Novel mutation in DOCK8-HIES with severe phenotype and successful transplantation.

BACKGROUND

Hyper-IgE syndrome (HIES) due to DOCK8 deficiency is an autosomal recessive (AR) primary combined immunodeficiency which results in significant morbidity and mortality at a young age. Different mutations in the DOCK8 gene can lead to variable severity of the disease.

OBJECTIVE

We evaluated the genetic mutations in three related patients with severe clinical manifestations suggestive of AR HIES. We also explored whether treatment with stem cell transplantation could lead to complete disease resolution.

METHOD: We examined the clinical manifestations and immunological workup of these patients. Their DNA was also screened for causative mutation. Post transplantation, clinical and immunological data for the transplanted patient was also collected.

RESULTS

All patients had a severe course of the disease with rarely reported severe complications in HIES. One patient died with lymphoma while another died with progressive multifocal leukoencephalopathy (PML) due to a slow virus. All our patients had two novel mutations in the DOCK8 gene. One of these mutations was a novel pathogenic mutation and explains the severity of the disease (homozygous splice site mutation at position 5 after the end of exon 45), while the other mutation was mostly non-pathogenic. Hematopoietic stem cell transplantation (HSCT) was performed in the youngest patient with excellent engraftment and full reversibility of the clinical manifestations.

CONCLUSION

We report 3 patients from a consanguineous family diagnosed with AR-HIES due to a novel pathogenic mutation in DOCK8 gene leading to fatal outcome in 2 patients and complete resolution of the clinical and immunological features in the third patient by HSCT.