Fetal Fentanyl Syndrome: A Novel Syndrome Associated With Prenatal Fentanyl Exposure (105)

Abstract Text:

Background: Infants with significant prenatal fentanyl exposure exhibit phenotypic similarities to Smith-Lemli-Opitz syndrome (SLOS), prompting investigation into a potential novel embryopathy. SLOS causes inhibition of DHCR7 in the cholesterol pathway. Despite negative genetic testing for SLOS, these infants display overlapping physical and biochemical features.

Purpose: This study aims to determine whether infants with prenatal fentanyl exposure and congenital anomalies share a unique embryopathy resulting from extensive fentanyl exposure.

Methods: Ten patients, including six enrolled in an IRB-approved study and four external cases, underwent comprehensive analysis. Medical records were reviewed for phenotypic findings, prenatal drug exposure, genetic test results, and laboratory studies. Facial photographs were assessed using the Face2Gene GestaltMatcher algorithm and compared to age-matched cohorts.

Results: Patients exhibited a consistent facial phenotype, including microcephaly, bitemporal narrowing, short and upturned nasal tip, long philtrum, thin vermillion, and micrognathia. Additional anomalies included cleft palate, adducted thumbs, single palmar crease, talipes equinovarus or rocker bottom feet, 2/3 toe syndactyly, male genital anomalies, and corpus callosum abnormalities. Elevated 7- and 8-dehydrocholesterol levels were found, which normalized over time. Face2Gene analysis revealed a statistically significant unique gestalt for this cohort.

Conclusions: Despite negative genetic testing for SLOS, the striking physical and biochemical similarities suggest a phenocopy of SLOS induced by heavy prenatal fentanyl exposure. Based on fentanyl’s chemical structure, the consistent phenotype and biochemical studies across cases, along with the unique gestalt identified by Face2Gene, support the proposal that early fentanyl exposure inhibits DHCR7, resulting in a novel embryopathy.

Needs Assessment and Presentation Description: A novel syndrome has been delineated after babies born to mothers taking high levels of street fentanyl were noted to share similar striking features including short stature, microcephaly, congenital anomalies and a distinctive facial phenotype (bitemporal narrowing, short and upturned nasal tip, long philtrum, thin vermillion and micrognathia). Anomalies included cleft palate, single palmar crease, short, broad and adducted thumbs, talipes equinovarus or rocker bottom feet, 2/3 toe syndactyly, male genital anomalies, and abnormalities of the corpus callosum. They were also found to have elevations in 7- and 8-dehydrocholesterol (DHC). The physical and biochemical findings were highly suggestive of Smith-Lemli-Opitz syndrome (SLOS), which affects cholesterol metabolism. Extensive genetic testing was negative. It is suspected that fentanyl (or a contaminant) is inhibiting DHCR7, resulting in a phenocopy of SLOS and a novel syndromic embryopathy.