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Genetics of Fetal Micrognathia: One Fetal Center's Experience

Prenatal Genetics
  • Primary Categories:
    • Prenatal Genetics
  • Secondary Categories:
    • Prenatal Genetics
Introduction:
Fetal micrognathia is a common craniofacial abnormality, affecting around 1/1,500 births. There are multiple genetic syndromes known to cause micrognathia with variable neonatal outcomes. In some cases, micrognathia is seen as an isolated finding with or without a family history. Therefore, it becomes difficult to counsel families on the potential outcomes they may expect for their child. The aim of this research is to better understand the genetic contribution of prenatal micrognathia.

Methods:
114 cases of prenatally ascertained micrognathia and/or retrognathia were retrospectively identified a single tertiary care center. A chart review was performed to record the following: prenatal imaging and genetic testing results and outcomes of the pregnancies. Any cases where there was incomplete information were excluded.

 

Results:
The average age of the pregnant person at the time of evaluation was 31 years. Most pregnancies either resulted in a live born child (64.9%) or were terminated (30.7%), and a subset resulted in an intrauterine fetal demise (IUFD) (4.4%). A subset of the delivered pregnancies resulted in neonatal demise (12.2%).



111 (97.4%) cases presented with micrognathia, 44 (38.6%) with retrognathia, and 41 (36.9%) with both micro and retrognathia, noted on either ultrasound or magnetic resonance imaging (MRI). In 22.8% of cases, polyhydramnios was present between the 2nd-3rd trimester of pregnancy.



85.6% of cases had additional ultrasound anomalies outside of micrognathia, of which skeletal (57.9%), neurological (50.9%), and cardiac anomalies (39.5%) were the most common. In 14.0% of cases micrognathia was thought to be isolated. Of those fetuses with additional anomalies, most had between 1-3 additional organ groups involved (72.7%).



There was a genetic diagnosis among 4/5 IUFDs and 5/7 neonatal demises who had diagnostic testing. The most common cause of neonatal demise was pulmonary hypoplasia/respiratory compromise. 7/9 neonatal deaths were in the setting of palliative care, with the majority (5/7) of these fetuses having a diagnosis of Trisomy 13 or 18 on diagnostic testing or through prenatal cell-free DNA (cfDNA) screening.



102 (89.5%) cases had diagnostic genetic testing. 2 of the remaining cases had prenatal cfDNA screening that was high risk for Trisomy 21 or Trisomy 18. 72 cases had findings on genetic testing, 61 of which were consistent with the findings on ultrasound, thus genetic testing explained the ultrasound findings in 60.0% of cases that underwent diagnostic genetic testing. There was 1 truly uncertain result.



Of the tests utilized, cytogenetic testing was performed in 59.6% of cases and sequencing in 60.5%. Of the common chromosomal anomalies seen, 22q11.2 (3.9%), Trisomy 13 (3.9%), and 18 (5.9%) were most common. The most common Single-gene disorders were Stickler Syndrome (5.9%) Osteogenesis Imperfecta (2.0%), tubulinopathies (2.9%), and CHARGE Syndrome (2.0%).



33.3% of apparently isolated micrognathia cases who underwent genetic testing had a genetic diagnosis, most frequently Stickler Syndrome. 61.5% of cases where there was one additional anomaly, 58.3% where there were 2, and 63.2% of cases where there were 3 had an underlying genetic diagnosis.

Conclusion:
Genetic diagnosis in this heterogenous group of fetuses with micrognathia was high, representing 60.0% of all cases who underwent diagnostic testing. While the diagnostic rate was highest in the groups where micrognathia was non-isolated 33.3% of fetuses with isolated micrognathia received a genetic diagnosis. These findings support that genetic testing should be considered for any case of prenatal micrognathia, and that cytogenetics may not be sufficient for all cases, as 54.1% involved single-gene disorders. Testing like exome or genome sequencing should be considered to provide the most comprehensive diagnosis to families.

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