Hyper-Ige Recurrent Infection Syndrome 3, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive hyper-IgE recurrent infection syndrome-3 (HIES3) is caused by homozygous mutation in the ZNF341 gene (618269) on chromosome 20q11.

Description

Hyper-IgE recurrent infection syndrome-3 is an autosomal recessive immunologic disorder characterized by childhood onset of atopic dermatitis, skin infections particularly with Staphylococcus aureus, recurrent sinopulmonary infections, and increased serum IgE and IgG. Patients are susceptible to bacterial and fungal infections, including chronic mucocutaneous candidiasis. Immunologic work-up shows impaired differentiation of CD4+ T cells into T-helper 17 cells, decreased memory B cells, and often decreased NK cells (summary by Beziat et al., 2018).

For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see HIES1 (147060).

Clinical Features

Frey-Jakobs et al. (2018) reported 8 patients from 3 unrelated consanguineous Arab-Israeli families from the same village with a similar immunologic phenotype. Most of the patients were young adults at the time of the report (17 to 24 years of age), but 2 were 10 and 13 years of age and 1 was 6 months. The patients presented in infancy or early childhood with atopic dermatitis and eczema, bacterial skin infections and abscesses (usually Staphylococcus aureus), and recurrent upper and lower respiratory infections. Some had osteomyelitis and candidal infections, including oral thrush. Laboratory studies showed increased serum IgE; some patients had mild eosinophilia. Some patients had abnormal dentition with retained primary teeth and mild facial abnormalities, such as increased nose width and high-arched palate, as well as skeletal/connective tissue abnormalities. The patients did not have viral infections, warts, allergies, autoimmune features, or evidence of lymphoproliferation. Three sisters from a consanguineous Turkish family (family D) with a similar phenotype were also reported. Laboratory studies showed increased serum IgE and IgG; some patients had mild eosinophilia. Immunologic work-up showed normal CD19 B lymphocytes but an increased percentage of naive B cells and reduced memory B cells. CD4+ and CD8+ T cells were normal, but patients had reduced percentage of T-helper 17 CD4+ T cells and reduced expression of CCR6 (601835). Patient peripheral mononuclear cells failed to differentiate into IL17-producing CD4+ T cells. Most of the patients also had delayed development and impaired intellectual development.

Beziat et al. (2018) reported 8 patients from 6 unrelated consanguineous families with HIES3. The families were of Moroccan, Afro-Caribbean, Iranian, Turkish, and Lebanese descent. The patients ranged from 14 to 47 years of age at the time of the report; 1 patient died of sepsis at age 28. The patients presented in infancy or early childhood with dermatitis, pruritis, excoriated skin lesions, and eczema. Most patients had skin infections with Staphylococcus aureus and chronic mucocutaneous candidiasis, including thrush. Other more variable features included recurrent respiratory infections, food and other allergies, aphthous stomatitis, and alopecia. Some patients had coarse facial features with broad nose, micrognathia, high-arched palate, and dental abnormalities, and/or joint hyperextensibility and bone fractures. Immunologic work-up showed increased IgE and IgG, eosinophilia (in some patients), decreased NK cells, increased naive CD4+ T cells, lower proportions of central memory CD4+ and CD8+ T cells, and decreased CD4+ T helper 17 cells and circulating memory B cells.

Inheritance

The transmission pattern of HIES3 in the families reported by Frey-Jakobs et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 11 patients from 4 unrelated consanguineous families with HIES3, Frey-Jakobs et al. (2018) identified homozygous loss-of-function nonsense mutations in the ZNF341 gene (R302X, 618269.0001 and R386X, 618269.0002). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. In vitro functional expression studies and studies of patient cells showed that the mutations resulted in absence of the full-length ZNF341 protein, decreased STAT3 (102582) protein levels, decreased STAT3 Y705 phosphorylation, and impaired ZNF341 signaling and activation of STAT3 due to nuclear translocation failure or poor binding to chromatin. The clinical and cellular phenotype thus mimicked HIES1 (147060), which is caused by mutations in the STAT3 gene.

Simultaneously and independently, Beziat et al. (2018) identified homozygous loss-of-function mutations in the ZNF341 gene (618269.0001; 618269.0003-618269.0005) in 8 patients from 6 unrelated consanguineous families with HIES3. The mutations, which were found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient cells showed slightly higher mutant mRNA levels compared to controls, suggesting that the mutations do not cause nonsense-mediated mRNA decay. However, patient cells showed absence of the full-length ZNF341 protein. Mutant proteins showed variably impaired binding to the STAT3 promoter and showed decreased or absent ability to induce STAT3 expression compared to wildtype. Patient cells showed decreased levels of STAT3 protein and low levels of STAT3 phosphorylation and activation.