Retrospective Diagnosis of OTC Deficiency in a Deceased Neonate Following Presentation in a Subsequent Sibling - A Case for Postmortem Genomic Screening in All Neonatal Deaths

Background: Ornithine Transcarbamylase Deficiency (OTCD) is an X-linked disorder that can result in severe neonatal presentations in males. Early recognition of urea cycle disorders is important for the initiation of life-saving treatment to reduce hyperammonaemia.

Case study: We report the case of a male infant who was diagnosed with OTCD after he presented with severe hyperammonaemia within the first week of life. He deteriorated at 24 hours of life with an increased respiratory rate in the context of respiratory alkalosis, seizures and encephalopathy. He was admitted to a neonatal unit and was found to have an initial ammonia of 1760 umol/L with a peak ammonia of 3912 umol/L that required treatment with haemodialysis and ammonia scavenging therapy. The family history was significant for his elder brother who was deceased without medical explanation on day 3 of life.

Results: Our proband was confirmed to have a novel variant in the OTC gene c.717GT (p.?) that was classed as a likely pathogenic variant. This variant was confirmed to be maternally inherited and subsequent testing was performed on the samples from the deceased elder brother that confirmed carriage of the familial OTC variant.

Conclusion: Families need to have answers for unexpected neonatal demise in the neonatal period as it can have consequences for future pregnancies and neonatal management of affected infants. Our case highlights the importance of considering further genomic testing in cases of unexplained neonatal death, as well as reporting a novel pathogenic variant that resulted in a severe neonatal presentation in two infants. This case also highlights the importance of measuring ammonia levels in neonates with respiratory alkalosis.