byl719 and Syndrome

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

Topics: Adult; Animals; Child; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Female; Heart Failure; HeLa Cells; Humans; Lipoma; Male; Mice; Molecular Targeted Therapy; Musculoskeletal Abnormalities; Nevus; Phenotype; Scoliosis; Sirolimus; Syndrome; Thiazoles; Vascular Malformations; Vascular Neoplasms

CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA-related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. The results have been promising and suggest that compassionate use of these treatments in patients with PROS disorders could have clinical benefits. Another promising drug is alpelisib (BYL719), which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signalling pathway. Compassionate use of low-dose alpelisib had striking effects in an uncontrolled case series of 19 PROS patients, several with life-threatening complications. Moreover, there were few adverse effects and the treatment did not impair linear growth, despite the young age of many of the patients. We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggests that low-dose PI3K inhibition may provide collateral benefits that extend beyond mitigation of disease-specific features of PROS.

Topics: Catalytic Domain; Class I Phosphatidylinositol 3-Kinases; Growth Disorders; Humans; Lipoma; Musculoskeletal Abnormalities; Mutation; Nevus; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Syndrome; Thiazoles; Vascular Malformations

Mosaic PIK3R1 variants have recently been demonstrated in patients with complex vascular malformations and overgrowth in a syndrome resembling PIK3CA-related overgrowth syndrome (PROS). The PIK3CA-inhibitor, alpelisib, seems to be a promising treatment option for PROS patients. We describe a young boy with overgrowth and a pathogenic mosaic variant in PIK3R1; c.1699A > G, p.(Lys567Glu). He was prenatally suspected of a syndrome on the presence of unusual transient fluctuating subcutaneous edemas and lymphedema of his left shoulder. The pathogenic variant, later found to be causative, was below detection threshold in whole-genome sequencing (WGS) analysis of amniotic fluid. Upon delivery a mosaic pathogenic PIK3R1 variant, was identified by whole-exome sequencing (WES) of a skin biopsy. With no proven treatment options available, and based on the theoretical disease mechanism, alpelisib therapy was initiated at nine months of age. In the first year of treatment growth normalized and the affected vascular and lymphatic tissue regressed. No side effects have been observed. This report underlines the importance of early variant detection in children suspected of having severe mosaic overgrowth, and proves that prenatal diagnosis is possible, enabling prompt treatment. Furthermore, it demonstrates the promising effects of alpelisib in this patient group.

Topics: Child; Class I Phosphatidylinositol 3-Kinases; Class Ia Phosphatidylinositol 3-Kinase; Early Diagnosis; Female; Humans; Male; Musculoskeletal Abnormalities; Mutation; Precision Medicine; Pregnancy; Syndrome; Thiazoles; Transcription Factors; Vascular Malformations