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

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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.
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脑海绵畸形1和侯格-扬森综合征2双重发病机制下的出血性休克和脑病综合征
背景失血性休克和脑病综合征是一种致命的儿童急性脑病,可在各种神经发育疾病的背景下发生。在未确诊的患者中,5% 的患者通过外显子组测序确定了双重基因诊断。临床报告一名男婴被送到我们诊所就诊,他有海绵畸形综合征家族史,伴有严重的发育迟缓和肌张力低下。基于三组外显子组的分析确定了双重基因诊断:因 KRIT1 基因的母系遗传性杂合框移位突变导致的脑海绵状畸形 1(OMIM#116860)和因 PPP2R1A 基因的新生杂合突变导致的 Houge-Janssens 综合征 2(OMIM#616362)。讨论双重基因诊断很好地解释了患者的整体临床和神经放射表型。从遗传咨询的角度来看,两种独立疾病复发风险的不同具有参考价值。在发生失血性休克和脑病综合征的病例中,已知的潜在神经系统合并症似乎没有共同的分子机制,但可能存在基底神经元活动紊乱,容易导致急性致死性脑病。多重潜在遗传病可能会增加儿童急性脑病的发病风险。
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