Clinical features for diagnosis and management of patients with PRDM12 congenital insensitivity to pain

Zhang, Stella; Sharif, Saghira Malik; Chen, Ya-Chun; Valente, Enza Maria; Ahmed, Mushtaq; Sheridan, Eamonn; Bennett, Christopher; Woods, Geoffrey

doi:10.1136/jmedgenet-2015-103646

Cited by 37 publications

(40 citation statements)

References 16 publications

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“…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 ].…”

Section: Discussionsupporting

confidence: 76%

“…[ 68 ] III N/A USA/ Caucasian CR 1 31 y M Insensitivity to pain, blotching of skin, diminished lacrimation Orofacial mutilation (including auto-extraction of teeth), diminished taste sensation 2016 Zhang et al . [ 30 ] VIII PRDM12 N/A CS 5 23–57 y 4 M 1 F Insensitivity to pain, normal neurological examinations and intellect, corneal abrasions, lack of tear production, recurrent infections, unexplained self-mutilation Unexplained orofacial mutilation Review articles 2015 Haga et al . [ 5 ] IV, V NTRK1, NGFB Japan/ N/A RA N/A N/A N/A Repeated fractures, joint dislocations, arthritis, osteomyelitis, avascular necrosis, Charcot arthropathy Oral self-mutilation (including auto-extraction of teeth) 2014 Kumar et al .…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2017

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BackgroundHereditary 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 presentationWe 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.ConclusionsThe 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.

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“…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 ].…”

Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…SCN9A inactivating mutations should be searched in patients with anosmia, normal intelligence and normal or mildly abnormal large sensory nerve fiber function. In patients with normal intelligence showing a pattern of pain insensitivity restricted to the limbs rather than diffuse and no anosmia, mutations in PRDM12 should be considered . CIP patients with normal intelligence, hyperhidrosis, gastrointestinal dysfunction and mild muscular weakness, without anosmia, neuropathy, or cardiovascular dysautonomia could harbor SCN11A mutations .…”

Section: Discussionmentioning

confidence: 99%

A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia

Marchi

Provitera

Nolano

et al. 2018

J Peripheral Nervous Sys

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Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder presenting with a spectrum of clinical features caused by mutations in different genes. A 10-year-old girl with CIP, hyposmia and hypogeusia, and her unaffected twin and parents underwent next generation sequencing of SCN9A exons and flanking splice sites. Transcript analysis from whole blood successfully assayed the effect of the mutation on the mRNA splicing by polymerase chain reaction amplification on cDNA and Sanger sequencing. We identified the novel splicing variant c.1108-2A>G compound with the p.Arg896Gln (c.2687G>A) missense mutation previously described in a homozygous patient. The new intronic variant was predicted to induce exon 10 skipping. Conversely, SCN9A mRNA assay demonstrated its partial deletion with a loss of 46 nucleotides causing a premature stop codon in position p.Gln369 (NP_002968). Genetic analysis showed that the two variants were biallelic, being the mother and brother heterozygous carriers of the missense mutation, and the father heterozygous for the splicing mutation. Skin biopsy showed lack of Meissner's corpuscles, loss of epidermal nociceptors and normal autonomic organ innervation. We report a novel splicing mutation and provide clues on its pathogenic effect, broadening the spectrum of genotypes and phenotypes associated to CIP.

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“…More recently, additional mutations have been identified to cause CIP (Nahorski et al, 2015), including those of the transcription factor PRDM12 (PRDI-BF1-RIZ homologous domain-containing family) (Chen et al, 2015). As in other forms of CIP, patients with Prdm12-associated CIP are unable to feel pain due to noxious chemical, thermal, or mechanical stimuli, but retain normal touch, proprioception, and tickle sensations (Chen et al, 2015;Saini et al, 2017;Zhang et al, 2016). Therefore, Prdm12 or its downstream effectors may serve as potential novel analgesic targets similar to drugs that have been developed targeting other genes underlying CIP, NGF and Nav1.7 (Hoffman et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Loss ofPrdm12during development, but not in mature nociceptors, causes defects in pain sensation

Landy

Goyal

Casey

et al. 2020

Preprint

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Prdm12 is as a key transcription factor in nociceptor neurogenesis. Mutations of Prdm12 cause Congenital Insensitivity to Pain (CIP) due to failure of nociceptor development. However, precisely how deletion of Prdm12 during development or adulthood affects nociception is unknown. Here, we employ tissue- and temporal-specific knockout mouse models to test the function of Prdm12 during development and in adulthood. We find that constitutive loss of Prdm12 causes deficiencies in proliferation during sensory neurogenesis. We also demonstrate that conditional knockout from dorsal root ganglia (DRGs) during embryogenesis causes defects in nociception. In contrast, we find that in adult DRGs, Prdm12 is dispensable for pain sensation and injury-induced hypersensitivity. Using transcriptomic analysis, we found unique changes in adult Prdm12 knockout DRGs compared to embryonic knockout, and that PRDM12 is likely a transcriptional activator in the adult. Overall, we find that the function of PRDM12 changes over developmental time.

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Clinical features for diagnosis and management of patients with PRDM12 congenital insensitivity to pain

Cited by 37 publications

References 16 publications

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

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

A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia

Loss ofPrdm12during development, but not in mature nociceptors, causes defects in pain sensation

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