Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature

The pediatric dentist was the first to refer our patient to the human genetics department with the suspicion of HSAN syndrome, based on the premature loss of primary teeth and self-mutilation behavior. The initial diagnosis of our patient of CIPA or HSAN-IV was not confirmed by molecular analysis, since it did not detect a mutation in the neurotrophic tyrosine kinase-1 receptor gene (NTRK1), which is the receptor for nerve growth factor (NGF) related to CIPA syndrome [12]. Our patient harbored a homozygous mutation in the recently discovered gene PRDM12 [6]. Therefore, HSAN-VIII was his final diagnosis. Deoxyribonucleic acid (DNA) sequencing of the parents confirmed the segregation of the mutation in the family. The mode of inheritance was autosomal recessive [6]. Self-mutilation behavior is one of the most outstanding characteristics of HSAN syndrome. However, it is also common in other auto-aggression diseases, which makes the diagnosis challenging. Smith–Magenis syndrome was a differential diagnosis concerning the self-inflicted injuries [14], but a causative 17p.11.2 microdeletion was excluded by fluorescence in situ hybridization. As for Lesch–Nyhan syndrome, patients have dystonia and ballism [15], which were not symptoms of our patient. Further analysis did not reveal defects in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme, confirming the false diagnosis. PKAN is also characterized by dystonia and therefore was ruled out [16‐19]. Blood tests excluded the systemic diseases of Langerhans cell histiocytosis and hypophosphatasia [20]. Hypophosphatasia was also excluded because of our patient’s normal total serum alkaline phosphatase activity [21‐23]. Papillon–Lefèvre syndrome was not confirmed due to the absence of the diffuse palmoplantar hyperkeratosis and the progressive periodontitis [24]. Oral manifestations of HSAN are important, since they are one of the first complaints presented by affected patients. They can be detected early in life, starting with the eruption of the primary dentition [25]. Because of the variability and rarity of the clinical presentation of HSAN, no standard dental management protocols have been established. Patients with HSAN should be treated individually [26]. The dental treatment planning can be affected by several factors, such as age, mental development, and patient’s and parents’ compliance [27]. In the 1960s, the treatment approach for patients with HSAN was extraction of all primary teeth and construction of dentures in order to prevent self-mutilation. Nowadays, there are many dental treatment options for the prevention of self-mutilating behavior, varying from the elimination of sharp tooth surfaces by grinding or restoring them with resin composite, to the use of intraoral appliances such as mouthguards. Since the self-mutilation behavior of patients with HSAN-VIII starts in infancy, it may prove difficult to use intraoral appliances at that point. However, tooth extractions should be considered the last line of treatment. Early loss of teeth is one of the most frequent dental complications of HSAN. It is important to be able to deal with its consequences, such as speech impairment and increased incidence of malocclusions [25, 26, 28]. Professional dental cleaning, behavioral management, and routine check-up appointments were the cornerstones of our treatment plan. Prevention of dental disease is required in patients with HSAN, since caries progression and pulpal involvement can occur without causing any pain or discomfort. The parents of patients with HSAN play a crucial role in the management of the condition, since their psychological support is necessary to help the child understand his or her condition and prevent further injuries [27, 28]. The most critical phase of managing patients with HSAN would be building an understanding of the emotional experience of pain. A psychological approach should be introduced as early as possible [27]. Cognitive behavioral models for self-management and distress regulation have been proposed [29].

The literature search revealed that HSAN-IV (CIPA) is the most discussed form of HSAN in dentistry. Self-mutilation and auto-aggression are the first and most common clinical characteristics in all mentioned HSAN types (Table 2). The literature review results mainly consisted of case reports and case series, which is understandable due to the rarity of the syndrome. In contrast to our case report, a long follow-up period was not reported in the majority of publications. Our case report is, to the best of our knowledge, the first to discuss the oral manifestations and management of HSAN-VIII. Zhang et al. [30] also reported on the clinical characteristics of five patients with HSAN-VIII and was in line with Chen et al. [6]. The clinical characteristics described by Zhang et al. [30] that were found in all patients were: insensitivity to pain, normal neurological examinations and intellect, corneal abrasions, lack of tear production, recurrent infections, and unexplained oral self-mutilation (especially tongue injuries). There is a need for further dental and medical management solutions for these patients, as well as for well-educated practitioners [29]. There are many obstacles that have to be overcome since often there is a lack of resources for research and international collaboration and for accessible database and diagnostic and treatment tools. By expanding our knowledge on genetic and epigenetic factors that are critical for pain sensation, new fields are opened for therapeutic intervention in chronic and neuropathic pain conditions [6, 31, 32].