DOCK8 immunodeficiency syndrome is a disorder of the immune system. The condition is characterized by recurrent infections that are severe and can be life-threatening. The infections can be caused by bacteria, viruses, or fungi. Skin infections cause rashes, blisters, accumulations of pus (abscesses), open sores, and scaling. People with DOCK8 immunodeficiency syndrome also tend to have frequent bouts of pneumonia and other respiratory tract infections. Other immune system-related problems in people with DOCK8 immunodeficiency syndrome include an inflammatory skin disorder called eczema, food or environmental allergies, and asthma.

DOCK8 immunodeficiency syndrome is characterized by abnormally high levels of an immune system protein called immunoglobulin E (IgE) in the blood; the levels can be more than 10 times higher than normal for no known reason. IgE normally triggers an immune response against foreign invaders in the body, particularly parasitic worms, and plays a role in allergies. It is unclear why people with DOCK8 immunodeficiency syndrome have such high levels of this protein. People with DOCK8 immunodeficiency syndrome also have highly elevated numbers of certain white blood cells called eosinophils (hypereosinophilia). Eosinophils aid in the immune response and are involved in allergic reactions.

Some people with DOCK8 immunodeficiency syndrome have neurological problems, such as paralysis that affects the face or one side of the body (hemiplegia). Blockage of blood flow in the brain or abnormal bleeding in the brain, both of which can lead to stroke, can also occur in DOCK8 immunodeficiency syndrome.

People with DOCK8 immunodeficiency syndrome have a greater-than-average risk of developing cancer, particularly cancers of the blood or skin.

DOCK8 immunodeficiency syndrome is also commonly called autosomal recessive hyper-IgE syndrome. However, researchers have identified several conditions that feature elevated levels of IgE and that follow an autosomal recessive pattern of inheritance. Each of these conditions has its own set of additional signs and symptoms and a different genetic cause. Some doctors consider these conditions forms of hyper-IgE syndrome, while others consider them independent disorders.

DOCK8 immunodeficiency syndrome is a rare disorder whose prevalence is unknown.

DOCK8 immunodeficiency syndrome is caused by mutations in the DOCK8 gene. The protein produced from this gene plays a critical role in the survival and function of several types of immune system cells. One of the functions of the DOCK8 protein is to help maintain the structure and integrity of immune cells called T cells and NK cells, which recognize and attack foreign invaders, particularly as these cells travel to sites of infection within the body. In addition, the DOCK8 protein is involved in chemical signaling pathways that stimulate other immune cells called B cells to mature and produce antibodies, which are specialized proteins that attach to foreign particles and germs, marking them for destruction.

DOCK8 gene mutations result in the production of little or no functional DOCK8 protein. Shortage of this protein impairs normal immune cell development and function. It is thought that T cells and NK cells lacking DOCK8 protein are abnormal and die too easily, particularly when moving through the layers of skin. A shortage of these immune cells impairs the immune response to foreign invaders, accounting for the severe skin infections common in DOCK8 immunodeficiency syndrome. A lack of DOCK8 protein also impairs B cell maturation and the production of antibodies. Impairment of this type of immune response leads to recurrent respiratory tract infections in people with this disorder. It is unclear how DOCK8 gene mutations are involved in other features of DOCK8 immunodeficiency syndrome, such as the elevation of IgE levels, and neurological problems.

Genetic Testing Information

• Genetic Testing Registry: Combined immunodeficiency due to DOCK8 deficiency

Genetic and Rare Diseases Information Center

• Combined immunodeficiency due to DOCK8 deficiency

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• HYPER-IgE SYNDROME 2, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS; HIES2

Scientific Articles on PubMed

• PubMed

• Engelhardt KR, Gertz ME, Keles S, Schaffer AA, Sigmund EC, Glocker C, Saghafi S, Pourpak Z, Ceja R, Sassi A, Graham LE, Massaad MJ, Mellouli F, Ben-Mustapha I, Khemiri M, Kilic SS, Etzioni A, Freeman AF, Thiel J, Schulze I, Al-Herz W, Metin A, Sanal O, Tezcan I, Yeganeh M, Niehues T, Dueckers G, Weinspach S, Patiroglu T, Unal E, Dasouki M, Yilmaz M, Genel F, Aytekin C, Kutukculer N, Somer A, Kilic M, Reisli I, Camcioglu Y, Gennery AR, Cant AJ, Jones A, Gaspar BH, Arkwright PD, Pietrogrande MC, Baz Z, Al-Tamemi S, Lougaris V, Lefranc G, Megarbane A, Boutros J, Galal N, Bejaoui M, Barbouche MR, Geha RS, Chatila TA, Grimbacher B. The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2015 Aug;136(2):402-12. doi: 10.1016/j.jaci.2014.12.1945. Epub 2015 Feb 25. Citation on PubMed or Free article on PubMed Central
• 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, Kutukculer 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 Dec;124(6):1289-302.e4. doi: 10.1016/j.jaci.2009.10.038. Citation on PubMed or Free article on PubMed Central
• Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, Rauter I, Benson H, Schneider L, Baxi S, Recher M, Notarangelo LD, Wakim R, Dbaibo G, Dasouki M, Al-Herz W, Barlan I, Baris S, Kutukculer N, Ochs HD, Plebani A, Kanariou M, Lefranc G, Reisli I, Fitzgerald KA, Golenbock D, Manis J, Keles S, Ceja R, Chatila TA, Geha RS. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol. 2012 May 13;13(6):612-20. doi: 10.1038/ni.2305. Citation on PubMed or Free article on PubMed Central
• Mizesko MC, Banerjee PP, Monaco-Shawver L, Mace EM, Bernal WE, Sawalle-Belohradsky J, Belohradsky BH, Heinz V, Freeman AF, Sullivan KE, Holland SM, Torgerson TR, Al-Herz W, Chou J, Hanson IC, Albert MH, Geha RS, Renner ED, Orange JS. Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2013 Mar;131(3):840-8. doi: 10.1016/j.jaci.2012.12.1568. Epub 2013 Feb 4. Citation on PubMed or Free article on PubMed Central
• Renner ED, Puck JM, Holland SM, Schmitt M, Weiss M, Frosch M, Bergmann M, Davis J, Belohradsky BH, Grimbacher B. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr. 2004 Jan;144(1):93-9. doi: 10.1016/S0022-3476(03)00449-9. Citation on PubMed
• Su HC, Jing H, Angelus P, Freeman AF. Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome. Immunol Rev. 2019 Jan;287(1):9-19. doi: 10.1111/imr.12723. Citation on PubMed or Free article on PubMed Central
• Zhang Q, Dove CG, Hor JL, Murdock HM, Strauss-Albee DM, Garcia JA, Mandl JN, Grodick RA, Jing H, Chandler-Brown DB, Lenardo TE, Crawford G, Matthews HF, Freeman AF, Cornall RJ, Germain RN, Mueller SN, Su HC. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. J Exp Med. 2014 Dec 15;211(13):2549-66. doi: 10.1084/jem.20141307. Epub 2014 Nov 24. Citation on PubMed or Free article on PubMed Central
• Zhang Q, Jing H, Su HC. Recent Advances in DOCK8 Immunodeficiency Syndrome. J Clin Immunol. 2016 Jul;36(5):441-9. doi: 10.1007/s10875-016-0296-z. Epub 2016 May 20. Citation on PubMed or Free article on PubMed Central