Immunodeficiency 30


A number sign (#) is used with this entry because immunodeficiency-30 (IMD30) is caused by homozygous or compound heterozygous mutation in the IL12RB1 gene (601604) on chromosome 19p13.


IMD30 results from autosomal recessive IL12RB1 deficiency and is the most common form of susceptibility to mycobacterial disease. Activated T and natural killer lymphocytes from IMD30 patients do not express IL12RB1 on their surface or, more rarely, express nonfunctional IL12RB1 on their surface. IMD30 patients therefore lack responses to IL12 (see 161560) and IL23 (see 605580). The clinical presentation of IL12RB1-deficient patients is similar to that of IL12B-deficient patients (see IMD29, 614890). Bacillus Calmette-Guerin (BCG) disease and salmonellosis are the most frequent infections. Salmonellosis is present in about half of IL12RB1-deficient patients, and significant numbers of patients present with isolated salmonellosis. Severe tuberculosis has been reported in several unrelated patients, and other infections have been reported in single patients. IMD30 has low penetrance, and patients have relatively mild disease and good prognosis (review by Al-Muhsen and Casanova, 2008).

Clinical Features

Fieschi et al. (2003) identified 41 patients in 29 kindreds from 17 countries in Africa, America, Europe, and Asia with complete IL12RB1 surface expression deficiency. Opportunistic childhood infections with weakly virulent Salmonella and Mycobacteria were observed in 34 patients, but 3 patients had clinical tuberculosis, including 1 with salmonellosis. Salmonellosis, but not the mycobacterial infections, was recurrent. BCG vaccination and disease protected against environmental mycobacteriosis, but not against salmonellosis. BCG disease occurred in only 9 of 27 inoculated children. Fatality before age 8 occurred in 5 patients, 3 due to M. avium in non-BCG-vaccinated children and 2 due to disseminated BCG; the remaining patients were alive and well. Fieschi et al. (2003) proposed that IL12RB1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis and that the diagnosis should be pursued in healthy sibs of probands and in selected cases of tuberculosis. They concluded that the overall prognosis is good due to broad resistance to infection, low clinical penetrance, and the favorable outcome of the infections. Fieschi et al. (2003) noted the unexpected finding that IL12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella, possibly reflecting the difference in the natural course of infection in humans as opposed to the courses of experimental infections in animal models.

Ozbek et al. (2005) reported an 11-year-old Turkish girl with severe abdominal tuberculosis and autosomal recessive IL12RB1 deficiency. She was the fourth child of healthy, consanguineous parents. Like her parents and sibs, she had had no adverse effect from BCG vaccination, and there was no family history of mycobacterial disease or other intracellular infectious diseases. The patient did not show augmented production of IFNG (147570) in response to antigen plus IL12. Ozbek et al. (2005) concluded that a diagnosis of IL12RB1 deficiency should be considered for children with unusually severe tuberculosis, even if they have no personal or family history of infection with weakly virulent Mycobacterium or Salmonella species.

Tabarsi et al. (2011) reported a 33-year-old engineer in Iran with complete autosomal recessive IL12RB1 deficiency who succumbed to disseminated multidrug (isoniazid and rifampin)-resistant TB. The patient had a history of uncomplicated BCG vaccination, normal chest and abdominal radiography, normal immune function, no smoking history, and negative HIV serology and PCR. Two courses of standard anti-TB treatment had not been curative, and sputum tests were persistently positive for acid-fast bacilli (AFB), confirmed by PCR to be M. tuberculosis. Blood cells failed to produce IFNG in response to IL12, but they produced IL12 in response to BCG and IFNG. In response to second-line anti-TB treatment, the patient regained weight during the first 6 months, then developed profuse diarrhea after 8 months of treatment with no detectable pathogens. Colonoscopy and histologic analysis revealed diffuse polypoid ulcers and histiocytes filled with AFB. Tabarsi et al. (2011) concluded that genetic defects in the IL12-IFNG circuit must be considered in adults with disseminated TB, as some of these patients may benefit from IFNG therapy as an adjunct to antimicrobial treatment.

Ramirez-Alejo et al. (2014) reported 5 unrelated Mexican children with IMD30 confirmed by genetic analysis. All 5 received BCG vaccinations at birth with no immediate adverse effects, and 4 of the 5 developed disseminated mycobacterial disease several months later. Other infections, particularly candidal, were also present in most patients. One girl presented at age 14 years with features of systemic lupus erythematosus (SLE; 152700) and developed fatal disseminated infections with mycobacteria and Candida species following immunosuppressive treatment for SLE. Laboratory studies of all patient cells showed impaired IFNG responses to IL12 as well as decreased or absent expression of IL12RB1 on T cells.

Molecular Genetics

Altare et al. (1998) and de Jong et al. (1998) found that severe atypical mycobacterial infections, as well as Salmonella infections, occurred in patients with mutations in the IL12RB1 gene (601604.0001-601604.0004).

By SSCP and sequence analysis of the IL12RB1 gene in 120 unrelated probands, including 100 with atypical mycobacteriosis, Fieschi et al. (2003) identified 41 patients in 29 kindreds from 17 countries in Africa, America, Europe, and Asia with complete IL12RB1 surface expression deficiency. The patients were homozygous or compound heterozygous for 4 nonsense mutations, 4 splice site mutations, 6 missense mutations, 1 small insertion, 2 large deletions, and 4 deletion/insertions, for a total of 21 mutant alleles. None of the mutations were found in 50 unrelated healthy individuals from corresponding ethnic groups.

In an 11-year-old Turkish girl with severe abdominal tuberculosis due to IL12RB1 deficiency, Ozbek et al. (2005) identified a homozygous splice site mutation in the IL12RB1 gene that led to skipping of exon 9 (601604.0006).

In an adult patient with complete autosomal recessive IL12RB1 deficiency and lethal TB, Tabarsi et al. (2011) identified a homozygous 3-bp deletion in exon 10 of the IL12RB1 gene (601604.0008) that was not found in 100 controls.

Van de Vosse et al. (2013) reviewed the molecular genetics of all IL12RB1 mutations and variants and introduced an IL12RB1 variation database.