Hyper-Ige Recurrent Infection Syndrome 2, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive hyper-IgE recurrent infection syndrome-2 (HIES2) is caused by homozygous or compound heterozygous mutation in the DOCK8 gene (611432) on chromosome 9p24.

Description

Autosomal dominant hyper-IgE recurrent infection syndrome-1 (HIES1; 147060) is a primary immunodeficiency disorder characterized by recurrent Staphylococcus aureus skin abscesses, increased serum IgE, and abnormalities of the connective tissue, skeleton, and dentition (Buckley et al., 1972; Grimbacher et al., 1999).

Autosomal recessive HIES2 shares hyper-IgE, eosinophilia, and recurrent Staphylococcal infections, but is distinguished from autosomal dominant HIES1 by the lack of connective tissue and skeletal involvement (Renner et al., 2004).

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).

For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see 147060.

Clinical Features

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.

Molecular Genetics

In 11 affected individuals from 8 unrelated families with autosomal recessive hyper-IgE recurrent infection syndrome, 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.