Clinical Research| Volume 88, P233-238, January 2023

Download started.


Undergrowth Of First Toe In PiK3CA-Related Overgrowth Spectrum (PROS)


      PIK3CA-related overgrowth syndrome (PROS) include a heterogeneous group of disorders characterized by segmental overgrowth secondary to somatic mosaic activating variants in PIK3CA. Segmental undergrowth is more uncommon and has been less studied but pathogenic variants in PIK3CA have also been found. With this in mind, we have noticed a group of patients with PROS that present an undergrowth component associated with their focal overgrowth.


      Retrospective review of patients with PROS presenting overgrowth of the lower limb and undergrowth of the ipsilateral first toe was performed.


      Six patients were included, 4 female and 2 male with a median age of 16.8 years. All patients presented a PROS phenotype with overgrowth of the lower limb and undergrowth of ipsilateral first toe. A PIK3CA pathogenic variant was confirmed in all patients. Patients underwent multiple treatments, currently all are receiving alpelisib with a mean duration of 15.8 months (1–39) and partial response in lipomatosis and vascular anomalies but no response in overgrowth and undergrowth so far.


      Pathogenic variants in the same gene can create different phenotypes depending on the time and place of the mutation. There is little information regarding opposing phenotpyes in the same patient with PROS. The presence of undergrowth in our series might be explained by genetic, embryogenic, maternal, or placental factors but needs to be further investigated.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Annals of Vascular Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Keppler-Noreuil K.M.
        • Rios J.J.
        • Parker V.E.
        • et al.
        PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation.
        Am J Med Genet A. 2015; 167A: 287-295
        • Triana P.
        • Dore M.
        • Cerezo V.N.
        • et al.
        Sirolimus in the treatment of vascular anomalies.
        Eur J Pediatr Surg. 2017; 27: 86-90
        • Hammill A.M.
        • Wentzel M.
        • Gupta A.
        • et al.
        Sirolimus for the treatment of complicated vascular anomalies in children.
        Pediatr Blood Cancer. 2011; 57: 1018-1024
        • Venot Q.
        • Blanc T.
        • Rabia S.H.
        • et al.
        Targeted therapy in patients with PIK3CA-related overgrowth syndrome.
        Nature. 2018; 558: 540-546
        • Martorell F.
        Hemangiomatosis braquial osteolitica.
        Angiologia. 1949; 27: 163-166
        • Servelle M.T.
        • Trinquecoste P.
        Des angiomes veineux (about venous angiomas).
        Arch Mal Couer. 1948; 41: 436-438
        • Martinez-Glez V.
        • Rodriguez-Laguna L.
        • Viana-Huete V.
        • et al.
        Segmental undergrowth is associated with pathogenic variants in vascular malformation genes: a retrospective case-series study.
        Clin Genet. 2022; 101: 296-306
        • 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: 882-889
        • Canaud G.
        • Hammill A.M.
        • Adams D.
        • et al.
        A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations.
        Orphanet J Rare Dis. 2021; 16: 306
        • Danarti R.
        • König A.
        • Bittar M.
        • et al.
        Inverse Klippel-Trenaunay syndrome: review of cases showing deficient growth.
        Dermatology. 2007; 214: 130-132
        • Uihlein L.C.
        • Liang M.G.
        • Fishman S.J.
        • et al.
        Capillary-venous malformation in the lower limb.
        Pediatr Dermatol. 2013; 30: 541-548
        • Mirzaa G.
        • Timms A.E.
        • Conti V.
        • et al.
        PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.
        JCI Insight. 2016; 1: e87623
        • Martínez-Glez V.
        • Tenorio J.
        • Nevado J.
        • et al.
        A six-attribute classification of genetic mosaicism.
        Genet Med. 2020; 22: 1743-1757
        • Keppler-Noreuil K.M.
        • Sapp J.C.
        • Lindhurst M.J.
        • et al.
        Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.
        Am J Med Genet A. 2014; 164A: 1713-1733
        • Glimm T.
        • Bhat R.
        • Newman S.A.
        Multiscale modeling of vertebrate limb development.
        Wiley Interdiscip Rev Syst Biol Med. 2020; 12: e1485
        • Grzeschik K.H.
        Human limb malformations; an approach to the molecular basis of development.
        Int J Dev Biol. 2002; 46: 983-991
        • Nirala N.
        • Periyasamy R.
        • Kumar A.
        Noninvasive diagnostic methods for better screening of peripheral arterial disease.
        Ann Vasc Surg. 2018; 52: 263-272
        • López Gutiérrez J.C.
        • Lizarraga R.
        • Delgado C.
        • et al.
        Alpelisib treatment for genital vascular malformation in a patient with congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis (CLOVES) syndrome.
        J Pediatr Adolesc Gynecol. 2019; 32: 648-650