Introduction: Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is a rare autosomal recessive disorder caused by biallelic variants in the tartrate-resistant acid phosphatase 5 (ACP5) and characterized by variable skeletal, immunological, and neurological manifestations. Because early skeletal abnormalities may be subtle, diagnosis can be challenging in infancy. Materials and methods: We conducted a detailed clinical, immunological, radiological, and molecular evaluation of an infant with early-onset cytopenia, recurrent infections, seizures, and developmental delay. Genomic analysis was performed using whole exome sequencing (WES) and copy number variation sequencing (CNV-seq). In addition, we performed a structured narrative review of published ACP5-related SPENCDI cases to summarize the clinical spectrum and the currently reported use of Janus kinase (JAK) inhibitors. Results: Genomic analysis identified an ACP5 stop-gain variant (c.311G>A; p.Trp104*) with an apparently homozygous signal on WES. Re-evaluation of the copy-number data demonstrated an overlapping heterozygous 19p13.2–p13.13 deletion encompassing ACP5, indicating biallelic ACP5 defects consisting of a sequence variant on one allele and deletion of the other allele. Clinically, the patient showed prominent extra-osseous manifestations, including impaired T- and NK-cell cytotoxicity, before the emergence of definite radiographic skeletal abnormalities. Our literature review showed that skeletal abnormalities were repeatedly documented across published ACP5-related SPENCDI reports, although radiographic changes were often subtle and could be preceded by immune manifestations. Reported use of JAK inhibitors suggests potential benefit for immune dysregulation in selected patients, whereas the neurological response remains uncertain. Conclusions: This study reports a novel ACP5 variant and expands the known phenotypic spectrum of SPENCDI. SPENCDI should be considered in children with unexplained immune dysfunction and developmental delay, and suggestive neuroimaging findings, even when overt skeletal deformities are absent. Early genetic testing and targeted skeletal imaging may facilitate diagnosis.
Li et al. (Sun,) studied this question.