PA04 Germline activating variants in PIK3CA result in a diffuse overgrowth phenotype characterized by macrocephaly, cardiovascular and renal anomalies: recommendations for screening and monitoring

Abstract Somatic activating mutations in PIK3CA cause a wide spectrum of clinical phenotypes characterized by mosaic pattern overgrowth of tissues. These are grouped under the umbrella term ‘PIK3CA-related overgrowth syndrome’ (PROS). Mosaic PROS has a reported prevalence of 1 in 28 000 live births. However, germline heterozygous PIK3CA variants leading to an overgrowth phenotype are extremely rare, reported in fewer than 20 cases to date. Here we report three new patients with germline PI3KCA variants and present this in the context of the existing literature, highlighting key clinical findings with recommendations for baseline evaluation and monitoring. Patient 1, an 11-year-old girl, was diagnosed antenatally with a single umbilical artery and presented with multiple congenital cardiac anomalies: dysplastic pulmonary valve, multiple apical muscular ventricular septal defects, patent ductus arteriosus, and secundum atrial septal defects. Other features noted include marked hypotonia, developmental delay, digit abnormalities, cutaneous capillary malformations, and bilateral duplex kidneys. Macrocephaly has been prominent throughout childhood, but with normal cranial imaging. Patient 2, a 6-year-old boy, presented with macrosomia, macrocephaly (normal cranial imaging) and subtle left-sided overgrowth with one small area of capillary malformation. He has mild developmental delay. Patient 3, a 20-month-old girl, presented with macrocephaly, left-sided capillary malformations and mild gross motor developmental delay with hypermobility. Magnetic resonance imaging findings include macrocephaly with polymicrogyria, thick corpus callosum and large cerebellum. Including our three patients, 21 patients with germline PIK3CA variants have been reported to date. Macrocephaly was a predominant feature in 95% (20 of 21), as was developmental delay 100% (9 of 9), where data were available. Importantly, of those with available data, 33% of patients had renal anomalies (3 of 9) and 71% had cardiac or vascular anomalies (10 of 14), neither of which are frequently observed in mosaic PROS. Germline heterozygous activating PIK3CA variants cause diffuse overgrowth, forming a rare but distinct part of PROS. We characterize here a cohort of patients, adding three new cases to the existing literature. Macrocephaly and developmental delay are observed almost universally in this cohort, and in contrast to mosaic PROS there is a high proportion of renal and cardiovascular anomalies. Clinicians should be alerted to these salient features and perform baseline neurological, cardiac and renal imaging at diagnosis, and ensure close neurodevelopmental monitoring. Unlike mosaic PROS, where the risk of passing the variant to offspring is small, in rare cases of gonadal mosaicism, inheritance of germline PIK3CA variants will follow an autosomal dominant pattern, thus referral to clinical genetics for counselling is critical for this cohort.