Megalencephaly capillary malformation-polymicrogyria syndrome Q87.22

Moore et al.1997

MCAP is a rare developmental disorder, an overgrowth syndrome characterized by excessive growth of the brain and multiple tissues, capillary malformations, and cortical brain abnormalities such as polymicrogyria.

Common features include macrocephaly, capillary malformations, body and brain asymmetry, digital abnormalities and connective tissue dysplasia.

Other manifestations may include facial dysmorphia, developmental delays, seizures and low muscle tone. The gene associated with MCAP, the PIK3CA gene (PIK3CA stands for: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) is a protein-coding gene located on chromosome 3q26.32.

PI 3-kinases (phosphoinositide 3-kinases, PI 3-Ks) are a family of lipid kinases that are able to phosphorylate the 3'OH of the inositol ring of phosphoinositides. They are responsible for coordinating a variety of cell functions, including proliferation and survival. The phosphatidylinositol 3-kinase encoded by the PIK3CA gene consists of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene is the catalytic subunit that utilizes ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. The PIK3CA kinase is an integral part of the PI3K signaling pathway and has long been described as an oncogene with two major hotspots for activating mutations: the 542/545 region of the helical domain and the 1047 region of the kinase domain.

In people with MCAP, megalencephaly leads to an unusually large head (macrocephaly), which is usually already visible at birth. After birth, the brain and head continue to grow rapidly in the first few years of life, after which growth slows down to a normal rate, although the head remains larger than average. People with MCAP often have additional brain abnormalities, such as hydrocephalus and abnormalities in brain structure, such as Chiari malformation and polymicrogyria. The abnormal development of the brain leads to mental retardation in most of those affected and can also cause seizures or weak muscle tone (hypotonia). Polymicrogyria in particular is associated with speech delays and difficulties with chewing and swallowing.

Capillary malformations are noticeable on the skin. In most patients, capillary malformations occur on the face, particularly on the nose, upper lip and the area between the nose and the philtrum (mesotropic port wine stain). The capillary malformations can also appear as a reddish net-like pattern on the skin(cutis marmorata teleangiectatica congenita).

In some people with MCAP, the excessive growth affects not only the brain but also other parts of the body, which is called segmental overgrowth. This can result in one arm or leg being larger or longer than the other, or a few fingers or toes being too big. In some affected individuals, the skin between two or more fingers or toes is fused (cutaneous syndactyly).

The gene involved in MCAP is also associated with various types of cancer. Only a small number of people with MCAP develop tumors (in particular a Wilms tumor and meningiomas).

Various authors refer to this overgrowth syndrome as livedo-reticularis-congenita-megalencephaly syndrome, a term which on the one hand does not correspond to the international literature and on the other hand causes further irritation with the term "livedo reticularis", which is generally equated with a hamrlossen functional disorder (cutis marmorata). In this respect, the language used in this encyclopedia is adapted to the ISSVA system - see also vascular malformations.

1. Buchanan CM et al. (2013) Oncogenic mutations of p110α isoform of PI 3-kinase upregulate its protein kinase activity. PLoS One 8:e71337.
2. Clayton-Smith J et al. (1997) Macrocephaly with cutis marmorata, haemangioma and syndactyly--a distinctive overgrowth syndrome. Clin Dysmorphol 6:291-302.

3. Fortin O et al.(2020) Megalencephaly-Capillary Malformation-Polymicrogyria with Cerebral Venous Thrombosis. Can J Neurol Sci 47:828-829.

4. Maheshwari S et al. (2017) Kinetic and structural analyses reveal residues in phosphoinositide 3-kinase α that are critical for catalysis and substrate recognition. J Biol Chem 292:13541-13550.
5. Meier TI et al. (2004) Cloning, expression, purification, and characterization of the human Class Ia phosphoinositide 3-kinase isoforms. Protein Expr Purif 35:218-24.
6. Moore CA et al. (1997) Macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities. Am J Med Genet70:67-73.
7. Sarma K et al. (2022) Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome (MCAP): A Rare Dynamic Genetic Disorder. Cureus 14:e25123.