Hyperonitinemia-Hyperammonemia-Homocitrullinuria syndrome. Neonatal presentation with acute liver failure.

Introduction and Objectives

Urea cycle defects occur in 1/35,000 live births and Hyperonitinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome represents 1-4% of this group of diseases, which represents an autosomal recessive defect due to variants of the SLC25A15 gene. The present work describes the first case of HHH syndrome reported in Mexico.

Materials and Patients

We present a 5-month-old female infant, daughter of the second pregnancy of non-consanguineous parents, originally from Quintana Roo, born at term with intrauterine growth restriction, presented early neonatal sepsis and required ventilatory and hemodynamic treatment, in the second week she presented Cholestasis with normal GGT, coagulopathy, which did not correct after treatment with vitamin K, and irritability with hyperammonemia up to 640umol/L, which led to the diagnosis of neonatal acute liver failure.

At the initial approach, infectious etiology was ruled out, with high suspicion of gestational alloimmune liver disease, due to the presence of elevations of alpha-fetoprotein 12,410ng/mL and ferritin 1,590ng/mL. Gaucher disease, Niemann Pick, and lysosomal acid lipase deficiency were ruled out. Metabolic screen with hyperornithinemia (435.79 mmol/L). The genetic study found a pathogenic variant in a homozygous state of the acceptor site of the splicing of intron 2 of the SLC25A15 gene.

Two doses of human immunoglobulin and supportive treatment for liver failure with menadione and ammonium binders were administered with a favorable therapeutic response; the liver failure was remitted 4 weeks after the established management.

Results

The present work describes the first case of HHH syndrome reported in Mexico, which presented with neonatal acute liver failure associated with two of the three biochemical characteristics described due to hyperammonemia and hyperornithinemia. Likewise, a homozygous variant was identified in SLC25A15 and classified as pathogenic.

Conclusions

This report highlights the first documented case of HHH syndrome in Mexico, emphasizing its association with neonatal acute liver failure, hyperammonemia, and hyperornithinemia. The identification of a pathogenic homozygous variant in the SLC25A15 gene reinforces the importance of genetic studies for early diagnosis and targeted management of urea cycle disorders.