<p>Mycobacterium Intracellulare Infection Associated with TYK2 Deficiency: A Case Report and Review of the Literature</p>

Abstract

Individuals with genetic defects show an increased susceptibility to poorly pathogenic mycobacteria including nontuberculous mycobacteria and Bacillus Calmette-Guerin (BCG). In previous studies, defects in multiple genes were identified to be associated with mycobacterium infection including tyrosine kinase 2 (TYK2). The mutations lead to insufficient production of interferon (IFN)-γ or an insufficient response to IFN-α/β, interleukin (IL)-6, IL-10, IL-12 and IL-23. Herein, we describe a case of Mycobacterium intracellulare infection in a male with abdominal pain and diarrhea. Whole exome sequencing of the genomes revealed a compound heterozygous mutation (c.3083A>G/c.2590C>T, p.N1028S/p.R864C) in the TYK2 gene. The patient recovered after two years of anti-mycobacterial treatment and no relapse was observed so far. We also reviewed 24 cases of mycobacterial infection associated with TYK2 deficiency which provides evidence of how personalised genomics can improve outcomes.

Impaired IL-23–dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency

“…We herein described 13 patients with pLOF variants, including nine new patients. Among the latter, 33% suffered from mycobacterial diseases, 66% from viral diseases, and 33% from fungal diseases, whereas the percentages were 60, 53, and 6%, respectively, for the previously reported 15 patients ( Fuchs et al, 2016 ; Guo et al, 2020 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ). Interestingly, six of these 13 patients suffered from COVID-19 before vaccination (P7, P12, P14, P16, P17, and P19), including four with hypoxemic pneumonia (P7, P12, P16, and P19; Table 1 ).…”

“…1 and Table 1 ): P1 is homozygous for a previously reported 4-bp deletion in exon 4 (c.208_211:GCTTdel; p.C70Hfs*21; Minegishi et al, 2006 ); P2 is homozygous for a copy number variant consisting of a large deletion spanning exons 19–25 (g.10467969_10459969del; E19_25del; Fig. S1 ); P3 and his sister (P4) are homozygous for a substitution in exon 18 (c.2590 C>T; predicted p.R864C) previously reported in a patient compound heterozygous for this allele and p.N1028S ( Guo et al, 2020 ); P5 is homozygous for a missense substitution in exon 13 (c.1901 G>A; p.G634E); P6 is homozygous for a missense substitution in exon 21 (c. 2986 G>C; p.G996R); P7, P11, P12, P14, P16, and P19 are homozygous for a single base-pair deletion in exon 7 (c.647delC; p.P216Hfs*14) already described elsewhere ( Fuchs et al, 2016 ; Sarrafzadeh et al, 2020 ; Zhang et al, 2022 ); P8 is homozygous for an essential splice-site mutation at the end of exon 17 (c.2466+1G>T); P9 is homozygous for a missense variant in exon 22 (c.3029G>A; p.G1010D); P10 is compound heterozygous for two missense variants, one in exon 20 (g.2783C>T; p.A928V) and the other in exon 23, the common allele P1104A ( Boisson-Dupuis et al, 2018 ); P13 is homozygous for a nonsense variant in exon 5 (c.460G>T; p.E154*; Kreins et al, 2015 ); P15 is homozygous for a 9-bp deletion in exon 16 (c.2303_2311del; p.L767*; Kreins et al, 2015 ); and P17 and P18 are homozygous for an essential splice-site mutation at the end of exon 5 (c.466-1G>A).…”

“…One of the four rare missense variants has already been reported but is not yet functionally characterized ( Guo et al, 2020 ), whereas the common P1104A variant has been thoroughly studied ( Boisson-Dupuis et al, 2018 ). Among the patients bearing one or two of these missense variants, P3 (R864C/R864C) had mycobacterial (BCG) infections and had one episode of oral thrush due to C. albicans, whereas his sister, P4 (R864C/R864C), who was not vaccinated with BCG, remains asymptomatic.…”

“…Autosomal recessive (AR) complete TYK2 deficiency is characterized by mycobacterial and/or viral diseases ( Table 1 ; Fuchs et al, 2016 ; Guo et al, 2020 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ). Only 15 patients with AR TYK2 deficiency from 13 families have been reported (including one for whom functional characterization is incomplete; Table 1 ; Fuchs et al, 2016 ; Guo et al, 2020 ; Kilic et al, 2012 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ).…”

“…Autosomal recessive (AR) complete TYK2 deficiency is characterized by mycobacterial and/or viral diseases ( Table 1 ; Fuchs et al, 2016 ; Guo et al, 2020 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ). Only 15 patients with AR TYK2 deficiency from 13 families have been reported (including one for whom functional characterization is incomplete; Table 1 ; Fuchs et al, 2016 ; Guo et al, 2020 ; Kilic et al, 2012 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ). Nine of these patients had mycobacterial diseases, including BCG disease ( n = 6), EM disease ( n = 1), and tuberculosis (TB; n = 3), and five had unusually severe viral illnesses, including mucocutaneous herpes simplex virus 1 (HSV-1) infections ( n = 3), HSV-1 encephalitis (HSE; n = 1), cutaneous varicella-zoster virus (VZV; n = 2) or Molluscum contagiosum ( n = 1) infections, human parainfluenza type 3 virus (PIV3) pneumonia ( n = 1), COVID-19 pneumonia ( n = 4), influenza A pneumonia ( n = 1), and measles-mumps-rubella (MMR) vaccine disease ( n = 1; Fuchs et al, 2016 ; Guo et al, 2020 ; Kilic et al, 2012 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ).…”