Pitfalls in the Diagnosis of Hereditary Fructose Intolerance.

Establishing the diagnosis of hereditary fructose intolerance (HFI) remains difficult despite the availability of specific molecular genetic testing of the gene. This is attributable, at least in part, to the lack of a specific and practical biomarker. We report the incidental diagnosis of HFI as a consequence of nontargeted genetic testing ordered for alternative indications in 5 patients, including 3 children and 2 adults. Two of the children were diagnosed with HFI after extensive evaluations that ultimately involved clinical or research exome sequencing. The third child was diagnosed with HFI during subsequent genetic testing of at-risk family members. Both adults learned to avoid fructose and remained asymptomatic of HFI before diagnosis. One was diagnosed with HFI during preconception, nontargeted expanded carrier screening. For the other, concern for HFI was initially raised by indeterminate direct-to-consumer genetic testing results. None of these patients presented with infantile acute liver failure or other acute decompensation. Our findings suggest that the emphasis of classic teaching on infantile liver failure after first exposure to fructose may be inadvertently increasing the likelihood of missing cases of HFI characterized by other manifestations. HFI is likely underdiagnosed and should be considered for patients with nonspecific findings as well as for individuals with significant aversion to sweets.