Pik3Ca Related Overgrowth Spectrum
PIK3CA-Related Overgrowth Spectrum (PROS) is a group of rare disorders characterized by segmental overgrowth of various tissues, resulting from postzygotic, somatic activating mutations in the PIK3CA gene. The PIK3CA gene encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), a crucial signaling protein involved in regulating cell growth, survival, and metabolism. Pathogenetically, mosaic mutations in PIK3CA lead to hyperactivation of the PI3K/AKT/mTOR pathway in affected tissues, causing abnormal proliferation, hypertrophy, and differentiation of cells. This results in asymmetric and disproportionate overgrowth of skin, subcutaneous tissue, muscle, bone, vasculature, and sometimes internal organs. Health impacts vary widely, from mild cosmetic concerns to severe functional impairment, chronic pain, orthopedic complications, organ dysfunction, and increased risk of vascular malformations, thrombosis, and, in rare cases, malignant transformation.
Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, and Skeletal/Spinal Anomalies (CLOVES) syndrome is characterized by congenital, complex truncal overgrowth with mixed vascular malformations, lipomatous masses, epidermal nevi, and skeletal/spinal deformities. Patients often present with asymmetric overgrowth of soft tissues, scoliosis, and complex vascular anomalies, which may involve the central nervous system.
FAH is defined by segmental overgrowth of fibrous and adipose tissues, typically presenting as painless, progressive enlargement of affected body regions, often in the limbs. The overgrowth can be associated with mild vascular changes and may cause functional limitations depending on the extent and location.
MCAP, formerly known as Megalencephaly-Capillary Malformation syndrome, is characterized by brain overgrowth (megalencephaly), cutaneous capillary malformations, developmental delay, cortical brain malformations, and connective tissue dysplasia. Neurological manifestations, including seizures and intellectual disability, are common.
KTS presents with a triad of capillary malformations (port-wine stains), venous and lymphatic anomalies, and soft tissue and bony overgrowth, usually affecting one or more limbs. Complications include chronic pain, limb length discrepancy, and risk of thrombosis or bleeding.
This form involves segmental or multifocal lymphatic malformations, often presenting as cystic masses in the skin, subcutaneous tissue, or internal organs. These lesions can cause swelling, pain, and, in some cases, infection or bleeding.
Hemimegalencephaly is a severe, congenital brain malformation characterized by overgrowth of one cerebral hemisphere, leading to intractable epilepsy, developmental delay, and neurological deficits. It is often associated with other features of PROS.
PIK3CA-Related Overgrowth Spectrum is a rare group of disorders, with precise prevalence and incidence rates not fully established due to underdiagnosis and phenotypic variability. Current estimates suggest that PROS conditions collectively affect fewer than 1 in 1,000,000 individuals. There is no clear gender predilection, and cases are reported worldwide across diverse populations. Most cases arise sporadically due to postzygotic mosaic mutations, and familial transmission is exceedingly rare. The spectrum of clinical severity and organ involvement contributes to considerable heterogeneity in reported cases, and the true epidemiological burden is likely underestimated.
Diagnosis of PROS is based on a combination of clinical evaluation, imaging studies, and molecular genetic testing. Clinically, the diagnosis is suspected in individuals with segmental, asymmetric overgrowth involving multiple tissue types, often associated with vascular, lymphatic, or epidermal anomalies. Detailed physical examination, assessment of growth patterns, and documentation of onset and progression are essential. Imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound are used to characterize the extent and nature of overgrowth and to identify associated vascular or lymphatic malformations. Definitive diagnosis requires molecular confirmation of a somatic, activating PIK3CA mutation in affected tissue, which is typically achieved through targeted next-generation sequencing or digital droplet PCR on biopsy specimens. Diagnostic criteria often include the presence of characteristic clinical features, radiological evidence of segmental overgrowth, and molecular identification of a pathogenic PIK3CA variant. Differential diagnosis includes other overgrowth syndromes and vascular anomalies not associated with PIK3CA mutations.
Alpelisib is an orally administered, selective inhibitor of the phosphatidylinositol 3-kinase (PI3K) p110α subunit, which is encoded by the PIK3CA gene. It is indicated for the treatment of patients with PIK3CA-Related Overgrowth Spectrum, targeting the underlying pathogenic mechanism by inhibiting the aberrant PI3K/AKT/mTOR signaling pathway that drives tissue overgrowth and vascular malformations. Clinical studies have demonstrated that alpelisib can reduce the size and symptoms of overgrown tissues and vascular anomalies, improve function, and decrease pain in affected individuals. The drug is administered under medical supervision, with monitoring for potential adverse effects such as hyperglycemia, rash, and gastrointestinal disturbances. Its use represents a significant advancement in the targeted management of PROS, offering a disease-modifying approach for patients with confirmed PIK3CA mutations.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | alpelisib (Rec INN; USAN) | 1217486-61-7 | C19 H22 F3 N5 O2 S | 441.47 |
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