Congenital IL-12R1B receptor deficiency and thrombophilia in a girl homozygous for anIL12RB1mutation and compound heterozygous forMTFHRmutations: A case report and literature review

Abstract

Interleukin-12 (IL-12) plays an important role in the production of interferon gamma from T cells and natural killer cells and is essential for protection against intra-macrophagic pathogens such as Mycobacterium and Salmonella. Here, we describe a 16-year-old girl with homozygous mutation in exon 12 of the IL12RB1 gene, which causes complete IL-12Rβ1 deficiency in association with heterozygous mutation (C677T and A1298C) in the methylenetetrahydrofolate reductase gene. She presented with disseminated Mycobacterium tuberculosis complex infection, retroperitoneal fungal abscess and also thrombosis in the superior mesenteric-portal vein junction. This is the first case report of a primary immunodeficiency associated with a genetically determined venous thrombosis.

Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

“…Functional IL-12 receptors are expressed primarily on activated T and NK cells. In total, 180 patients from 136 kindreds have been described [2, 21, 25, 28, 30, 31, 34–36, 38–40, 43, 44, 86, 102, 188–233]. The list of known IL12RB1 mutations is increasing, with 78 identified to date, including nonsense ( n =18), missense ( n =24), and splice-site mutations ( n =13), small deletions ( n =16), large deletions ( n =3) insertions ( n =1), and duplications ( n =3) (www.LOVD.nl/IL12RB1) [191] (Figure 1).…”

“…Indeed, 47 of the 179 patients died (26%), 8 are asymptomatic (the oldest being 22 years old in 2010) and 124 were alive at the time of their description, the oldest of these patients being 51 years old in 2010 [28, 198]. Mycobacterial infections are the most frequent infections observed in these patients (BCG, M. avium , M. avium intracellulare complex, M. chelonae , M. fortuitum , M. fortuitum - chelonae complex, M. genevense , M. gordonae , M. tilburgii , M. triplex , M. simiae ) [28, 34, 36, 86, 116, 190, 193, 194, 198, 199, 204, 206, 208–210, 214, 215, 235, 236]. Remarkably, BCG vaccination or disease protects against subsequent EM disease [28, 194] (Figure 5).…”

“…Pneumococcal disease and nocardiosis have each been reported once [39, 210]. A significant minority of patients (48 of 179, 27%) also suffered from mucocutaneous Candida infections, probably because of impaired IL-23-dependent IL-17 immunity [31–36]. Other fungal diseases have been observed in only one or two patients, and were caused by Paraccocidiodes brasiliensis , Coccidiodes spp., Histoplasma spp.…”

“…About half of them also suffer from clinical disease caused by non-typhoidal or, more rarely, typhoidal Salmonella [28–30]. Mild forms of chronic mucocutaneous candidiasis (CMC) have been described [31–36]. Other severe infections have been reported more rarely, typically in single patients, and include infections caused by various intramacrophagic bacteria (listeriosis, nocardiosis, klebsiellosis) [26, 37–39], fungi (candidiasis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis) [31–36, 40–43] and parasites (leishmaniasis, toxoplasmosis) [44, 45].…”

“…Mild forms of chronic mucocutaneous candidiasis (CMC) have been described [31–36]. Other severe infections have been reported more rarely, typically in single patients, and include infections caused by various intramacrophagic bacteria (listeriosis, nocardiosis, klebsiellosis) [26, 37–39], fungi (candidiasis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis) [31–36, 40–43] and parasites (leishmaniasis, toxoplasmosis) [44, 45]. Viral infections have also been reported, including diseases caused by cytomegalovirus (CMV), human herpes virus 8 (HHV8), parainfluenza virus type 3 (PRV-3), respiratory syncitial virus (RSV) and varicella zoster virus (VZV) [46–49].…”