Fetal fentanyl syndrome (FFS) is a recently identified condition occurring in the context of maternal opioid use disorder. Neonates present with distinctive facial features including ptosis and short nasal tip, cleft palate and micrognathia, single palmar crease, adducted and slighly short thumb, male genital anomalies, rocker bottomor talipes equinovarus and 2,3 toe syndactyly, amongst other findings. The presentation resembles Smith-Lemli-Opitz syndrome (SLOS). In the early neonatal period, 7- or 8-dehydrocholesterol are elevated, further supporting SLOS as potential diagnosis. Ongoing research confirmed that fentanyl is a multi-step inhibitor of post-lanosterol biosynthesis. 

Session moderator: Karen W. Gripp, MD, FACMG  (intro to the topic in the context of the fentanyl use epidemic; intro of the speakers; 10 min)

Presenters 1: Erin Wadman, MS, CGC   (10 minutes) Ms. Wadman will report on the phenotypic findings in FFS. She will review the clinical evaluation of these patients resulting in non-diagnostic genetic testing. Abnormal results on cholesterol metabolism studies showed elevated 7-dehydrocholestrol (7-DHC), but normalized subsequently. The shared prenatal history of opioid use disorder  with known fentanyl use throughout pregnancy appeared as potential cause for this novel condition. Bradford Hill and Shepard criteria for teratogenicity appeared not inconsistent with fentanyl teratogenicity.

2: Sarah Savage, MS, CGC (10 m)  Ms. Savage will discuss the use of machine learning supported facial feature analysis in the evaluation of pediatric patients suspected of having an underlying syndromic diagnosis. Advanced algorithms allowing for single-image to single- image comparison can assess similarity between facial photographs of different individuals. This algorithm identified statistically significant differences in the facial photographs of the FFS patients compared to images from age matched patients with SLOS, fetal alcohol syndrome and typical individuals. These results support the distinctiveness of the novel syndrome and may be considered in the Bradford Hill and Shepard criteria for teratogenicity. 

3: Karoly Mirnics, MD  (10 m) Dr. Mirnics will present laboratory data.  Fetal fentanyl syndrome is biochemically characterized by elevated 7-DHC levels, suggesting that fentanyl inhibition of the dehydrocholesterol reductase 7 (DHCR7) enzyme as causal for the emergence of the pathophysiological and phenotypic features.  Experiments exposed primary mouse neuronal and astrocytic cultures, and human dermal fibroblasts, to increasing doses of fentanyl. Analysis of the post-lanosterol profile using LC-MS/MS revealed a dose dependent pattern of post-lanosterol changes including the signature of DHCR7 enzyme inhibition, with accumulation of the substrates (7-DHC, 8-DHC and 7-DHD) and decrease in product.

4:  Erica Fernandes, DO, FACMG  (10 min) Dr. Fernandes will report additional patients with fetal fentanyl syndrome identified throughout the US, highlighting the need for clinicians to be familiar with this condition. New clinical information on growth and development will be shared. The relevant clinical findings and suggested evaluation are discussed in light of the emerging information on the metabolic underpinnings of FFS .

Questions and answers (10 min)