Information on HIES4A
Name: Hyper-IgE recurrent infection syndrome 4A | Acronym: HIES4A
Alt. names: IL6 signal transducer (partial) deficiency
Gene: IL6ST | MOI: Autosomal dominant | Mechanism of action: Negative Dominance
No. of cases in DB: 22 | First reported in: 2020
Last updated on: 2023-04-01 by Xiao P. Peng
Description
To date, 12 patients from 8 families have been described with this dominant negative (DN) condition, which clinically resembles STAT3-DN HIES and shows significant phenotypic variability even within families (PMID: 32207811). Affected individuals present predominantly with recurrent sinopulmonary and skin infections, though osteomyelitis, pyelonephritis, and onychomycosis have also been described. Those affected by lung infections earlier in childhood tend to develop complications such as bronchiectasis, pneumatoceles, or hemoptysis. Additionally, patients have asthma, atopic dermatitis, and various non-immune features such as high-arched palate and other craniofacial dysmorphisms, retained primary teeth, joint hypermobility, scoliosis, and increased fracture susceptibility. Unlike patients with STAT3-DN or HIES4B, craniosynostosis has not been reported, presumably due to residual activity in IL-11 signaling. Labs typically show eosinophilia with elevated IgE levels and decreased memory B cells, as well as variable deficits in other immunoglobulin classes, lymphocyte populations and myeloid lineages.
Management
Currently treatment is symptomatic. Anti-microbial prophylaxis and/or Ig supplementation may be considered given the infectious risks. Dupilumab has been used successfully to treat individuals with other forms of HIES.
Summary of clinical findings
[Considering only Definitive and Possible cases]
| Rank | Clinical phenotype | Present | Absent | Unreported |
|---|---|---|---|---|
| 1 | Abnormal circulating IgE level |
19 (86.4%) | 1 (4.6%) | 2 (9.1%) |
| 2 | Increased IgE levels |
19 (86.4%) | 1 (4.6%) | 2 (9.1%) |
| 3 | Atopy |
19 (86.4%) | 3 (13.6%) | 0 (0.0%) |
| 4 | Hypergammaglobulinaemia |
19 (86.4%) | 1 (4.6%) | 2 (9.1%) |
| 5 | (unusual) Respiratory tract infection |
16 (72.7%) | 4 (18.2%) | 2 (9.1%) |
| 6 | Recurrent respiratory infections |
16 (72.7%) | 4 (18.2%) | 2 (9.1%) |
| 7 | Lung disease |
16 (72.7%) | 4 (18.2%) | 2 (9.1%) |
| 8 | Pneumonia |
16 (72.7%) | 4 (18.2%) | 2 (9.1%) |
| 9 | Increased inflammatory response |
16 (72.7%) | 4 (18.2%) | 2 (9.1%) |
| 10 | Recurrent lower respiratory tract infections |
14 (63.6%) | 4 (18.2%) | 4 (18.2%) |
| 11 | Abnormality of dental eruption |
14 (63.6%) | 5 (22.7%) | 3 (13.6%) |
| 12 | Abnormality of primary teeth |
14 (63.6%) | 5 (22.7%) | 3 (13.6%) |
| 13 | Eczema |
14 (63.6%) | 4 (18.2%) | 4 (18.2%) |
| 14 | Abnormality of the dentition |
14 (63.6%) | 5 (22.7%) | 3 (13.6%) |
| 15 | Retained primary teeth |
14 (63.6%) | 5 (22.7%) | 3 (13.6%) |
| 16 | Abnormal respiratory system physiology |
13 (59.1%) | 4 (18.2%) | 5 (22.7%) |
| 17 | obstructive lung disease |
13 (59.1%) | 4 (18.2%) | 5 (22.7%) |
| 18 | Asthma |
13 (59.1%) | 4 (18.2%) | 5 (22.7%) |
| 19 | Atopic dermatitis |
12 (54.6%) | 4 (18.2%) | 6 (27.3%) |
| 20 | Recurrent upper respiratory tract infections |
12 (54.6%) | 4 (18.2%) | 6 (27.3%) |
| 21 | Scoliosis |
12 (54.6%) | 3 (13.6%) | 7 (31.8%) |
| 22 | Vertebral column abnormality |
12 (54.6%) | 3 (13.6%) | 7 (31.8%) |
| 23 | Abnormality of the curvature of the vertebral column |
12 (54.6%) | 3 (13.6%) | 7 (31.8%) |
| 24 | Abnormal bronchus morphology |
11 (50.0%) | 3 (13.6%) | 8 (36.4%) |
| 25 | Leukocytosis |
11 (50.0%) | 5 (22.7%) | 6 (27.3%) |
| 26 | Bronchiectasis |
11 (50.0%) | 3 (13.6%) | 8 (36.4%) |
| 27 | Eosinophilia |
10 (45.5%) | 5 (22.7%) | 7 (31.8%) |
| 28 | Abnormal eosinophil count |
10 (45.5%) | 5 (22.7%) | 7 (31.8%) |
| 29 | Joint hypermobility |
10 (45.5%) | 6 (27.3%) | 6 (27.3%) |
| 30 | Abnormality of joint mobility |
10 (45.5%) | 6 (27.3%) | 6 (27.3%) |
| 31 | Dermatitis |
8 (36.4%) | 6 (27.3%) | 8 (36.4%) |
| 32 | Abscess |
7 (31.8%) | 7 (31.8%) | 8 (36.4%) |
| 33 | Increased susceptibility to fractures |
7 (31.8%) | 5 (22.7%) | 10 (45.5%) |
| 34 | Pulmonary cyst |
7 (31.8%) | 6 (27.3%) | 9 (40.9%) |
| 35 | Pneumatocele |
7 (31.8%) | 6 (27.3%) | 9 (40.9%) |
| 36 | Musculoskeletal physiology abnormality |
7 (31.8%) | 5 (22.7%) | 10 (45.5%) |
| 37 | (unusual) Skin infection |
6 (27.3%) | 7 (31.8%) | 9 (40.9%) |
| 38 | Allergy |
6 (27.3%) | 5 (22.7%) | 11 (50.0%) |
| 39 | Hypogammaglobulinemia |
6 (27.3%) | 2 (9.1%) | 14 (63.6%) |
| 40 | Cutaneous abscess |
6 (27.3%) | 8 (36.4%) | 8 (36.4%) |
| 41 | Frequent skin infections |
6 (27.3%) | 7 (31.8%) | 9 (40.9%) |
| 42 | Decreased IgG levels |
4 (18.2%) | 2 (9.1%) | 16 (72.7%) |
| 43 | Aspergillosis |
4 (18.2%) | 0 (0.0%) | 18 (81.8%) |
| 44 | Allergic rhinitis |
4 (18.2%) | 4 (18.2%) | 14 (63.6%) |
| 45 | Rhinitis |
4 (18.2%) | 4 (18.2%) | 14 (63.6%) |
| 46 | Allergic bronchopulmonary aspergillosis |
4 (18.2%) | 0 (0.0%) | 18 (81.8%) |
| 47 | Abnormal proportion of CD8 T cells |
4 (18.2%) | 0 (0.0%) | 18 (81.8%) |
| 48 | Facial abnormality |
4 (18.2%) | 9 (40.9%) | 9 (40.9%) |
| 49 | Facial dysmorphism |
4 (18.2%) | 9 (40.9%) | 9 (40.9%) |
| 50 | Abnormal palate morphology |
3 (13.6%) | 10 (45.5%) | 9 (40.9%) |
| 51 | Decreased IgA levels |
3 (13.6%) | 1 (4.6%) | 18 (81.8%) |
| 52 | Decreased circulating IgG subclass level |
3 (13.6%) | 0 (0.0%) | 19 (86.4%) |
| 53 | Acute phase response |
3 (13.6%) | 1 (4.6%) | 18 (81.8%) |
| 54 | Abnormal circulating IgA level |
3 (13.6%) | 1 (4.6%) | 18 (81.8%) |
| 55 | Severe viral infection |
3 (13.6%) | 9 (40.9%) | 10 (45.5%) |
| 56 | Metabolism abnormality |
3 (13.6%) | 0 (0.0%) | 19 (86.4%) |
| 57 | Increased proportion of CD8 T cells |
3 (13.6%) | 0 (0.0%) | 19 (86.4%) |
| 58 | Reduced IgG1 levels |
3 (13.6%) | 0 (0.0%) | 19 (86.4%) |
| 59 | Herpes Simplex Virus Infection |
3 (13.6%) | 9 (40.9%) | 10 (45.5%) |
| 60 | Abnormal number of teeth |
3 (13.6%) | 9 (40.9%) | 10 (45.5%) |
| 61 | Dust mite allergy |
3 (13.6%) | 0 (0.0%) | 19 (86.4%) |
| 62 | Varicella zoster virus infection |
3 (13.6%) | 9 (40.9%) | 10 (45.5%) |
| 63 | (unusual) Viral infection |
3 (13.6%) | 9 (40.9%) | 10 (45.5%) |
| 64 | Supernumerary teeth |
3 (13.6%) | 9 (40.9%) | 10 (45.5%) |
| 65 | Abnormality of the mouth |
3 (13.6%) | 10 (45.5%) | 9 (40.9%) |
| 66 | High palate |
3 (13.6%) | 10 (45.5%) | 9 (40.9%) |
| 67 | Reduced NK cell number |
2 (9.1%) | 1 (4.6%) | 19 (86.4%) |
| 68 | Abnormal circulating IgG level |
2 (9.1%) | 2 (9.1%) | 18 (81.8%) |
| 69 | Abnormal circulating IgM level |
2 (9.1%) | 1 (4.6%) | 19 (86.4%) |
| 70 | Lymphopenia |
2 (9.1%) | 1 (4.6%) | 19 (86.4%) |
| 71 | Talipes equinovarus |
2 (9.1%) | 9 (40.9%) | 11 (50.0%) |
| 72 | Decreased IgM levels |
2 (9.1%) | 1 (4.6%) | 19 (86.4%) |
| 73 | Talipes |
2 (9.1%) | 9 (40.9%) | 11 (50.0%) |
| 74 | Pleural effusion |
2 (9.1%) | 0 (0.0%) | 20 (90.9%) |
| 75 | (unusual) Bacterial infection |
2 (9.1%) | 0 (0.0%) | 20 (90.9%) |
| 76 | Reduced bone mineral density |
2 (9.1%) | 0 (0.0%) | 20 (90.9%) |
| 77 | Reduced T cell count |
2 (9.1%) | 1 (4.6%) | 19 (86.4%) |
| 78 | Food allergy |
2 (9.1%) | 7 (31.8%) | 13 (59.1%) |
| 79 | Recurrent staphylococcal infections |
2 (9.1%) | 0 (0.0%) | 20 (90.9%) |
| 80 | Abnormal leukocyte count |
2 (9.1%) | 1 (4.6%) | 19 (86.4%) |
| 81 | Abnormal monocyte count |
2 (9.1%) | 0 (0.0%) | 20 (90.9%) |
| 82 | Abnormal NK cell count |
2 (9.1%) | 1 (4.6%) | 19 (86.4%) |
| 83 | Lung abscess |
2 (9.1%) | 0 (0.0%) | 20 (90.9%) |
| 84 | Abnormal proportion of memory B cells |
1 (4.6%) | 1 (4.6%) | 20 (90.9%) |
| 85 | Decreased proportion of memory B cells |
1 (4.6%) | 1 (4.6%) | 20 (90.9%) |
| 86 | Abnormality of the forehead |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 87 | Thrombocytopenia |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 88 | Mucocutaneous candidiasis |
1 (4.6%) | 10 (45.5%) | 11 (50.0%) |
| 89 | Osteoporosis |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 90 | Abnormal liver morphology |
1 (4.6%) | 1 (4.6%) | 20 (90.9%) |
| 91 | Osteopenia |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 92 | Animal protein allergy |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 93 | Animal dander allergy |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 94 | Mycobacterium Tuberculosis infection |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 95 | Chronic mucocutaneous candidiasis |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 96 | Frontal bossing |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 97 | Abnormal pleura morphology |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 98 | Reduced proportion of CD8 T cells |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 99 | Recurrent Aspergillus infections |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 100 | Recurrent fungal infections |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 101 | Skeletal system abnormality |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 102 | Neutropenia |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 103 | Pruritus |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 104 | Pneumothorax |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 105 | Acne vulgaris |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 106 | Leukopenia |
1 (4.6%) | 1 (4.6%) | 20 (90.9%) |
| 107 | edema |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 108 | Pleural empyema |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 109 | Abnormal lymphocyte count |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 110 | Abnormal T cell count |
1 (4.6%) | 1 (4.6%) | 20 (90.9%) |
| 111 | Abnormal neutrophil count |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 112 | Abnormal platelet count |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 113 | Monocytosis |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 114 | Extrapulmonary tuberculosis |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 115 | Liver abscess |
1 (4.6%) | 1 (4.6%) | 20 (90.9%) |
| 116 | Abnormality of immune system physiology |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 117 | Abnormality of skin physiology |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 118 | Abnormal shape of the frontal region |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 119 | Frequent cutaneous fungal infections |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 120 | Monocytopenia |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 121 | Decreased proportion of switched memory B cells |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 122 | Abnormal B cell subset distribution |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 123 | Abnormal proportion of naive B cells |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 124 | Abnormal proportion of class-switched memory B cells |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 125 | Abnormality of the midface |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 126 | Wide nose |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 127 | Abnormal proportion of unswitched memory B cells |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 128 | Unusual infection by anatomical site |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 129 | Abnormal C-reactive protein level |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 130 | Fatal infection |
0 (0.0%) | 10 (45.5%) | 12 (54.6%) |
| 131 | Midline anomaly |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 132 | Candidiasis |
0 (0.0%) | 10 (45.5%) | 12 (54.6%) |
| 133 | Reduced number of B cells |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 134 | Hematological neoplasm |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 135 | Abnormal nasal morphology |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 136 | Lymphoma |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 137 | Unusual infection |
0 (0.0%) | 10 (45.5%) | 12 (54.6%) |
| 138 | Abnormal B cell count |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 139 | Skin rash |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 140 | Elevated C-reactive protein |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 141 | Abnormality of skeletal morphology |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 142 | Bone fracture |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
Age of onset
distribution
Summary of treatment outcomes
[Considering only Definitive and Possible cases]
| Treatment ⓘ | Responses & clinical indications |
|---|---|
| Omalizumab [Monoclonal antibodies] |
Absent (1) for Allergic bronchopulmonary aspergillosis |
| Biological agents | Absent (2) for Allergic bronchopulmonary aspergillosis; Asthma. Good (1) for Atopic dermatitis |
| Monoclonal antibodies [Biological agents] |
Absent (2) for Allergic bronchopulmonary aspergillosis; Asthma. Good (1) for Atopic dermatitis |
| Antibiotics | Good (1) for unspecified. Unspecified (1) for Lung abscess |
| Antifungal agents | Absent (1) for Allergic bronchopulmonary aspergillosis |
| Co-trimoxazole [Antibiotics] |
Good (1) for unspecified |
| Dupilumab [Monoclonal antibodies] |
Absent (1) for Asthma. Good (1) for Atopic dermatitis |
22 reported cases added to GenIA
| SubjectID | Sex | Fam.ID | AD | AFM | Validity | Country | Population | Reference & Pub.code |
|---|---|---|---|---|---|---|---|---|
| 102421 |
M | 214949 |
16 | 0 | France | French | PMID:32207811 [Fam.A:III.1(P3)] | |
| 102423 |
M | 214949 |
72 | 0 | France | French/Greek | PMID:32207811 [Fam.A:I.2(P1)] | |
| 102425 |
M | 214949 |
47 | 0 | France | French | PMID:32207811 [Fam.A:II.2(P2)] | |
| 102426 |
F | 214949 |
13 | 0 | France | French | PMID:32207811 [Fam.A:III.2(P4)] | |
| 102427 |
M | 214950 |
26 | 4 | France | French | PMID:32207811 [Fam.B:II.3(P5)] | |
| 102436 |
F | 214956 |
12 | 0 | Bulgaria | Bulgarian | PMID:32207811 [Fam.C:III.1(P7)] | |
| 102439 |
M | 214956 |
38 | 0 | Bulgaria | Bulgarian | PMID:32207811 [Fam.C:II.2(P6)] | |
| 102444 |
M | 214957 |
25 | 0 | Slovakia | Slovak | PMID:32207811 [Fam.D:II.3(P8)] | |
| 102449 |
F | 214958 |
28 | 0 | U.S.A. | Mexican/Salvadoran | PMID:32207811 [Fam.E:II.1(P9)] | |
| 102453 |
F | 214959 |
22 | 0 | Turkey | Turkish | PMID:32207811 [Fam.F:II.2(P10)] | |
| 102460 |
M | 214960 |
18 | 0 | U.S.A. | European | PMID:32207811 [Fam.G:II.1(P11)] | |
| 102463 |
M | 214961 |
22 | 0 | U.S.A. | European | PMID:32207811 [Fam.H:II.1(P12)] | |
| 105911 |
F | 215906 |
11 | 6 | Definitive | France | French | PMID:37273120 [Fam.A:III.1(P2)] |
| 105915 |
M | 215906 |
38 | 6 | Definitive | France | French | PMID:37273120 [Fam.A:II.2(P1)] |
| 105918 |
F | 215908 |
70 | Definitive | Morocco | Moroccan | PMID:37273120 [Fam.B:I.1(P3)] | |
| 105920 |
F | 215908 |
47 | Definitive | Morocco | Moroccan | PMID:37273120 [Fam.B:II.1(P4)] | |
| 105921 |
F | 215908 |
45 | Definitive | Morocco | Moroccan | PMID:37273120 [Fam.B:II.2(P5)] | |
| 105923 |
M | 215908 |
33 | Definitive | Morocco | Moroccan | PMID:37273120 [Fam.B:II.4(P7)] | |
| 105924 |
F | 215908 |
41 | Definitive | Morocco | Moroccan | PMID:37273120 [Fam.B:II.5(P6)] | |
| 105943 |
M | 215912 |
20 | Definitive | Switzerland | Colombian/Swiss | PMID:37273120 [Fam.C:II.1(P8)] | |
| 106413 |
M | 216011 |
14 | 1 | Definitive | India | Indian | PMID:38578568 [Fam.1:II.2(index)] |
| 106415 |
F | 216011 |
Definitive | India | Indian | PMID:38578568 [Fam.1:I.2(mother)] |
AD: Age at genetic diagnosis; AFM: age at first manifestation; PMID: PubMed ID; GRID: GenIA reference ID (ref. not in PubMed).