Clinical and Immunological Characterization of a Netherton Syndrome Infant with a Large SPINK Gene Cluster Deletion and a c.1258A>G Polymorphism in SPINK5

Yaning Guan^1,2Qian Li^1,2Pingping Zhang^1,2Maolin Huang^2,3Yimin Guo^2,3Yan Chen^1,2,3*Zuochen Du^1,3,4*Pei Huang^1,2*

• ¹Laboratory of Hematology and Immunology, Guizhou Children's Hospital, zunyi, China
• ²Affiliated Hospital of Zunyi Medical University, Zunyi, China
• ³Guizhou Children's Hospital, zunyi, China
• ⁴Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China

Netherton syndrome (NS) which is a rare autosomal recessive disorder resulted by the causative gene, serine peptidase inhibitor Kazal type 5 (SPINK5), encoding the serine protease inhibitor LEKTI (Lympho-Epithelial Kazal-type-related Inhibitor). It resulted congenital ichthyosis, hair shaft abnormalities and atopic manifestations. Previously, intravenous immunoglobulin (IVIG) was found to mildly alleviate the clinical manifestations of NS. In this study, we discovered IVIG could effectively alleviate clinical symptoms through assessing a 1-year and 6-month-old boy with typical clinical manifestations of NS caused by new compound heterozygote mutations in the SPINK5 gene. Whole-exome and Sanger sequencing results manifested a novel heterozygous deletion mutation (chr5: 147,443,561-147,719,327) including the SPINK5 gene and the G1258A polymorphism (NM 00684; exon14 c.1258A>G, p.K420E). To verify the effect of the deletion and polymorphism, we detected a significant decrease in the expression of the LEKTI. We also monitored changes in lymphocyte subsets and cytokine level after IVIG treatment, which showed a marked recovery of immune modulation following IVIG therapy. This case is a typical example of a patient with a large deletion in SPINK5 who showed significant improvement after IVIG treatment, highlighting the importance of IVIG in the treatment of immunodeficiency diseases.