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What is CLOVES?

Deciphering the CLOVES Acronym

 

C is for Congenital, which means something you are born with. All people diagnosed with CLOVES had some symptoms at birth or in utero.

L is for Lipomatous, which means fatty or having to do with fat. Typically most CLOVES patients have a soft fatty mass at birth, often visible on one or both sides of the back and abdomen.

O is for Overgrowth, which means people with CLOVES may grow some areas of their bodies, at a much faster rate than others. 

V is for Vascular Malformations.  These can range from mild to complex. People with CLOVES have ‘different’ venous, capillary and lymphatic channels (the systems that are responsible for blood flow and the lymph system). Typically capillary, venous, and lymphatic malformations are known as “slow flow” lesions. Capillary malformations are reddish/pinkish birthmarks. Prominent veins are also common. Some people with CLOVES have fast-flow vascular malformations (known as Arterio-Venous Malformations – AVM) which are rare and aggressive. Some people with CLOVES have overgrowth over/nearby their vascular malformations. The effect of a vascular malformation on a person has much to do with the kind, size, location, etc. of the malformation, and symptoms can vary greatly.

E is for Epidermal Nevus, which is a skin lesion that can be flat, tan, or slightly raised.

S is for Spinal/Skeletal Anomalies or Scoliosis. Some people with CLOVES have tethered spinal cord, vascular malformations in/around their spines and other spinal differences. High flow, aggressive spinal lesions (like AVM) can cause serious neurological deficits/paralysis.

There are a variety of signs and symptoms not covered in the CLOVES acronym. These include: overgrowth of extremities (usually located on the arms or legs), large wide hands or feet, large fingers or toes, wide space between the toes and fingers and asymmetry of body parts. Other skin anomalies include lymphatic vesicles (look like blisters) and other birthmarks. Some people with CLOVES have different orthopedic challenges related to knees or hips. Some people with CLOVES have different sizes or absence of a kidney.

CLOVES is caused by a somatic genetic mutation in a gene called PIK3CA that increases the activity of the gene. CLOVES belongs to a category of diseases known as PIK3CA-related overgrowth spectrum or PROS.


Clinical Signs

 

CLOVES Syndrome is an overgrowth syndrome with complex vascular anomalies. CLOVES stands for Congenital, Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies. The syndrome was described independently by Saap et al. and Alomari [1,2]. The syndrome shows no inheritance among families of affected patients.

CLOVES syndrome is rare and very variable; ranging from mild to severe. The common features in most patients allow for proper diagnosis and distinction from other syndromes. The most consistent features of the syndrome are:

  1. Fatty Truncal Mass: Typically, a soft fatty mass of variable size is noted at birth. The mass can be seen in one or both sides of the back and abdominal wall and extending into gluteal or groin regions. The skin over the mass is covered with a red-pinkish birthmark known as a port-wine stain or capillary malformation. The fatty mass may extend into the chest, abdomen or into the spinal canal (around the spinal cord).
  2. Vascular Anomalies: In addition to the skin birthmark, patients with CLOVES syndrome have abnormal lymphatic and venous channels. In addition, a group of patients suffer from a more aggressive vascular anomaly (Arteriovenous malformation – AVM) around the area of the spinal cord.
  3. Abnormal extremities (arms and legs) and scoliosis (curving of the spine) are common. A person with CLOVES may have large wide hands or feet, large fingers or toes, wide space between digits and uneven size of extremities.
  4. Skin abnormalities include birthmarks, prominent veins, lymphatic vesicles, moles and epidermal nevus (light brownish slightly raised skin in the upper chest, neck or face).
  5. Other abnormalities include small or absent kidney, abnormal patella (knee cap), knee and hip joints.

Most people with CLOVES syndrome do not have all these signs, but rather a combination of abnormalities; though some can be subtle or deeply seated and requires a dedicated physical exam and proper imaging studies.

The diagnosis can be established right after birth, though prenatal diagnosis with modern imaging tools may be feasible [3].

Diagnosis:

Historically CLOVES Syndrome diagnosis has been made by medical exam, observed physical characteristics and clinical information/history. With the discovery of genetic mutation in CLOVES and PROS conditions, tissue testing for PIK3CA can be performed. The diagnosis can be established right after birth, though prenatal diagnosis with modern imaging tools may be feasible.

Criteria:

  • Fatty Truncal Mass
  • Vascular Anomalies
  • Abnormal extremities
  • Skin abnormalities
  • Other abnormalities include small or absent kidney, abnormal, knee and hip joints, and/or scoliosis.

The management of CLOVES syndrome can be very challenging and requires an interdisciplinary team of physicians with experience in overgrowth and vascular anomalies.

References:

  1. Sapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry RB, Biesecker LG. 2007. Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients. AmJ Med Genet Part A 143A: 2944-2958.
  2. Alomari AI. 2009. 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;18:1-7.
  3. Fernandez-Pineda I, Fajardo M, Chaudry G, Alomari AI. Perinatal clinical and imaging features of CLOVES syndrome. Pediatr Radiol.

PIK3CA Related Overgrowth Spectrum (PROS)

 

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term for rare syndromes characterized by malformations and tissue overgrowth caused by somatic mutations in the PIK3CA gene. In PROS conditions, malformations are seen in several different tissues such as skin, vasculature, bones, fat and brain tissue depending on the specific disease.

Some people with a PIK3CA mutation fall clearly into one of the diagnoses below, whereas others have symptoms of several different PROS syndromes. Additionally some clinicians diagnose patients with PROS, the umbrella term, instead of one of the syndromes under the PIK3CA umbrella. This can be confusing to providers as well as patients and families.

The clinical diagnoses in patients with PIK3CA activating mutations have included Fibroadipose hyperplasia or Overgrowth (FAO/FAVA), Hemihyperplasia Multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, macrodactyly, Facial Infiltrating Lipomatosis (FIL), and the related megalencephaly syndromes, Megalencephaly‐Capillary Malformation (MCAP or M‐CM) and Dysplastic Megalencephaly (DMEG) – (Keppler-Noreuil et al)

Additionally PIK3CA mutations have been found in Klippel-Trenaunay Syndrome as well as Lymphatic Malformation.

(Image above from PIK3CA‐related overgrowth spectrum (PROS): Diagnostic and testing eligibility criteria, differential diagnosis, and evaluation – Kim Keppler – Noreuil et al.)

Some people with a PIK3CA mutation fall clearly into one of the diagnoses above, whereas others have symptoms of several different PROS syndromes.  Additionally some clinicians diagnose patients with PROS, the umbrella term, instead of one of the syndromes under the PIK3CA umbrella.  This can be confusing to providers as well as patients and families.

Novartis Launches “Meet the PROS” Educational Campaign to Raise Awareness for PROS Conditions
Novartis PROS Website for Health Care Providers
Novartis PROS Website for Patients and Families 

Patient Advocacy Organizations for other PROS Disorders are below:

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