Partial Loss of NEMO Function in a Female Carrier with No Incontinentia Pigmenti.

Background/

Objectives

The nuclear factor (NF)-kB essential modulator (NEMO) has a crucial role in the NFκB pathway. Hypomorphic IKBKG pathogenic variants cause ectodermal dysplasia with immunodeficiency (EDA-ID) in affected males. However, heterozygous amorphic IKBKG variants could be responsible for Incontinentia Pigmenti (IP) in female carriers. Typically, IP patients do not exhibit immunodeficiency, although hypomorphic variants might lead to immunodeficiency in female IP patients. Here, we report the case of an IKBKG female carrier, with no IP but an unexpected picture of immunodeficiency. She had a positive family history for the same genetic condition.

Methods

We performed immunological, molecular, and functional analysis to evaluate NEMO contribution.

Results

The patient was healthy until the age of 25 when severe asthma and Hashimoto thyroiditis occurred. She had HLAB27-positive ankylosing spondylitis, non-tubercular mycobacteriosis, and pulmonary aspergillosis infections. We found CD19+ B cell lymphopenia and T cell subset alterations. Sanger sequencing revealed a heterozygous IKBKG variant at position +1 of the 5' UTR of the gene which disrupted the normal pre-mRNA splicing. We observed a decreased NEMO protein expression, a reduced level of mRNA, and a defective NF-κB pathway.

Conclusions

These findings suggest a possible correlation between the partial loss of NEMO function and the immunodeficiency observed in this patient. This case could expand our understanding of NEMO deficiency in female carriers.