Abstract
Segmental overgrowth of the skeletal muscles with bone involvement in body extremities, predominantly affecting the upper limb, is an extremely rare condition with only 40–50 affected children described clinically. The molecular pathogenesis of this disorder remains largely unclear except for the identification of a somatic PIK3CA mutation in each of the six patients genetically tested, all restricted to upper limbs in the literature. This study aimed to further characterize the molecular defects for patients affected with segmental overgrowth of the skeletal muscles by analyzing a 9-gene panel selected from the PI3K/AKT/mTOR pathway and genes associated with other related conditions. Nineteen unrelated patients were chosen for this study, comprising ten upper limb (nine unilateral and one bilateral) and nine lower limb (eight unilateral and one bilateral) cases with variable bone involvement. In each case, an activating PIK3CA mutation (p.E110del, p.N345K, p.E542K, p.E545K, p.H1047R, or p.H1047L) was identified in the affected muscle tissue with variant allele frequencies ranging from 13.88 to 30.43%, while no mutation was detected in the paired peripheral blood sample, indicating somatic mosaicism. All detected mutations were limited to PIK3CA and were previously reported in other overgrowth syndromes currently categorized under the PIK3CA-Related Overgrowth Spectrum (PROS). Our study provides strong molecular evidence that isolated segmental overgrowth of the skeletal muscle with bone involvement is a subtype of PROS. Our findings expand the PROS clinical presentations with a newly molecularly classified condition and can provide guidance in clinical and molecular diagnosis and treatment for patients with this condition.
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taken from Huang et al. (2007). The p110α has five domains: an N-terminal domain that binds to its regulatory unit p85α, a Ras-binding domain, a domain called C2 that has been proposed to bind to cellular membranes, a helical domain of the unknown function, and a kinase catalytic domain. The mutations discovered in the present study are graphed with the amino acid substitutions or deletion indicated. *Cases adapted from literature
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The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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References
Akgumus G, Chang F, Li MM (2017) Overgrowth syndromes caused by somatic variants in the phosphatidylinositol 3-kinase/AKT/Mammalian target of rapamycin pathway. J Mol Diagn 19:487–497. https://doi.org/10.1016/j.jmoldx.2017.04.001
Al-Qattan MM (2014) Muscle overgrowth of the upper limb in a proximo-distal gradient and concurrent hypoplasia of the index finger. J Pediatr Orthop 34:715–719. https://doi.org/10.1097/BPO.0000000000000192
Al-Qattan MM, Hadadi A, Al-Thunayan AM, Eldali AA (2018) Upper limb muscle overgrowth with hypoplasia of the index finger: a new over-growth syndrome caused by the somatic PIK3CA mutation c.3140A>G. BMC Med Genet 19:158. https://doi.org/10.1186/s12881-018-0672-z
Burke JE, Perisic O, Masson GR, Vadas O, Williams RL (2012) Oncogenic mutation mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA). Proc Natl Acad Sci USA 109:15259–15264. https://doi.org/10.1073/pnas.1205508109
Castiglioni C, Bertini E, Orellana P, Villarroel C, Heras LF, Hinzpeter D, Paolinelli P, Bevilacqua JA, Alvarez K (2014) Activating PIK3CA somatic mutation in congenital unilateral isolated muscle overgrowth of the upper extremity. Am J Med Genet Part A 164A:2365–2369. https://doi.org/10.1002/ajmg.a.36651
Chang F, Liu L, Fang E, Zhang G, Chen T, Cao K, Li Y, Li MM (2017) Molecular diagnosis of mosaic overgrowth syndromes using a custom-designed next-generation sequencing panel. J Mol Diagn 19:613–624. https://doi.org/10.1016/j.jmoldx.2017.04.006
Dahan E, Chaves C, Bachy M, Fitoussi F (2018) Upper limb congenital muscular hypertrophy and aberrant muscle syndrome in children. J Hand Surg Eur 43:751–755. https://doi.org/10.1177/1753193418774459
Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619. https://doi.org/10.1038/nrg1879
Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H, Ding M, Bamford S, Cole C, Ward S, Kok CY, Jia M, De T, Teague JW, Stratton M, McDermott U, Campbell PJ (2015) COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acid Res 43(Database issue):D805–D811. https://doi.org/10.1093/nar/gku1075
Frisk S, Taylan F, Blaszczyk I, Nennesmo I, Annerén G, Herm B, Stattin E, Zachariadis V, Lindstrand A, Tesi B, Laurell T, Nordgren A (2019) Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth. Clin Genet 96:118–125. https://doi.org/10.1111/cge.13543
Gilhuis HJ, Zöphel OT, Lammens M, Zwarts MJ (2009) Congenital monomelic muscular hypertrophy of the upper extremity. Neuromuscul Disord 19:714–717. https://doi.org/10.1016/j.nmd.2009.07.010
Gymnopoulos M, Elsliger MA, Vogt PK (2007) Rare cancer-specific mutations in PIK3CA show gain of function. Proc Natl Acad Sci USA 104:5569–5574. https://doi.org/10.1073/pnas.0701005104
Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, Vogelstein B, Gabelli SB, Amzel LM (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744–1748. https://doi.org/10.1126/science.1150799
Hellwinkel JE, York PJ, Leaseburg JT, Hunt KJ (2019) Congenial unilateral hypertrophy of the foot intrinsics: a rare case and review of the literature. J Orthop Case Rep 9:34–37. https://doi.org/10.13107/jocr.2250-0685.1358
Jahss MH (1974) Pseudotumors of the foot. Orthop Clin North AM 5:67–87
Kalay T, Gilhuis HJ, Kraan G, VanAlfen N (2016) Congenital bimelic hypertrophy of the hands. Case Rep Neurol 8:34–38. https://doi.org/10.1159/000443326
Kandoth C, McLellan MD, Vandin F et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339. https://doi.org/10.1038/nature12634
Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Biesecker LG (2015) PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis and evaluation. Am J Med Genet A 167A:287–295. https://doi.org/10.1002/ajmg.a.36836
Leoni C, Gullo G, Resta N, Fagotti A, Onesimo R, Schwartz B, Kazakin J, Abbadessa G, Crown J, Collins CD, Ranieri C, Scambia G, Zampino G (2019) First evidence of a therapeutic effect of miransertib in a teenager with Proteus syndrome and ovarian carcinoma. Am J Med Genet A 179:1319–1324. https://doi.org/10.1002/ajmg.a.61160
Lindhurst MJ, Yourick MR, Yu Y, Savage RE, Ferrari D, Biesecker LG (2015) Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome. Sci Rep 5:17162. https://doi.org/10.1038/srep17162
Loconte DC, Grossi V, Bozzao C, Forte G, Bagnulo R, Stella A, Lastella P, Cutrone M, Benedicenti F, Susca FC, Patruno D, Germani A, Chessa L, Laforgia N, Tenconi R, Simone C, Resta N (2015) 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 10:e0123092. https://doi.org/10.1371/journal.pone.0123092
Madsen RR, Vanhaesebroeck B, Semple RK (2018) Cancer-associated PIK3CA mutations in overgrowth disorders. Trends Mol Med 24:856–870. https://doi.org/10.1016/j.molmed.2018.08.003
Mirzaa G, Timms AE, Conti V et al (2016) PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression tissue distribution. JCI Insight 1:e87623. https://doi.org/10.1172/jci.insight.87623
Mitchell CB, Phillips WA (2019) Mouse models for exploring the biological consequences and clinical significance of PIK3CA mutations. Biomolecules 9:158. https://doi.org/10.3390/biom9040158
Mizuoka J, Horio S, Ohmiya K (1962) Duplication of thenar and hypothenar muscles in an incestuous offspring: a case report. Seikeigeka 13:963–965
Ogino T, Satake H, Takahara M, Kikuchi N, Watanabe T, Iba W, Ishii S (2010) Aberrant muscle syndrome: hypertrophy of the hand and arm due to aberrant muscles with or without hypertrophy of the muscles. Congenit Anom (kyoto) 50:133–138. https://doi.org/10.1111/j.1741-4520.2010.00277.x
Ranieri C, Di Tommaso S, Loconte DC et al (2018) In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS). Neurogenetics 19:77–91. https://doi.org/10.1007/s10048-018-0540-1
Rasmussen M, Sunde L, Weigert KP, Bogaard PW, Lildballe DL (2014) Segmental overgrowth syndrome due to an activating PIK3CA mutation identified in affected muscle tissue by exome sequencing. Am J Med Genet Part A 164A:1318–1321. https://doi.org/10.1002/ajmg.a.36454
Samuels Y, Ericson K (2006) Oncogenic PI3K and its role in cancer. Curr Opin Oncol 18:77–82. https://doi.org/10.1097/01.cco.0000198021.99347.b9
Takka S, Doi K, Hattori Y, Kitajima I, Sano K (2005) Proposal of new category for congenital unilateral upper limb muscular hypertrophy. Ann Plast Surg 54:97–102. https://doi.org/10.1097/01.sap.0000130701.63585.b7
Tanabe K, Tada K, Doi T (1997) Unilateral hypertrophy of the upper extremity due to aberrant muscles. J Hand Surg Br 22:253–257. https://doi.org/10.1016/S0266-7681(97)80075-7
Venot Q, Blanc T, Rabia SH et al (2018) Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 558:540–546. https://doi.org/10.1038/s41586-018-0217-9
Zhang Y, Ng PKS, Kucherlapati M et al (2017) A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations. Cancer Cell 31:820–832. https://doi.org/10.1016/j.ccell.2017.04.013
Funding
This work was supported by The National Key Research and Development Program of China (no. 2016YFC0901500); Beijing JST Research Funding (2019-YJ03; ZR-201907); Beijing Jishuitan Hospital Nova Program (XKXX201818); Capital’s Funds for Health Improvement and Research (2020-4-40114 to N. W.); and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (no. 2019PT320025).
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ZW, PF, WT, LS, and FC conceived and designed this study. WT, LS, JZ, WZ, YG, YH, YY, ZZ, QL, and NZ enrolled the cohort. NW, PF, JZ, LL, KM, and ST assisted with study organization and manuscript revision. QZ conducted the bioinformatics analyses. WT, LS, QZ, and FC analyzed the data and assisted with data interpretation. WT, LS, FC, and ZW wrote the manuscript. All the authors read and approved the final manuscript.
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This study was approved by the Ethics Committees of Beijing Union Hospital (JS-1233) and Beijing Jishuitan Hospital (201808-09; 201904-13).
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Tian, W., Sun, L., Zhang, Q. et al. Activating PIK3CA postzygotic mutations in segmental overgrowth of muscles with bone involvement in the body extremities. Mol Genet Genomics 297, 387–396 (2022). https://doi.org/10.1007/s00438-022-01853-x
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DOI: https://doi.org/10.1007/s00438-022-01853-x