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

Figures & data

Figure 1 Hematoxylin and eosin stain (H&E) of biopsy specimens. (A) Intestinal biopsy specimen revealed acid-fast bacilli. (B) Intestinal biopsy specimen showed acid-fast bacilli (arrows). (C) Lymph node biopsy specimen revealed acid-fast bacilli. (D) Lymph node biopsy specimen showed acid-fast bacilli (arrows). (E) Bronchial biopsy specimen revealed acid-fast bacilli. (F) Bronchial biopsy specimen showed acid-fast bacilli (arrow). Original magnifications: (A) 100X; (B, D and F) 1000X; (C and E) 200X.

Figure 2 Computed tomography and Bronchoscopy findings. (A) Chest CT showed a nodular lesion in the right main bronchus (arrow). (B) Abdominal CT showed a mass in the right lower abdomen (arrow). (C) Bronchoscopy showed nodules in the right bronchus (arrow). (D) The nodule in the right bronchus was smaller after five months of treatment (arrow).

Figure 3 Identification of TYK2 compound heterozygous mutation. (A) Validation by Sanger sequencing of theTYK2 mutations in the patient and his parents. (B) Pedigree of a family in our case. Squares and circles indicate males and females, respectively. Darkened symbols represent the affected individuals. The proband is indicated by an arrow. W, wild-type; M1, c.3083A>G (p.N1028S); M2, c.2590C>T (p. R864C).

Table 1 Summary of Demographic and Clinical Characteristics

Patient/Sex/Age (y)	Country	Other Infections	Bacterial Infections	Mutation	BCG Vaccination	Disease	Treatment	Results
P1^Citation16/M/1	Japan	HSV, PRV-3, MCV, C. albicans	BCG-itis, Salmonella	C70HfsX21	Yes	HIES	/	A
P2^Citation9/M/1	Turkey	VZV	BCG-osis, Brucella	L767X	Yes	Disseminated BCG disease	Ab	A
P3^Citation9/F/13	Morocco	No	M.tuberculosis	T1106HfsX4	Yes	Disseminated tuberculosis	Ab	D
P4^Citation9/M/1	Morocco	Yes?	Yes?	T1106HfsX4	Yes	Meningitis	No	A
P5^Citation9/M/1	Iran	No	BCG-osis	E154X	Yes	Disseminated BCG disease	Ab	A
P6^Citation9/F/1	Iran	Yes	BCG-itis	E155X	Yes	BCG disease	/	A
P7^Citation9/F/9	Iran	No	M.tuberculosis	S50HfsX1	Yes	Miliary tuberculosis	/	A
P8^Citation9/M/1	Argentina	HSV	No	R638X	Yes	Disseminated HSV disease	Acyclovir	A
P9^Citation12/F/5	Kurdistan	No	No	Pro216Argfs*14	No	HIES	/	A
P10^15/M/12	Japan	EBV	No	Cys70Serfs*21/R231W	Yes	T-cell lymphopenia, EBV-associated B-cell lymphoma	Chemotherapy, BMT	D
P11^Citation15/F/13	Japan	EBV	No	Cys70Serfs*21/R231W	Yes	T-cell lymphopenia, EBV-associated B-cell lymphoma	Chemotherapy	A
P12^Citation14/M/1	Sweden	No	Mycobacterium bovis BCG	P1104A	Yes	BCG osteomyelitis	Ab	A
P13^Citation14/M/1	Mexico	No	M.avium complex	P1104A	No	MAC osteomyelitis	Ab	A
P14^Citation14/M/2	Iran	No	BCG-osis	P1104A	Yes	Disseminated BCG disease	Ab, IFN-γ	A
P15^Citation14/M/6	Brazil	No	M.tuberculosis	P1104A	Yes	Pulmonary tuberculosis	Ab	A
P16^Citation14/F/40	Algeria	Aspergillus	M.tuberculosis	P1104A	Yes	Pulmonary tuberculosis	Ab	A
P17^Citation14/M/27	Morocco	No	M.tuberculosis	P1104A	Yes	Pulmonary tuberculosis	Ab	A
P18^Citation14/M/15	turkey	No	M.tuberculosis	P1104A	Yes	Miliary tuberculosis	Ab	A
P19^Citation14/M/13	Chile	No	M.tuberculosis	P1104A	Yes	Pulmonary tuberculosis	Ab	A
P20^Citation14/M/35	Morocco	No	M.tuberculosis	P1104A	Yes	Pulmonary tuberculosis	Ab	A
P21^Citation14/M/33	Chile	No	M.tuberculosis	P1104A	Yes	Pulmonary tuberculosis	Ab	A
P22^Citation17/M/1	Iran	HSV, VZV	Mycobacterium bovis BCG	P216Rfs*14	Yes	BCG disease	/	A
P23^Citation18/M/1	China	No	Mycobacterium bovis BCG, Salmonella	G799R	Yes	BCG disease	/	A
P24, our case/M/24	China	No	Mycobacterium intracellulare	N1028S/R864C	Yes	Disseminated NTM disease	Ab	A

Abbreviations: M, male; F, female; HSV, herpes simplex virus; PRV-3, parainfluenza virus type 3; MCV, molluscum contagiosum virus; VZV, varicella zoster virus; EBV, Epstein-Barr virus; HIES, hyper-IgE syndrome; BCG, Bacillus Calmette-Guerin; IFN-γ, interferon gamma; NTM, nontuberculous mycobacteria; D, died; A, alive; Ab, antibiotic.

Minegishi Y, Saito M, Morio T, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25(5):745–755. doi:10.1016/j.immuni.2006.09.00917088085

 PubMed Web of Science ®Google Scholar

Kreins AY, Ciancanelli MJ, Okada S, et al. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med. 2015;212(10):1641–1662. doi:10.1084/jem.2014028026304966

 PubMed Web of Science ®Google Scholar

Fuchs S, Kaiser-Labusch P, Bank J, et al. Tyrosine kinase 2 is not limiting human antiviral type III interferon responses. Eur J Immunol. 2016;46(11):2639–2649. doi:10.1002/eji.20164651927615517

 PubMed Web of Science ®Google Scholar

Nemoto M, Hattori H, Maeda N, et al. Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia. Sci Rep. 2018;8(1):6956. doi:10.1038/s41598-018-25260-829725107

 PubMed Web of Science ®Google Scholar

Boisson-Dupuis S, Ramirez-Alejo N, Li Z, et al. Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant. Sci Immunol. 2018;3(30):30. doi:10.1126/sciimmunol.aau8714

 Web of Science ®Google Scholar

Sarrafzadeh SA, Mahloojirad M, Casanova JL, et al. A new patient with inherited TYK2 deficiency. J Clin Immunol. 2020;40(1):232–235. doi:10.1007/s10875-019-00713-531713088

 PubMed Web of Science ®Google Scholar

Wu P, Chen S, Wu B, Chen J, Lv G. A TYK2 gene mutation c.2395G>A leads to TYK2 deficiency: a case report and literature review. Front Pediatr. 2020;8:253. doi:10.3389/fped.2020.0025332537443

 PubMed Web of Science ®Google Scholar