ADAM17 – Neonatal Inflammatory Skin and Bowel Disease 1

ADAM17, encoding a membrane-bound metalloprotease (TACE), mediates ectodomain shedding of key substrates including TNFα and EGFR ligands. Loss-of-function variants in ADAM17 cause neonatal inflammatory skin and bowel disease 1 (NISBD1), an autosomal recessive syndrome marked by erythroderma, nail dystrophy, oesophageal strictures, intractable diarrhoea and recurrent infections. Genetic testing is critical for early diagnosis and guiding targeted therapy.

Biallelic ADAM17 variants have been identified in at least 7 unrelated families (8 patients) with NISBD1, including homozygous frameshift, compound heterozygous large deletion-and-splice defects and missense alleles ([PMID:34993966], [PMID:25804906], [PMID:33953303]). A representative variant, c.1799G>A (p.Cys600Tyr), occurs in trans with an exon 6–7 deletion in a patient whose severe skin and intestinal manifestations improved with combined anti-TNFα and anti-IL-12/23 therapy ([PMID:34993966]).

Segregation analysis demonstrates multiple affected sibships (two independent sibling pairs) consistent with autosomal recessive inheritance. The variant spectrum comprises large genomic deletions, splice-site variants causing exon skipping, frameshifts and cysteine-disrupting missense changes that abrogate ADAM17 expression or function.

Functional studies show that Met435 substitutions (M435I, M435L, M435S) inactivate ectodomain shedding of TNFα, TGFα and L-selectin in vitro ([PMID:17464354]). Cell-based assays in ADAM10/17 knockout fibroblasts confirm that p.Cys600Tyr and other missense alleles abolish PMA-stimulated sheddase activity, correlating with impaired cytokine release in patient immune cells ([PMID:33953303], [PMID:25804906]).

No studies have refuted this gene–disease link. Mouse models with hypomorphic or tissue-specific loss of Adam17 recapitulate skin barrier and intestinal defects, strengthening mechanistic validity.

In summary, moderate clinical validity is supported by multiple unrelated AR cases, segregation in families and concordant functional assays. Early molecular diagnosis enables prompt immunosuppressive intervention.

Key take-home: Biallelic ADAM17 testing confirms NISBD1 diagnosis and directs combined anti-TNFα/IL-12/23 therapy for optimal patient management.

References

• The British journal of dermatology • 2022 • Neonatal inflammatory skin and bowel disease type 1 caused by a complex genetic defect and responsive to combined anti-tumour necrosis factor-α and interleukin-12/23 blockade PMID:34993966
• Human pathology • 2015 • Loss of ADAM17 is associated with severe multiorgan dysfunction. PMID:25804906
• Scientific reports • 2021 • Functionally confirmed compound heterozygous ADAM17 missense loss-of-function variants cause neonatal inflammatory skin and bowel disease 1. PMID:33953303
• Biochemistry and cell biology = Biochimie et biologie cellulaire • 2007 • Substitution of methionine 435 with leucine, isoleucine, and serine in tumor necrosis factor alpha converting enzyme inactivates ectodomain shedding activity. PMID:17464354

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