Intraoral and maxillofacial abnormalities in patients with autosomal dominant hyper-IgE syndrome.

DOI: https://doi.org/10.5114/ceji.2023.130874 Clinical immunology Intraoral and maxillofacial abnormalities in patients with autosomal dominant hyper-IgE syndrome ILDIKÓ TAR1, MÁRTA SZEGEDI1, EWA KRASUSKA-SŁAWIŃSKA2, EDYTA HEROPOLITAŃSKAPLISZKA3, EWA A. BERNATOWSKA3, ELIF ÖNCÜ4, SEVGI KELES5, SUKRU N. GUNER5, ISMAIL REISLI5, NEVENA GESHEVA6, ELISSAVETA NAUMOVA6, LYDIE IZAKOVICOVA-HOLLA7, JIRI LITZMAN8, IGOR SAVCHAK9, LARYSA KOSTYUCHENKO9, MELINDA ERDÕS10 Faculty of Dentistry, University of Debrecen, Debrecen, Hungary Dental Surgical Clinic for Children, Children’s Memorial Health Institute, Warsaw, Poland 3 Department of Immunology, Children’s Memorial Health Institute, Warsaw, Poland 4 Department of Periodontology, Lokman Hekim University, Ankara, Turkey 5 Division of Pediatric Allergy and Immunology, Necmettin Erbakan University, Konya, Turkey 6 Department of Clinical Immunology and Stem Cell Bank, University Hospital “Aleksandrovska”, Sofia, Bulgaria 7 Department of Stomatology, St Anne’s University Hospital, Faculty of Medicine, Masaryk University, Brno, Czech Republic 8 Department of Clinical Immunology and Allergology, St Anne’s University Hospital, Faculty of Medicine, Masaryk University, Brno, Czech Republic 9 Department of Pediatric Immunology and Rheumatology, Western Ukrainian Specialized Children’s Medical Center, Lviv, Ukraine 10 J Project Education and Research Network, Debrecen, Hungary 1 2 Abstract Autosomal dominant hyper-IgE syndrome (AD-HIES) is an inborn error of immunity (IEI) caused by a dominant-negative mutation in the signal transducer and activator of transcription 3 (STAT 3). This disease is characterized by chronic eczematoid dermatitis, recurrent staphylococcal skin abscesses, pneumonia, pneumatoceles, and extremely high serum IgE levels. Loss-of-function STAT3 mutations may also result in distinct non-immunologic features such as dental, facial, skeletal, and vascular abnormalities, central nervous system malformations and an increased risk for bone fractures. Prophylactic treatment of Candida infections and prophylactic antimicrobial therapy for staphylococcal skin infections and sinopulmonary infections are essential. An awareness of the oral and maxillofacial features of HIES may facilitate early diagnosis with genetic counselling and may improve future patient care. This study describes oral, dental, and maxillofacial manifestations in 14 patients with genetically defined AD-HIES. We also review the literature and propose recommendations for the complex care of patients with this rare primary immunodeficiency. Key words: dentist, hyper-IgE syndrome, maxillofacial, intraoral. (Cent Eur J Immunol 2023; 48 (3): 228-236) Introduction Autosomal dominant hyper-IgE syndrome (AD-HIES; OMIM 147060) is an inborn error of immunity (IEI) characterized by increased susceptibility to infections, chronic eczematoid dermatitis, and elevated levels of serum immunoglobulin E (IgE) [1-3]. Affected patients are particularly susceptible to infections with Staphylococcus aureus and Candida albicans and display chronic mucocutaneous candidiasis. A hallmark of AD-HIES is a poor tissue inflammatory response resulting in cold abscesses. Additional clinical abnormalities include coarse facial features, abnormal dentition with retention of the primary teeth, cranial synostosis, scoliosis, hyperextensibility of joints, osteoporosis, pathological fractures, central nervous system abnormalities and various vascular malformations including coronary artery aneurysms [2-4]. AD-HIES is caused by heterozygous loss-of-function (LOF) mutations in the signal transducer and activator of transcription 3 (STAT3) [5-7]. STAT3 is a central regulator of immune homeostasis, and as a key effector of T helper (Th) 17 cytokines and Th17 differentiation it plays an essential role in eliminating extracellular bacteria and fungi [8-10]. The immunological Correspondence: Melinda Erdös, J Project Education and Research Network, Debrecen, Hungary, e-mail: Submitted: 10.12.2022, Accepted: 24.05.2023 228 This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/) Intraoral and maxillofacial abnormalities in patients with autosomal dominant hyper-IgE syndrome Table 1. Demographics, genetic data and IgE level of patients with hyper-IgE syndrome (HIES) Fam No Pt No Country 1 1 BG F 11 DNA-binding c.1144>T p.R382W 9740 2 2 CZ F 45 DNA-binding c.982_990dupT C328_P330 10500 3 3 HU F 31 DNA-binding c.994C>T p.H332Y > 10000 M 12 DNA-binding c. 994C>T p.H332Y > 10000 4 Sex Age STAT3 domain STAT3 mutation cDNA AA change IgE max (IU/ml) 5 M 10 DNA-binding c. 994C>T p.H332Y > 10000 4 6 M 12 DNA-binding c.1144C>T p.R382W > 10000 5 7 F 6 SH2 c.1865C>T p.T6221 > 3000 6 8 7 9 8 10 9 11 10 12 PL TR 13 11 14 UA F 26 DNA-binding c.1110-3c>G* – < 1000 M 20 DNA-binding c.1144C>T p. R382W 45300 M 28 SH2 c.1909G>A p.V637M 13500 F 22 DNA-binding c.1145G>A p.R382Q 39700 M 39 DNA-binding c.1151T>A* p.F384Y* 19100 F 12 DNA-binding c. 1151T>A* p.F384Y* 66500 F 7 SH2 c.1831A>G p.S611G 9152 IgE max normal value: < 200 IU/ml, *novel mutation AA – amino acid, BG – Bulgaria, CZ – Czech Republic, F – female, Fam – family, HU – Hungary, M – male, PL – Poland, Pt – patient, STAT3 – signal transducer and activator of transcription, TR – Turkey, UA – Ukraine phenotype includes a high serum concentration of IgE, eosinophilia, a low number of Th17 cells, and B memory cell lymphopenia [10]. Serum IgE tends to decline with age, particularly in adult patients [10, 11]. The characteristic facial appearance in AD-HIES typically develops by late adolescence and is characterized by facial asymmetry, a prominent forehead, deep-set eyes, increased inter-alar width (IAW), a broad nasal bridge, a swollen lower lip, and coarse facies with dryness and prominent pores [4]. Oral manifestations include the retention of primary teeth and delayed eruption of permanent teeth [11-15]. Approximately 70% of patients with AD-HIES have delayed exfoliation of three or more primary teeth [11]. Prolonged retention of primary teeth can lead to permanent teeth impaction or formation of double rows, in which succedaneous teeth erupt lingual to the deciduous teeth and predispose to malocclusion. Importantly, permanent teeth erupt normally if retained primary teeth are extracted around the physiological exfoliation age [16]. An abnormal number of primary teeth has also been reported [17]. Further oral manifestations include ectopic eruption or retention of permanent teeth, double dentition, a higharched palate, severe caries, mucosal plaques, and fissures of the tongue and the palate [12]. Asymptomatic palatal and tongue lesions of the oral mucosa and gingiva may develop in (...truncated)