Loss of ADAM17 is associated with severe multiorgan dysfunction

Area of Science:

• Genetics
• Immunology
• Dermatology

Background:

• ADAM metallopeptidase domain 17 (ADAM17) is crucial for processing numerous proteins, including those vital for immune function.
• Previous reports identified a rare syndrome associated with ADAM17 mutations, characterized by skin lesions and diarrhea.

Observation:

• This study details a second family with a novel homozygous frameshift mutation (c.308dupA) in ADAM17.
• The proband exhibited severe diarrhea, rash, recurrent sepsis, hypertension, and hepatitis, succumbing at 10 months.

Findings:

• Exome sequencing confirmed a premature stop codon due to the identified ADAM17 mutation.
• Immunological assays revealed significantly reduced tumor necrosis factor-α and interleukin-2 production upon T-cell stimulation.
• Pathological examination of skin biopsies showed neutrophilic infiltrate and spongiotic dermatitis.

Implications:

• This research confirms ADAM17's critical role in human immune responses and highlights its involvement in multiorgan pathologies.
• Understanding ADAM17 function is vital for diagnosing and potentially treating this severe genetic immunodeficiency syndrome.