JPGN Reports · 3 authors, 2 centres
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Hereditary fructose intolerance (HFI) can present in neonates due to hidden fructose/sucrose in infant formulas, causing acute liver failure. This case report describes a 17-day-old formula-fed infant diagnosed via expedited whole exome sequencing (WES) in 5 days, with rapid recovery after switching to fructose-free formula. Clinicians should consider HFI in neonatal acute liver failure and utilize rapid genomic testing for early diagnosis.
**Background:** Hereditary fructose intolerance (HFI) is a rare autosomal recessive disorder caused by deficiency of aldolase B due to mutations in the ALDOB gene. This deficiency leads to accumulation of fructose-1-phosphate, causing hypoglycemia, lactic acidosis, and liver dysfunction. Classic teaching states HFI presents when infants are introduced to fructose/sucrose in table foods, but recent reports show that fructose and sucrose additives in infant formulas can trigger neonatal onset. Diagnosis is challenging due to nonspecific symptoms and lack of specific biomarkers. This case highlights the role of rapid whole exome sequencing (WES) in diagnosing HFI in a neonate with acute liver failure (ALF).
**Methods:** This is a case report of a 17-day-old full-term formula-fed infant presenting with lethargy, low-grade fever, and poor feeding. Laboratory findings included ALF with international normalized ratio (INR) of 11, elevated total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), along with hypoglycemia and lactic acidosis but normal ammonia. Initial workup for infection, hemophagocytic lymphohistiocytosis, and metabolic disorders was inconclusive. Newborn screening was normal. Urine organic acids showed markedly elevated alpha-ketoglutarate and nonspecific elevations of lactic acid, pyruvic acid, para-hydroxyphenyl lactate, and para-hydroxyphenylpyruvate. The infant was empirically treated with acyclovir and antibiotics. Liver dysfunction improved over 5 days, but at follow-up one week later, recurrent liver synthetic dysfunction with hypoglycemia and lactic acidosis was noted. Expedited WES was ordered for suspected mitochondrial disorder.
**Key Results:** WES results were available in 5 days and revealed two heterozygous pathogenic ALDOB variants: maternal c.448G>C (p.Ala150Pro) and paternal c.324+2T>A. After switching to a fructose-free formula, the infant had rapid resolution of lactic acidosis and normalization of liver synthetic function. The authors also compiled a table of sugar additives in common infant formulas, noting that many contain fructo-oligosaccharides, galacto-oligosaccharides, lactose, or corn syrup solids, which can be sources of fructose/sucrose. For example, Parent's Choice formulas contain fructo-oligosaccharides, while Enfamil A.R. contains galacto-oligosaccharides and lactose. The authors emphasize that product labeling is often vague, making it difficult to identify fructose/sucrose content.
**Clinical Implications:** This case demonstrates that HFI should be considered in the differential diagnosis of neonatal ALF, especially in formula-fed infants. Rapid WES can provide a definitive diagnosis within days, avoiding invasive procedures like liver biopsy and enabling prompt dietary intervention. The authors advocate for transparent labeling of infant formulas to clearly indicate fructose and sucrose additives. They also note that rapid genomic testing is becoming more accessible and cost-effective, with turnaround times ranging from less than 24 hours to 8 days, and can reduce unnecessary testing and improve outcomes. Physicians should be trained to recognize HFI in neonates and utilize rapid genomic sequencing when indicated.