P443: Alport syndrome with a novel COL4A3 gene alteration presenting with recurrent vertebral artery dissections: Case report and literature review

Introduction: Macroglossia is a distinctive feature often identified early in the neonatal period.While it has a broad diagnostic differential, it is recommended to rule out Beckwith-Wiedemann Syndrome (BWS) even in isolated cases.Elevated lactate is a common feature of mitochondrial and other metabolic conditions, and individuals with RASopathies may exhibit secondary mitochondrial dysfunction.Cardiofaciocutaneous (CFC) syndrome is an autosomal dominant condition characterized by cardiac abnormalities, distinctive craniofacial features, and cutaneous anomalies.Additional features include poor growth, developmental delays, feeding issues, sparse hair, hypotonia, vomiting, dysmotility, hip dysplasia, and joint contractures.Case Presentation: The proband, a female infant conceived via in vitro fertilization, was delivered at 32 weeks gestation by cesarean section due to severe preeclampsia.She had birth weight of 1.42 kg (97.4th centile), length of 47 cm (22.37th centile), and head circumference of 36 cm (100th centile).She was admitted to the NICU for apnea and required intubation for 5 days due to respiratory distress.A dysmorphology exam revealed macroglossia, dolichocephaly, sparse hair, down-slanting palpebral fissures, absent eyebrows with mild ulerythema, coarse facial features, ulnar hand deviation, and decreased muscle bulk with bilateral hip and knee contractures.Initial laboratory results showed elevated lactate at 3.5 mmol/L (reference range: 0.5-2.2mmol/L), peaking at 4.2 mmol/L.Her clinical course was complicated by poor weight gain, dysphagia, and feeding difficulties requiring gastrostomy tube (g-tube) placement.She experienced recurrent, unexplained fevers and elevated white blood cell counts without identifiable infections.The proband also had episodes of perioral cyanosis and desaturation, which resolved with repositioning, potentially related to macroglossia.An EEG showed occasional isolated bilateral multifocal sharp activity but no clinical seizures.She was discharged from the NICU at 10 weeks old.Diagnostic Workup: Genetic testing for BWS, including methylation studies and CDKN1C sequencing, was negative, though the broad spectrum of BWS and associated malignancy risks necessitate ongoing surveillance.Abdominal and renal ultrasounds ruled out hepatoblastoma and nephroblastoma.Elevated lactate levels suggested a possible mitochondrial disorder.Rapid exome sequencing (ES) identified heterozygous de novo variants of uncertain significance in MAP2K1 (c.