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As molecular knowledge of PROS expands, lesions contract


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By Warren R. Heymann, MD
April 19, 2018

PIK3CA
PIK3CA patient showing hemifacial hypertrophy.
Credit: JAAD

Somatic activating mutations in the phosphatidylinositol-3-kinase/AKT/mTOR pathway manifest as heterogeneous segmental overgrowth phenotypes Historically, the clinical diagnoses in patients with PIK3CA activating mutations have included Fibroadipose Hyperplasia or Overgrowth (FAO), Hemihyperplasia Multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, macrodactyly, Fibroadipose Infiltrating Lipomatosis, and the related megalencephaly syndromes, Megalencephaly-Capillary Malformation (MCAP or M-CM) and Dysplastic Megalencephaly (DMEG). (1) Although the Klippel-Trenaunay-Weber syndrome is caused by mutations in RASA1, some patients have had overlapping features with other overgrowth syndromes, such as Proteus syndrome – these presentations are also due to mutations of PIK3CA.(2) The term of “PIK3CA-Related Overgrowth Spectrum (PROS)” is now utilized to encompass both defined and emerging clinical entities associated with somatic PIK3CA mutations.

The phenotypic expression of these syndromes reflects the temporal and spacial occurrence of a postzygotic mutation and primary cell types being affected, resulting in differential tissue distribution. (3) Complications may vary depending on the clinical phenotype, with some patients at risk for Wilms tumor (with recommendations to follow patients with abdominal ultrasounds as is in patients with hemihyperplasia — see DI&I July 24, 2017), spinal/neurological involvement (necessitating MRIs), and increased risk of thrombosis (with consideration of anticoagulant prophylaxis). (2)

Vahidnezhad state: “As PI3K resides upstream of AKT and mTOR1 and as rapamycin is an inhibitor of mTOR1, rapamycin could potentially be useful for treatment at the early stages of the development of those cases of overgrowth syndromes, including KTS, which harbour mutations in the PIK3CA gene. Mechanistically, rapamycin binds to FK506-binding protein 12, and this complex inhibits mTOR1 resulting in cell cycle arrest in mid-to-late G1 phase. Rapamycin also inhibits protein synthesis in the cells by selective inactivation of S6K through inactivation of mTOR1. As a result of these activities, rapamycin has antiproliferative effects and could prevent tissue overgrowth in patients with PIK3CA mutations. Furthermore, specific inhibitors for other components of the PI3K-AKT-mTOR and other interconnected signalling pathways have been developed. Consequently, precise knowledge of the mutated gene and specific mutations is a prerequisite for ascertainment of treatment options in the future as part of personalized healthcare delivery.” (2)

Sildenfil has been reported to soften and improve lymphatic malformations, as in the case of a 30-year-old man with extensive capillary-lymphatic malformations of his right leg and thorax due to a somatic PIK3A mutation. Sildenafil is a selective inhibitor of phosphodiesterase-5, which inhibits the breakdown of cGMP into GMP. The increased levels of cGMP results in vascular smooth muscle relaxation, thereby facilitating cystic decompression and drainage of lymphatic fluid into the venous system. (4)

Despite these therapeutic advances, surgical debulking and orthopedic procedures remain as the main focus of therapy in patients with PROS (5)

How do PROS patients handle their debulking procedures? Are their wounds at risk for further growth and poor wound healing? Steiner et al addressed these questions in their study of 6 patients with PROS who underwent such procedures. Four of the 6 developed excessive scarring, but only within the tissue affected overgrowth; one patient had a surgical incision that extended into unaffected tissue – that portion of the scar demonstrated normal healing. The authors suggest that gain of function variants of PIK3CA may predispose patients to overgrowth of scar tissue. None of the study patients were receiving sirolumus. (6) Could perioperative use of topical sirolimus prevent these scars?

I’m not sure what is proliferating faster in PROS — the soft tissue or our knowledge of the molecular biology. Further research in the latter will one day negate the former.

Point to remember: Patients with PROS should be informed that excess scar tissue could result from surgery at affected sites.

1. Keppler-Noreuil KM, et al. PIK3CA-related overgrowth spectrum (PROS): Diagnostic criteria, differential diagnosis, and evaluation. Am J Hum Genet A 2015; 167A: 287-95.
2. Vahidnezhad H, et al. Klippel-Trenaunay syndrome belongs to the PIK3CA-related overgrowth overgrowth spectrum. Exp Dermatol 2016; 25: 17-9.
3. Vahidnezhad H, et al. Phenotypic heterogeneity in PIK3CA overgrowth spectrum Br J Dermatol 2016; 175: 810-14.
4. Horbach SER, et al. Oral sildenafil as a treatment option for lymphatic malformations in PIK3CA-related tissue overgrowth syndromes. Dermatol Ther 2016; 29: 466-9.
5. Loconte C, et al. Molecular and functional characterization of three different postzygotic mutations in PIK3CA-related overgrowth spectrum (PROS) patients. Effects on PI3K/AKT/mTOR signaling and sensitivity to PIK3 inhibitors. PLoS One 2015 Apr 27;10(4):e0123092.
6. Steiner JE, et al. Scarring in patients with PIK3CA-related overgrowth syndromes. JAMA Dermatol 2018; 154: 452-5.


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