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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.

SUBMITTER: Prando C

PROVIDER: S-EPMC3822760 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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

Prando Carolina C Samarina Arina A Bustamante Jacinta J Boisson-Dupuis Stéphanie S Cobat Aurelie A Picard Capucine C AlSum Zobaida Z Al-Jumaah Suliman S Al-Hajjar Sami S Frayha Husn H Al-Mousa Hamoud H Ben-Mustapha Imen I Adimi Parisa P Feinberg Jacqueline J de Suremain Maylis M Jannière Lucile L Filipe-Santos Orchidée O Mansouri Nahal N Stephan Jean-Louis JL Nallusamy Revathy R Kumararatne Dinakantha S DS Bloorsaz Mohamad Reza MR Ben-Ali Meriem M Elloumi-Zghal Houda H Chemli Jalel J Bouguila Jihene J Bejaoui Mohamed M Alaki Emadia E AlFawaz Tariq S TS Al Idrissi Eman E ElGhazali Gehad G Pollard Andrew J AJ Murugasu Belinda B Wah Lee Bee B Halwani Rabih R Al-Zahrani Mohammed M Al Shehri Mohammed A MA Al-Zahrani Mofareh M Bin-Hussain Ibrahim I Mahdaviani Seyed Alireza SA Parvaneh Nima N Abel Laurent L Mansouri Davood D Barbouche Ridha R Al-Muhsen Saleh S Casanova Jean-Laurent JL

Medicine 20130301 2

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 an ...[more]

PMID: 23429356

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Project description:Background: Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the ZAP70 gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. Methods: We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Results: ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the ZAP70 gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Conclusion: Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.

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

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

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