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CASE REPORT
Year : 2020  |  Volume : 38  |  Issue : 3  |  Page : 315-318
 

Hereditary sensory autonomic neuropathy Type VIII: A rare clinical presentation, genomics, diagnosis, and management in an infant


1 Associate Professor of Pedodontia, Department of Pedodontics & Preventive Dentistry, Government Dental College & Hospital, Hyderabad, Telangana State, India
2 Pediatric Dentist, Toothbuddies, Hyderabad, Telangana State, India
3 Professor & HOD, Department of Pedodontics & Preventive Dentistry, Government Dental College & Hospital, Hyderabad, Telangana State, India

Date of Submission15-Oct-2019
Date of Decision21-Feb-2020
Date of Acceptance16-Aug-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Dr. Shaik Hasanuddin
Associate Professor of Pedodontia, Department of Pedodontics & Preventive Dentistry, Room No. 301, 2nd Floor, Government Dental College & Hospital, Hyderabad,T.S., Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JISPPD.JISPPD_310_19

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   Abstract 


A 7-month-old female child born to nonconsanguineous parents with a history of global developmental delay, since early infancy had reported to the department with facial features of mild dysmorphism. History of finger sucking and finger biting was evident, as there was a massive scab tissue over the dorsal aspect of the index finger, above the finger nail bed. A huge ulcer was evident on the right side of the dorsal aspect of anterior two-thirds of the tongue. Genetic evaluation through targeted gene sequencing confirmed the diagnosis as hereditary sensory, autonomic neuropathy Type VIII (Online Mendelian Inheritance in Man – 616488). A homozygous missense variation in exon 3 of PRDM12 was detected. A multidisciplinary approach was planned for the management of the child. A soft splint on the maxilla was fabricated and stabilized with an adhesive. However, the final diagnosis was confirmed by a DNA genomic sequencing test, namely a multigene panel testing or comprehensive genomic sequencing.


Keywords: DNA mutational analysis, hereditary sensory autonomic neuropathies, pain insensitivity, self-mutilation


How to cite this article:
Hasanuddin S, Moghe G, Reddy J S. Hereditary sensory autonomic neuropathy Type VIII: A rare clinical presentation, genomics, diagnosis, and management in an infant. J Indian Soc Pedod Prev Dent 2020;38:315-8

How to cite this URL:
Hasanuddin S, Moghe G, Reddy J S. Hereditary sensory autonomic neuropathy Type VIII: A rare clinical presentation, genomics, diagnosis, and management in an infant. J Indian Soc Pedod Prev Dent [serial online] 2020 [cited 2020 Oct 24];38:315-8. Available from: https://www.jisppd.com/text.asp?2020/38/3/315/296632





   Introduction Top


Pain is detected by a complex system of mechanical and chemical sensors called nociceptors, which send required information through spinal interneuronal pathways to the brain. However, in few congenital genetic anomalies, components of the pain signaling pathways may be impaired or fail to develop.[1] Hereditary sensory autonomic neuropathy (HSAN) or congenital insensitivity to pain (CIP) is one such condition, where individuals are unable to perceive pain since birth. Individuals with CIP do not feel pain from any noxious stimuli, including inflammation and heat.[2] Due to the overlapping clinical signs and symptoms with different pathogenic variants of the genes causing HSAN, diagnosis of the condition becomes difficult and requires the assistance of various genetic tests. Published data on the prevalence of HSAN are unclear till date.

The present case report is about a very rare “missense variation” of the PRDM12 gene with clinical symptoms of huge ulcerations on the dorsum of the tongue due to self-mutilating behavior in a 7-month-old female child. The aim of this case report is to describe the clinical characteristics of HSAN Type VIII, to provide an evaluation strategy, to identify the genetic cause, and consider management options to prevent oral injuries in HSAN cases.


   Case Report Top


A 7-month-old female child born to nonconsanguineous parents with a history of global developmental delay noted since early infancy had reported to the department. Prenatal history of oligohydramnios (in 9 months) and low birthweight was revealed by the parents. On general examination, the child was conscious, irritable, restless, and spontaneously crying with jerking neck movements. Generalized hypotonia and poor eye-to-eye contact were evident with brisk reflexes. Informed consent was obtained from the child's parents in their local language.

Facial features included a prominent occiput, bilateral down slanted eyes, bilateral low set ears, occasional squint, and short nose indicating mild dysmorphism. Intraorally, a huge ulcer on the dorsal aspect of anterior two-thirds of the tongue extending from the tip and anterior border till the midline was present. The ulcer measured 14 mm × 10 mm approximately at the center [Figure 1]. The parents/caretakers of the child had given a history of tongue-biting with the newly-erupted maxillary lateral incisors. History of finger sucking and finger biting was evident, as there was a massive scab tissue over the dorsal aspect of the index finger, above the fingernail bed [Figure 2]. There was a positive history of self-mutilation by the child, which was mild initially and later became aggressive on resistance by the caretakers.
Figure 1: A huge ulceration on the dorsal surface of tongue caused by self-mutilating behavior in a child

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Figure 2: A massive scab on the index finger due to self-injurious finger biting habit

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A multidisciplinary approach was planned for the management of the child, which focused basically on the prevention of further self-inflicted injuries on the other parts of the face, eye, and body. The child was referred to a pediatric strabismus specialist and occuloplastic surgeon to evaluate lazy eye and corneal ailments. A soft splint on the maxilla was fabricated and denture adhesive was used for stability [Figure 3]. However, extraction became inevitable after a few days. During the 8 months, the eruption of the lower incisors caused ulceration on the ventral surface of the tongue. Hence, the extraction of the teeth was performed immediately. The parents were counseled regarding other issues related to injury prevention.
Figure 3: A soft palatal splint stabilized through a denture adhesive

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Laboratory investigations revealed normal uric acid levels, reduced sensory and motor nerve conduction velocity in both upper and lower limbs. The child was provisionally diagnosed with CIP without Anhidrosis.

Mutational analysis

On genetic evaluation, the DNA test confirmed the diagnosis of the condition as HSAN Type VIII, through targeted gene sequencing. A homozygous missense variation in exon 3 of PRDM12 that results in the amino acid substitution of cysteine for argentine at codon 168 (p. Arg168Cys) was detected. This variant has never been reported in the 1000 genomes and internal databases of the Indian population. It has a minor allele frequency of 0.0008% in the ExAC database. Hence, this rare anomaly is essential to be reported in the literature. However, validation of the variants by Sanger sequencing is recommended to rule out false positives.


   Discussion Top


There are no consensual clinical diagnostic criteria for HSAN. Diagnosis requires a visible proof of lack of nociception in a conscious individual of normal intellectual ability, which cannot be expected from an infant or a young child, as in the present case. HSAN, as a pathological entity, has been classified by Dyck and Ohta[3] into five Types (I, II, III, IV, and V). However, a newer variant involving the PRDM12 gene has been recently diagnosed and categorized as HSAN Type VIII. Chen et al.[4] recently identified the causative gene and characterized biallelic mutations in the PRDM12 gene, which plays a role in the development of pain-sensing nerve cells. 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.[4] PRDM proteins are a family of epigenetic regulators that control neural specifications and neurogenesis. PRDM12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Mutations in the PRDM12 gene cause developmental defects in sensory neurons prior to their transition to nociceptors. HSAN results in either non-functional nociceptors or failure of nociceptor neurodevelopment. The basic defect in all cases of PRDM12 hAN is the homozygous mutations, missense or expansion of the C-terminal of PRDM12 polyalanine tract, which is proved to be pathogenic.[5] In the present case, both the parents did not have any related signs and symptoms of a similar genetic disease. The variant might be a result of a sporadic mutation at the affected loci. As the PRDM gene plays a role in the orchestration of sensory neurogenesis, a clear insensitivity to pain is evident in the present case.

Individuals with PRDM12 mutations could experience nonglobal pain insensitivity. However they can feel a completely normal range of emotions, including painful emotions. They have normal intellect and show positive neurological responses, including fine and deep touch, pressure, vibration, sensation of itch, and tickle.[5] Genetically, two common forms of HSAN or CIP are identified. The first genetic form is caused due to loss-of-function mutation in the SCN9A gene, which renders nociceptors to respond to any noxious stimulus, and the second genetic form is caused due to loss-of-function mutation in the NTRK1 gene, which leads to a failure of nociceptors to develop.[6],[7] A new form of HSAN or CIP has been described in the present case report, caused by mutations in exon 3 of an epigenetic regulator PRDM12. However, in a recent case report, mutations in the exon 5 of the PRDM12 gene with similar signs and symptoms was reported.[8] Thus, all mutations involving PRDM12 can be considered as HSAN Type VIII.

The differential diagnosis of HSAN Type VIII includes similar hereditary conditions or auto aggression syndromes of congenital pain insensitivity and anhidrosis such as hereditary ectodermal dysplasia, Smith-Magenis syndrome, Lesch-Nyhan Syndrome, and familial dysautonomia (HSAN Type III) [Table 1]. As the genes causing these conditions are distinct, a targeted gene sequencing, as done in the present case report is helpful in the final diagnosis of similar diseases. Although all these clinical entities have similar kinds of signs and symptoms with marginal variations, they cannot be relied upon for a confirmative diagnosis and treatment planning. In slightly older children, acquired diseases such as leprosy or nonaccidental injuries due to child abuse might show similar clinical characteristics.
Table 1: Differential diagnosis of HSAN Type VIII basing on the genetic diagnosis

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HSAN or CIP often presents with unexplained oral injuries and burns, bruises, fractures, and joint injuries.[5] The phenotype of all variants of CIP involves individuals who are unable to sense acute pain or chronic pain. Due to their inability to sense pain, a large number of unusual self-inflicted injuries are generally evident. Loss of tongue tip due to auto amputation, injuries to their lips, tongue, gums and inside of the cheeks are certain common oral injuries present in these children,[5] similar to the phenotype of HSAN Type VIII, as in the present case.

Treatment is supportive and symptomatic as no consensus regarding treatment or surveillance guidelines has been developed till date. Oral symptoms in all cases of CIP are evident with the eruption of primary teeth, post 6 months of birth. According to Bodner et al., tooth extraction or filing or smoothening of sharp incisal edges are recommended in all cases of CIP.[9] In older children, the use of mouthguards was suggested to avoid self-inflicted oral injuries.[10] Hence, a soft splint stabilized with a denture adhesive was used temporarily to prevent oral injuries in the present case. In developed countries, children under 0–3 years affected with global development delay or intellectual disability, as observed in Clathrin Heavy Chain Like 1 (CTCL1), Nerve Growth Factor (NGF), Neurotrophic-Tyrosine Receptor Kinase 1 - Congenital Insensitivity to Pain (NTRK-CIP) are referred to as an early intervention program for access to occupational, physical, speech and feeding therapy. For corneal abrasions, annual ophthalmic evaluations are recommended. Artificial tears should be prescribed for HSAN Type VIII, as in the present case. Good hand hygiene and care, use of antiseptic soaps, and early use of topical antibiotics is recommended to prevent staphylococcal infections in older individuals.

Conclusion

HSAN Type VIII, a very rare variant of PDRM12 gene can always be diagnosed clinically, by the presence of nonglobal pain insensitivity, absence of anhidrosis, self-inflicted injurious behaviors, frequent tongue and oral ulcerations, absence of corneal reflex, impaired tear production, susceptibility to Staphylococcus aureus infections, etc,. However, the final diagnosis has to be confirmed by a DNA test such as a targeted gene sequencing or multigene panel testing or comprehensive genomic sequencing. A new form of HSAN, Type VIII has been described in the present case report, caused by mutations in the exon 3 of an epigenetic regulator PRDM12. Mutations in this gene cause developmental defects in sensory neurons before their transition to nociceptors.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

We are thankful to the patient's family members for allowing us to use their medical and genetic records for the benefit of others. We would like to acknowledge the work done by Med Genome Laboratories, Bangalore, India, for their support in delivering the DNA test report for the case subject.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Bennett DL, Woods CG. Painful and painless channelopathies. Lancet Neurol 2014;13:587-99.  Back to cited text no. 1
    
2.
Goldberg YP, MacFarlane J, MacDonald ML, Thompson J, Dube MP, Mattice M, et al. Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet 2007;71:311-9.  Back to cited text no. 2
    
3.
Dyck PJ, Ohta M. Neural atrophy and degeneration predominantly affecting peripheral sensory neurons. In: Dyck PJ, Thomas PK, Lambert EH, editors. Peripheral Neuropathy. Vol. 2. Toronto: WB Saunders Co.; 1975. p. 791-812.  Back to cited text no. 3
    
4.
Chen YC, Auer-Grumbach M, Matsukawa S, Zitzelsberger M, Themistocleous AC, Strom TM, et al. Transcriptional regulator PRDM12 is essential for human pain perception. Nat Genet 2015;47:803-8.  Back to cited text no. 4
    
5.
Zhang S, Malik Sharif S, Chen YC, Valente EM, Ahmed M, Sheridan E, et al. Clinical features for diagnosis and management of patients with PRDM12 congenital insensitivity to pain. J Med Genet 2016;53:533-5.  Back to cited text no. 5
    
6.
Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006;444:894-8.  Back to cited text no. 6
    
7.
Indo Y. Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy Type IV. Clinical, biological and molecular aspects of mutations in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clin Auton Res 2002;12 Suppl 1:I20-32.  Back to cited text no. 7
    
8.
Navya MK, Pramod GV, Sujatha GP, Ashok L. Congenital insensitivity to pain in a 1-year-old boy. J Indian Soc Pedod Prev Dent 2019;37:308-10.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Bodner L, Woldenberg Y, Pinsk V, Levy J. Orofacial manifestations of congenital insensitivity to pain with anhidrosis: A report of 24 cases. ASDC J Dent Child 2002;69:293-6.  Back to cited text no. 9
    
10.
Hutton A, McKaig S. The dental management of a child with congenital insensitivity to pain. Dent Update 2010;37:180-2, 185.  Back to cited text no. 10
    


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