Dental history of two STAT3-HIES patients
Dental histories of two patients exemplary show the outcome of different treatment strategies: In patient #4 primary teeth were all extracted at the average exfoliation time, while patient #3 received tooth extractions partly later in life.
All primary teeth erupted without problems in the average eruption time in patient #4. Up to the age of 9 years all primary mandible and maxillary central and lateral incisors were extracted. The successor permanent teeth erupted shortly afterwards (Fig. 1a, b). Radiograph at 12 years of age showed unresorbed and only slightly resorbed roots of the remaining primary teeth. Her remaining primary teeth were all subsequently extracted up to the age of 13 years with the permanent successor teeth erupting shortly afterwards.
In patient #3 primary teeth eruption was unremarkable and within the average eruption time. Primary incisors of patient #3 were extracted between 7 and 9 years of age with the exception of 2 incisors which exfoliated spontaneously. Permanent incisors erupted shortly afterwards. Primary canines and molars did not exfoliate spontaneously and persisted during the physiologic eruption period of the corresponding successor teeth. At 15 years of age all 4 retained canines were extracted. The successor teeth remained impacted in the jaw. In order to obtain additional space for the permanent canines, the still persistent primary first molars were removed at 16 years of age. The successor teeth still failed to erupt (Figure 2a, b). Therefore, bone ablation superior of the impacted permanent teeth was performed under anaesthesia and a complex orthodontic treatment to pull the permanent canines and first premolars into the oral cavity was started. After this operation, the canines and first premolars began to erupt. At 17 years of age the last 4 primary teeth were removed and the second premolars were included in the orthodontic treatment (Figure 2c, d). Finally, the top of the second premolars erupted 3 weeks after the last operation and all permanent teeth, which had been included in the orthodontic treatment, had erupted at 17 years of age The extracted primary molars showed almost completely unresorbed roots (Figure 2e, f). To align the dental arch and to reach optimum teeth positioning, over 2 years of complex orthodontic treatment followed.
Primary teeth: eruption, spontaneous exfoliation, retention, and root resorption in STAT3-HIES
Eruption time, tooth size, tooth appearance, and number of primary teeth were unremarkable in all 13 STAT3-HIES patients. Due to age, patient #2 (5 years of age) had not yet lost any primary teeth. In 2 patients (#1, #5) all primary teeth exfoliated naturally within the normal age range, while 10 patients (83%) presented with retained primary teeth (2 to 20 teeth per patient) and delayed eruption of permanent teeth up to 35 years of age (Figure 3, Table 1). In 3 patients (#4, #6, #9) no primary tooth exfoliated spontaneously within the normal age range. Two patients (#10, #12) presented with retained incisors while the presence of their primary canines and molars was adequate to age. In 5 patients (#3, #7, #8, #11, #13) both, spontaneous exfoliation and retention of 2 to 8 incisors, up to 2 canines and up to 6 molars was observed.
Thus, only 36% of incisors, 29% of canines, and 27% of molars exfoliated spontaneously within the physiological exfoliation time [21] in the investigated STAT3-HIES patients with retained primary teeth.
In all these patients except for patient #3 and #12 the permanent first and second molars erupted on time (first molar: 5.5-7 years of age, second molar: 12-14 years of age). The first permanent molars of patient #12 appeared with a delay of approximately 2 years at 9 years of age and the maxillary second permanent molars of patient #3 had not yet reached the occlusal level at 17 years of age.
Delayed primary tooth root resorption was observed in 8 of the 10 (80%) STAT3-HIES patients older than 8 years of age, of whom radiographs were available. Detailed root resorption was assessed in 22 panoramic radiographs (Suppl. Table S2) in 3 age groups: (i) up to 9 years of age when physiologically all incisors should have exfoliated, (ii) 10 to 13 years of age when also canines and molars exfoliate and (iii) older than 13 years of age when no primary teeth should remain.
Between 8 and 9 years of age 4 patients (#4, #9, #11, #12) showed delayed root resorption of primary teeth with unresorbed roots in incisors, canines, and molars (Figure 4). Between 10 and 13 years of age 4 patients (#4, #6, #7, #9) still had up to 4 primary canines and 4 to 8 primary molars of which some had unresorbed roots. The assessment of panoramic radiographs in 3 patients (#3, #7, #8) above 13 years of age revealed in patient #3 3 primary canines and one primary molar in patient #7 with unresorbed primary tooth roots.
Extraction therapy of retained primary teeth, orthodontic and conservative treatment
Nine patients (#3, #4, #6 to #12) had one up to 20 primary teeth per patient extracted between 7 and 17 years of age to enable eruption of permanent teeth. In 7 of the 9 patients sequential tooth extraction was required including series of 2 to 8 extractions per patient. In 8 of 9 STAT3-HIES patients permanent teeth erupted shortly after the primary teeth had been extracted around the physiological exfoliation age.
Nine patients received an orthodontic treatment including removable or fixed dental braces. In patient #9 one permanent premolar in each quadrant had to be removed for orthodontic reasons to obtain more space for the remaining teeth. To correct the nasal and upper jaw configuration, patient #1 received an osteotomy of the maxilla including orthodontic correction. Five patients (#1, #5, #7, #8, #13) needed conservative dentistry while the other 8 patients did not have any fillings, endodontic treatments or inlays.
No complication after extraction or orthodontic treatment
Despite repeated oral candidiasis in 7 (54%), recurrent aphthous ulcers (1-12 times per year) in 2 (15%), and gingivitis in 4 (31%) patients, there were no infections after tooth extraction or orthodontic treatment in any of the patients (Table 1). Wound healing was unremarkable in all patients after extractions. As a measure of precaution, amoxicillin was given prior to complex dental treatment in patient #3 in addition to patient`s continued standard antibiotictreatment and immunoglobulin substitution therapy.
Abnormal dental and oral anatomy
There were 3 patients (#4, #7, #12) with abnormal dental anatomy of permanent teeth: agenesis of both maxillary second premolars in patient #4, an agenesis of the right-sided maxillary second premolar in patient #12, and a twice the normal size right-sided mandibular second premolar in patient #7. In 4 patients (#3, #8, #10, #11) permanent incisors were temporarily present lingual together with the primary incisors until the primary teeth were extracted. Patient #2 had an abnormal fissuring of the tongue (Supp. Figure S1).