Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.

Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed

Commitment versus persuasion in the three-party constrained voter model

In the framework of the three-party constrained voter model, where voters of two radical parties (A and B) interact with "centrists" (C and Cz), we study the competition between a persuasive majority and a committed minority. In this model, A's and B's are incompatible voters that can convince centrists or be swayed by them. Here, radical voters are more persuasive than centrists, whose sub-population consists of susceptible agents C and a fraction zeta of centrist zealots Cz. Whereas C's may adopt the opinions A and B with respective rates 1+delta_A and 1+delta_B (with delta_A>=delta_B>0), Cz's are committed individuals that always remain centrists. Furthermore, A and B voters can become (susceptible) centrists C with a rate 1. The resulting competition between commitment and persuasion is studied in the mean field limit and for a finite population on a complete graph. At mean field level, there is a continuous transition from a coexistence phase when zeta= Delta_c. In a finite population of size N, demographic fluctuations lead to centrism consensus and the dynamics is characterized by the mean consensus time tau. Because of the competition between commitment and persuasion, here consensus is reached much slower (zeta=Delta_c) than in the absence of zealots (when tau\simN). In fact, when zeta<Delta_c and there is an initial minority of centrists, the mean consensus time asymptotically grows as tau\simN^{-1/2} e^{N gamma}, where gamma is determined. The dynamics is thus characterized by a metastable state where the most persuasive voters and centrists coexist when delta_A>delta_B, whereas all species coexist when delta_A=delta_B. When zeta>=Delta_c and the initial density of centrists is low, one finds tau\simln N (when N>>1). Our analytical findings are corroborated by stochastic simulations.Comment: 25 pages, 6 figures. Final version for the Journal of Statistical Physics (special issue on the "applications of statistical mechanics to social phenomena"