Wilson's disease (WD) is an autosomal recessive disorder caused by defective function of the copper-transporting ATP7B protein. Symptoms are typically related to the brain and liver, while endocrinologic abnormalities are rare. Here, we reported a 12-year-old female patient that was initially presented with unusual skin darkening and low serum level of adrenocorticotropic hormone and diagnosed as having adrenocortical insufficiency. We further screened the mutation in ATP7B by direct DNA sequencing and found compound heterozygous mutations: a known pathogenic mutation in exon8:c.2333G>T (Arg778Leu) inherited from her mother and a variant in intron4:c.1707 + 5G>A inherited from her father. To explore the pathogenicity of the intronic variant, a minigene splicing assay was used to determine the effects of the splicing variant by analyzing reverse transcription PCR of ATP7B minigene transcript production. The result indicated that the c.1707 + 5G>A variant resulted in exon 4 skipping. We herein identified that 1707 + 5G>A intron 4 variant is a pathogenic mutation. Molecular genetic analysis and laboratory examination definitely confirmed the patient's condition as WD. Clinical status improved considerably after penicillamine treatment. Our results extended the mutation spectrum of ATP7B gene and highlighted the importance of molecular genetic analysis for the accurate diagnosis of atypical WD. WD may have diverse presentations and should be considered in children especially presenting with adrenocortical insufficiency as initial symptom, and this study highlights the importance of screening for hormone abnormal in WD.
Keywords: ATP7B; Mutation; Secondary adrenocortical insufficiency; Wilson’s disease.