Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.
Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.
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DOI：
10.1002/ajmg.a.36552
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发表时间：
2014-07
影响因子：
2
通讯作者：
Biesecker, Leslie G.
中科院分区：
文献类型：
--
作者：
Keppler-Noreuil, Kim M.;Sapp, Julie C.;Lindhurst, Marjorie J.;Parker, Victoria E. R.;Blumhorst, Cathy;Darling, Thomas;Tosi, Laura L.;Huson, Susan M.;Whitehouse, Richard W.;Jakkula, Eveliina;Grant, Ian;Balasubramanian, Meena;Chandler, Kate E.;Fraser, Jamie L.;Gucev, Zoran;Crow, Yanick J.;Brennan, Leslie Manace;Clark, Robin;Sellars, Elizabeth A.;Pena, Loren D. M.;Krishnamurty, Vidya;Shuen, Andrew;Braverman, Nancy;Cunningham, Michael L.;Sutton, V. Reid;Tasic, Velibor;Graham, John M., Jr.;Geer, Joseph, Jr.;Henderson, Alex;Semple, Robert K.;Biesecker, Leslie G.
关键词：
磷脂酰肌醇/AKT/mTOR通路的体细胞突变导致节段性过度生长障碍。与PIK3CA突变相关的诊断描述词包括纤维脂肪过度生长（FAO）、半增生性多发性脂肪瘤病（HHML）、先天性脂肪瘤过度生长、血管畸形、表皮痣、脊柱侧凸/骨骼和脊柱（CLOVES）综合征、大趾畸形和巨脑畸形综合征、巨脑-毛细血管畸形（MCAP）综合征。我们开始完善对这些表型的临床谱和自然史的理解，现在描述了35例片段性过度生长和体细胞PIK3CA突变的患者。表型数据表明，这些先前描述的疾病实体有相当大的重叠，并代表一个频谱。虽然该谱系与变形综合征（散发性、花叶性和进行性）重叠，但可以通过没有脑样结缔组织痣和独特的自然史来区分。血管畸形15/35(43%)，表皮痣4/35(11%)，均低于Proteus综合征。与Proteus综合征不同，31/35（89%）的PIK3CA突变患者有先天性过度生长，其中35/35的患者是不对称和不成比例的。大多数情况下，过度生长是轻微的，几乎没有产后进展，而在其他情况下，过度生长是严重的，需要多次手术。新的发现包括：所有患者均存在脂肪失调，以左侧为主的单侧过度生长，过度生长对下肢的影响大于上肢，并以远端到近端模式进展，在最严重的患者中，未受影响区域的脂肪组织明显缺乏。虽然目前的数据与一些基因型-表型相关性一致，但这还不能得到证实。©作者。美国医学遗传学杂志A部分由Wiley期刊公司出版。
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. © The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.
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