Follow the Family History: Neonatal Diagnosis of YARSopathy and Congenital CMV
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
YARSopathy is an extremely rare, recently described disorder caused by biallelic pathogenic variants in YARS, which encodes tyrosyl-tRNA synthetase essential to translation and protein synthesis. Shortened lifespan and multisystemic involvement have been described, including growth failure, sensorineural hearing loss (SNHL), nystagmus, brain dysmyelination, developmental delay, chronic anemia, hypoglycemia, progressive cholestatic liver disease, pancreatic insufficiency, renal dysfunction, recurrent infections, and chronic pulmonary disease. Prenatal course can be complicated by premature birth, placental abnormalities, fetal growth restriction (FGR), and decreased fetal movement. We report the 12th documented individual with YARSopathy, whose clinical picture was complicated by a dual diagnosis with overlapping features.
Case Presentation
43-year-old G9P6116 referred at 33 weeks 2 days gestation for amniotic bands. This was a spontaneous pregnancy. All illnesses and exposures were denied. Obstetric history was notable for a prior pregnancy complicated by severe FGR and fetal demise at 36 weeks (no genetic work-up). Family history was significant for distant maternal and paternal relatives with YARSopathy. The couple was from the Amish community and reported no consanguinity.
Ultrasound identified FGR (<2nd percentile), abnormal umbilical artery Dopplers with absent end diastolic flow, thickened placenta, and multiple amniotic bands without constriction. Fetal echocardiogram noted diffuse dilation of the left and right coronary arteries. The patient noted decreased fetal movement and biophysical profile was poor, which in combination with severe FGR and abnormal Dopplers raised concern for increased risk of fetal demise, prompting delivery via cesarean.
Diagnostic Workup
Postnatal Genetics evaluation on DOL 1 revealed a female neonate with microcephaly, short stature, low weight (<1st percentile), and limited subcutaneous tissue.
Targeted YARS testing resulted on DOL 10 and confirmed homozygosity for an Amish founder variant (c.499C>A, p.Pro167Thr), consistent with YARSopathy.
Urine testing for cytomegalovirus (CMV) was positive on DOL 2, consistent with congenital CMV infection. Her history of FGR, microcephaly, and mildly elevated AST were felt to be compatible with congenital CMV.
Treatment and Management
Initial postnatal echocardiogram, abdominal ultrasound, and brain ultrasound were normal. Antiviral therapy for congenital CMV was initiated on DOL 3 and discontinued after 6 weeks per parental preference given the risk for complications already associated with YARSopathy. Screening fecal elastase recommended due to risk for pancreatic insufficiency was normal. She was diagnosed with hypertension. Bilateral, profound SNHL was diagnosed at 3 months and cochlear implantation is being explored. Ophthalmology evaluation on DOL 3 was normal. MRI of the brain/orbits at 8 months was suggestive of dysmyelination with normal orbits/optic nerves. At 7 months she was found to have persistently elevated aminotransferases, GGT, and hyperbilirubinemia suggestive of acute bacterial cholangitis. Abdominal ultrasound and MRI at 7 months identified hepatic lesions, most characteristic of dysplastic nodules.
Outcome and Follow-Up
The infant is currently 9 months old and is followed for feeding difficulties/slow growth with oropharyngeal dysphagia and G-tube dependence, hypoglycemia, cholestatic liver disease, SNHL, and transfusion-dependent anemia.
Discussion
The infant received dual diagnoses of YARSopathy and congenital CMV, which share a considerable degree of overlap in their manifestations. As several of this neonate’s features could have been attributed solely to congenital CMV, such as FGR, placental abnormalities, developmental delays, and SNHL, the detailed family history was pertinent to making the genetic diagnosis. We suspect that their prior fetal demise was similarly affected with YARSopathy. Knowledge of the YARSopathy diagnosis has altered this infant’s care, including supportive therapies and anticipatory screening, with the goal of improving prognosis compared to previous reports.
Conclusion
This case therefore emphasizes the value of a thorough family history evaluation in guiding a genomics-based approach to congenital anomalies. It also adds to the literature regarding the clinical spectrum of this rarely reported condition, thus aiding in future research to elucidate the complete YARSopathy phenotype and potential therapeutics.
YARSopathy is an extremely rare, recently described disorder caused by biallelic pathogenic variants in YARS, which encodes tyrosyl-tRNA synthetase essential to translation and protein synthesis. Shortened lifespan and multisystemic involvement have been described, including growth failure, sensorineural hearing loss (SNHL), nystagmus, brain dysmyelination, developmental delay, chronic anemia, hypoglycemia, progressive cholestatic liver disease, pancreatic insufficiency, renal dysfunction, recurrent infections, and chronic pulmonary disease. Prenatal course can be complicated by premature birth, placental abnormalities, fetal growth restriction (FGR), and decreased fetal movement. We report the 12th documented individual with YARSopathy, whose clinical picture was complicated by a dual diagnosis with overlapping features.
Case Presentation
43-year-old G9P6116 referred at 33 weeks 2 days gestation for amniotic bands. This was a spontaneous pregnancy. All illnesses and exposures were denied. Obstetric history was notable for a prior pregnancy complicated by severe FGR and fetal demise at 36 weeks (no genetic work-up). Family history was significant for distant maternal and paternal relatives with YARSopathy. The couple was from the Amish community and reported no consanguinity.
Ultrasound identified FGR (<2nd percentile), abnormal umbilical artery Dopplers with absent end diastolic flow, thickened placenta, and multiple amniotic bands without constriction. Fetal echocardiogram noted diffuse dilation of the left and right coronary arteries. The patient noted decreased fetal movement and biophysical profile was poor, which in combination with severe FGR and abnormal Dopplers raised concern for increased risk of fetal demise, prompting delivery via cesarean.
Diagnostic Workup
Postnatal Genetics evaluation on DOL 1 revealed a female neonate with microcephaly, short stature, low weight (<1st percentile), and limited subcutaneous tissue.
Targeted YARS testing resulted on DOL 10 and confirmed homozygosity for an Amish founder variant (c.499C>A, p.Pro167Thr), consistent with YARSopathy.
Urine testing for cytomegalovirus (CMV) was positive on DOL 2, consistent with congenital CMV infection. Her history of FGR, microcephaly, and mildly elevated AST were felt to be compatible with congenital CMV.
Treatment and Management
Initial postnatal echocardiogram, abdominal ultrasound, and brain ultrasound were normal. Antiviral therapy for congenital CMV was initiated on DOL 3 and discontinued after 6 weeks per parental preference given the risk for complications already associated with YARSopathy. Screening fecal elastase recommended due to risk for pancreatic insufficiency was normal. She was diagnosed with hypertension. Bilateral, profound SNHL was diagnosed at 3 months and cochlear implantation is being explored. Ophthalmology evaluation on DOL 3 was normal. MRI of the brain/orbits at 8 months was suggestive of dysmyelination with normal orbits/optic nerves. At 7 months she was found to have persistently elevated aminotransferases, GGT, and hyperbilirubinemia suggestive of acute bacterial cholangitis. Abdominal ultrasound and MRI at 7 months identified hepatic lesions, most characteristic of dysplastic nodules.
Outcome and Follow-Up
The infant is currently 9 months old and is followed for feeding difficulties/slow growth with oropharyngeal dysphagia and G-tube dependence, hypoglycemia, cholestatic liver disease, SNHL, and transfusion-dependent anemia.
Discussion
The infant received dual diagnoses of YARSopathy and congenital CMV, which share a considerable degree of overlap in their manifestations. As several of this neonate’s features could have been attributed solely to congenital CMV, such as FGR, placental abnormalities, developmental delays, and SNHL, the detailed family history was pertinent to making the genetic diagnosis. We suspect that their prior fetal demise was similarly affected with YARSopathy. Knowledge of the YARSopathy diagnosis has altered this infant’s care, including supportive therapies and anticipatory screening, with the goal of improving prognosis compared to previous reports.
Conclusion
This case therefore emphasizes the value of a thorough family history evaluation in guiding a genomics-based approach to congenital anomalies. It also adds to the literature regarding the clinical spectrum of this rarely reported condition, thus aiding in future research to elucidate the complete YARSopathy phenotype and potential therapeutics.