Alternative titles; symbols
ORPHA: 217390; DO: 0080594;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9p24.3 | Hyper-IgE syndrome 2, autosomal recessive, with recurrent infections | 243700 | Autosomal recessive | 3 | DOCK8 | 611432 |
A number sign (#) is used with this entry because autosomal recessive hyper-IgE syndrome-2 with recurrent infections (HIES2) is caused by homozygous or compound heterozygous mutation in the DOCK8 gene (611432) on chromosome 9p24.
Hyper-IgE syndrome-2 with recurrent infections (HIES2) is an autosomal recessive immunologic disorder characterized by recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. It is distinguished from autosomal dominant HIES1 (147060) by the lack of connective tissue and skeletal involvement (Renner et al., 2004).
For a discussion of genetic heterogeneity of hyper-IgE syndrome, see 147060.
See also TYK2 deficiency (611521), a clinically distinct disease entity that includes characteristic features of both autosomal recessive HIES2 and mendelian susceptibility to mycobacterial disease (MSMD; 209950) (Minegishi et al., 2006).
Renner et al. (2004) reported 13 patients from 6 consanguineous families with hyper-IgE syndrome and recurrent infections. Five of the families were of Turkish origin. Patients were between 6 months and 5 years of age. Eight patients died between 6 months and 12 years of age. Similar to the classic autosomal dominant form, patients had eczema, recurrent Staphylococcal infections of the skin and respiratory tract, increased serum IgE, and eosinophilia. In addition, patients had severe recurrent fungal and viral infections with molluscum contagiosum, herpes zoster, and herpes simplex. Two patients had recurrent autoimmune hemolytic anemia. Central nervous system sequelae, such as hemiplegia, ischemic infarction, and subarachnoid hemorrhages, were common. Lymphocyte assays showed poor mitogen response and failure to proliferate in response to antigens, indicating impairment of cellular immunity. Notably, patients with autosomal recessive HIES did not have the coarse facial features, or skeletal or dental abnormalities usually seen in autosomal dominant HIES1. The patients reported by Renner et al. (2004) also did not develop lung abscesses or pneumatoceles. Renner et al. (2004) concluded that autosomal recessive HIES2 is a distinct disorder from autosomal dominant HIES1.
Zhang et al. (2009) reported 11 patients from 8 families with recurrent sinopulmonary infections and cutaneous viral infections associated with combined immunodeficiency and increased serum IgE levels. Three of the families were consanguineous; some of the patients had been reported by Renner et al. (2004) and Milner et al. (2008). Clinical features included atopic dermatitis, recurrent upper and lower respiratory tract infections, recurrent otitis media, and recurrent sinusitis. Pulmonary pathogens included Streptococcus pneumoniae, Haemophilus influenzae, respiratory adenovirus, and respiratory syncytial virus. All patients had extensive, frequently coexisting, cutaneous viral infections with herpes simplex virus, molluscum contagiosum, or herpes zoster, among other. Other infections included Staphylococcus aureus skin infections or osteomyelitis, mucosal or nail candidiasis, cryptococcal and H. influenzae meningitis, and salmonella enteritis, giardiasis, and pericarditis. Nine patients had severe and extensive food or environmental allergies, including anaphylaxis, and 6 had asthma or reactive airway disease. Two had eosinophilic esophagitis or lung disease. Patients with long-standing herpes simplex virus, human papillomavirus, and molluscum contagiosum infections developed vulvar, facial, and anal squamous cell dysplasia and carcinomas. Except for 1 of the patients reported by Renner et al. (2004), none had neurologic, vasculitic, or autoimmune findings. Laboratory findings were significant for decreased numbers of T cells in 10 of 11 patients, decreased natural killer cells in 6 of 10, decreased B cells in 5 of 11, and mild to moderate eosinophilia in 10. Six patients had hypergammaglobulinemia, all had low IgM, and 10 had very high IgE. CD8 T cells showed impaired proliferation and activation, with normal cytotoxic activity.
The transmission pattern of HIES2 in the families reported by Zhang et al. (2009) was consistent with autosomal recessive inheritance.
In 11 affected individuals from 8 unrelated families with autosomal recessive hyper-IgE syndrome-2 with recurrent infections, Zhang et al. (2009) identified homozygosity or compound heterozygosity for deletions or mutations in the DOCK8 gene (see, e.g., 611432.0001-611432.0005). All the DOCK8 mutations resulted in loss of protein function. DOCK8 protein was not detected in primary T-cell cultures or transformed lymphocyte lines from all 11 patients tested.
Pillay et al. (2021) reported 3 unrelated individuals with HIES2 and compound heterozygous mutations in the DOCK8 gene (611432.0006-611432.0011). Each of the patients acquired a somatic reversion of one of their DOCK8 mutations in multiple lymphocyte subsets. Flow cytometry in lymphocytes from each of the patients demonstrated a subset of cells that expressed DOCK8 protein, including subsets of CD8+ T cells, CD4+ T cells, B cells, and NK cells. In vitro studies of the revertant lymphocytes demonstrated improved proliferation, survival, differentiation, and function of CD8+ T cells, CD4+ T cells, and B cells. Clinical improvement was seen in each of the patients over time, and the patients experienced reduction in the incidence of infectious diseases, improved eosinophilia, and reduction in allergen-specific IgE.
Milner, J. D., Brenchley, J. M., Laurence, A., Freeman, A. F., Hill, B. J., Elias, K. M., Kanno, Y., Spalding, C., Elloumi, H. Z., Paulson, M. L., Davis, J., Hsu, A., Asher, A. I., O'Shea, J., Holland, S. M., Paul, W. E., Douek, D. C. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452: 773-776, 2008. [PubMed: 18337720] [Full Text: https://doi.org/10.1038/nature06764]
Minegishi, Y., Saito, M., Morio, T., Watanabe, K., Agematsu, K., Tsuchiya, S., Takada, H., Hara, T., Kawamura, N., Ariga, T., Kaneko, H., Kondo, N., and 24 others. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25: 745-755, 2006. [PubMed: 17088085] [Full Text: https://doi.org/10.1016/j.immuni.2006.09.009]
Pillay, B. A., Fusaro, M., Gray, P. E., Statham, A. L., Burnett, L., Bezrodnik, L., Kane, A., Tong, W., Abdo, C., Winter, S., Chevalier, S., Levy, R., and 18 others. Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency. J. Clin. Invest. 131: e142434, 2021. [PubMed: 33290277] [Full Text: https://doi.org/10.1172/JCI142434]
Renner, E. D., Puck, J. M., Holland, S. M., Schmitt, M., Weiss, M., Frosch, M., Bergmann, M., Davis, J., Belohradsky, B. H., Grimbacher, B. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J. Pediat. 144: 93-99, 2004. [PubMed: 14722525] [Full Text: https://doi.org/10.1016/S0022-3476(03)00449-9]
Zhang, Q., Davis, J. C., Lamborn, I. T., Freeman, A. F., Jing, H., Favreau, A. J., Matthews, H. F., Davis, J., Turner, M. L., Uzel, G., Holland, S. M., Su, H. C. Combined immunodeficiency associated with DOCK8 mutations. New Eng. J. Med. 361: 2046-2055, 2009. [PubMed: 19776401] [Full Text: https://doi.org/10.1056/NEJMoa0905506]