Additional Diverse Findings Expand the Clinical Presentation of DOCK8 Deficiency
- 643 Downloads
We describe seven Turkish children with DOCK8 deficiency who have not been previously reported. Three patients presented with typical features of recurrent or severe cutaneous viral infections, atopic dermatitis, and recurrent respiratory or gastrointestinal tract infections. However, four patients presented with other features. Patient 1–1 featured sclerosing cholangitis and colitis; patient 2–1, granulomatous soft tissue lesion and central nervous system involvement, with primary central nervous system lymphoma found on follow-up; patient 3–1, a fatal metastatic leiomyosarcoma; and patient 4–2 showed no other symptoms initially besides atopic dermatitis. Similar to other previously reported Turkish patients, but in contrast to patients of non-Turkish ethnicity, the patients’ lymphopenia was primarily restricted to CD4+ T cells. Patients had homozygous mutations in DOCK8 that altered splicing, introduced premature terminations, destabilized protein, or involved large deletions within the gene. Genotyping of remaining family members showed that DOCK8 deficiency is a fully penetrant, autosomal recessive disease. In our patients, bone marrow transplantation resulted in rapid improvement followed by disappearance of viral skin lesions, including lesions resembling epidermodysplasia verruciformis, atopic dermatitis, and recurrent infections. Particularly for patients who feature unusual clinical manifestations, immunological testing, in conjunction with genetic testing, can prove invaluable in diagnosing DOCK8 deficiency and providing potentially curative treatment.
KeywordsDOCK8 combined immunodeficiency epidermodysplasia verruciformis sclerosing cholangitis CNS lymphoma leiomyosarcoma
We thank the physicians who referred their patients to us and the patients and their relatives who participated in this study. We also thank Baran Erman for isolating RNA and performing the RT-PCR reaction on PBMC from patient 1–1. This work was supported in part by the Intramural Research Program of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, through the Lymphocyte Molecular Genetics Unit (LMGU) program. Sequencing was performed by the Genomics Unit of the Rocky Mountain Laboratories Research Technologies Section of the National Institute of Allergy and Infectious Diseases.
- 2.Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, Chen A, Kim HS, Lloret MG, Schulze I, Ehl S, Thiel J, Pfeifer D, Veelken H, Niehues T, Siepermann K, Weinspach S, Reisli I, Keles S, Genel F, Kutuculer N, Camcioglu Y, Somer A, Karakoc-Aydiner E, Barlan I, Gennery A, Metin A, Degerliyurt A, Pietrogrande MC, Yeganeh M, Baz Z, Al-Tamemi S, Klein C, Puck JM, Holland SM, McCabe ER, Grimbacher B, Chatila TA. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol. 2009;124:1289–1302.e1284.PubMedCrossRefGoogle Scholar
- 6.Gatz SA, Benninghoff U, Schutz C, Schulz A, Honig M, Pannicke U, Holzmann KH, Schwarz K, Friedrich W: Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation. Bone Marrow Transplant. 2010;46:552–6.Google Scholar
- 7.Bittner TC, Pannicke U, Renner ED, Notheis G, Hoffmann F, Belohradsky BH, Wintergerst U, Hauser M, Klein B, Schwarz K, Schmid I, Albert MH. Successful long-term correction of autosomal recessive hyper-IgE syndrome due to DOCK8 deficiency by hematopoietic stem cell transplantation. Klin Padiatr. 2010;222:351–5.PubMedCrossRefGoogle Scholar
- 8.McDonald DR, Massaad MJ, Johnston A, Keles S, Chatila T, Geha RS, Pai SY: Successful engraftment of donor marrow after allogeneic hematopoietic cell transplantation in autosomal-recessive hyper-IgE syndrome caused by dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2010;126:1304–5.e3.Google Scholar
- 9.Barlogis V, Galambrun C, Chambost H, Lamoureux-Toth S, Petit P, Stephan JL, Michel G, Fischer A, Picard C: Successful allogeneic hematopoietic stem cell transplantation for DOCK8 deficiency. J Allergy Clin Immunol. 2011;128:420–22.e2.Google Scholar
- 10.Chu EY, Freeman AF, Jing H, Cowen EW, Davis J, Su HC, Holland SM, Turner ML: Cutaneous Manifestations of DOCK8 Deficiency Syndrome. Arch Dermatol. 2011;148:79–84.Google Scholar
- 11.Dasouki M, Okonkwo KC, Ray A, Folmsbeel CK, Gozales D, Keles S, Puck JM, Chatila T: Deficient T Cell Receptor Excision Circles (TRECs) in autosomal recessive hyper IgE syndrome caused by DOCK8 mutation: Implications for pathogenesis and potential detection by newborn screening. Clin Immunol. 2011;141:128–32.Google Scholar
- 14.Thrasher AJ: New insights into the biology of Wiskott-Aldrich syndrome (WAS). Hematology Am Soc Hematol Educ Program. 132–138, 2009Google Scholar
- 22.Azzimonti B, Mondini M, De Andrea M, Gioia D, Dianzani U, Mesturini R, Leigheb G, Tiberio R, Landolfo S, Gariglio M. CD8+ T-cell lymphocytopenia and lack of EVER mutations in a patient with clinically and virologically typical epidermodysplasia verruciformis. Arch Dermatol. 2005;141:1323–5.PubMedCrossRefGoogle Scholar