Table 2_Early neonatal diagnosis of SSR4-related congenital disorder of glycosylation with severe congenital heart defects: a case report and systematic review.docx

BackgroundCongenital disorders of glycosylation type Iy (SSR4-CDG, CDG1Y) is an ultra-rare X-linked disorder caused by pathogenic variants in the SSR4 gene, encoding a subunit of the translocon-associated protein (TRAP) complex. While typically recognized for neurodevelopmental and facial features, its full neonatal spectrum, particularly regarding cardiac involvement, remains under-characterized.
Case presentationWe report a male neonate with the earliest postnatal diagnosis of SSR4-CDG (day of life 6). Prenatal testing revealed a novel, maternally inherited 65.63 kb hemizygous deletion at Xq28, encompassing SSR4 and partially deleting ABCD1. The neonatal presentation was dominated by multiple congenital heart defects (CHDs): Membranous ventricular septal defect, secundum atrial septal defect, persistent left superior vena cava, a narrow proximal left pulmonary artery, and coronary sinus dilation. Additional features included classic dysmorphism (wide mouth, deep-set eyes, micrognathia), severe hypotonia, feeding difficulties, and coagulopathy. Brain MRI revealed a thin corpus callosum.
Literature review & analysisA systematic review of the literature, including reports published up to December 2025, identified 24 previously published cases. Pooled analysis incorporating the present patient (n = 28) confirmed that developmental delay/intellectual disability, hypotonia, characteristic facial features, and microcephaly were observed in 100% of cases. Congenital heart defects (CHDs) were present in 32.1% (9/28) of patients; however, the current case represents the first reported patient in whom severe CHDs constituted the predominant clinical manifestation. Detailed subgroup analyses further demonstrated that the frequency of clinical features varied across different age groups, indicating age-dependent phenotypic expression. All analyses were descriptive in nature, and no formal meta-analysis was performed due to the limited number of reported cases and heterogeneity in clinical data.
ConclusionsThis case expands the neonatal phenotype of SSR4-CDG and highlights that, in some patients, severe congenital heart defects may represent an early and clinically significant manifestation. However, based on currently available evidence, cardiac anomalies remain an uncommon feature of the disorder. Prompt genetic evaluation should be considered in affected male neonates with syndromic features.