A number sign (#) is used with this entry because microcephaly-capillary malformation syndrome (MICCAP) is caused by homozygous or compound heterozygous mutation in the STAMBP gene (606247) on chromosome 2p13.

The microcephaly-capillary malformation syndrome is a congenital disorder characterized by severe progressive microcephaly, early-onset refractory epilepsy, profound developmental delay, and multiple small capillary malformations spread diffusely on the body. Additional more variable features include dysmorphic facial features, distal limb abnormalities, and mild heart defects (summary by Carter et al., 2011 and Mirzaa et al., 2011).

Carter et al. (2011) reported 2 unrelated male infants with a similar congenital neurologic disorder. At birth, both were small for gestational age and were noted to have microcephaly and multiple capillary malformations of the skin affecting all areas of the body and ranging in size from 2 to 25 mm in 1 boy and 2 to 5 mm in the other. Dysmorphic facial features included whorled hair pattern, hypertelorism, ptosis, and downturned mouth. One had epicanthal folds, long palpebral fissures, and low-set ears, whereas the other had a short nose, asymmetric maxillary hypoplasia, and narrow cleft palate. Both had abnormalities of the distal limbs, including hypoplastic distal phalanges, brachydactyly of the hands and feet, hypoplastic nails, and displaced toes. Both developed intractable seizures in the first months of life and showed profound developmental delay. One patient had myoclonus; both had central hypotonia. Variable features included atrial or ventricular septal defect, hearing loss, and vesicoureteral reflux. Serial brain MRI of 1 child showed progressive cerebral atrophy, delayed myelination, and thin corpus callosum. The second child, who died at age 17 months, had cerebral atrophy with white matter loss, thin corpus callosum, and hippocampal atrophy.

Mirzaa et al. (2011) reported 3 children from 2 unrelated families with what they termed microcephaly-capillary (MIC-CAP) malformation syndrome. Two sibs, born of African American parents, had severe microcephaly (6 to 8 SD below the mean), dysmorphic facial features, and multiple capillary malformations. Both had failure to thrive with feeding difficulties, early-onset intractable seizures, severe developmental delay, and spasticity. Multiple capillary malformations ranged in size from 2 to 10 mm. Other features included optic nerve atrophy, sloping forehead, broad nasal bridge, hypertelorism, and distal limb anomalies, such as brachydactyly and nail hypoplasia. The boy had patent foramen ovale, mild concentric right ventricular hypertrophy, and dilated median pulmonary artery. The third child was born prematurely (36 weeks and 5 days' gestation) of a pregnancy complicated by oligohydramnios, intrauterine growth restriction, and chorioamnionitis. He developed refractory seizures and myoclonus soon after birth. He had microcephaly, multiple capillary malformations ranging in size from 1 to 15 mm, and mild micrognathia. He had essentially no development and spastic quadriparesis. Brain imaging of all 3 infants showed a simplified gyral pattern and enlarged extraaxial space. Mirzaa et al. (2011) concluded that this constellation of findings represents a novel autosomal recessive syndrome characterized by severe microcephaly, capillary malformations, and developmental handicap.

Isidor et al. (2011) reported a girl, born to unrelated parents, with a phenotype similar to, but less severe than, that described by Carter et al. (2011). She was born at term after an uneventful pregnancy, and showed neonatal feeding difficulties. Physical examination showed large anterior fontanel, anteverted nares, thin upper lip, short fifth fingers with hypoplastic nails on the second and fifth fingers, short toes, and axial hypotonia. She also had multiple small capillary malformations over the trunk, abdomen, and limbs. Around age 12 months, she developed severe refractory hemiclonic seizures with secondary generalization. Later in childhood, she showed delayed psychomotor development, poor speech development, aggressive behavior, and progressive microcephaly. The capillary malformations appeared to grow with body size. She had moderate mental retardation; brain MRI was normal.

The family reported by Mirzaa et al. (2011) with MICCAP included an affected brother and sister, suggesting autosomal recessive inheritance.

In 10 patients from 9 families with MICCAP, McDonell et al. (2013) identified biallelic mutations in the STAMBP gene (see, e.g., 600247.0001-600247.0007). The mutation types included 6 missense variants, 2 nonsense mutations, 2 frameshift mutations, and 3 intronic mutations. The first mutations were identified by exome sequencing. Some of the patients had previously been reported by Carter et al. (2011), Isidor et al. (2011), and Mirzaa et al. (2011). Protein studies showed decreased or absent STAMBP protein in mutant cells. Cellular studies by McDonell et al. (2013) showed that siRNA-mediated silencing of STAMBP in human medulloblastoma cells caused increased amounts of conjugated-ubiquitin aggregates; patient lymphocytes showed a similar aggregation pattern that could be rescued by transfection with wildtype STAMBP. The abnormal cellular phenotype was associated with induction of apoptosis and increased autophagic flux. Patient cells also showed increases in the downstream RAS signaling pathway and increased phosphorylation of downstream proteins compared to controls, indicating persistent activation and insensitive active signal transduction, even under starvation conditions. McDonell et al. (2013) hypothesized that the induction of apoptosis may be responsible for microcephaly, whereas overactivation of the RAS pathway may be responsible for the capillary malformations.