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CLOVES syndrome

Author: Tae Yeb (Terry) Kim, House Officer, North Shore Hospital, Auckland, New Zealand. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. April 2020.

What is CLOVES syndrome?

CLOVES syndrome is a rare, progressive congenital disorder that involves multiple organs including the skin, the vascular system, and the musculoskeletal system [1].

CLOVES is a mnemonic acronym for:

  • Congenital lipomatous overgrowth
  • Vascular malformations
  • Epidermal naevi
  • Spinal/skeletal anomalies/scoliosis.

Who gets CLOVES syndrome?

CLOVES syndrome is extremely rare — about 40 cases have been reported as of 2020 — and there is no accurate estimation of the incidence or prevalence globally. The mutation is sporadic and there is no known familial predisposition.

What causes CLOVES syndrome?

CLOVES syndrome is caused by a somatic mosaic gain-of-function mutation (a mutation that occurs after the creation of the zygote) in the PIK3CA gene [2]. It is a part of the PIK3CA-Related Overgrowth Spectrum (PROS), a group of rare overgrowth disorders [3].

What are the clinical features of CLOVES syndrome?

CLOVES syndrome presents at birth with vascular malformations, adipose tissue overgrowth (lipomas), epidermal naevi, and varying degrees of bony deformities [4]. Asymmetrical, disproportionate growth may be evident in prenatal scans [5].

The characteristic features of CLOVES syndrome include:

  • A large lipoma on the trunk, which may invade nearby structures and organs such as the spinal area [4]
  • There is an overlying vascular malformation, which may be low-flow (capillary, venous, lymphatic) or less often, high-flow (arteriovenous)
  • Venous malformations present as phlebectasia; arteriovenous malformations tend to be paraspinal [4]
  • Lipomatous overgrowth may also affect the legs and feet, with relative lipoatrophy in other parts of the body [1,3,5,6]
  • External genitalia may also be involved [7]
  • Papillomatous and hyperkeratotic linear epidermal naevi may follow Blaschko lines or vascular/neural structures [8]
  • Skeletal changes may be physically debilitating and impair mobility; they may include scoliosis, asymmetrical macrodactyly, widened triangular feet, large hands, and an increased metatarsal gap [4].

What are the complications of CLOVES syndrome?

The complications of CLOVES syndrome depend on its extent. These can include:

  • Invasion into the spinal cord may cause spinal compression with neurological compromise
  • A severe vascular malformation may lead to anaemia and may cause myelopathy if the syndrome is spinal or paraspinal
  • A large tumour-like mass may compress adjacent structures
  • Heart failure may occur
  • Cognitive impairment and epilepsy have been reported [1,6]
  • CLOVES has resulted in postoperative deep vein thrombosis (DVT) and pulmonary embolism (PE) [9]
  • Nephroblastoma (Wilms tumour), an embryogenic tumour of developing kidneys, has been associated with CLOVES syndrome [10].

How is CLOVES syndrome diagnosed?

The diagnosis of CLOVES syndrome is based upon:

  • The patient's history, which is distinct from other overgrowth syndromes [1]
  • The findings on physical examination
  • Genetic testing to detect mutation in the PIK3CA gene.

Radiological findings can support the diagnosis. Vascular malformations and lipomatous masses can be assessed by magnetic resonance imaging (MRI) [11].

What is the differential diagnosis for CLOVES syndrome?

The main disorder to be distinguished from CLOVES is proteus syndrome, in which there is no body overgrowth at birth, and no truncal lipomatous mass, acral, or skeletal abnormalities [12].

Other differential diagnoses for CLOVES syndrome include:

What is the treatment for CLOVES syndrome?

There is no cure for CLOVES syndrome. Improvements in patient condition have been reported from experimental treatments with:

  • Rapamycin [13,14]
  • Inhibitors of PIK3CA gene mutations, such as alpelisib (approved for the treatment of advanced or metastatic breast cancer) [14–16].

What is the outcome for CLOVES syndrome?

The prognosis of CLOVES syndrome is usually poor, due to its complications. However, there are indications that treatments with PIK3CA inhibitors will prove effective.

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References

  1. Sapp JC, Turner JT, van de Kamp, Jiddeke M, 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 Gen A 2007; 143: 2944–58. DOI: 10.1002/ajmg.a.32023. PubMed
  2. Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. The Am J Hum Genet 2012; 90: 1108–15. DOI: 10.1016/j.ajhg.2012.05.006. PubMed Central
  3. Kang HC, Baek ST, Song S, Gleeson JG. Clinical and Genetic Aspects of the Segmental Overgrowth Spectrum Due to Somatic Mutations in PIK3CA. J Pediatr 2015; 167: 957–62. DOI: 10.1016/j.jpeds.2015.07.049. PubMed
  4. 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: 1–7. DOI: 10.1097/MCD.0b013e328317a716. PubMed
  5. Schreiber A, Grenier PO, Auger I. A case of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies and/or scoliosis syndrome with lipoatrophy as an important clinical manifestation. Pediatr Dermatol 2017; 34: 735–6. DOI: 10.1111/pde.13256. PubMed
  6. Kasinathan A, Sankhyan N, Ahuja CK, Singhi P. CLOVE Syndrome. Indian J Pediatr 2018; 85: 79–80. DOI: 10.1007/s12098-017-2416-z. PubMed
  7. Lopez Gutierrez JC, Lizarraga R, Delgado C, Martinez Urrutia MJ, Diaz M, Miguel M, 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: 648–50. DOI: 10.1016/j.jpag.2019.07.003. PubMed
  8. Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, Herrera-Garcia JD, Luque-Valenzuela M, Sanchez-Cano D, et al. CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clin Genet 2017; 91: 14–21. DOI: 10.1111/cge.12832. PubMed
  9. Reis J,3rd, Alomari AI, Trenor CC,3rd, Adams DM, Fishman SJ, Spencer SA, et al. Pulmonary thromboembolic events in patients with congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal abnormalities and Klippel-Trenaunay syndrome. J Vasc Surg Venous Lymphat Disord 2018; 6: 511–6. DOI: 10.1016/j.jvsv.2018.01.015. PubMed
  10. Peterman CM, Fevurly RD, Alomari AI, Trenor CC,3rd, Adams DM, Vadeboncoeur S, et al. Sonographic screening for Wilms tumor in children with CLOVES syndrome. Pediatr Blood Cancer 2017; 64: 10.1002/pbc.26684. DOI: 10.1002/pbc.26684. PubMed
  11. Bertino F, Braithwaite KA, Hawkins CM, Gill AE, Briones MA, Swerdlin R, et al. Congenital Limb Overgrowth Syndromes Associated with Vascular Anomalies. Radiographics 2019; 39: 491–515. DOI: 10.1148/rg.2019180136. PubMed
  12. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham Jr JM, Viljoen DL, et al. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 1999; 84: 389–95. DOI: 10.1002/(sici)1096-8628(19990611)84:5<389::aid-ajmg1>3.0.co;2-o. PubMed
  13. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304(5670): 554. DOI: 10.1126/science.1096502. PubMed
  14. Hammill AM, Wentzel M, Gupta A, Nelson S, Lucky A, Elluru R, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011; 57: 1018–24. DOI: 10.1002/pbc.23124. PubMed
  15. Venot Q, Blanc T, Rabia SH, Berteloot L, Ladraa S, Duong JP, et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 2018; 558(7711): 540–6. DOI: 10.1038/s41586-018-0217-9. PubMed
  16. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Reviews Cancer 2009; 9: 550–62. DOI: 10.1038/nrc2664. PubMed

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