Objective To investigate the clinical and laboratory diagnosis in a rare case with dwarfism and multisystem abnormalities. Methods Whole-exome sequencing was performed and data was processed using high-throughput data analysis pipeline. Genetic test result is verified by Sanger sequencing. Results This is a 14 -year-old boy with short stature (the height is 132 cm) and autoimmune hemolytic anemia. He was treated with long-term oral prednisone. Head CT from other hospital found multiple calcifications on both sides of the basal ganglia, two sides of the frontal lobe, and the left side of parietal lobe. Lateral spinal X-ray photography showed flat in thoracolumbar vertebral body. Valgus was surgically corrected. He also has facial pigmentation spot and onychomycosis. Whole-exome sequencing combined with Sanger sequencing identified a known homozygous pathogenic mutation in ACP5 genes (c. 643 G>A, p.G 215 R). Identification of such a mutation results in the diagnosis of spondylo enchondrody splasia with immune dysregulation (SPENCDI). Conclusions Wholeexome sequencing is one of the effective methods for detection of rare disease, the SPENCDI case reported here is a good example of it.