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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
Journal of Medical Case Reportsvolume 11, Article number: 233 (2017)
Hereditary sensory and autonomic neuropathy type VIII is a rare autosomal recessive inherited disorder. Chen et al. recently identified the causative gene and characterized biallelic mutations in the PR domain-containing protein 12 gene, which plays a role in the development of pain-sensing nerve cells. Our patient’s family was included in Chen and colleagues’ study. We performed a literature review of the PubMed library (January 1985 to December 2016) on hereditary sensory and autonomic neuropathy type I to VIII genetic disorders and their orofacial manifestations. This case report is the first to describe the oral manifestations, and their treatment, of the recently discovered hereditary sensory and autonomic neuropathy type VIII in the medical and dental literature.
We report on the oral manifestations and dental management of an 8-month-old white boy with hereditary sensory and autonomic neuropathy-VIII over a period of 16 years. Our patient was homozygous for a mutation of PR domain-containing protein 12 gene and was characterized by insensitivity to pain and thermal stimuli, self-mutilation behavior, reduced sweat and tear production, absence of corneal reflexes, and multiple skin and bone infections. Oral manifestations included premature loss of teeth, associated with dental traumata and self-mutilation, severe soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary teeth, and mandibular osteomyelitis.
The lack of scientific knowledge on hereditary sensory and autonomic neuropathy due to the rarity of the disease often results in a delay in diagnosis, which is of substantial importance for the prevention of many complications and symptoms. Interdisciplinary work of specialized medical and dental teams and development of a standardized treatment protocols are essential for the management of the disease. There are many knowledge gaps concerning the management of patients with hereditary sensory and autonomic neuropathy-VIII, therefore more research on an international basis is needed.
Hereditary sensory and autonomic neuropathy (HSAN) comprises a group of genetic disorders involving sensory and autonomic dysfunctions . HSAN was classified into five main types . Later, it was modified into subtypes [3,4,5] according to gene mutations, mode of inheritance, and clinical characteristics. HSAN types VI and VII were mentioned in the classification of Haga et al. : Online Mendelian Inheritance in Man (OMIM) 614653 and 615548 respectively. HSAN type VIII (OMIM 616488) was recently characterized by Chen et al.  as a rare autosomal recessive disorder. Our patient’s family was included in their study. General characteristics, mode of inheritance, onset, and genes involved in each type of HSAN are presented in Table 1.
HSAN-VIII is characterized by five main features: insensitivity to pain and thermal stimuli, self-mutilation behavior, altered sweat and tear formation, absence of corneal reflexes, and presence of repeated infections of the skin and bone . The syndrome was confirmed in 21 patients  and 10 different homozygous mutations in the PR domain-containing protein 12 gene (PRDM12) were identified . Mutations in the PRDM12 gene in humans cause developmental defects in the sensory neurons, leading to loss of pain perception. Great loss of the small myelinated Aδ fibers occurred in patients with HSAN-VIII. Skin biopsies revealed that the peripheral terminals of unmyelinated C fibers were altered .
Patients carrying PRDM12 mutations lack the sensation of acute pain and temperature. Thus, these patients have numerous injuries, which may lead to recurrent infections of skin and bones, and bone deformities later in life. In addition, they lack corneal reflexes, which leads to progressive corneal scarring. However, other senses like light touch, vibration, and proprioception are normal. The only autonomic dysfunction observed was the reduction in sweating and tears formation. Intellectual abilities in patients with HSAN-VIII are normal .
Insensitivity to pain leads to severe oral mutilations, such as tooth luxation, severe dental attrition, premature tooth loss, bite wounds, and ulcerations [7,8,9]. The tongue, followed by the lips, and the oral mucosa, are the most common sites of self-inflicted injuries [10, 11]. The diagnosis of HSAN is challenging due to its rarity, similarity in clinical presentation to other auto-aggression or self-mutilation diseases, and lack of simple diagnostic tests . It is mainly confirmed by the clinical presentation, genetic analysis, pharmacological tests, and neuropathological examinations . Management of patients affected by HSAN-VIII is complicated due to the patients’ lack of awareness and perception of pain.
We aimed to present the manifestations and dental management of a patient with HSAN-VIII harboring the homozygous mutation c.516G>C (p. Glu172Asp) in the PRDM12 gene , who has been followed up in our clinic for 16 years. A review on PubMed library (January 1985 to December 2016) on patients with HSAN with oral manifestations was performed (Table 2).
An 8-month-old white boy of Turkish origin initially presented to the Department of Pedodontics, at Charité – Universitätsmedizin Berlin Hospital, due to an unexplained early loss of his primary lower central incisors. He was the first child of healthy consanguineous parents (second-degree relatives); their younger daughter was healthy. Our patient had multiple injuries on his face and body and in his oral cavity due to self-mutilation (Fig. 1). Further medical history revealed that he was born with a bilateral foot deformity (Fig. 2), which resulted in the mandatory use of an orthopedic appliance, enabling him to walk normally (Fig. 3). At the age of 6 years and 2 months, he had a fracture in the metatarsal bone, leading to bone necrosis. This resulted in the placement of bone plates and the use of a wheelchair for long walking distances. He had several accidents, such as severe burns from boiling water without feeling any pain.
Prior to the first visit to the Department of Pedodontics at the age of 8 months, he had lost both mandibular primary central incisors for unknown reasons only 3 months after they erupted. His mandibular left lateral incisor was loose (mobility, grade 2). In addition, his mandibular left primary second molar (75) showed signs of enamel hypoplasia. He experienced no pain or discomfort during the dental procedures. A year later, he presented at our department due to the further loss of ten of his primary teeth (Fig. 4). The early loss of so many teeth raised suspicion of a systemic disorder. He was referred to the Department of Human Genetics at Charité – Universitätsmedizin Berlin. The following differential diagnoses of auto-aggression syndromes were suspected: congenital insensitivity to pain and anhidrosis (CIPA), Smith–Magenis syndrome, Lesch–Nyhan syndrome, or pantothenate kinase-associated neurodegeneration (PKAN). In addition, the following systemic diseases, which might cause premature loss of teeth, were suspected: Langerhans cell histiocytosis, hypophosphatasia, and Papillon–Lefèvre syndrome. The diagnosis of CIPA syndrome was thought to be closest to his condition. All other suspected auto-aggression syndromes and systemic diseases were excluded based on blood tests, genetic diagnosis, and further clinical examination. However, after deeper investigations, the diagnosis HSAN-VIII was considered the definitive diagnosis of our patient.
Partial dentures for maxilla and mandible were constructed to prevent speech impairment and to enhance his lower facial height (Fig. 5). Due to his high caries activity, an intensive prophylaxis program with continuous follow-up was implemented to avoid further dental deterioration and improve his oral health status. Over the years, with the help of an interdisciplinary medical team and his parents, he has shown great cooperation and completely ceased any sort of self-mutilation behavior.
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 . Our patient harbored a homozygous mutation in the recently discovered gene PRDM12 . 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 . 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 , but a causative 17p.11.2 microdeletion was excluded by fluorescence in situ hybridization. As for Lesch–Nyhan syndrome, patients have dystonia and ballism , 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 [16,17,18,19]. Blood tests excluded the systemic diseases of Langerhans cell histiocytosis and hypophosphatasia . Hypophosphatasia was also excluded because of our patient’s normal total serum alkaline phosphatase activity [21,22,23]. Papillon–Lefèvre syndrome was not confirmed due to the absence of the diffuse palmoplantar hyperkeratosis and the progressive periodontitis . 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 . 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 . The dental treatment planning can be affected by several factors, such as age, mental development, and patient’s and parents’ compliance . 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 . Cognitive behavioral models for self-management and distress regulation have been proposed .
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.  also reported on the clinical characteristics of five patients with HSAN-VIII and was in line with Chen et al. . The clinical characteristics described by Zhang et al.  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 . 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].
HSAN-VIII is a rare, complex, recently identified condition mainly characterized by insensitivity to pain and thermal stimuli. The affected persons are vulnerable to various complications and in severe cases, self-mutilation can lead to death. Early identification of the disease is important to prevent all these consequences. The literature contains mainly case reports and case series of patients with HSAN, therefore, there are many knowledge gaps concerning preventive and therapeutic approaches. Treatment efficacy depends on educating the family and supporting the child psychologically. Moreover, an interdisciplinary treatment approach, in which there is medical and dental interdisciplinary cooperation, is required for such patients. A homozygous mutation of the PRDM12 gene, which is responsible for the HSAN-VIII condition, was identified in our patient. Mutations in this gene cause developmental defects in sensory neurons before their transition to nociceptors.
Congenital insensitivity to pain and anhidrosis
Hereditary sensory and autonomic neuropathy type VIII
Nerve growth factor
Online Mendelian Inheritance in Man
- NTRK1 :
Neurotrophic tyrosine kinase-1 receptor
Pantothenate kinase-associated neurodegeneration
- PRDM12 :
PR domain-containing protein 12 gene
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