Hyper-IgE-syndrome 4, autosomal recessive D82.4

Genetic heterogeneity of hyper IgE syndrome (HIES):

• HIES1 (147060) caused by an autosomal dominant mutation in the STAT3 gene (102582
• HIES2 (243700) caused by a mutation in the DOCK8 gene (611432),
• HIES3 (618282) caused by a mutation in the ZNF431 gene (618269),
• HIES4A (619752) and HIES4B (618523), both caused by a mutation in the IL6ST gene (600694),
• HIES5 (618944), caused by a mutation in the IL6R gene (147880).

Hyper IgE syndrome 4 is associated with mutations in the IL6ST gene (interleukin 6 cytokine family signal transducer).

The disease begins in early childhood.

Increased serum IgE levels, intermittent eosinophilia, impaired IL6 (147620) and IL27 (608273) downstream signaling. Development and function of certain B and T cell populations and acute phase response are impaired; IL-11 (147681) signaling in fibroblasts is also affected (Shahin et al. 2019).

Schwerd et al (2017) reported on a seven-year-old girl born to consanguineous parents of South Asian origin with HIES4B. In infancy, she had craniosynostosis and other skeletal abnormalities, including congenital hip dislocation, elbow and finger contractures, and progressive scoliosis. Furthermore, retained teeth. At the same time, she developed recurrent infections, including eye infections, recidiv. Pneumonias leading to bronchiectasis, erysipelas, and sepsis associated with thrombotic cerebral infarction. The patient developed atopic dermatitis, global developmental delay with speech disorders. Lab: elevated IgE, intermittent eosinophilia. Antibody titers to Haemophilus, pneumococcus, and tetanus were normal. In infections, delayed or absent acute phase reaction with decreased fibrinogen and C-reactive protein.

Shahin et al (2019) reported a 12-year-old boy born to consanguineous Turkish parents with HIES4B. Already in early infancy diarrheal symptoms, recurrent otitis media, bilateral keratitis, recurrent bacterial respiratory infections, including pneumonias with empyema and pneumothorax. Furthermore: severe atopic dermatitis, food allergies. Skeletal abnormalities: flexion contractures of the wrists, scaphocephaly, scoliosis, crowded teeth and hip dislocation. Lab: elevated serum IgE levels, eosinophilia, B cells decreased, Family history revealed early death of 3 siblings who were probably affected.

Chen et al (2021) reported an 8-year-old boy of mixed ethnicity who presented at 4 years of age with chronic osteomyelitis and recurrent septic arthritis due to infection with Staphylococcus aureus. Immunologic examination revealed elevated serum IgE levels, eosinophilia, normal lymphocyte counts.

1. Chen YH et al (2021) Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome. J Allergy Clin Immun 148: 585-598.
2. Schwerd T et al (2017) A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. J Exp Med 214: 2547-2562.
3. Shahin T et al. (2019) Selective loss of function variants in IL6ST cause hyper-IgE syndrome with distinct impairments of T-cell phenotype and function. Haematologica 104: 609-621.