Hyper-Ige Recurrent Infection Syndrome 4, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive hyper-IgE recurrent infection syndrome-4 (HIES4) is caused by homozygous mutation in the IL6ST gene (600694) on chromosome 5q11.

Description

Hyper-IgE recurrent infection syndrome-4 (HIES4) is an autosomal recessive immunologic disorder characterized by early childhood onset of recurrent infections and skeletal abnormalities, including craniosynostosis and scoliosis. Patients are susceptible to infections, mainly bacterial infections that affect the respiratory tract, skin, and eye. Immunologic workup shows increased serum IgE, intermittent eosinophilia, and impaired IL6 (147620) and IL27 (608273) downstream signaling that affects the development and function of certain B- and T-cell populations, as well as the acute-phase response; IL11 (147681) signaling in fibroblasts is also affected (summary by Shahin et al., 2019).

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

Clinical Features

Schwerd et al. (2017) reported a 7-year-old girl, born of consanguineous parents of South Asian origin, with HIES4. She presented in infancy with craniosynostosis and other skeletal anomalies, including congenital hip dislocation, elbow and finger contractures, and progressive scoliosis. At the same time, she developed recurrent infections, including eye infections, chest infections resulting in bronchiectasis, cellulitis, and sepsis associated with a thrombotic brain infarction. She had eczema and global developmental delay with poor speech. Laboratory studies showed increased IgE, intermittent eosinophilia, and a decreased number of class-switched memory B cells. However, levels of antibodies to Haemophilus, Pneumococcus, and tetanus were normal. During infections, she had a delayed or absent acute-phase response, with decreased fibrinogen and C-reactive protein. Shahin et al. (2019) stated that this patient also had retained teeth.

Shahin et al. (2019) reported a 12-year-old boy, born of consanguineous Turkish parents, with HIES4. He presented in early infancy with diarrhea, recurrent otitis media, bilateral keratitis, and recurrent bacterial respiratory infections, including pneumonia complicated by empyema and pneumothorax. He also had severe eczema and food allergies. Soon after birth, he was noted to have skeletal abnormalities, including flexion contractures of the hand joints, scaphocephaly suggesting craniosynostosis, scoliosis, crowded teeth, and hip dislocation. There was evidence of a destructive arthropathy. He also had mild global developmental delay. Laboratory studies showed increased serum IgE, eosinophilia, a decline in absolute B-cell numbers, and low central memory T cells. Family history revealed early death of 3 sibs who were likely affected. Shahin et al. (2019) noted that the phenotype of this patient and the patient reported by Schwerd et al. (2017) was remarkably similar to patients with HIES1.

Inheritance

The transmission pattern of HIES4 in the family reported by schwerd et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a girl, born of consanguineous parents of South Asian descent, with HIES4, Schwerd et al. (2017) identified a homozygous missense mutation in the IL6ST gene (N404Y; 600694.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient-derived cells showed a complete loss of STAT3 response to IL6 stimulation compared to controls; these defects were rescued by expression of wildtype GP130. Knockdown of GP130 in HEK293 cells using CRISPR/Cas9 technology showed that mutant cells did not phosphorylate STAT1 or STAT3 in response to stimulation with the known ligands IL6, IL11, IL27, OSM (165095), or LIF (159540), but did respond to stimulation with interferon. GP130-null cells transfected with the mutation showed absent response to IL11 stimulation and decreased response to IL6, IL27, and OSM; LIF response was largely intact. Transfection of wildtype GP130 rescued the defect. In vitro functional expression studies in GP130-null human hepatoma cells showed a defective IL6-mediated acute-phase response. The findings were consistent with a loss of function and impaired IL6ST-mediated downstream signaling. Direct sequencing of the IL6ST gene in over 400 patients with craniosynostosis and over 200 patients with HIES did not identify any pathogenic variants.

In a boy, born of consanguineous Turkish parents, with HIES4, Shahin et al. (2019) identified a homozygous missense mutation in the IL6ST gene (P498L; 600694.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Detailed in vitro functional studies of patient-derived cells and HEK293 cells transfected with the mutation showed impaired STAT3 response particularly to IL6, IL11, and IL27 compared to controls. These defects could be rescued by expression of wildtype IL6ST. The effects were apparent in both B- and T-cell subsets, as well as fibroblasts. The findings were consistent with a loss-of-function effect and variably impaired downstream IL6ST signaling.