Hemorrhagic shock and encephalopathy syndrome occurring in the setting of dual pathogenesis of cerebral cavernous malformation 1 and Houge-Janssens syndrome 2

Abstract

Background

Hemorrhagic shock and encephalopathy syndrome is a lethal form of acute childhood encephalopathy that occurs in the setting of various neurodevelopmental conditions. In undiagnosed patients, exome sequencing identifies dual genetic diagnoses in 5% of affected individuals.

Clinical Report

A male infant with a family history of cavernous malformation syndrome with profound developmental delay and hypotonia was brought to our clinic. A trio-based exome analysis identified dual genetic diagnoses: cerebral cavernous malformation 1 (OMIM#116860) due to a maternally inherited heterozygous frameshift mutation in KRIT1 and Houge-Janssens syndrome 2 (OMIM#616362) due to a de novo heterozygous mutation in PPP2R1A. At the age of two years, the child developed hemorrhagic shock and encephalopathy syndrome and died.

Discussion

The dual genetic diagnoses well explained the patient's overall clinical and neuroradiographic phenotype. The differential risk of recurrence of two independent disorders was informative from a genetic counseling standpoint. Known underlying neurological comorbidities in cases developing hemorrhagic shock and encephalopathy syndrome do not appear to have a shared molecular mechanism, but perhaps have perturbations in the basal neuronal activity, predisposing to acute lethal encephalopathy.

Conclusion

A thorough genetic investigation to search for multiple genetic causes to fully explain a patient's overall phenotype is critical. Multiplicity of the underlying genetic conditions may increase the risk of development of acute childhood encephalopathy.