Introduction
History of STAT3-HIES
Clinical Spectrum of STAT3-HIES
Overall | France (2012) [31] | USA (2016) [3]* | Shanghai, China (2017) [49] | Iran (2019) [119] | Italy (2019) [30] | Chongqing, China (2020) [48] | Fudan, China (2020) [120] | India (2021) [58] | Arora et al. [79] | |
---|---|---|---|---|---|---|---|---|---|---|
Demographics | ||||||||||
Cohort size (patients) | – | 60 | 85 | 17 | 19 | 28 | 20 | 11 | 27 | 70 |
Mean age at symptom onset (months) | 13.9 | 10.5 | 24 | 12 | 4.8 | 11.5 | 1.5 | 1.9 | – | – |
Median age at diagnosis (years) | 10.2 | 6.8 | 13.8 | 12 | 6 | 14.7 | 5.3 | 4.7 | 9.8 | – |
Mortality (patients) | 17/235 | 4/60 | 3/83 | 3/17 | – | 1/28 | 3/20 | – | 3/27 | – |
Dermatological | ||||||||||
Dermatological symptom as first manifestation (%) | 70.0 | 70 | – | 100 | 78 | 43 | – | – | 77.8 | – |
Eczema (%) | 92.0 | 92 | 57.7 | 100 | 89.4 | 88.5 | 100 | 100 | 37 | – |
Skin abscess (%) | 73.0 | 73 | 74 | 53 | 84 | 78 | 85 | 54.6 | 77.8 | – |
Chronic mucocutaneous candidiasis (%) | 85.0 | 85 | – | 53 | 42 | 70 | 70 | 45.5 | – | – |
Respiratory | ||||||||||
Pneumonia (%) | 90.0 | 90 | 72 | 100 | 84.2 | 60 | 95 | – | 62.9 | – |
Bronchiectasis (%) | 65.0 | 65 | 24.7 | 17.7 | 21.1 | 53.4 | 15 | – | – | – |
Pneumatocele (%) | 52.0 | 52 | 18.8 | 41.2 | 68.4 | 39.4 | 50 | – | 25.9 | – |
Surgical intervention (%) | 22.0 | 22 | 33 | 23.5 | – | 35.7 | 30 | 18.2 | – | – |
Connective tissue | ||||||||||
Facial dysmorphism (%) | 95.0 | 95 | – | 100 | – | 84 | 100 | 27.3 | 55.5 | – |
Retained primary teeth (%) | 65.0 | 65 | 41.4 | 90.9 | 68.4 | 65.4 | 25 | 27.3 | 7.4 | – |
Scoliosis (%) | 38.0 | 38 | 34.1 | 5.9 | 42.1 | 42.3 | 10 | 9.1 | 7.4 | – |
Fracture (%) | 42.0 | 42 | 39 | 41.2 | – | 20 | – | 11.1 | – | |
Joint hyperextensibility (%) | 50.0 | 50 | 8.5 | – | – | 32 | 100 | – | 22.2 | – |
Gastrointestinal | ||||||||||
Gastro-esophageal reflux disease (%) | – | – | – | – | – | – | – | – | – | 40 |
Dysphagia (%) | – | – | – | – | – | – | – | – | – | 31 |
Gastric ulceration (%) | – | – | – | – | – | – | – | – | – | 26 |
Intestinal strictures (%) | – | – | – | – | – | – | – | – | – | 9 |
Other features | ||||||||||
Allergy (%) | 48.9 | – | 65 | 35.2 | 42.1 | ~ 25 | – | 18.2 | – | – |
BCG-related complication (%) | 13.4 | 0 | – | 37.5 | 15.7 | – | 38.8 | – | 7.4 | – |
Treatment | ||||||||||
IVIG (%) | 53.0 | 53 | 30.6 | – | – | – | 25 | 72.7 | 13.0 | – |
Antibiotic prophylaxis (%) | 90.0 | 90 | > 66 | – | – | – | 56 | 100 | 65.2 | – |
Dermatological | Recommendation | Indication/notes |
---|---|---|
Eczema | Emollients and antihistamines | Reduction of pruritus |
Monoclonal antibodies (dupilumab, anti-IL-4; omalizumab, anti-IgE) | May also reduce rates of skin abscess [121] | |
Staphylococcal colonization | Topical antiseptics (e.g., dilute bleach baths, swimming in pools with chlorine) | |
Anti-staphylococcal spectrum antibiotics, e.g., twice-daily co-trimoxazole [50] | Monitor for antibiotic resistance, which is seen at increased rates [122] | |
Mucocutaneous candidiasis | Topical antifungal treatment or daily azole antifungal prophylaxis | Warn patients of side effects such as medication interactions and photosensitivity (for voriconazole) |
Pulmonary | ||
Recurrent pulmonary infection | Offer twice-daily co-trimoxazole prophylaxis | |
Consider antifungal prophylaxis with mold-active azoles such as itraconazole in patients with parenchymal disease (bronchiectasis, pneumatocele) | ||
CPA or ABPA may require prolonged antifungal therapy due to poor penetration into parenchymal lung disease | ||
Consider immunoglobulin replacement | May reduce frequency of pneumonia, though data are limited [128] | |
Offer routine immunization schedules, including live vaccinations, with the exception of the 23-valent pneumococcal polysaccharide vaccine (PPSV) Offer booster vaccinations if specific subtherapeutic IgG are observed | Avoid the 23-valent pneumococcal polysaccharide vaccine due to reports of significant local reaction, including skin necrosis [3] | |
Monitor microbiological culture and sensitivities regularly | Some authors propose intravenous antibiotic therapy for Pseudomonas bronchiectasis exacerbations [43] | |
Acute infective episode | High index of suspicion for complications, e.g., empyema | Patients may lack fever or other evidence of systemic inflammation Operative management risks complications, e.g., bronchopleural fistula formation [43] |
Extend spectrum to include gram-negative bacteria (e.g., Pseudomonas aeruginosa) and Aspergillus in parenchymal disease awaiting microbiologic studies | ||
Parenchymal lung disease | Chest physiotherapy, airway clearance devices, and/or hypertonic saline nebulization to augment mucus clearance | May risk hemoptysis [43] |
Bone and connective tissue | ||
Minimal trauma fractures | Optimize bone health with vitamin D supplementation | Bisphosphonates have an unclear role [72] |
Monitor bone mineral density | May not predict risk of fracture, though a reduced z-score in the distal radius may be informative [72] | |
Scoliosis | Monitor for development through adolescence | |
Delayed exfoliation of primary dentition | Regular surveillance through childhood and adolescence, and consider removal | Consider removal to allow eruption of secondary teeth [77] |
Vascular | ||
Coronary arterial disease | Optimize modifiable risk factors (e.g., hypertension, hyperlipidemia) | |
Consider antiplatelet agents, e.g., for primary prevention [129] | May risk hemoptysis, particularly if significant parenchymal lung disease or pulmonary arterial aneurysm is present | |
Other arterial aneurysms | Surveillance every 3–5 years [91] | Management of asymptomatic aneurysms is challenging, due to limited data on their natural history and the implicit risk of intervention |
Reproductive health and pregnancy | ||
Contraception | Consider medication interactions when offering pharmacological contraception | E.g., combined oral contraceptive with azole antifungals |
Pre-conception | Offer genetic counseling | |
Pregnancy | Risk of teratogenicity | |
Low threshold for presentation with pulmonary symptoms | Pregnancy may exacerbate pulmonary disease |
Bacterial Infection
Fungal Infection
Mycobacterial Infection
Viral Infection
Non-infectious Manifestations
Allergy
Connective Tissue Abnormalities and Poor Wound Healing in STAT3-HIES
Vasculopathy
Obstetric and Gynecological Health
Malignancy and Autoimmunity
Investigations
Genetics of STAT3
Laboratory Analysis
Investigation | Comments |
---|---|
Full blood count | Eosinophilia in 70% |
Lymphocyte subsets | Total lymphocyte count is normal Reduced memory T-lymphocytes [34] |
Immunoglobulins | Total IgA, IgM, IgG normal Specific IgG to recall antigens is reduced Raised IgE, usually > 1000 IU/ml, which peaks in infancy and may normalize in adulthood [13] |
Specialist immunophenotyping | Absent IL-17-producing Th17-lymphocytes |
Molecular analysis of STAT3 | Heterozygous mutations are typically missense or short in-frame deletions; identification of new variants is complicated by dominant-negative and gain-of-function mutations sharing the same codon [3, 103] Any identified variant should be confirmed to be deleterious prior to attributing pathogenicity Panels may include other candidate genes for HIES, e.g., PGM3, IL6ST, and ZNF341 (which is a recessive phenocopy of STAT3-HIES), or DOCK8 (a combined immunodeficiency sharing features with HIES) |
NIH-HIES Score
Clinical finding | Points | Scaling factor | |||||
---|---|---|---|---|---|---|---|
0 | 2 | 4 | 5 | 6 | 8 | ||
Pneumonia (X-ray proven, total no.) | None | 1 | 2 | – | 3 | > 3 | 2.5 |
Newborn rash | Absent | – | Present | – | – | – | 2.08 |
Pathological bone fractures (total no.) | None | – | 1–2 | – | – | > 2 | 3.33 |
Characteristic facies | Absent | Mild | – | Present | – | – | 3.33 |
High-arched palate | Absent | Present | – | – | – | – | 2.5 |
Quality of Life, Natural History, and Mortality
The Uncertain Role of HSCT
Series | Sex | Age at HSCT | Donor | Conditioning | Lymphoma | GvHD | Donor chimerism | Organ status post-HSCT | Survival | ||
---|---|---|---|---|---|---|---|---|---|---|---|
Skin | Lung | Other | |||||||||
Nester et al. [115] | M | 46 | MSD | MAC | Y | Acute | Not known | – | Interstitial pneumonitis leading to death | – | N |
Goussetis et al. [118] | M | 15 | MSD | MAC | Y | – | Full | – | Infection-free | – | Y |
F | 16 | MSD | MAC | Y | – | Full | – | Infection-free | – | Y | |
Patel et al. [135]* | F | 14 | Haploidentical | RIC | – | – | Full | Abscess formation once | Infection-free | – | Y |
Yanagimachi et al. [136] | F | 8 | MUD | RIC | – | Acute | Full | – | Recurrent aspergillosis | – | Y |
M | 23 | MSD | RIC | – | – | Mixed | – | Recurrent pneumatocele | – | Y | |
Harrison et al. [117] | M | 7 | MUD | RIC | – | – | Full | – | Requires nocturnal CPAP | Scoliosis, fracture | Y |
F^ | 7 | MUD | MAC | – | Acute | Full | – | Stable appearance on CT, improved PFTs | Scoliosis, HTN | Y | |
M | 13 | MSD | RIC | – | Acute | Full | – | Stable appearance on CT, improved PFTs | Anterior MI | Y | |
M | 14 | MSD | RIC | – | Acute | Full | Dry, no infection | Improved appearance on CT, improved PFTs | Resolved autoimmune neutropenia | Y | |
F | 17 | MUD | RIC | – | Acute | Full | – | Improved appearance on CT | – | Y | |
M | 18 | MUD, MUD | RIC, RIC | – | – | Full* | – | Stable CXR changes | Septic arthritis of hip | Y | |
M | 13 | MUD | RIC | – | – | Full | Dry, no infection | Improved symptoms | – | Y | |
F | 6 | MSD | RIC | – | – | Full | Dry, no infection | Improved symptoms | – | Y |