Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds

Abstract

Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

FIGURE 1

Pedigrees of 30 families with IL-12p40 deficiency. Each kindred is designated by an integer (numbers 1–30), each generation is designated by a roman numeral (numerals I–II), and each individual by an arabic numeral (each individual studied is identified by these 3 numbers, organized from left to right). Symbols are split in 2 by a horizontal line. The upper part of the symbol indicates mycobacterial infection (black for BCG or atypical mycobacteriosis, gray for tuberculosis); the lower part of the symbol indicates salmonellosis status (black indicating the patient has had salmonellosis). The probands are indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?” Asymptomatic individuals carrying 2 mutant IL12B alleles are represented by a vertical line.

FIGURE 10

Penetrance of infection in patients with IL-12p40 deficiency. Estimation was based on findings for 14 genetically affected relatives with complete follow-up data. The onset of the first infection is indicated as an upward step in the curve. The crosses indicate the age at last follow-up for asymptomatic relatives.

FIGURE 2

Origin of the kindreds. Geographic origin of the 49 patients with complete IL-12p40 deficiency. These patients originated from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). The numbers indicate the number of patients originating from a given country. The numbers of kindreds and mutations for each country are shown. [This figure can be viewed in color online at http://www.md-journal.com].

FIGURE 3

Mutated alleles of the IL12B gene. Schematic representation of the coding region of the IL12B gene containing 6 coding exons and encoding a 328-amino acid protein. Exons I and VIII are not translated. The coding region for each mutant IL12B allele is presented, together with the number of kindreds (n) and the date of the founder effect (FE). Gray regions correspond to stretches of new amino acids resulting from frameshift mutation. [This figure can be viewed in color online at http://www.md-journal.com].

FIGURE 4

Clinical phenotypes for IL-12p40-deficient index cases. Each patient is classified as a function of mycobacterial infection status (BCG, TB, EM) and Salmonella infection status, as labeled. [This figure can be viewed in color online at http://www.md-journal.com].

FIGURE 5

Impaired cellular response in IL-12p40-deficient patients. A logarithmic scale depicting the production of IL-12p40 (A), IL-12p70 (B), and IFN-γ (C) by whole blood cells from 44 healthy travel control patients (left side of each graph [black circles in color representation]), and from 22 IL-12p40-deficient patients (right side of each graph [red circles in color representation]), either unstimulated (medium) or stimulated with BCG alone or with BCG plus recombinant IFN-γ or IL-12. The horizontal bars indicate the mean. We calculated p values for differences between healthy travel controls and IL-12p40-deficient patients in the nonparametric Kruskal-Wallis rank sum test. ***p < 0.001. [This figure can be viewed in color online at http://www.md-journal.com].

FIGURE 6

Haplotype sharing in the IL12B region. Long contiguous stretches of homozygosity were observed around the gene, consistent with its mode of inheritance. Mutations 315_insA and 526del2 were studied.

FIGURE 7

Clinical phenotypes for IL-12p40-deficient relatives. Each patient is classified as a function of mycobacterial infection status (BCG and TB) and Salmonella infection status, as labeled. [This figure can be viewed in color online at http://www.md-journal.com].

FIGURE 8

First onset of MSMD-related infections in IL-12p40-deficient patients (BCG, EM, Salmonella, and TB).

FIGURE 9

Survival curve for IL-12p40-deficient patients. Each death is indicated as a downward step in the curve. The crosses indicate the age at last follow-up for living patients. The continuous line represents survival for the total patient population (n = 49). The dashed line represents survival for the 44 symptomatic patients.