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Four Infants with Genetic Variants Previously Associated with Lethal Osteogenesis Imperfecta Who Survived the Neonatal Period: A Case Series

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Osteogenesis imperfecta (OI) has clinical manifestations that include risk of fractures, hearing loss and dentinogenesis imperfecta and is primarily caused by pathogenic variants in COL1A1 or COL1A2. The clinical classification for type 1 collagen related OI lists four major types, with type I as mild, type II as perinatal lethal, type III as severe/progressive and type IV as moderate. While genotype/phenotype correlations are established, phenotypic variability exists making counseling on prognosis challenging. This case series documents our observations of the clinical course of four infants with genetic variants that previously have been associated with lethal OI.



 

Methods:
We completed chart reviews of patients treated in our center’s NICU from 2019-2024. Utilizing ClinVar we compared each infant’s genetic variant with diagnostic classification and completed a review of previously published medical literature to identify infants harboring variants that previously have been described in individuals with lethal OI. We reviewed clinical charts from birth until present and provide descriptions of clinical course in the NICU, as well as after discharge.

 

Results:
We identified four infants who had variants previously associated with lethal presentations of OI. All the variants identified were missense variants in either COL1A1 or COL1A2, and families were counseled on a lethal/possibly lethal prognosis. Three individuals are living, and one died after discharge. In the NICU, maximal respiratory support was CPAP for three infants and high flow nasal canula for the fourth. Two infants were discharged without oxygen support requirements. Today, the three surviving individuals do not require oxygen support. At discharge from the NICU, one infant had gastrostomy tube (GT) placed and one had nasogastric feeding, and subsequently required a GT. The remaining two fed by mouth at discharge and continue to today. One of the three surviving individuals is now 47 months of age and can stand bearing weight on lower extremities while the other two are below 1 year of age.

 

Conclusion:
We describe the clinical course of four infants with molecular variants that previously have been associated with lethal OI. All four infants survived to hospital discharge and did not require intubation. These observations support that phenotypic variability exists in OI, and that making prenatal assessments on lethality are nuanced. In our cohort, we found that genotype did not predict perinatal lethality. For this reason, regardless of genotype we believe all families should be offered the option of postnatal medical intervention.

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