be identified; however, it is not always evident.3,5

Epidermal nevus, benign lichenoid keratosis, or seborrheic keratosis

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.5,13

Benign lichenoid keratosis is a skin lesion that presents as raised plaque or as a papule.5,14

Seborrheic keratosis is a skin lesion that is often pigmented and appears wart-like or as a smooth papule.5,15

Other disorders may be identified and characterized as PROS

 
 
References:
  1. 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.
  2. Parker VER, Keppler-Noreuil KM, Faivre L, et al. Genet Med. 2019;21(5):1189-1198.
  3. Rodriguez-Laguna L, Ibañez 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. Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P. Klippel-Trénaunay syndrome: spectrum and management. Mayo Clin Proc. 1998;73(1):28-36.
  5. 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.
  6. Alomari AI. Characterization of a distinct syndrome that associates complex truncal overgrowth, vascular, and acral anomalies: a descriptive study of 18 cases of CLOVES syndrome. Clin Dysmorphol. 2009;18(1):1-7.
  7. Luks VL, Kamitaki N, Vivero MP, et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr. 2015;166(4):1048-1054.e1-5.
  8. Elluru RG, Azizkhan RG. Cervicofacial vascular anomalies. II. Vascular malformations. Semin Pediatr Surg. 2006;15(2):133-139.
  9. Del Campos Braojos F, Guimaraes CVA. Dysplastic megalencephaly phenotype presenting with prenatal high-output cardiac failure. Pediatr Radiol. 2018;48(8):1172-1177.
  10. Alomari AI, Spencer SA, Arnold RW, et al. Fibro-adipose vascular anomaly: clinical-radiologic-pathologic features of a newly delineated disorder of the extremity. J Pediatr Orthop. 2014;34(1):109-117.
  11. Ezaki M. Insights into the pathogenesis of macrodactyly. J Hand Surg Eur Vol. 2019;44(1):25-31.
  12. Schultz BD, Coon D, Medina M, Hoover-Fong J, Sponseller PD, Dorafshar AH. Isolated pediatric hemihyperplasia requiring surgical debulking of the thigh. J Pediatr Surg Case Rep. 2015;3(2):53-57.
  13. Arora B, Khinda VIS, Bajaj N, Brar GS. Congenital epidermal nevus. Int J Clin Pediatr Dent. 2014;7(1):43-46.
  14. Mhatre A, Nadkarni N, Patil S, Agarwal S. A case of benign lichenoid keratosis. Indian J Dermatopathol Diagn Dermatol. 2015;2:49-51.
  15. Norman RA, Young EM Jr. Seborrheic keratoses. In: Atlas of Geriatric Dermatology. London, England: Springer-Verlag; 2014:233-237.