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Clinical, Immunological and Molecular Characterization of DOCK8 and DOCK8-like Deficient Patients: Single Center Experience of Twenty Five Patients

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Abstract

Purpose

Autosomal recessive hyper-IgE syndrome is a rare combined immunodeficiency characterized by susceptibility to viral infections, atopic eczema, high serum IgE and defective T cell activation. The genetic etiologies are diverse. Null mutations in DOCK8 and TYK2 are responsible for many cases. This study aims to provide a detailed clinical and immunological characterization of the disease and explore the underlying genetic defects among a large series of patients followed by a single center. The available data might improve our understanding of the disease pathogenesis and prognosis.

Methods

Clinical data of twenty-five patients diagnosed with AR-HIES were collected. Seventeen patients screened for STAT3, TYK2 and DOCK8 mutations.

Results

Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. The rate of hepatic disorders and systemic infections were high. Twelve patients died with a median age of 10 years. CMV infection was the only statistically significant predicting factor for poor prognosis (early death). Three novel DOCK8 mutations and two large deletions were found in thirteen patients. No mutations found in STAT3 or TYK2 genes.

Conclusion

Autosomal recessive hyper-IgE syndrome is a combined immunodeficiency disease characterized by high morbidity and mortality rate. The different genetic background and environmental factors may explain the more severe phenotypes seen in our series. DOCK8 defect is the most common identified genetic cause. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.

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Authors and Affiliations

  1. Pediatric Allergy and Clinical Immunology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

    Zobaida Alsum, Rand Arnaout, Abdulaziz Al-ghonaium, Saleh Al-Muhsen, Hasan Al-Dhekri, Bandar Al-Saud & Hamoud Al-Mousa

  2. College of Medicine, Alfaisal university, Riyadh, Saudi Arabia

    Hamoud Al-Mousa

  3. Prince Naif Centre for Immunology Research, King Saud University, Riyadh, Saudi Arabia

    Saleh Al-Muhsen

  4. Department of Genetics, Research Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

    Abbas Hawwari, Safa Al-Hissi, Esteban Borrero, Asma’ Abu-staiteh, Hanif G. Khalak, Salma Wakil & Hamoud Al-Mousa

  5. Saudi Diagnostic Laboratory, King Faisal Specialist Hospital and Research centre, Riyadh, Saudi Arabia

    Osama Alsmadi

  6. Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

    Abdelmoneim M. Eldali

  7. Pediatric Allergy & Immunology, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, MBC 58, P.O.Box 3354, Riyadh, 11211, Saudi Arabia

    Hamoud Al-Mousa

  8. Immunogenetic Section, Department of Genetics, Research Center, MBC 03, P.O.Box 3354, Riyadh, 11211, Saudi Arabia

    Abbas Hawwari

Authors
  1. Zobaida Alsum
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  2. Abbas Hawwari
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  3. Osama Alsmadi
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  4. Safa Al-Hissi
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  8. Salma Wakil
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  9. Abdelmoneim M. Eldali
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  10. Rand Arnaout
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  11. Abdulaziz Al-ghonaium
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  12. Saleh Al-Muhsen
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  13. Hasan Al-Dhekri
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  14. Bandar Al-Saud
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  15. Hamoud Al-Mousa
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Corresponding author

Correspondence to Hamoud Al-Mousa.

Additional information

Hamoud Al-Mousa and Abbas Hawwari share senior co-authorship.

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Fig. S1

The family pedigrees. Note the high rate of death. (PPT 148 kb)

Fig. S2

Schematic representation of the wild-type variant 1 DOCK8 protein and the expected effect of the indicated mutations on the structure of the protein. Yellow and red boxes indicate the locations of the main domains of the DOCK8 protein. (PPT 72 kb)

Fig. S3

ChAS output showing no deletions for the negative patients: The absence of any DOCK8 deletions are shown of the patients whom no mutations were detected by sequencing of the coding region of the DOCK8 gene. See the legend of figure 4 for description of the ChAS output. (PPT 563 kb)

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Alsum, Z., Hawwari, A., Alsmadi, O. et al. Clinical, Immunological and Molecular Characterization of DOCK8 and DOCK8-like Deficient Patients: Single Center Experience of Twenty Five Patients. J Clin Immunol 33, 55–67 (2013). https://doi.org/10.1007/s10875-012-9769-x

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  • DOI: https://doi.org/10.1007/s10875-012-9769-x

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