Netherton syndrome caused by compound heterozygous mutation, c.80A>G mutation in SPINK5 and large-sized genomic deletion mutation, and successful treatment of intravenous immunoglobulin

Background: Netherton syndrome (NS) is an autosomal recessive disorder due to mutations in the SPINK5 gene. Here, we report the first case of NS caused by a large genomic deletion.

Methods: We present the clinical data of a 3-year-old Chinese boy who was initially misdiagnosed with severe atopic dermatitis. Subsequently, the patient presented with typical ichthyosis linearis circumflexa and had representative hair shaft of trichorrhexis invaginate, which alerted the physician of the high possibility of NS. A genomic DNA sample was extracted from peripheral blood and whole-exome sequencing (WES) was performed. Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to verify the mutation and genomic deletion, respectively, in the pedigree.

Results: WES revealed compound heterozygous mutations in SPINK5, including a c.80A>G mutation and a ~275 Kb-sized genomic deletion (chr5:147443576-147719312). The c.80A>G mutation was verified by Sanger sequencing in the pedigree. The father had the same heterozygous mutation; however, the mutation was absent in the proband's mother. The qRT-PCR results identified a large deletion (chr5:147444834-147445034) in SPINK5 in the proband and his mother. The eruptions improved remarkably after intravenous immunoglobulin (IVIG) therapy.

Conclusions: This is the first observation of NS caused by a large deletion. Our findings have important implications for mutation screening and genetic counseling in NS. Our report also verifies and supports the safety and efficacy of IVIG therapy in patients with NS.