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CLOVES syndrome
CLOVES syndrome is a rare condition where certain body tissues grow too much, or in unusual ways. It results from changes in the PIK3CA gene that happen after conception, affecting specific parts of the body.
Overview
CLOVES syndrome is a rare condition known as a PIK3CA-related overgrowth spectrum (PROS) disorder. It involves the abnormal growth of tissues such as fat, blood vessels, and bones, and can lead to a variety of physical differences [PMID:27088927]. The acronym CLOVES stands for Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal naevi, and Skeletal anomalies, which are some of the key features of the condition. However, not everyone with CLOVES syndrome will have all these features, and the severity can vary widely amongst individuals.
This condition is not typically inherited in families. Instead, it is caused by genetic changes that occur early in development, meaning only some cells in the body carry the change (mosaicism). The parts of the body affected depend on which cells have the genetic change [PMID:22609945].
Symptoms & clinical features
The symptoms of CLOVES syndrome are diverse and can affect many parts of the body. One common feature is overgrowth of fatty tissue, particularly on the trunk (torso) or limbs, which can be soft, doughy, or firm. Individuals may also have vascular malformations, which are abnormal formations of blood vessels such as capillaries, veins, or lymphatic vessels [PMID:22609945]. These can sometimes cause discomfort or other medical issues.
Skeletal anomalies, including differences in bone growth or shape, are also frequent. These might include curvature of the spine (scoliosis), abnormally large hands or feet, or issues with joints. Epidermal naevi, which are skin lesions or birthmarks, can also be present. Other possible features include kidney problems, brain abnormalities, or issues with the nervous system. The specific combination and severity of these symptoms are unique to each person with CLOVES syndrome.
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Affected organs
CLOVES syndrome primarily affects tissues that grow and develop from the mesoderm and ectoderm layers during embryonic development. This means that various body systems can be involved. The skin and subcutaneous tissues (fat and connective tissue beneath the skin) are often prominently affected, leading to characteristic fatty overgrowths and vascular malformations.
Musculoskeletal structures, including bones, muscles, and joints, can also show anomalies, leading to limb asymmetry or skeletal deformities. Internal organs such as the kidneys, bladder, and brain may also be affected by overgrowth or malformations. The extent of organ involvement contributes to the variable presentation of the syndrome.
Risks & severity
The severity of CLOVES syndrome is highly variable, ranging from relatively mild forms with localised overgrowth to more severe presentations affecting multiple body systems. The specific parts of the body affected and the extent of overgrowth can influence potential complications. For example, large vascular malformations can sometimes lead to problems such as blood clots or excessive bleeding.
Spinal abnormalities, such as scoliosis, may require careful monitoring and intervention. Some individuals might experience challenges with mobility due to limb differences or joint issues. While specific lifetime risks for all complications are not fully established due to the rarity of the condition, regular medical follow-up is generally recommended to manage symptoms and monitor for potential issues as they arise.
Genetic causes
CLOVES syndrome is caused by changes in the PIK3CA gene. This gene provides instructions for making a protein called p110 alpha, which is a key component of an enzyme called phosphatidylinositol-3-kinase (PI3K) [PMID:22609945]. The PI3K enzyme plays a crucial role in cell growth, proliferation, differentiation, and survival by adding phosphate groups to other molecules, thereby initiating important signalling pathways within cells.
In individuals with CLOVES syndrome, a specific type of genetic change, known as a somatic mutation, occurs in the PIK3CA gene. 'Somatic' means that the change happens in some body cells after conception, rather than being inherited from a parent. These changes lead to the PI3K enzyme being overactive, which then promotes excessive cell growth and division in the affected tissues, resulting in the characteristic overgrowth and malformations seen in the condition [PMID:22609945].
- PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alphaThe PIK3CA gene provides instructions for a crucial enzyme involved in fundamental cellular processes such as growth, division, and survival.
Inheritance pattern
CLOVES syndrome typically has a somatic inheritance pattern, which means the genetic change in the PIK3CA gene occurs spontaneously in a single cell early in an individual's development after conception. As this cell divides, the genetic change is passed on to subsequent cells, but only in a specific lineage of cells.
This results in a 'mosaic' distribution, where some cells in the body have the genetic change, and others do not. Because the change is not present in all cells (including germ cells, which are involved in reproduction), CLOVES syndrome is generally not inherited from parents and is not usually passed on to children. Recurrence in future children of affected parents is considered very low.
Diagnosis & testing
Diagnosing CLOVES syndrome often begins with a clinical assessment based on the characteristic physical features. Due to the wide range of symptoms, a diagnosis may be suspected based on the presence of certain combinations of overgrowth, vascular malformations, and skeletal anomalies.
Genetic testing is used to confirm the diagnosis by identifying a somatic (mosaic) variant in the PIK3CA gene. This testing often involves looking at affected tissues where the overgrowth is present, as the genetic change may not be detectable in a standard blood sample if only a small proportion of cells are affected. In the UK, genetic testing for CLOVES syndrome and other PIK3CA-related overgrowth spectrum disorders is available through the NHS Genomic Medicine Service (GMS) under specific testing pathways. Referral to a clinical genetics service is usually made by a specialist paediatrician or other relevant consultant.
Management & lifestyle
Management of CLOVES syndrome is typically multidisciplinary, involving a team of specialists to address the diverse symptoms. Care is individualised based on the specific manifestations and severity for each person. This often includes regular monitoring for changes in overgrowth, vascular malformations, and skeletal issues. Physiotherapy, occupational therapy, and orthopaedic interventions may be required to manage skeletal anomalies and improve mobility.
Vascular malformations may be managed through medical treatments, sclerotherapy (injections to shrink malformations), or surgical interventions. Some targeted therapies that inhibit the PI3K pathway are being researched and, in some cases, used to manage severe symptoms. Access to these treatments is usually via specialist centres within the NHS. Regular follow-up appointments with appropriate specialists are essential to adapt care as the individual grows and develops.
UK care pathway
In the UK, individuals suspected of having CLOVES syndrome are typically referred to a clinical genetics service or a specialist centre within the NHS. Genetic testing is available through the NHS Genomic Medicine Service (GMS) as part of national testing pathways for overgrowth syndromes (e.g., R-code R115, R137, R148 for PIK3CA-related conditions). A genetic counsellor will often be part of the care team, providing information, support, and discussions about the genetic diagnosis and its implications for the individual and their family.
Frequently asked questions
Is CLOVES syndrome inherited?
No, CLOVES syndrome is generally not inherited. It is caused by a genetic change that occurs spontaneously in some body cells early in development, meaning it is not passed down from parents to children.
What does 'somatic mosaicism' mean in CLOVES syndrome?
'Somatic mosaicism' means that the genetic change causing CLOVES syndrome is present in some cells of the body, but not all. This happens after conception, during early development, and explains why symptoms can be localised to specific body parts.
Can CLOVES syndrome be cured?
There is currently no cure for CLOVES syndrome. Management focuses on treating the specific symptoms and complications that arise. Research into targeted therapies that may help control the overgrowth is ongoing.
What kind of doctors treat CLOVES syndrome?
Because CLOVES syndrome affects many body systems, a team of specialists usually provides care. This often includes paediatricians, geneticists, orthopaedic surgeons, vascular specialists, plastic surgeons, and physiotherapists.
Why is genetic testing for CLOVES syndrome sometimes done on affected tissue?
Since the genetic change in CLOVES syndrome is mosaic (present only in some cells), it may not be detectable in routine blood samples. Testing affected tissue, where the changed cells are concentrated, increases the chance of finding the causative genetic variant.
References
- Venot Q, Blanc T, Rabia SH. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature. 2018. PMID: 29899452
- Escobar K, Pandher K, Jahnke MN. Capillary Malformations. Dermatologic clinics. 2022. PMID: 36243429
- Adam MP, Bick S, Mirzaa GM. PIK3CA-Related Overgrowth Spectrum. 1993. PMID: 23946963
- Kanji A, Cobben J, Laguda B. CLOVES Syndrome. JAMA dermatology. 2023. PMID: 37017999
- Bloom J, Upton J 3rd. CLOVES syndrome. The Journal of hand surgery. 2013. PMID: 24161472
- Keppler-Noreuil KM, Rios JJ, Parker VE. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. American journal of medical genetics. Part A. 2015. PMID: 25557259
- Öztürk Durmaz E, Demircioğlu D, Yalınay Dikmen P. A Review on Cutaneous and Musculoskeletal Manifestations of CLOVES Syndrome. Clinical, cosmetic and investigational dermatology. 2022. PMID: 35444443
- Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I. CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clinical genetics. 2017. PMID: 27426476