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Background: Partial DiGeorge syndrome (pDGS) is caused by deletion of the 22q11.2 region. Within this region lies CrK-like (CRKL), a gene encoding an adapter protein belonging to the Crk family that is involved in the signaling cascade of IL-2, stromal cell-derived factor 1α, and type I interferon. Although recurrent infections can be observed in patients with deletion of chromosome 22 syndrome, the immune pathogenesis of this condition is yet not fully understood., Objective: We aimed to investigate the role of CRKL in T-cell functional responses in patients affected with pDGS., Methods: Protein expression levels and phosphorylation of CRKL were evaluated in patients with pDGS. T-cell functional assays in vitro and gene-silencing experiments were also performed., Results: CRKL protein expression, as well as its phosphorylation, were reduced in all patients with pDGS, especially on IL-2 stimulation. Moreover, T cells presented impaired proliferation and reduced IL-2 production on anti-CD3/CD28 stimulation and decreased c-Fos expression. Finally, CRKL silencing in Jurkat T cells resulted in impaired T-cell proliferation and reduced c-Fos expression., Conclusions: The impaired T-cell proliferation and reduction of CRKL, phosphorylated CRKL, and c-Fos levels suggest a possible role of CRKL in functional deficiencies of T cells in patients with pDGS., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Correlating human papillomavirus (HPV) type with the clinical and histopathological features of skin lesions (from genital and nongenital sites) can present a diagnostic challenge., Objective: In this study, HPV infection patterns were correlated with pathology and clinical presentation in lesional and nonlesional body sites from a young patient with a primary T-cell immunodeficiency., Methods: HPV infection was evaluated at both DNA and protein levels by polymerase chain reaction and immunohistochemistry., Results: The patient's genital lesions were caused exclusively by α-genotypes (high-risk type HPV-51 in the anal and low-risk type HPV-72 in the penile condylomas). The opposite was true for the skin lesions, which were infected by β-genotypes alone (HPV-8 and HPV-24). HPV-24 was the predominant type in terms of viral load, and the only one found in productive areas of infection. The patient had already developed high-grade dysplasia in the anal condyloma-like lesions, and showed areas of early-stage dysplasia in the lesions caused by the β-genotype HPV-24., Limitations: The basic origin of the immunodeficiency is not yet defined., Conclusion: These findings provide proof of principle that both α- and β-genotypes can cause overt dysplastic lesions when immunosurveillance is lost, which is not restricted to epidermodysplasia verruciformis., (Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects., Objective: We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families., Methods: We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA., Results: Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA., Conclusions: We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Omenn syndrome (OS) is an autosomal-recessive disorder characterized by severe immunodeficiency and T-cell-mediated autoimmunity. The disease is caused by hypomorphic mutations in recombination-activating genes that hamper the process of Variable (V) Diversity (D) Joining (J) recombination, leading to the generation of autoreactive T cells. We have previously shown that in OS the expression of autoimmune regulator, a key factor governing central tolerance, is markedly reduced., Objective: Here, we have addressed the role of peripheral tolerance in the disease pathogenesis., Methods: We have analyzed forkhead box protein P3 (FOXP3) expression in peripheral blood T cells of 4 patients with OS and in lymphoid organs of 8 patients with OS and have tested the suppressive activity of sorted CD4(+) CD25(high) peripheral blood T cells in 2 of these patients., Results: We have observed that CD4(+)CD25(high)T cells isolated ex vivo from patients with OS failed to suppress proliferation of autologous or allogenic CD4(+) responder T cells. Moreover, despite individual variability in the fraction of circulating FOXP3(+) CD4 cells in patients with OS, the immunohistochemical analysis of FOXP3 expression in lymph nodes and thymus of patients with OS demonstrated a severe reduction of this cell subset compared with control tissues., Conclusion: Overall, these results suggest a defect of regulatory T cells in OS leading to a breakdown of peripheral tolerance, which may actively concur to the development of autoimmune manifestations in the disease., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

We report the case of an infant with severe respiratory infections, chronic diarrhea, failure to thrive, and disseminated Cryptosporidium parvum infection. Laboratory investigations disclosed a diagnosis of hyper-IgM syndrome caused by CD40 deficiency.