NCF4 mutation in 9yo boy (neutrophil superoxide dysfunction) with chronic granulomatous disease

[Matthew Taylor]

My first post here! | IFMC-MD Family physician. New to SSRP. Love it so far. Want to gather insight on the challenging question, “What do you do for someone whose superoxide production by neutrophils basically doesn’t work?” Here’s the brief story:

9yo boy with recurrent pyogenic skin and URI Staph and Candidal infections; after two years found splice-site mutations in Neutrophil cytosolic factor 4 (and 1) — inborn malfunction in encoding of the p40- and p47-phox (phagocyte oxidase) proteins, on chromosomes 22 and 7. These are subunits of the NADPH oxidase complex. Would call this “Chronic granulomatous disease t.3, autosomal recessive (CGD3).” 1 in 300,000. Here are the OMIM references:

https://omim.org/entry/613960 (CGD3)

https://omim.org/entry/601488 (NCF4)

Some effects of this: increased production of IL-17, gamma-delta T-cell reactivity, and failure of cleavage of tryptophan (requires superoxide, mediated by IFN-gamma) to yield kynurenine.  According to OMIM references, “replacement of a natural kynurenine,… which often includes coadministration of recombinant IFN-gamma,” restores the downstream metabolites and function of a class of T-cells that may reverse the hyperinflammatory state.  I am uncertain what would qualify as a candidate for a ‘natural kynurenine.’

If you’re open to digging in to this a little and have some ideas on translating the above into therapy (other than the conventional recs of prophylactic antibiotics forever, or stem-cell transplant), I know a stressed out family and flummoxed doc who would appreciate it.

Some initial insights I received via Cogence Immunology:

• “Super interesting example of how important adequate IFN-gamma is and how you end up with Th17 dominance without it…” (may need to give recombinant IFN-gamma)
• “If his neuts aren’t going to do the heavy lifting, he needs more work from his M1 macs to kill pathogens. That would suggest support for NK cells (astragalus, andrographis, reishi/ganoderma) and for Th1 response. With all that mucosal dysregulation in GI and lungs, it will be key to avoid Th2 dominance promoting effects generated by the epithelia, to avoid yet more downregulation of IFNg.”
• “He may need to avoid high nickel foods. They can promote IgE-mediated allergic rxn.” (I have done IgE food testing on the kiddo and am looking into this…)
• “It certainly makes sense to think of stress-inflammation coactivation. To the extent that neurogenic inflammation (known to drive skin rxn’s) is participating, or if histamine is being driven up by other factors in the Th2 process, like mast cell activation, downregulation of histamine may be suitable.” (Gabaergics had helped his skin reactions at one point in the last year, since stopped, and we thought we were on to something…)

Open to sharing more about the story for any interested.  Thank you.

[Kristelle Reyes]

Hello @byurthgmail-com @drhusaininterlinkedmd-com @drerikaeshealth-com @infouzzireissmd-com would love to have your input here.

Thank you! 🙂

[Elizabeth Yurth]

Phew–this is a tough one. Need to put some thought into it. Maybe brilliant pathway guru @amybodyscience-life can be of some help here??

Betsy

[Matthew Taylor]

Quote from Elizabeth Yurth on June 15, 2021, 11:05 pm

Phew–this is a tough one. Need to put some thought into it. Maybe brilliant pathway guru @amybodyscience-life can be of some help here??

Betsy

Appreciate any insights.  Interested also in whether anyone familiar with recombinant IFN-gamma useage, as this lad’s parents are considering it at specialist’s suggestion.

[Author]

Posts