The clinical spectrum of the Fetal Fentanyl Syndrome in 23 cases
Clinical Genetics and Therapeutics
-
Primary Categories:
- Clinical- Pediatric
-
Secondary Categories:
- Clinical- Pediatric
Introduction:
A novel syndrome was reported by Wadman et al. in 2023 in 10 infants with growth deficiency, microcephaly, distinctive facial features and congenital anomalies, who were prenatally exposed to high doses of Fentanyl. Major birth defects included cleft palate, talipes equinovarus, rocker bottom feet, chordee and/or hypospadias. A hypoplastic corpus callosum was noted in 3 out of the 5 patients that had brain imaging. Their poor growth, abnormal physical findings and abnormal cholesterol metabolites in the newborn period were suggestive of Smith-Lemli-Opitz syndrome, but no patient showed DHCR7 genetic variants.
Methods:
We conducted a review of medical records of patients seen in the Rady Children’s Hospital or University of California San Diego NICUs and in the Genetics or Fetal Alcohol Spectrum Disorders (FASD) clinics, who had confirmed exposure to Fentanyl in pregnancy. Fentanyl exposure was considered confirmed when biological mother admitted to the exposure or when there was a positive toxicology screen for Fentanyl. We aimed to investigate the spectrum of malformations and abnormalities of growth and development associated with prenatal Fentanyl exposure.
Results:
This series is comprised of 23 cases, 15 males and 8 females, examined between a few days of life and 38 months. Of those, 2 were exposed to Fentanyl alone, 10 patients had additional exposure to methamphetamine, 2 patients were also exposed to alcohol, and the remainder were exposed to Fentanyl and at least two other substances including methamphetamines, alcohol, cannabis, heroin and/or methadone.
Fifteen patients (65%) had significant feeding difficulties that persisted for several months or years, and 9 of them (39%) eventually required G tube placement.
Whereas only 1 patient was born with low weight (<2 z-score for his gestational age), 9 cases (39%) developed failure to thrive, with low weight and length at the time of the exam. Similarly, only 2 patients had microcephaly at birth, while 11 (48%) had acquired microcephaly at the time of their last exam.
The patients exhibit a distinct pattern of craniofacial features including bitemporal narrowing (6), ptosis (8), short anteverted nose (13), downturned corners of the mouth (14) and micro/retrognathia (11). Palate abnormalities were seen in 8 cases, ranging from bifid uvula to cleft palate. We identified club feet in 5 patients, and abnormal palmar creases in 14 patients. Three patients had significant 2-3 toe syndactyly, and 2 males had hypospadias.
Global developmental delays were evident in 17 cases (74%), sometimes severe. Brain MRI was obtained in 13 patients and 2 had a thin corpus callosum, the rest did not have any abnormalities noted. Genetic testing was performed in 15 patients and did not identify a primary cause for the phenotype in any. Fourteen had chromosomal microarrays and 7 had gene panels and/or whole exome sequencing. Two siblings were found to have a likely pathogenic variant in COL3A1, an incidental finding consistent with a diagnosis of vascular Ehlers-Danlos syndrome. Biochemical studies of cholesterol metabolites were performed in 7 patients, and only the 2 that were tested in the first week of life had elevated 7-dehydrocholesterol.
Conclusion:
Prenatal exposure to Fentanyl may alter fetal growth and morphogenesis and most often affects growth and development in the postnatal period. Our case series supports the delineation of a novel syndrome associated with prenatal Fentanyl exposure. The Fetal Fentanyl Syndrome (FFS) is characterized by a distinctive combination of dysmorphic features, major malformations (cleft palate, club feet, hypospadias), feeding difficulties, growth deficits and developmental delays. Our results also indicate that there might be a Fetal Fentanyl Spectrum of Disorders (FFSD) that goes beyond FFS. Further studies are needed to better understand the variability of the consequences of the exposure to this newly recognized teratogen.
A novel syndrome was reported by Wadman et al. in 2023 in 10 infants with growth deficiency, microcephaly, distinctive facial features and congenital anomalies, who were prenatally exposed to high doses of Fentanyl. Major birth defects included cleft palate, talipes equinovarus, rocker bottom feet, chordee and/or hypospadias. A hypoplastic corpus callosum was noted in 3 out of the 5 patients that had brain imaging. Their poor growth, abnormal physical findings and abnormal cholesterol metabolites in the newborn period were suggestive of Smith-Lemli-Opitz syndrome, but no patient showed DHCR7 genetic variants.
Methods:
We conducted a review of medical records of patients seen in the Rady Children’s Hospital or University of California San Diego NICUs and in the Genetics or Fetal Alcohol Spectrum Disorders (FASD) clinics, who had confirmed exposure to Fentanyl in pregnancy. Fentanyl exposure was considered confirmed when biological mother admitted to the exposure or when there was a positive toxicology screen for Fentanyl. We aimed to investigate the spectrum of malformations and abnormalities of growth and development associated with prenatal Fentanyl exposure.
Results:
This series is comprised of 23 cases, 15 males and 8 females, examined between a few days of life and 38 months. Of those, 2 were exposed to Fentanyl alone, 10 patients had additional exposure to methamphetamine, 2 patients were also exposed to alcohol, and the remainder were exposed to Fentanyl and at least two other substances including methamphetamines, alcohol, cannabis, heroin and/or methadone.
Fifteen patients (65%) had significant feeding difficulties that persisted for several months or years, and 9 of them (39%) eventually required G tube placement.
Whereas only 1 patient was born with low weight (<2 z-score for his gestational age), 9 cases (39%) developed failure to thrive, with low weight and length at the time of the exam. Similarly, only 2 patients had microcephaly at birth, while 11 (48%) had acquired microcephaly at the time of their last exam.
The patients exhibit a distinct pattern of craniofacial features including bitemporal narrowing (6), ptosis (8), short anteverted nose (13), downturned corners of the mouth (14) and micro/retrognathia (11). Palate abnormalities were seen in 8 cases, ranging from bifid uvula to cleft palate. We identified club feet in 5 patients, and abnormal palmar creases in 14 patients. Three patients had significant 2-3 toe syndactyly, and 2 males had hypospadias.
Global developmental delays were evident in 17 cases (74%), sometimes severe. Brain MRI was obtained in 13 patients and 2 had a thin corpus callosum, the rest did not have any abnormalities noted. Genetic testing was performed in 15 patients and did not identify a primary cause for the phenotype in any. Fourteen had chromosomal microarrays and 7 had gene panels and/or whole exome sequencing. Two siblings were found to have a likely pathogenic variant in COL3A1, an incidental finding consistent with a diagnosis of vascular Ehlers-Danlos syndrome. Biochemical studies of cholesterol metabolites were performed in 7 patients, and only the 2 that were tested in the first week of life had elevated 7-dehydrocholesterol.
Conclusion:
Prenatal exposure to Fentanyl may alter fetal growth and morphogenesis and most often affects growth and development in the postnatal period. Our case series supports the delineation of a novel syndrome associated with prenatal Fentanyl exposure. The Fetal Fentanyl Syndrome (FFS) is characterized by a distinctive combination of dysmorphic features, major malformations (cleft palate, club feet, hypospadias), feeding difficulties, growth deficits and developmental delays. Our results also indicate that there might be a Fetal Fentanyl Spectrum of Disorders (FFSD) that goes beyond FFS. Further studies are needed to better understand the variability of the consequences of the exposure to this newly recognized teratogen.