NORD gratefully acknowledges Ahmad I. Alomari, MD, MSc, FSIR, Associate Professor; Program Director, Pediatric Vascular and Interventional Radiology Fellowship; Co-Director, Vascular Anomalies Center, Children's Hospital Boston, for the preparation of this report.
CLOVES syndrome (CS) is a recently described rare disorder characterized by tissue overgrowth and complex vascular anomalies. CLOVES stands for congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomalies.
CLOVES syndrome was described independently by Saap and colleagues in 2007 and Alomari in 2009. A case report by the German physician Hermann Friedberg "gigantism of the right lower limb" published in 1867 is probably the first known written account of CLOVES syndrome.
CLOVES syndrome belongs to the spectrum of overgrowth syndromes with complex vascular anomalies caused by mosaic mutations in the PIK3CA gene. The rare CS may affect the soft tissue, blood vessels, bone and internal organs. The manifestations are very variable ranging from mild to severe anomalies. These abnormalities are typically present at birth.
The most common features are:
1. Fatty overgrowth. Soft fatty masses of variable size are noted at birth and can be located in the back, flanks, axilla, abdomen and buttocks. These masses may affect one or both sides of the body. The skin over the mass is typically covered with a red-pinkish birthmark (capillary malformation or port-wine stain).
2. Vascular anomalies: Dilated veins in the chest, upper and lower extremities may cause clot formation and occasionally serious pulmonary embolism (clot travelling from the vein to the lungs). Lymphatic malformations are abnormal, large spaces filled with lymph. These malformations are frequently noted within the fatty masses or in the abdomen, chest and extremities. A small subgroup of patients may suffer from the more aggressive arteriovenous malformation around the area of the spinal cord.
3. Abnormal extremities (arms and legs) are common. Large wide hands or feet, large fingers or toes, wide space between digits (sandal gap toe) and uneven size of extremities are common.
4. Spinal anomalies include scoliosis (curving of the spine), fatty masses and vessels pushing on the spinal cord and tethered cord (spinal cord fixed by abnormal band).
5. Skin birthmarks include port-wine stains, prominent veins, lymphatic vesicles, moles and epidermal nevus (slightly raised areas of skin with light brownish color).
6. Kidney anomalies: The size of the kidneys could be asymmetric (one is larger) and may show some abnormal features on imaging studies. Wilms tumor has been noted in a small number of young patients with CLOVES syndrome. This requires screening with serial ultrasound examinations during childhood.
Additional findings can occur in CLOVES syndrome including bleeding from the intestine, urinary bladder and asymmetric face and head.
Not all patients with CLOVES syndrome have all these signs, but rather a combination of abnormalities. Some can be subtle and a dedicated physical exam and proper imaging studies are required.
CLOVES syndrome is a nonhereditary disorder caused by a somatic (body cell) mutation in a gene known as PIK3CA. Mutations in this growth regulatory gene result in two sets of cells within the body (mosaic status): those with the mutation and those without the mutation. The mutated cells give rise to the abnormal tissue.
CLOVES syndrome is rare and evident at birth. It affects males and females equally regardless of their race or ethnicity. Many of the patients with CS are misdiagnosed as having other syndromes such as Klippel-Trenaunay syndrome or Proteus syndrome.
The diagnosis is evident at birth based on physical signs and symptoms. Confirmation of diagnosis can be done with molecular genetic testing for the PIK3CA gene mutation. Imaging studies include plain x-rays (radiography), magnetic resonance imaging (MRI) of the chest, abdomen, pelvis, spine and limbs and ultrasound for vascular anomalies and kidneys. Prenatal diagnosis with imaging tools is feasible.
The management of CLOVES syndrome can be very challenging and requires an interdisciplinary team of physicians with experience in overgrowth and vascular anomalies. The treatment should address the specific problems in the affected child. Debulking operations are necessary to reduce the size of the significant overgrown tissue. Orthopedic procedures are usually necessary for large limb anomalies. Large veins and lymphatic malformations should be treated with minimally invasive procedures such as sclerotherapy, embolization and laser treatment before undergoing surgical procedures due to the risk of vein thrombosis. Tethered cord is treated surgically.
Medical therapy with sirolimus demonstrated promising results; particularly for patients with lymphatic malformation and pain. The use of sirolimus or other medical therapies is rapidly changing in CLOVES and other vascular anomalies and should be guided by an experienced hematologist/oncologist.
The “Clinical Practice Guidelines for Management of CLOVES Syndrome” based on the institutional experience of the Vascular Anomalies Center at Boston Children’s Hospital is available at this link: http://www.clovessyndrome.org/sites/default/files/CLOVES_Syndrome_Management_Guidelines_For_Families_6-21-2014-2.pdf
Clinical Testing and Work-Up
Screening for Wilms tumor with serial ultrasounds up to age 8 years is recommended.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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Contact for additional information about CLOVES syndrome:
Ahmad I. Alomari, MD, MSc, FSIR
Program Director, Pediatric Vascular and Interventional Radiology Fellowship
Co-Director, Vascular Anomalies Center
Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 22115
Office (Main 242): 617-355-6541
Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Biesecker LG. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015 Feb;167A(2):287-95. https://www.ncbi.nlm.nih.gov/pubmed/25557259
Kurek KC, Luks VL, Ayturk UM, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet. 2012;90:1108-1115. http://www.ncbi.nlm.nih.gov/pubmed/22658544
Alomari AI, Chaudry G, Rodesch G, et al. Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome: analysis of clinical and imaging findings in 6 patients. AJNR Am J Neuroradiol. 2011;32:1812-1817. http://www.ncbi.nlm.nih.gov/pubmed/21310861
Alomari AI, Burrows PE, Lee EY, Hedequist DJ, Mulliken JB, Fishman SJ. CLOVES syndrome with thoracic and central phlebectasia: increased risk of pulmonary embolism. J Thorac Cardiovasc Surg. 2010;140:459-463. http://www.ncbi.nlm.nih.gov/pubmed/20537357
Alomari AI, Thiex R, Mulliken JB. Hermann Friedberg’s case report: an early description of CLOVES syndrome. Clin Gene. 2010;78:342-7. http://www.ncbi.nlm.nih.gov/pubmed/21050185
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. http://www.ncbi.nlm.nih.gov/pubmed/19011570
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. 2007;143A:2944-2958. http://www.ncbi.nlm.nih.gov/pubmed/17963221
Clinical Practice Guidelines for CLOVES Syndrome. CLOVES Syndrome Workgroup, Vascular Anomalies Center, Boston’s Children’s Hospital. Updated 6/20/2014. Available at: http://www.clovessyndrome.org/sites/default/files/CLOVES_Syndrome_Management_Guidelines_For_Families_6-21-2014-2.pdf Updated 6/20/2014. Accessed July 2, 2018.
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