Name: Hyper-IgE recurrent infection syndrome 1 | Acronym: HIES1
Alt. names: STAT3 deficiency | Job syndrome | STAT3-LOF | AD-HIES

Gene: STAT3 | MOI: Autosomal dominant | Mechanism of action: Negative Dominance

No. of cases in DB: 404 | First reported in: 2007

Last updated on: 2023-04-01 05:42:32 by Xiao P. Peng

OMIM: 147060

Orphanet: 2314

MONDO: 0007818

DOID: 0003261

ClinGen: Definitive (2021-12-24)

Thus far, over 300 patients from over 250 families have been described with this form of HIES due to heterozygous dominant negative STAT3 mutations leading to enhanced Th2 polarization at the cost of Th1 and Th17 lineages (PMID: 17676033, 17881745, 18602572, 18706697, 20093388, 20159255, 30466772, 34390440). Individuals suffer from recurrent mucocutaneous and sinopulmonary infections (bacterial, viral and fungal – particularly candidiasis), significant atopy (particularly eczematous dermatitis), vascular, connective tissue and skeletal abnormalities, as well as increased susceptibility to malignancy (particularly lymphoma). Non-immune features include craniofacial dysmorphisms (craniosynostosis, prominent forehead, deep-set eyes, broad nasal bridge, high-arched palate, retained primary teeth), joint hyperextensibility, scoliosis, and osteopenia/osteoporosis with increased fracture susceptibility. Labs are notable for peripheral eosinophilia and elevated IgE levels with variably low levels of other Ig classes.

Currently, treatment is based on prevention and symptomatic management. The mainstay of treatment is prevention of staphylococcal abscesses and pneumonias with anti-staphylococcal prophylactic antibiotics as well as early aggressive treatment of infections. Antibiotic and antifungal choice depends on the nature of the infection and the extent of involvement. Antiseptic therapies for the skin such as dilute bleach baths and chlorhexidine are beneficial. Medications such as histamine-1 antagonists to control pruritus are helpful for more significant eczema. There is no known treatment or prevention for the nonimmunologic characteristics, although optimization of calcium and vitamin D intake may be considered to improve bone health. Successful hematopoietic cell transplantation (HSCT) has been shown to improve the immunodeficiency and atopy phenotypes, but effects on the nonimmunologic aspects of the disease remain unclear (PMID: 20584545, 25962528, 27091139, 33523338). Impressively, long-term follow-up found that even patients with severe pre-transplant morbidities such as progressive lung disease survived, with stabilized and sometimes improved post-HSCT pulmonary disease, while GvHD was infrequent and insignificant (PMID: 33523338). Dupilumab has been used successfully in a number of patients to treat severe atopic disease (PMID: 32360519, 33898684, 34280586, 34536614, 34927771, 35734823, 35470938, 36605204). Recently, omalizumab has also been reported to help at least partially improve atopic and chronic airway disease complications (PMID: 31820738, 33628541, 35602476). In terms of surveillance, periodic chest imaging and high clinical suspicion assist in early detection of lung infections, while skin and sputum cultures may help direct therapy. Routine screening of adolescents for early signs of scoliosis is recommended. Dental monitoring is necessary to ensure timely removal of primary teeth to allow eruption of secondary teeth. Evaluation for coronary artery and cerebral aneurysms every three years in adulthood is recommended as well as monitoring for lymphadenopathy given the potential risk of lymphoma development.