Impact of prenatal fentanyl exposure on sterol analysis for Smith-Lemli-Opitz syndrome in newborns
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
Introduction: Prenatal exposure to fentanyl is increasingly linked to metabolic abnormalities resembling Smith-Lemli-Opitz syndrome (SLO), a congenital disorder affecting cholesterol biosynthesis. This novel syndrome, called fetal fentanyl syndrome, was identified in 6 cases based on clinical features suggestive of SLO, elevated 7-dehydrocholesterol (7-DHC) and/or 8-dehydrocholesterol (8-DHC) which normalized over time, and non-diagnostic exome analysis (Wadman et al. Genet Med Open 2023). This discovery prompted us to review patient outcomes of sterols testing resulting in elevated 7-DHC or 8-DHC.
Methods:
Methods: A retrospective review of results from December 2023 to August 2024 identified 15 confirmed cases of prenatal fentanyl exposure with elevations of 7-DHC and/or 8-DHC concentrations in plasma. This patient cohort consisted of 6 male and 9 female infants with a median age of approximately 1 week (range of 1.2 days to 8.6 weeks). SLO testing was performed using a laboratory developed test on plasma specimens by gas chromatography-mass spectrometry (unpublished method).
Results:
Results: Clinical findings were provided for 8 of the 15 patients. These infants exhibited features also observed in SLO, such as single palmar creases (n=2), micrognathia (n=3), cleft palate (n=2), webbed neck (n=2), cardiac structural anomalies (n=2), syndactyly (n=3), and hydrops (n=2).
The majority of cases had minor elevations of 7-DHC and/or 8-DHC (n=12; 7-DHC median: 3.8, min: 0.4, max: 14, reference range ≤2.0 mg/L; 8-DHC median: 5.8, min: 0.7, max: 33.9, reference range ≤0.3 mg/L), whereas 3 had elevations comparable to patients with SLO (7-DHC of 61.1, 96.4, 150.1 mg/L; and 8-DHC of 50.4, 28.7, 20.8 mg/L, respectively).
Maternal fentanyl use up to the day of delivery was confirmed by healthcare providers for 2 of 3 cases with significantly elevated levels of 7- and 8-DHC. Four patients had repeat SLO testing which showed reduction or normalization of both analytes over time. Only 2 patients had molecular genetic testing of DHCR7, which were both negative.
Conclusion:
Conclusion: These findings provide further evidence that fentanyl is a teratogen that may interfere with enzymes involved in cholesterol biosynthesis (Korade et al. Mol Psychiatry 2024). Other drugs, like trazadone and aripiprazole, have been shown to interfere with cholesterol biosynthesis likely in a similar way, causing elevations of 7-DHC and 8-DHC and an SLO-like phenotype (Hall et al. Mol Genet Metab 2013). Our findings provide further evidence of fentanyl’s teratogenic potential and suggest that a shorter interval between last exposure to fentanyl prior to birth and postnatal age at specimen collection are positively correlated to measured 7- and 8-DHC plasma concentrations in newborns.
Introduction: Prenatal exposure to fentanyl is increasingly linked to metabolic abnormalities resembling Smith-Lemli-Opitz syndrome (SLO), a congenital disorder affecting cholesterol biosynthesis. This novel syndrome, called fetal fentanyl syndrome, was identified in 6 cases based on clinical features suggestive of SLO, elevated 7-dehydrocholesterol (7-DHC) and/or 8-dehydrocholesterol (8-DHC) which normalized over time, and non-diagnostic exome analysis (Wadman et al. Genet Med Open 2023). This discovery prompted us to review patient outcomes of sterols testing resulting in elevated 7-DHC or 8-DHC.
Methods:
Methods: A retrospective review of results from December 2023 to August 2024 identified 15 confirmed cases of prenatal fentanyl exposure with elevations of 7-DHC and/or 8-DHC concentrations in plasma. This patient cohort consisted of 6 male and 9 female infants with a median age of approximately 1 week (range of 1.2 days to 8.6 weeks). SLO testing was performed using a laboratory developed test on plasma specimens by gas chromatography-mass spectrometry (unpublished method).
Results:
Results: Clinical findings were provided for 8 of the 15 patients. These infants exhibited features also observed in SLO, such as single palmar creases (n=2), micrognathia (n=3), cleft palate (n=2), webbed neck (n=2), cardiac structural anomalies (n=2), syndactyly (n=3), and hydrops (n=2).
The majority of cases had minor elevations of 7-DHC and/or 8-DHC (n=12; 7-DHC median: 3.8, min: 0.4, max: 14, reference range ≤2.0 mg/L; 8-DHC median: 5.8, min: 0.7, max: 33.9, reference range ≤0.3 mg/L), whereas 3 had elevations comparable to patients with SLO (7-DHC of 61.1, 96.4, 150.1 mg/L; and 8-DHC of 50.4, 28.7, 20.8 mg/L, respectively).
Maternal fentanyl use up to the day of delivery was confirmed by healthcare providers for 2 of 3 cases with significantly elevated levels of 7- and 8-DHC. Four patients had repeat SLO testing which showed reduction or normalization of both analytes over time. Only 2 patients had molecular genetic testing of DHCR7, which were both negative.
Conclusion:
Conclusion: These findings provide further evidence that fentanyl is a teratogen that may interfere with enzymes involved in cholesterol biosynthesis (Korade et al. Mol Psychiatry 2024). Other drugs, like trazadone and aripiprazole, have been shown to interfere with cholesterol biosynthesis likely in a similar way, causing elevations of 7-DHC and 8-DHC and an SLO-like phenotype (Hall et al. Mol Genet Metab 2013). Our findings provide further evidence of fentanyl’s teratogenic potential and suggest that a shorter interval between last exposure to fentanyl prior to birth and postnatal age at specimen collection are positively correlated to measured 7- and 8-DHC plasma concentrations in newborns.
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