P406: A novel UBA2 variant causing aplasia cutis congenita with ectrodactyly skeletal (ACCES) syndrome in a family with variable expressivity

Discussion: Fucosidosis is a progressive neurodegenerative disorder characterized by relentless symptom progression.It is classified into two types: Type I, presenting within the first year of life and associated with rapid disease progression and a life expectancy of 5-10 years, and Type II, which presents after age two with a slower progression and longer survival.Our patient aligns with Type I, displaying severe and progressive symptoms.However, diagnostic delays due to the diverse spectrum of clinical features associated with fucosidosis illustrate the ongoing challenges in early diagnosis and the need for increased awareness. Conclusion:The FUCA1 gene, located on chromosome 1p36.11,contains eight exons spanning 23 kb.To date, only 36 pathogenic variants in FUCA1 have been reported.The identification of this novel variant expands the mutation spectrum.This case highlights the importance of considering rare forms of LSD in patients presenting with a broad array of multisystemic symptoms.Further research is needed to develop therapies, including enzyme replacement, stem cell transplantation, and gene therapy.Introduction: Fucosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) with an incidence of less than 1 in 200,000.It is caused by pathogenic variants in the FUCA1 gene, resulting in a deficiency of the lysosomal enzyme -L-fucosidase.This enzyme deficiency disrupts the degradation of fucose-containing glycoconjugates, leading to their accumulation in various tissues and causing a range of neurodegenerative symptoms.Clinical manifestations of fucosidosis vary widely and include coarse facial features, growth retardation, recurrent respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum.The broad spectrum of presentations complicates early diagnosis, with approximately 120 cases reported globally to date.Case Presentation: We report the case of a two-year-old boy presenting with global developmental delay, nonverbal status, and inability to walk.He was born at 36 weeks to a 23-year-old mother via spontaneous vaginal delivery and experienced neonatal jaundice treated with phototherapy.Initial symptoms included significant hypotonia, dysphagia, exotropia, lumbar kyphosis, gibbus deformity, lower extremity spasticity, and in-toeing gait.Family history was unremarkable.Diagnostic Workup: Brain MRI revealed diffuse white matter abnormalities and signal changes in the bilateral globus pallidi, suggesting a lysosomal storage disorder or leukodystrophy.However, MPS enzyme screening, urine analysis, and ophthalmologic examination yielded no conclusive results.Chromosomal microarray analysis identified a 17.2 Mb region of homozygosity at 1p36.21, suggestive of consanguinity and possible autosomal recessive disorders.Exome sequencing could not be completed due to the family's relocation and the COVID-19 pandemic.At age six, the patient was admitted to the hospital with fever and hand, foot, and mouth lesions, which prompted further genetic investigation.Physical examination revealed muscle atrophy, hypotonia, and lower extremity spasticity with ankle contractures.A leukodystrophy panel revealed a novel homozygous pathogenic variant, c.557T>A (p.Leu186*) in the FUCA1 gene.Subsequent enzyme testing confirmed a complete absence of alpha-fucosidase activity, leading to a definitive diagnosis of fucosidosis.