Hemorrhagic Destruction Of The Brain, Subependymal Calcification, And Cataracts

A number sign (#) is used with this entry because the disorder, which comprises hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC), is caused by homozygous mutation in the JAM3 gene (606871) on chromosome 11q25.

Description

HDBSCC is an autosomal recessive disorder with a distinctive phenotype comprising hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Affected individuals have a catastrophic neurologic clinical course resulting in death in infancy (summary by Akawi et al., 2013).

Clinical Features

Mochida et al. (2010) reported a highly consanguineous Saudi Arabian family in which 8 individuals had a syndrome characterized by congenital cataracts and severe brain abnormalities apparently resulting from hemorrhagic destruction of the brain tissue, including the cerebral white matter and basal ganglia. Three patients died in early infancy. All had profound developmental delay, and other neurologic features included seizures, spasticity, and hyperreflexia. Brain imaging showed multifocal intraparenchymal hemorrhage with associated liquefaction and massive cystic degeneration resulting in large ventricles. There was also calcification in the subependymal region and in brain tissue. Some had thin midbrain, pons, and cerebellum, but it could not be determined if these were primary or secondary changes. There was no evidence of cortical malformation. The changes suggested a disorder of small vessels. Three patients had hepatomegaly, and 3 of 4 examined by ultrasound showed renal anomalies, mainly ectopic kidney and renal cystic dysplasia. There was no evidence of congenital infection, and Mochida et al. (2010) suggested that the syndrome resembled pseudo-TORCH syndrome (251290). Of note, a second autosomal recessive disorder, short rib-polydactyly syndrome type III (SRTD3; see 613091) also segregated independently in this family, and 1 individual had both disorders.

Akawi et al. (2013) reported 7 patients from 3 unrelated families with HDBSCC. Two of the families were consanguineous and of Turkish and Moroccan origin, respectively, and the third family was of Afghan origin. Affected individuals had a homogeneous phenotype, with neonatal onset of intracranial bleeding, intracranial calcification, and neurologic deterioration. All also had congenital cataracts. Some of the patients had seizures. Death occurred in infancy. Brain MRI, performed in some patients, showed edema, cystic changes of the brain parenchyma, white matter abnormalities, and necrotic hemorrhagic damage. Two sibs were found to have renal anomalies, including echogenic cortex, altered corticomedullary differentiation, and pelvicalyceal dilatation. Family histories revealed stillbirth or early neonatal death from unknown causes in 2 of the families.

Inheritance

The inheritance in the consanguineous family reported by Mochida et al. (2010) as having hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts, was consistent with an autosomal recessive pattern.

Molecular Genetics

By genomewide linkage analysis followed by candidate gene sequencing of a Saudi Arabian family with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts, Mochida et al. (2010) identified a homozygous loss-of-function mutation in the JAM3 gene (606871.0001). The findings indicated that JAM3 is important for maintaining the integrity of the cerebrovascular endothelium and for normal lens development in humans.

In affected members of 3 unrelated families with HDBSCC, Akawi et al. (2013) identified 3 different homozygous loss-of-function mutations in the JAM3 gene (606871.0002-606871.0004). The phenotype was similar to that reported by Mochida et al. (2010).