P278: Retrospective characterization of genetics work-up for individuals with RASopathy diagnosis

Introduction: Osteogenesis imperfecta (OI) is a genetic condition with improperly or inadequately produced Type I collagen.Manifestations include fractures and bowing deformities that require lifelong orthopedic care.Intellect has been described as typical and psychosocial quality of life measures described as similar to the general population.Moderate or severe OI follows a dominant-negative molecular mechanism and is often diagnosed prenatally based on ultrasound findings and genetic testing.Some may be labeled as lethal based on ultrasound findings (thoracic circumference/abdominal circumference, TC/AC < 0.6 and femur length/abdominal circumference, FL/AC < 0.16) and/or pathogenic variant that previously has been reported in a case of lethal OI.Here we present 18 infants with OI who received neonatal care at a single center over a 5-year period.Methods: We identified infants with moderate/severe [RC1] OI that were treated [RC2] in our NICU from 9/2019-8/2024 and completed chart review including prenatal, birth, neonatal, medical and surgical histories.We identified variants previously reported as associated with lethal OI and findings from second trimester anatomy ultrasounds.We completed Fisher Exact Test, Mann Whitney U Test and backward elimination regression to evaluate for correlations to length of hospital stay and outcomes, including need for respiratory and feeding support at discharge.Results: Our cohort consists of 12 infants with prenatal lethal/possibly lethal diagnosis, four with nonlethal diagnosis and two who are classified as unknown.We do not observe that lethal or possibly lethal diagnoses prenatally were correlated with medically relevant outcomes such as length of hospital stay (p=0.15),need for respiratory support at discharge (p=1.0), or need for feeding support at discharge (p=0.57).All infants received bisphosphonates at a median age of 14 days (range 6-110 days).17/18 received pamidronate and 1/18 received zoledronate.All 18 infants survived to neonatal discharge, with seven infants requiring respiratory support and nine infants requiring feeding support at discharge.16/18 individuals are alive, with a minority requiring either respiratory support (n=2) or feeding support (n=5).Of the four individuals with a genetic finding previously associated with lethal OI, three are living at median age six months (range 4-47 months).Of the four individuals with FL/AC < 0.16 all are living, with median age 23.5 months (range 11 -47 months).No infants had a reported TC/AC < 0.6.Of the living individuals with a genetic variant previously associated with lethal OI, or FL/AC <0.16 none require respiratory support, one requires feeding support and those above age two (n=2) are able to stand bearing weight on lower extremities.Conclusion: Our experience is that infants formerly diagnosed with lethal OI survive until hospital discharge and, when pursued, support from medical technology is often temporary.Future studies will include long-term follow up of this cohort to evaluate for the natural history of prenatal lethal/possibly lethal OI.Given our findings, and lack of correlation of prenatal assessments (specifically, pathogenic variants previously associated with lethal OI or ultrasound measurement of FL/AC<0.16) with survival and other medical outcomes, we recommend all families be given the option to pursue medical interventions.