Information on HIES4A
Basic details
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 04:25:22 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.
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).
Summary of clinical findings
[Considering only Definitive and Possible cases]
| Rank | Clinical term | Present | Absent | Unreported |
|---|---|---|---|---|
| 1 | Increased IgE levels |
19 (86.4%) | 1 (4.6%) | 2 (9.1%) |
| 2 | Atopy |
19 (86.4%) | 3 (13.6%) | 0 (0.0%) |
| 3 | (unusual) Respiratory tract infection |
18 (81.8%) | 3 (13.6%) | 1 (4.6%) |
| 4 | Lung disease |
17 (77.3%) | 3 (13.6%) | 2 (9.1%) |
| 5 | Pneumonia |
16 (72.7%) | 4 (18.2%) | 2 (9.1%) |
| 6 | Recurrent lower respiratory tract infections |
14 (63.6%) | 4 (18.2%) | 4 (18.2%) |
| 7 | Eczema |
14 (63.6%) | 4 (18.2%) | 4 (18.2%) |
| 8 | Retained primary teeth |
14 (63.6%) | 5 (22.7%) | 3 (13.6%) |
| 9 | Asthma |
13 (59.1%) | 4 (18.2%) | 5 (22.7%) |
| 10 | Atopic dermatitis |
12 (54.6%) | 4 (18.2%) | 6 (27.3%) |
| 11 | Recurrent upper respiratory tract infection |
12 (54.6%) | 4 (18.2%) | 6 (27.3%) |
| 12 | Scoliosis |
12 (54.6%) | 3 (13.6%) | 7 (31.8%) |
| 13 | Bronchiectasis |
11 (50.0%) | 3 (13.6%) | 8 (36.4%) |
| 14 | Eosinophilia |
10 (45.5%) | 5 (22.7%) | 7 (31.8%) |
| 15 | Joint hypermobility |
10 (45.5%) | 6 (27.3%) | 6 (27.3%) |
| 16 | Skin infections |
8 (36.4%) | 8 (36.4%) | 6 (27.3%) |
| 17 | Increased susceptibility to fractures |
7 (31.8%) | 5 (22.7%) | 10 (45.5%) |
| 18 | Pneumatocele |
7 (31.8%) | 6 (27.3%) | 9 (40.9%) |
| 19 | Allergy |
6 (27.3%) | 5 (22.7%) | 11 (50.0%) |
| 20 | Hypogammaglobulinemia |
6 (27.3%) | 2 (9.1%) | 14 (63.6%) |
| 21 | Cutaneous abscess |
6 (27.3%) | 8 (36.4%) | 8 (36.4%) |
| 22 | Allergic rhinitis |
4 (18.2%) | 4 (18.2%) | 14 (63.6%) |
| 23 | Allergic bronchopulmonary aspergillosis |
4 (18.2%) | 0 (0.0%) | 18 (81.8%) |
| 24 | Facial dysmorphism |
4 (18.2%) | 9 (40.9%) | 9 (40.9%) |
| 25 | Decreased IgA levels |
3 (13.6%) | 1 (4.6%) | 18 (81.8%) |
| 26 | Acute phase response |
3 (13.6%) | 0 (0.0%) | 19 (86.4%) |
| 27 | Increased proportion of CD8 T cells |
3 (13.6%) | 0 (0.0%) | 19 (86.4%) |
| 28 | Reduced IgG1 levels |
3 (13.6%) | 0 (0.0%) | 19 (86.4%) |
| 29 | Dust mite allergy |
3 (13.6%) | 0 (0.0%) | 19 (86.4%) |
| 30 | Varicella zoster virus infection |
3 (13.6%) | 9 (40.9%) | 10 (45.5%) |
| 31 | (unusual) Viral infection |
3 (13.6%) | 9 (40.9%) | 10 (45.5%) |
| 32 | Supernumerary teeth |
3 (13.6%) | 9 (40.9%) | 10 (45.5%) |
| 33 | High palate |
3 (13.6%) | 10 (45.5%) | 9 (40.9%) |
| 34 | Decreased IgG levels |
2 (9.1%) | 2 (9.1%) | 18 (81.8%) |
| 35 | Reduced NK cell number |
2 (9.1%) | 1 (4.6%) | 19 (86.4%) |
| 36 | Talipes equinovarus |
2 (9.1%) | 9 (40.9%) | 11 (50.0%) |
| 37 | Decreased IgM levels |
2 (9.1%) | 1 (4.6%) | 19 (86.4%) |
| 38 | (Unusual) bacterial infection |
2 (9.1%) | 0 (0.0%) | 20 (90.9%) |
| 39 | Food allergy |
2 (9.1%) | 7 (31.8%) | 13 (59.1%) |
| 40 | Recurrent staphylococcal infections |
2 (9.1%) | 0 (0.0%) | 20 (90.9%) |
| 41 | Lung abscess |
2 (9.1%) | 0 (0.0%) | 20 (90.9%) |
| 42 | Decreased proportion of memory B cells |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 43 | Thrombocytopenia |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 44 | Mucocutaneous candidiasis |
1 (4.6%) | 10 (45.5%) | 11 (50.0%) |
| 45 | Osteoporosis |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 46 | Osteopenia |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 47 | Animal dander allergy |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 48 | Lymphopenia |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 49 | Frontal bossing |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 50 | Pleural effusion |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 51 | Reduced proportion of CD8 T cells |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 52 | Leukocytosis |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 53 | Recurrent Aspergillus infections |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 54 | Neutropenia |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 55 | Pruritus |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 56 | Reduced T cell count |
1 (4.6%) | 1 (4.6%) | 20 (90.9%) |
| 57 | Pneumothorax |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 58 | Acne vulgaris |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 59 | Leukopenia |
1 (4.6%) | 1 (4.6%) | 20 (90.9%) |
| 60 | Pleural empyema |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 61 | Monocytosis |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 62 | Extrapulmonary tuberculosis |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 63 | Liver abscess |
1 (4.6%) | 1 (4.6%) | 20 (90.9%) |
| 64 | Monocytopenia |
1 (4.6%) | 0 (0.0%) | 21 (95.5%) |
| 65 | Decreased proportion of switched memory B cells |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 66 | Abnormal proportion of naive B cells |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 67 | Wide nose |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 68 | Abnormal proportion of unswitched memory B cells |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 69 | Fatal infection |
0 (0.0%) | 10 (45.5%) | 12 (54.6%) |
| 70 | Midline anomaly |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 71 | Reduced number of B cells |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 72 | Lymphoma |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 73 | Skin rash |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
| 74 | Elevated C-reactive protein |
0 (0.0%) | 1 (4.6%) | 21 (95.5%) |
| 75 | Bone fracture |
0 (0.0%) | 2 (9.1%) | 20 (90.9%) |
Summary of treatment outcomes
[Considering only Definitive and Possible cases]
| Treatment ⓘ | Responses & clinical indications |
|---|---|
| Omalizumab | Absent (1) for Allergic bronchopulmonary aspergillosis |
| Biological agents | Absent (2) for Allergic bronchopulmonary aspergillosis; Asthma. Good (1) for Atopic dermatitis |
| Monoclonal antibodies | 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 | Good (1) for unspecified |
| Dupilumab | Absent (1) for Asthma. Good (1) for Atopic dermatitis |