ADAM17, encoding ADAM metallopeptidase domain 17, is a membrane-bound shedding protease, which plays an essential role during normal development and in the regulation of inflammation. Biallelic variants in ADAM17, resulting in complete loss of ADAM17 expression, have been reported in individuals affected by rare neonatal inflammatory skin and bowel disease 1 (NISBD1). Here, we report on a young female individual with NISBD1 featuring erythroderma, atrichia, nail dystrophy, oesophageal strictures, intractable diarrhoea, profound failure to thrive and recurrent cutaneous and systemic infections. In this case, NISBD1 was found to result from a complex compound heterozygous defect consisting of a large genomic deletion spanning exons 6 and 7 in addition to a splice site variant causing exon 17 skipping. Skin manifestations dramatically improved in response to combined anti-tumour necrosis factor-α and interleukin-12/23 blockade, while gastrointestinal symptoms were controlled with budesonide. Our study further expands the phenotypic and genetic spectrum of NISBD1 and suggests that combined immunosuppressive treatments may be indicated in this complex condition. What is already known about this topic? Biallelic loss-of-function variants in ADAM17, encoding ADAM metallopeptidase domain 17, have to date been reported in only four families with neonatal inflammatory skin and bowel disease 1 (NISBD1). NISBD1 features variable disease phenotypes associated with different degrees of severity. What does this study add? We report a case of a patient with NISBD1 caused by a unique genetic defect consisting of a combination of a splice site variant leading to exon 17 skipping and a large deletion spanning exons 6-7 of the ADAM17 gene. The severe cutaneous phenotype in our patient responded to a combination of ustekinumab and certolizumab.
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