Knowledge on rare diseases and orphan drugs

The prevalence of Klippel-Trénaunay syndrome (KTS) is unknown. KTS is one of the overgrowth syndromes associated with a PIK3CA variant, also known as PROS (for PIK3CA-related overgrowth spectrum), which affects over 500 patients in France.

Clinical diagnosis is based on a clinical triad combining: planar angioma(s), truncal venous/lymphatic-venous slow-flow malformation, and soft tissues and bone hypertrophy in the area affected by vascular dysplasia. The existence of an incontinence of marginal venous system with very slow or even stagnant flow, leading to a risk of thrombosis (mostly superficial, less frequent in deep veins) with embolic potential and pain, coexisting with a deep venous system that may be dysplasic, are characteristic features. Blood stagnation can lead to coagulation activation and even chronic localized intravascular coagulation. Lymphatic malformations can be macro- or microcystic, the latter being at risk of inflammation.

The syndrome is due to heterozygous post-zygotic mosaic variation in the PIK3CA gene, occurring in early embryogenesis. It has to be noted that not all KTS appear to result from PIK3CA mosaic variation.

Diagnosis must be confirmed by identification of a PIK3CA mosaic variation on affected tissue (most often skin) without culture, using high-depth high-throughput sequencing.

The differential diagnosis includes: Parkes-Weber syndrome which is due to variants of the RASA1 and EPHB4 genes, and characterized by high-flow vascular malformations with arteriovenous fistula; CLOVES syndrome; other PROS syndromes and PTEN-related overgrowth disorders.

The diagnosis may be suspected during pregnancy in the presence of segmental hypertrophy. Prognosis will be based on the extent of vascular malformations. 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. Prenatal diagnosis is therefore 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 is not needed when the risk is less than 5%. Therapeutic management consists of preventing and treating complications: medical management of inflammatory or painful flare-ups, thromboembolic complications, superficial or non-disabling vascular malformations, correction of lower limb length discrepancy, and of a possibly associated scoliosis. Acute painful episodes due to the presence of phleboliths in venous malformations are relieved by anti-inflammatory drugs or even heparin rather than analgesics. Compression of vascular deformities of the limbs is often unavoidable. Some vascular malformations can be managed by interventional radiology, thus avoiding the need for surgery. Laser treatment may be required for superficial vascular malformations. Alpelisib, a PI3K pathway inhibitor, is currently 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 highly variable. Treatment with alpelisib changes the prognosis when a PIK3CA variant was identified.

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

* European Reference Network