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.

BACKGROUND: 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. CASE PRESENTATION: 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. CONCLUSIONS: 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.

Identification of a novel nonsense mutation of the neurotrophic tyrosine kinase receptor type 1 gene in two siblings with congenital insensitivity to pain with anhidrosis.

Objective To explore the aetiology of congenital insensitivity to pain with anhidrosis (CIPA) in two Chinese siblings with typical CIPA symptoms including insensitivity to pain, inability to sweat, and self-mutilating behaviours. Methods Clinical examination and genetic testing were conducted of all available family members, and the findings were used to create a pedigree. Mutation screening using PCR amplification and DNA Sanger sequencing of the entire neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1) including intron-exon boundaries was used to identify mutations associated with CIPA. Results A novel nonsense mutation (c.7C > T, p. Arg3Ter) and a known splice-site mutation (c.851-33 T > A) were detected in NTRK1 and shown to be associated with CIPA. Conclusion Our findings expand the known mutation spectrum of NTRK1 and provide insights into the aetiology of CIPA.

A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family.

BACKGROUND: Autosomal-recessive non-syndromic intellectual disability (ARNS-ID) is an aetiologically heterogeneous disorder. Although little is known about the function of human cereblon (CRBN), its relationship to mild cognitive deficits suggests that it is involved in the basic processes of human memory and learning. OBJECTIVES: We aim to identify the genetic cause of intellectual disability and self-mutilation in a consanguineous Saudi family with five affected members. METHODS: Clinical whole-exome sequencing was performed on the proband patient, and Sanger sequencing was done to validate and confirm segregation in other family members. RESULTS: A missense variant (c. 1171T>C) in the CRBN gene was identified in five individuals with severe intellectual disability (ID) in a consanguineous Saudi family. The homozygous variant was co-segregating in the family with the phenotype of severe ID, seizures and self-mutilating behaviour. The missense mutation (p.C391R) reported here results in the replacement of a conserved cysteine residue by an arginine in the CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide) domain of CRBN, which contains a zinc-binding site. CONCLUSIONS: These findings thus contribute to a growing list of ID disorders caused by CRBN mutations, broaden the spectrum of phenotypes attributable to ARNS-ID and provide new insight into genotype-phenotype correlations between CRBN mutations and the aetiology of ARNS-ID.

TWO CASES WITH DIFFERENT EPILEPSY TYPE AND DYSMORPHIC FEATURES ASSOCIATED WITH 17q21.31 MICRODELETION SYNDROME.

The 17q21.31 microdeletion syndrome is characterized by intellectual disability, epilepsy, facial dysmorphism and friendly behavior. Recently, KANSLJ gene has been considered as a major causal gene for this phenotype. Here we report on two Turkish patients with different seizure types and additional dysmorphic features associated with 17q21.31 microdeletion syndrome. A 4 year-old female patient with generalized tonic-clonic seizures, mild mental retardation, dysmorphic features and friendly behavior and a 14 years-old female with intractable epilepsy, different dysmorphic features, severe mental and motor retardation and self-mutilation were evaluated by array-based comparative genomic hybridization (microarray CGH). Array CGH identified 17q21.31 microdeletion that contains MAP7 CRHR1, KANSLI, PLEKHMI genes in case I and CRHR1, PLEKHM but not KANSLJgenes in case 2. To the best of our knowledge this is the first report of a patient with the 17q21.31 microdeletion which does not encompass KANSLI gene. These data imply another gene or genes causing similar phenotype in this patient.

Hereditary sensory and autosomal peripheral neuropathy-type IV: case series and review of literature.

Hereditary sensory and autonomic neuropathy (HSAN) IV is a rare autosomal recessive disorder which is characterized by a decrease in the number of myelinated and non-myelinated nerve fibers of peripheral nerves which causes diminished or absent pain sensation leading to increase in self-mutilative habits. A retrospective study of eight cases ranging from age group of 4 to 17 years for oral and digital signs and symptoms is presented. All the patients showed congenital insensitivity to pain and anhidrosis. Oral self-mutilations, such as autoextraction of teeth and severe bite injuries (with resultant scarring) of the finger tips and oral soft tissues (tongue, lip, and buccal mucosa) were found in most patients. Our study suggests that early diagnosis and specific treatment plan are important for prevention of characteristic of the oral as well as digital trauma associated with this disorder.

Temperamental and genetic predictors of suicide attempt and self-mutilation.

BACKGROUND AND AIMS: Literature findings mainly support the notion that suicide attempts (SA) and self-mutilating behavior (SMB) are distinct behaviors, although they may share common psychopathological features. In the present paper we aimed to identify behavioral phenotypes in patients with SA, SMB, or both (SAM) and to analyze the association with candidate genes. METHODS: One hundred forty-two inpatients with a history of SA (n = 86), SMB (n = 22), and SAM (n = 39) were included in this study. Subjects were evaluated using the Tridimensional Personality Questionnaire (TPQ) and the Buss-Durkee Hostility Inventory (BDHI). Polymorphisms within serotonin transporter (SLC6A4, HTTLPR), catechol-O-methyl transferase (COMT, Val158Met), and tryptophan hydroxylase (TPH, 218C>A) were also analyzed. RESULTS: Principal component factor analysis including the BDHI and TPQ produced 3 factors that could classify the 3 groups of patients with good sensitivity. However, only the 'pure suicidal' factor had a sufficient positive predictive value. This factor was characterized by high levels of persistence (PS) and, to a lower extent, reward dependence. The distribution of genotypes was not different across patient groups for all polymorphisms, but the SS genotype of HTTLPR was significantly associated with the 'self-mutilation' factor, characterized by high levels of hostile traits, novelty seeking, and harm avoidance. CONCLUSION: The results of the present study suggest that different and overlapping temperamental traits in suicidal and self-mutilating patients are present, although only high levels of PS could predict SA repetition. Finally, HTTLPR may mediate the risk for SMB through modulation of some temperamental traits.

Acral mutilation syndrome in a miniature pinscher.

Acral mutilation syndrome (AMS) is a rare canine hereditary sensory neuropathy that results in progressive mutilation of the distal extremities and which has been reported only in German short-haired pointers, English pointers, English springer spaniels and French spaniels. The present report describes a case of AMS in an 18-month-old female miniature pinscher with progressive self-mutilation of the hind feet. The dog did not respond to any treatment and was humanely destroyed at the age of 30 months. Microscopical findings post mortem were restricted to the nervous system and were compatible with AMS. This is the first case of AMS described in a miniature pinscher. It is not known if the disease was the result of a point mutation in this particular dog or if the miniature pinscher breed will evolve to become a breed predisposed to AMS.

Smith-Magenis syndrome in Puerto Rico: a case report.

Smith-Magenis syndrome (SMS) is characterized by deletions in the short arm of chromosome 17. Systemic findings in patients with the syndrome include: dysmorphic facies and skeletal deformities. Ophthalmic findings in patients with the SMS include: strabismus, refractive errors, microcornea, iris anomalies, microphthalmos, and coloboma. A 14-year-old boy with cytogenetic studies confirming the SMS underwent a comprehensive ophthalmologic examination. The patient has a history of strabismus surgery. Clinical findings in this patient include: developmental delay, facial dysmorphism, enamel hypoplasia, short broad hands, clinodactyly, and scoliosis. Ocular findings in our patient include: myopia, iris nodules, loose zonules, and ectopia lentis. To our knowledge this is the first reported case of SMS in the Caribbean basin and the first case that report ectopia lentis in SMS. There is a possibility that lens subluxation in our patient is due to self inflicted trauma.

Autotomy behavior correlates with the DRG and spinal expression of sodium channels in inbred mouse strains.

Patients who have suffered nerve injury show profound inter-individual variability in neuropathic pain even when the precipitating injury is nearly identical. Variability in pain behavior is also observed across inbred strains of mice where it has been attributed to genetic polymorphisms. Identification of cellular correlates of pain variability across strains can advance the understanding of underlying pain mechanisms. Voltage-gated sodium channels (VGSCs) play a major role in the generation and propagation of action potentials in the primary afferents and are therefore of obvious importance for pain phenotype. Here, we examined the mRNA expression levels of the VGSC alpha-subunits Na(v)1.3, Na(v)1.5, Na(v)1.6, and Na(v)1.7, as well as the auxiliary VGSC-related molecule, Contactin. Dorsal root ganglia (DRG) and spinal cords from 5 inbred mouse strains with contrasting pain phenotype (AKR/J, C3H/HeJ, C57BL/6J, C58/J and CBA/J) were analyzed 7 days following sciatic and saphenous nerve transection. In the DRG, Na(v)1.6, Na(v)1.7 and Contactin were abundantly expressed in control animals. Following nerve injury, the residual mRNA levels of Na(v)1.6 (downregulated in two of the strains) correlated tightly to the extent of autotomy behavior. A suggestive correlation was also seen for the post-injury mRNA levels of Contactin (downregulated in all strains) with autotomy. Thus, our results suggest a contribution by DRG Na(v)1.6, and possibly Contactin to neuropathic pain in the neuroma model in mice.

A novel 6.14 Mb duplication of chromosome 8p21 in a patient with autism and self mutilation.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with a strong genetic etiology. Cytogenetic abnormalities have been detected in 5-10% of the patients with autism. In this study, we present the clinical, cytogenetic and array-comparative genomic hybridization (array-CGH) evaluation of a 13-year-old male with severe developmental delay, facial dysmorphic features, autism and self mutilation. The patient was found to carry a de novo duplication of chromosome region 8p21 of minimally 6.14 and maximally 6.58 Mb as ascertained by bacterial artificial chromosome (BAC)-based array-CGH. Hitherto, only a few patients with autism with cytogenetically visible duplications involving the chromosome 8p21 region have been described, but the extent of these duplications has not been determined at the molecular level. This represents the smallest rearrangement of chromosomal region 8p21 as yet found in a patient with autism. For 11 of the 36 genes with known functions located within this duplication clear transcription in the brain was found. Of those the STMN4 and DPYSL2 genes are the most likely candidate genes to be involved in neuronal development, and, if altered in gene-dosage, in the autistic phenotype of our patient.

Sex-specific variability and a 'cage effect' independently mask a neuropathic pain quantitative trait locus detected in a whole genome scan.

Sex and environment may dramatically affect genetic studies, and thus should be carefully considered. Beginning with two inbred mouse strains with contrasting phenotype in the neuroma model of neuropathic pain (autotomy), we established a backcross population on which we conducted a genome-wide scan. The backcross population was partially maintained in small social groups and partially in isolation. The genome scan detected one previously reported quantitative trait locus (QTL) on chromosome 15 (pain1), but no additional QTLs were found. Interestingly, group caging introduced phenotypic noise large enough to completely mask the genetic effect of the chromosome 15 QTL. The reason appears to be that group-caging animals from the low-autotomy strain together with animals from the high-autotomy strain dramatically increases autotomy in the otherwise low-autotomy mice (males or females). The converse, suppression of pain behaviour in the high-autotomy strain when caged with the low-autotomy strain was also observed, but only in females. Even in isolated mice, the genetic effect of the chromosome 15 QTL was significant only in females. To determine why, we evaluated autotomy levels of females in 12 different inbred stains of mice and compared them to previously reported levels for males. Strikingly larger environmental variation was observed in males than in females for this pain phenotype. The high baseline variance in males can explain the difficulty in detecting the genetic effect, which was readily seen in females. Our study emphasizes the importance of sex and environment in the genetic analysis of pain.

Genetic, developmental and personality correlates of self-mutilation in depressed patients.

OBJECTIVE: To examine whether the T allele of G protein beta3 (GNbeta3) is associated with self-mutilation in depressed patients. METHOD: A history of self-mutilation was systematically inquired about when recruiting depressed patients for a long-term treatment trial. Risk factors such as borderline personality disorder and childhood abuse experiences were systematically assessed, and patients were genotyped for polymorphisms of GNbeta3. RESULTS: The T allele of GNbeta3, borderline personality disorder and childhood sexual abuse were all significantly associated with self-mutilation in depressed patients. These associations were significant in both univariate and multivariate analyses, and as predicted were stronger in young depressed patients than in depressed patients of all ages. CONCLUSIONS: If the association between the T allele of GNbeta3 and self-mutilation can be replicated, this may provide clues to understanding the neurobiology of self-mutilation.

Hereditary sensory autonomic neuropathy Type IV.

Hereditary sensory autonomic neuropathy Type IV is an autosomal recessive disorder due to lack of maturation of small myelinated and unmyelinated fibers of peripheral nerves, which convey sensation of pain and temperature, therefore, resulting in self mutilation. There is anhidrosis due to lack of innervation of normal sweat glands resulting in recurrent episodes of hyperpyrexia. The clinical presentation of two children with this rare disease is described.

Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review.

Hereditary sensory neuropathies (HSNs) are rare disorders characterized by progressive distal sensory loss, predominantly affecting the lower limbs. Foot ulcers, severe skin and bone infections, arthropathy, and amputations are frequent and feared complications. Occasionally, patients complain of spontaneous shooting or lancinating pain. Autonomic fibers can be affected to a variable degree. Patients with HSN can also have severe distal weakness, and some HSN variants have therefore been classified among the hereditary motor and sensory neuropathies (HMSNs). Molecular genetic studies of autosomal dominant inherited neuropathies with prominent sensory loss and ulceromutilating features have assigned the genetic loci for HMSN type 2B (Charcot-Marie-Tooth syndrome type 2B) and HSN type 1 to chromosomes 3q13-22 and 9q22.1-22.3, respectively. However, some families with HSN have been excluded for linkage to these loci, suggesting further genetic heterogeneity. Recently, disease-causing mutations in the SPTLC1 gene have been identified in patients with HSN type 1. In this review, we discuss the hallmark features associated with the distinct genetic subtypes of autosomal dominant inherited HSN and provide genotype-phenotype correlations.

Hyperexcitability in sensory neurons of rats selected for high versus low neuropathic pain phenotype.

Selection line rats congenitally high or low for autotomy in the neuroma model of neuropathic pain (HA and LA rats) were found to be correspondingly high and low in a second type of neuropathic pain, the Chung model, which employs an alternative phenotypic endpoint, tactile allodynia. It has been proposed that both phenotypes reflect ectopic hyperexcitability in axotomized primary sensory neurons. To test this hypothesis we made in vitro recordings from sensory neurons in the L4 and 5 dorsal root ganglia. Baseline excitability was similar in HA and LA rats, and axotomy caused an increase in both lines. However, in the one neuronal subclass previously linked to neuropathic pain in these models the increase was significantly greater in HA than LA rats, and only at the time when pain scores in the two lines were diverging. Heritable differences in electrical response to axotomy in a specific afferent cell type appear to be a fundamental determinant of neuropathic pain.

Differential sensory-motor effects of pentobarbital in intact rats genetically selected for high vs. low neuropathic pain-related behaviour.

Denervation of the hindpaw in rodents triggers autotomy, a behaviour of licking, scratching and self-mutilation of the denervated paw. This behaviour has been used as a model of paraesthesia, dysaesthesia and neuropathic pain. HA and LA rats are lines that have been genetically selected for high or low levels of autotomy, respectively. Compared to intact LA rats, HA rats are more sensitive to convulsions induced by pentylenetetrazol (PTZ), a blocker of the chloride channel associated with the GABA(A) receptor. Here we tested whether an acute administration of a sedative but not anaesthetic dose of pentobarbital (PB) would differentiate between these rat lines, in a number of sensory and motor tests performed in intact rats. This drug was tested since in contrast to PTZ, PB enhances central nervous system (CNS) inhibition by increasing chloride flux through the same channel. We found that PB was significantly more ataxic, antinociceptive, and reduced touch sensitivity in LA rats, compared to HA rats. These results suggest that HA and LA rats genetically differ in the levels of central inhibitions mediated by the GABA system presumably at the chloride channel. This difference may be associated with the dichotomous expression of neuropathic pain in these rat lines.

Carbamazepine trial for Lesch-Nyhan self-mutilation.

Anticonvulsants may reduce the self-mutilation of acquired sensory neuropathy, and one report described sensory neuropathy in an older patient with Lesch-Nyhan syndrome. We performed nerve and muscle biopsies on four patients with Lesch-Nyhan syndrome and initiated an uncontrolled pilot trial to see if carbamazepine would reduce the self-mutilation in these patients. All of the boys had clinical features typical of Lesch-Nyhan syndrome, and the diagnosis was confirmed in each by enzyme analysis. No specific abnormalities were identified in either nerve or muscle. Nevertheless, self-mutilation and the need for constant restraint diminished in all four patients, though in one the effect was only transient. Two patients had increased self-mutilation when carbamazepine was stopped, then improved a second time when treatment was restarted. Sensory neuropathy was not confirmed, so any effect of carbamazepine is likely to be on the central nervous system.