The microcephaly-capillary malformation syndrome is a highly recognizable severe congenital microcephaly syndrome. Its’ main features are usually identified at or shortly after birth as affected children have a strikingly small head size (or microcephaly), and cutaneous vascular malformations, also known as capillary malformations. These cutaneous lesions are usually scattered all over the body and vary in size from a few millimeters to a few centimeters. Early onset intractable epilepsy occurs in almost all affected children. Other unique features include distal digital hypoplasia (such as short, tapered digits and/or nail hypoplasia), spastic quadriparesis, poor body growth, and profound intellectual disability. Abnormal movements and optic nerve atrophy have been reported in some affected children as well. Brain neuroimaging universally shows microcephaly with simplified gyral pattern and increased extra axial space. Other MRI features include diffuse hypomyelination and variable degrees of hippocampal hypoplasia.

Like most congenital microcephaly syndromes, the microcephaly-capillary malformation syndrome is inherited in an autosomal recessive fashion. Mutations in STAMBP, a gene encoding a deubiquitinating enzyme, were recently identified in 10 affected children, including a pair of siblings from nonconsanguineous parents. The identified mutations include six missense mutations, two non­sense mutations, two translational frameshift mutations predicted to cause a premature truncation of the STAMBP protein and three intronic mutations leading to alternative splicing of the STAMBP transcript. STAMBP encodes the deupiquinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM). This enzyme plays a key role in cell surface receptor–mediated endocytosis and sorting. Reduced STAMBP expression in affected individuals was associated with accumulation of elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. These pathways are well implicated in disorders associated with similar vascular malformations.

Genetic testing for microcephaly-capillary malformation syndrome is available at the University of Chicago Genetic Services.


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