DOCK8 – Hyper-IgE Syndrome

DOCK8 deficiency is an autosomal recessive form of hyper-IgE syndrome characterized by elevated serum IgE, eosinophilia, severe eczema, and recurrent bacterial, viral, and fungal infections. The disorder is caused by biallelic loss-of-function variants in DOCK8, leading to combined immunodeficiency with high morbidity and mortality. Clinical and experimental studies have established a strong gene–disease association, supporting diagnostic decision-making and therapeutic interventions such as hematopoietic stem cell transplantation.

DOCK8 was identified as the causal gene for autosomal recessive hyper-IgE syndrome through genome-wide homozygosity mapping and single nucleotide polymorphism analysis in 27 probands from 12 unrelated families, revealing subtelomeric microdeletions and distinct homozygous mutations disrupting DOCK8 function (PMID:20004785). Segregation of variants within consanguineous pedigrees further confirmed autosomal recessive inheritance.

The variant spectrum includes at least 16 distinct homozygous or compound heterozygous alterations—nonsense, frameshift, splice site mutations, and large exon deletions. A representative mutation is c.1419G>C (p.Lys473Asn), which abrogates DOCK8 protein expression and impairs lymphocyte cytoskeletal regulation (PMID:20004785).

Clinically, DOCK8-deficient patients present with serum IgE levels often >5 000 IU/mL, peripheral eosinophilia, severe atopic dermatitis, recurrent sinopulmonary infections, cutaneous viral lesions, and increased risk of malignancy including lymphoma (PMID:21931011). Absence of typical features of STAT3-related HIES—such as retained primary teeth, pneumatoceles, and bone fractures—helps distinguish DOCK8 deficiency.

Functional studies demonstrate that DOCK8 loss impairs T-cell expansion and durable antibody responses in mouse models of DOCK8 deficiency (PMID:20864884), and human NK cells exhibit defective F-actin accumulation at the immunologic synapse with severely reduced cytotoxicity (PMID:23380217).

Allogeneic hematopoietic stem cell transplantation restores DOCK8 expression, corrects lymphocyte differentiation and function, and dramatically improves clinical outcomes in DOCK8-deficient patients. Early genetic diagnosis is therefore crucial to guide curative therapy.

Key Take-home: Biallelic DOCK8 variants cause a well-validated autosomal recessive hyper-IgE syndrome; genetic testing enables timely HSCT, transforming prognosis.

References

• The Journal of allergy and clinical immunology • 2009 • Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. PMID:20004785
• Current opinion in allergy and clinical immunology • 2010 • Dedicator of cytokinesis 8 (DOCK8) deficiency. PMID:20864884
• The Journal of allergy and clinical immunology • 2013 • Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency. PMID:23380217
• Archives of dermatology • 2012 • Cutaneous manifestations of DOCK8 deficiency syndrome. PMID:21931011

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