Rapidly progressing generalised tooth resorption associated with primary immunodeficiency due to XIAP/BIRC4 mutation: A case report

Primary immunodeficiency (PID) includes a variety of disorders affecting the immune system, including a rare inherited mutation of the X-linked inhibitor of apoptosis protein (XIAP/BIRC4; OMIM #300079). The XIAP/BIRC4 gene is involved in innate immunity and inflammation and has an important role in inhibiting apoptosis by blocking caspases 3, 7 and 9.1 Systemic manifestations of this mutation include haemophagocytic lymphohistiocytosis (HLH), recurrent splenomegaly and inflammatory bowel disease. Although oral manifestations of early exfoliation of primary teeth, infection, recurrent ulcers and periodontitis have been described for PID in general,2 there are no reports specific to the XIAP/BIRC4 mutation. A 5-year-old boy with PID caused by mutation in the XIAP/BIRC4 gene in exon 4 (with a truncation of the gene due to the introduction of a stop codon at amino acid 327) attended for routine examination at the Women's and Children's Hospital Paediatric Dentistry Department, South Australia, in August 2019. He was a regular dental attendee since initial referral by the immunologist at 18 months of age. His medical and dental history is presented in Table 1, and the mutation was diagnosed at 15 months of age. His parents and siblings had no history of dental anomalies nor PID. Informed consent was gained for this report. Initial dental examination Ongoing routine dental examination (6-monthly) Orthopantomogram (OPG) obtained at 5 years and 10 months of age showed altered pulpal dimensions on the distal portion of the #65 consistent with an ectopic #26 (Figure 1A), microdontia of #17, #15, #25, #27, #37, #47 and agenesis of #35 and #45. Clinical examination showed generalised, severe attrition and probable intrinsic erosion of the primary dentition (with exposed dentine), but first permanent molars were sound. Bitewing radiographs obtained at 6 years and 10 months of age revealed pulpal enlargement and rapid resorption in eight primary teeth: #54, #63, #64, #65, #74, #73, #83 and #84 (Figure 2A,B). A new OPG obtained at 7 years of age revealed pulpal enlargement in another tooth #75 (Figure 1B). Shared decision-making approach enabled the clinical providers (including immunologist and orthodontist), the patient and the parents to plan for extraction of the affected, asymptomatic teeth under general anaesthetic and to discuss the long-term consequences of early extractions. Periapical radiographs taken under general anaesthesia revealed further pulpal enlargement in the affected teeth and in additional tooth #85 (Figure 2C–F). Therefore, all remaining primary teeth were extracted under general anaesthesia. High-resolution micro-CT images of teeth #54 and #74 revealed enlarged pulp chambers containing aberrant calcifications (radiopacities), with pulpal changes extending from the apical third of roots to the furcation region (Figure 3A–D). Histological investigation of six teeth (#63, #64, #65, #75, #83 and #85) concluded a diagnosis of resorption and revealed a fibrous pulp space with cystic change and with inflammation only in two teeth (#75 and #85). Osteoclasts were noted at the dentine–pulp interface (Figure 3E) and islands of bone-like structure in the pulp chamber (Figure 3F). The enlarged pulp chambers were noted incidentally on an OPG at 5 years and 10 months of age, but the rapid progression of resorption, particularly within the 3 months leading up to extraction, was rather unusual. Bacterial invasion through perforated root surface around the furcation area could have led to pulpal necrosis and periapical infection in an immunocompromised child; therefore, all the (affected) primary teeth were extracted. The clinical consequences of potential resorption in the permanent dentition, and early extraction of the affected teeth, were considered during treatment planning. Resorption can be a physiological or a pathological process involving the loss of dentine, cementum and bone.3 The primary teeth initially displayed normal radiographic morphology, confirming the absence of any underlying congenital pathology (Figure 1), but were subjected to generalised severe attrition and probable intrinsic erosion. The periapical radiographs (Figure 2C–F) showed the initiation of the resorption around the inner dentine, and micro-CT images displayed bone-like structures in both the pulp chamber and the furcation area of the primary molars. These observations were corroborated by histopathological findings, indicating that the lesion resembled ‘internal replacement (invasive) cervical resorption’. The calcification could have occurred during the repair stage of cervical resorption.4 The underlying pathophysiology of resorption of the primary dentition that diverts from physiological root resorption, however, remains largely unexplored, with the resorption classification being adapted from the permanent dentition. Although physiological root resorption is initiated by the normal eruption of the succedaneous permanent teeth, teeth #75 and #85 displayed signs of internal resorption despite agenesis of teeth #35 and #45.5 The aggressive nature of the resorption may be linked to the significant treatment of PID through HLH2004 protocol (including administration of cytotoxic medications—dexamethasone and etoposide) early in life.6 The possible side effects of these medications could have exacerbated severely compromised immune homeostasis, including impaired vasculature in the pulp (hypoxia), altered regulation of inflammatory mediators (eg, interleukin-6 and RANKL/OPG) and altered ‘programming’ of osteoblasts/odontoblasts and osteoclasts/odontoclasts. Eventually, these could have led to a lack of apoptosis inhibition and rapid internal resorption. Some medications (eg, bisphosphonates, denosumab and a chemotherapy agent for ovarian cancer) and systemic conditions (eg, hypothyroidism, Paget's disease of the bone and Popillon–Lefevre syndrome) have been hypothesised to alter osteoclastic activity and lead to external root resorption.7 Although the role of gastric proteases from acid regurgitation in dentine resorption cannot be ruled out, a more plausible explanation is the developmental disturbances of teeth from cytotoxic medications given that resorption, microdontia (#17, #15, #25, #27, #37 and #47) and agenesis (#35 and #45) occurred concurrently.8 There are no evidence-based guidelines for managing premature physiologic resorption in the primary dentition; hence, future research is needed to better understand the pathogenesis of rapid resorption to inform clinical care. Its management should involve careful and frequent clinical and radiographic review to avoid overlooking idiopathic, widespread resorption in both the primary and permanent dentitions. E.D.J. and K.J.O. were involved in the provision of dental care for the individual; J.T. and S.R. ran the micro-CT imaging and analysis; E.D.J and S.R. led the writing with all authors contributing to the final manuscript. The authors gratefully acknowledge Professor Lynette Moore, senior consultant of anatomical pathology, and Professor Richard Logan, senior consultant of oral pathology, for the preparation of histopathology sections, images provided and expertise in interpretation. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians. All authors declare that they have no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.