Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials

Abstract

Megalencephaly‐CApillary malformation‐Polymicrogyria (MCAP) syndrome results from somatic mosaic gain‐of‐function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants

“…Clear-cut genotype/phenotype correlations for all PROS entities is not possible. Our analysis mostly confirmed previous observations and the few genotype-phenotype correlations already evidenced9–32 74: (a) some variants/domains interested seem to be exclusively associated with a specific phenotype; (b) strong variants are associated with non-CNS phenotypes, while weak/intermediate are associated with CNS ones; (c) there is often no correspondence between the VAF and the phenotype severity; (d) although in PROS PIK3CA variants are spread out across the entire gene, 10 hotspots are responsible for >70% of cases, making feasible a tailored first-tier approach to reduce analytic costs; (e) a molecular approach including testing for an angiogenic signalling pathways genes, than can be responsible for PROS-resembling phenotypes, leads to an increase in the diagnostic yield.…”

“…Prior studies have explored the wide spectrum of PIK3CA variants and the heterogeneity of related phenotypes in PROS 9–32. The aim of this study was to describe genotypes and phenotypes of a previously unreported cohort of 150 patients with overgrowth syndromes with clinical features in the PROS spectrum, which taken together provide the first comprehensive systematic review of >1000 PIK3CA -mutated cases.…”

A standard of care for individuals with PIK3CA‐related disorders: An international expert consensus statement

“…38 The precise incidence of epilepsy is not known but has been estimated to be as high as 50% in children with bilateral cortical malformations. 38,39 The effect of seizures on cognitive outcomes in PROS is not known.…”

Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K‐AKT‐mTOR signaling pathway

“…The presence of LOD at birth is suggestive of conditions related to gain of function of postzygotic PIK3CA variants 8,9 and LOD belongs clinically to the PIK3CA-related overgrowth spectrum (PROS). This spectrum includes phenotypes with brain overgrowth (MEG or HMEG), as seen in megalencephaly-capillary malformation syndrome (MCAP) syndrome, and phenotypes with extracerebral, mainly limb, overgrowth, such as CLOVES (congenital lipomatous overgrowth, vascular malformation, epidermal nevi, scoliosis/skeletal and spinal anomalies) syndrome, fibroadipose overgrowth and Klippel-Trenaunay syndrome (KTS) [10][11][12][13][14][15][16][17][18][19][20][21][22] . PROS is characterized by major phenotypic variability and overlap between the different clinical subtypes 8,10 .…”