CLOVES Syndrome: A Review of Clinical, Genetic, and Therapeutic Aspects
DOI:
https://doi.org/10.12775/QS.2025.38.58253Keywords
Congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal anomaly syndrome, asymmetric overgrowth, lipoma, PIK3CA gene, mTOR inhibitorsAbstract
Purpose of Research: The research aims to provide an in-depth understanding of CLOVES syndrome, detailing its clinical features, epidemiology, etiology, and diagnostic criteria. It focuses on the role of PIK3CA gene mutations, challenges in diagnosis, and treatment options, including PI3K/AKT/mTOR pathway inhibitors.
Research Materials and Methods: This article is based on a review of the current literature and clinical reports from various sources. The methodology includes a collection and synthesis of clinical data, imaging findings, and genetic analyses from published case studies and medical literature. The primary materials used in the research include: clinical case reports and studies, imaging studies, genetic analysis, therapeutic interventions, epidemiological data, literature review and data analysis.
Basic Results: CLOVES syndrome affects fewer than 200 individuals worldwide, with symptoms appearing at birth or early childhood. It can lead to serious complications such as nerve compression, deep vein thrombosis, and pulmonary embolism. Diagnosis involves genetic testing and imaging, and sirolimus shows potential in managing symptoms.
Conclusions: CLOVES syndrome is a rare, non-hereditary overgrowth disorder caused by a PIK3CA gene mutation. Early diagnosis and a multidisciplinary approach are vital for managing this complex condition and improving patient outcomes.
References
1. Gopal, Balaji, Shyamkumar N Keshava, i Deepak Selvaraj. „A Rare Newly Described Overgrowth Syndrome with Vascular Malformations-Cloves Syndrome”. Indian Journal of Radiology and Imaging 25, nr 01 (styczeń 2015): 71–73. https://doi.org/10.4103/0971-3026.150166.
2. Sapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry RB, Biesecker LG. Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients. Am J Med Genet A 2007;143A: 2944 58.
3. Akgumus G, Chang F, Li MM. Overgrowth syndromes caused by somatic variants in the phosphatidylinositol 3-Kinase/AKT/Mammalian target of rapamycin pathway. J Mol Diagn. 2017;19(4):487–497. doi:10.1016/j.jmoldx.2017.04.001
4. Vahidnezhad H, Youssefian L, Uitto J. Molecular genetics of the PI3K-AKT-mTOR pathway in genodermatoses: diagnostic implications and treatment opportunities. J Invest Dermatol. 2016;136(1):15–23. doi:10.1038/JID.2015.331
5. Öztürk Durmaz, Emel, Deniz Demircioğlu, Pınar Yalınay Dikmen, Yasemin Alanay, AhmetAlanay, Cüyan Demirkesen, Fatma Tokat, i Ercan Karaarslan. „A Review on Cutaneous and Musculoskeletal Manifestations of CLOVES Syndrome”. Clinical, Cosmetic and Investigational Dermatology Volume 15 (kwiecień 2022): 621–30. https://doi.org/10.2147/CCID.S351637
6. Mahajan VK, Gupta M, Chauhan P, Mehta KS. Cloves syndrome: a rare disorder of overgrowth with unusual features- an uncommon phenotype? Indian Dermatol Online J. 2019;10(4):447–452. doi:10.4103/idoj.IDOJ_418_18
7. Hanafusa H, Morisada N, Nomura T, et al. A girl with CLOVES syndrome with a recurrent PIK3CA somatic mutation and pancreatic steatosis. Hum Genome Var. 2019;6:31. doi:10.1038/s41439-019-0063-9
8. Puvabanditsin S, Memon N, Chekmareva M, Di Stefano V, Mehta R. Cloves syndrome: a case report and perinatal diagnostic findings. Genet Couns. 2014;25(3):265–270.
9. Vahidnezhad H, Youssefian L, Baghdadi T, et al. Phenotypic heterogeneity in PIK3CA-related overgrowth spectrum. Br J Dermatol. 2016;175 (4):810–814. doi:10.1111/bjd.14618
10. Alomar S, Khedr RE, Alajlan S. CLOVES syndrome in a nine-month-old infant. Cureus. 2019;11(9):e5772. doi:10.7759/cureus.5772
11. Quinn KE, Infante J, Thorson W, Thorson CM. Unique case of congenital lipomatous overgrowth with vascular malformations, epidermal nevi, and skeletal/spinal anomalies syndrome in a pediatric patient. Cureus. 2020;12(9):e10737. doi:10.7759/cureus.10737
12. Mathew L, George R, Sudhakar S, Keshava SN, Fouzia NA. Clinical profile of overgrowth syndromes consistent with PROS (PIK3CA-Related Overgrowth Syndromes)-A case series. Indian Dermatol Online J. 2020;11(5):738–746. doi:10.4103/idoj.IDOJ_520_19
13. Keppler-Noreuil KM, Rios JJ, Parker VE, et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015;167A(2):287–295. doi:10.1002/ajmg.a.36836
14. Keppler-Noreuil KM, Parker VE, Darling TN, Martinez-Agosto JA. Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. Am J Med Genet C Semin Med Genet. 2016;172(4):402–421. doi:10.1002/ajmg.c.31531
15. Kurek, Kyle C., Valerie L. Luks, Ugur M. Ayturk, Ahmad I. Alomari, Steven J. Fishman, Samantha A. Spencer, John B. Mulliken, i in. „Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES Syndrome”. The American Journal of Human Genetics 90, nr 6 (czerwiec 2012): 1108–15. https://doi.org/10.1016/j.ajhg.2012.05.006.
16. Panteliades M, Silva CM, Gontijo B. What is your diagnosis? An Bras Dermatol. 2016;91(3):378–380. doi:10.1590/abd1806-4841.20165897
17. Anderson, Sharon, i Susan Sklower Brooks. „An Extremely Rare Disorder of Somatic Mosaicism: CLOVES Syndrome”. Advances in Neonatal Care 16, nr 5 (październik 2016): 347–59. https://doi.org/10.1097/ANC.0000000000000342
18. Castiglioni C, Bertini E, Orellana P, et al. Activating PIK3CA somatic mutation in congenital unilateral isolated muscle overgrowth of the upper extremity. Am J Med Genet A. 2014;164A(9):2365–2369. doi:10.1002/ajmg.a.36651
19. Panteliades M, Silva CM, Gontijo B. What is your diagnosis? An Bras Dermatol. 2016;91(3):378–380. doi:10.1590/abd1806-4841.20165897
20. Alomari AI, Chaudry G, Rodesch G, et al. Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome: analysis of clinical and imaging f indings in 6 patients. AJNR Am J Neuroradiol. 2011;32(10):1812–1817. doi:10.3174/ajnr.A2349
21. Loconte DC, Grossi V, Bozzao 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;10(4):e0123092. doi:10.1371/journal.pone.0123092
22. Acosta S, Torres V, Paulos M, Cifuentes I. CLOVES syndrome: severe neonatal presentation. J Clin Diagn Res. 2017;11(4):TR01–TR03. doi:10.7860/JCDR/2017/23801.9719
23. Alomari AI. Characterization of a distinct syndrome that associates complex truncal overgrowth, vascular, and acral anomalies: a descriptive study of 18 cases of CLOVES syndrome. Clin Dysmorphol. 2009;18(1):1–7. doi:10.1097/MCD.0b013e328317a716
24. Manor J, Lalani SR. Overgrowth syndromes-evaluation, diagnosis, and management. Front Pediatr. 2020;8:574857. doi:10.3389/fped.2020.574857
25. Bloom, Jacob, i Joseph Upton. „CLOVES Syndrome”. The Journal of Hand Surgery 38,
nr 12 (grudzień 2013): 2508–12. https://doi.org/10.1016/j.jhsa.2013.08.120.
26. Alomari, Ahmad I., Patricia E. Burrows, Edward Y. Lee, Daniel J. Hedequist, John B. Mulliken, StevenJ. Fishman. „CLOVES Syndrome with Thoracic and Central Phlebectasia: Increased Risk of Pulmonary Embolism”. The Journal of Thoracic and Cardiovascular Surgery 140, nr 2 (sierpień 2010): 459–63. https://doi.org/10.1016/j.jtcvs.2010.04.023.
27. Bertino F, Braithwaite KA, Hawkins CM, et al. Congenital limb overgrowth syndromes associated with vascular anomalies. Radiographics. 2019;39(2):491–515. doi:10.1148/rg.2019180136
28. López-Gutiérrez JC, Redondo P, Ivars M. Fingertip capillary malformation and associated disorders: report of 9 cases. Pediatrics. 2017;140(1): e20162967. doi:10.1542/peds.2016-2967
29. Martinez-Lopez, A., Blasco-Morente, G., Perez-Lopez, I., Herrera-Garcia, J. D., Luque-Valenzuela, M., Sanchez-Cano, D., Lopez-Gutierrez, J. C., Ruiz-Villaverde, R., & Tercedor-Sanchez, J. (2017). CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). In Clinical Genetics (Vol. 91, Issue 1, pp. 14–21). Blackwell Publishing Ltd. https://doi.org/10.1111/cge.12832
30. Kolokythas A. Vascular Malformations and Their Treatment in the Growing Patient. Oral Maxillofac Surg Clin N Am. 2016;28:91–104. Kolokythas A. Vascular Malformations and Their Treatment in the Growing Patient. Oral Maxillofac Surg Clin N Am. 2016;28:91–104.
31. Fin De Grado, T., & Bodoano Sánchez, D. I. (n.d.). Grado en Medicina A NEW APPROACH TO CLOVES SYNDROME TREATMENT.
32. Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014;164A(7):1713–1733. doi:10.1002/ajmg.a.36552
33. Kuentz P, St Onge J, Duffourd Y, Courcet JB, Carmignac V, Jouan T, et al. Molecular diagnosis of PIK3CA related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing. Genet Med 2017;19:989 97
34. Venot Q, Blanc T, Rabia SH, et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature. 2018;558(7711):540–546. doi:10.1038/s41586-018-0217-9
35. Garreta Fontelles, Gemma, Júlia Pardo Pastor, i Carme Grande Moreillo. „Alpelisib to
Treat CLOVES Syndrome, a Member of the PIK3CA‐related Overgrowth Syndrome
Spectrum”. British Journal of Clinical Pharmacology 88, nr 8 (sierpień 2022): 3891–95.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Julianna Podolec, Silvia Ciraolo, Joanna Wojda, Adam Sobiński, Zuzanna Kościuszko, Katarzyna Kurza, Agnieszka Kulczycka-Rowicka, Matylda Czerwonka, Katarzyna Lesiczka-Fedoryj, Anna Walczak
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 39
Number of citations: 0
