Knowledge on rare diseases and orphan drugs

The prevalence of CLOVES syndrome is unknown and there is no sex predominance. CLOVES syndrome is the most common overgrowth syndrome associated with a PIK3CA variant, also known as PROS (for PIK3CA-related overgrowth spectrum), affecting over 500 patients in France.

CLOVES syndrome is defined by its acronym (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies). In most cases, hypertrophy, often asymmetrical, is present at birth. The postnatal progression of lesions is usually moderate, but some patients may present hypertrophy with a more severe course. Hypertrophies can affect different parts of the body, more or less extensive, and involve fatty, muscular, nervous and/or skeletal tissues. Associated vascular anomalies (capillary, venous and/or lymphatic) are present in almost half of patients, and epidermal hamartomas are less frequent. Extremity anomalies (syndactyly, polydactyly) are sometimes observed.

The syndrome is due to a heterozygous mosaic variation - also known as postzygotic - in the PIK3CA gene, occurring in early embryogenesis. The PIK3CA gene encodes the catalytic alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase protein.

Diagnosis must be confirmed by identification of a mosaic PIK3CA variation on affected tissue without culture, using high-depth high-throughput sequencing. Samples are usually taken by skin biopsy.

The differential diagnosis includes: 1) other PROS syndromes (Klippel-Trenaunay syndrome, megalencephaly-capillary malformation-polymicrogyria syndrome), 2) Proteus syndrome, which is due to a mosaic variation in the AKT1 gene, and is characterized by the absence of congenital manifestations, the onset of a pathognomonic cerebriform hamartoma, and a rapidly progressive natural course, 3) PTEN-related overgrowth disorders.

The diagnosis may be suspected during pregnancy in the presence of segmental tissue hypertrophy, possibly associated with abnormalities of the extremities. A negative amniocentesis does not exclude the diagnosis.

The risk for siblings of a proband with a PIK3CA mosaic variant is the same as in the general population if the parents are not variant carriers. Therefore, prenatal diagnosis is not particularly recommended.

Because of the multisystemic involvement, patient management requires multi-disciplinary care by expert teams, with at least one annual physical examination, and further investigations may be needed based on clinical presentation. Screening for Wilms tumor (nephroblastoma) is not needed when the risk is less than 5 %. Therapeutic management of CLOVES syndrome consists of preventing and treating complications: medical management of inflammatory or painful inflammatory flare-ups, thrombo-embolic complications, superficial or non-disabling vascular malformations, correction of lower limb length discrepancy, and of a possibly associated scoliosis. Alpelisb, a specific inhibitor of the PI3K-mTOR pathway, is proposed in therapeutic trials or on a compassionate basis, according to a therapeutic protocol. This treatment improves quality of life, reduces hypertrophy and vascular symptoms, and avoids the need for surgery.

The clinical presentation of the disease can be extremely variable, depending on the type of tissue affected by the variation and its extent. Treatment with alpelisib changes the prognosis of the disease for most of the patients.

Last update: January 2024 - Expert reviewer(s): Pr Laurent GUIBAUD | ERN CRANIO* - Pr Laurence OLIVIER-FAIVRE | ITHACA*

* European Reference Network