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Histopathological examination of a skin biopsy. (A) Normal epidermis and appendages in healthy control samples (H&E staining). (B) Hyperkeratosis, acanthosis and irregular stratum basale, few sweat glands, hair follicles and sebaceous glands in the CIPA patient's samples (H&E staining). (C, D) NSE immunoreactivity stains of control and CIPA patient's sections. Arrow indicates the area with positive staining. (Immunohistochemical staining, Bar = 100 mm) doi:10.1371/journal.pone.0066863.g003
Source publication
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare inherited disorder of the peripheral nervous system resulting from mutations in neurotrophic tyrosine kinase receptor 1 gene (NTRK1), which encodes the high-affinity nerve growth factor receptor TRKA. Here, we investigated the oral and craniofacial manifestations of a Chinese patient...
Contexts in source publication
Context 1
... skin biopsy revealed an aberrant hyperplastic epidermis, including hyperkeratosis, acanthosis and an irregular stratum basale. H&E stains showed a reduction in the number of sweat glands, hair follicles, blood vessels and sebaceous glands (Figure 3- A, B). NSE immunoreactivities are usually associated with both sensory and autonomic nerves of the skin, such as free nerve endings in the epidermis and dermis, sensory corpuscles, Merkel cells and sweat glands [11]. ...
Context 2
... immunoreactivities are usually associated with both sensory and autonomic nerves of the skin, such as free nerve endings in the epidermis and dermis, sensory corpuscles, Merkel cells and sweat glands [11]. NSE immunohistochemistry showed that the density of NSE immunoreactivity stains was significantly decreased in the patient's skin when compared to healthy skin ( Figure 3-C, D). ...
Citations
... The autoextraction of teeth or self-tooth extraction found in our patients has frequently been reported in other patients with congenital insensitivity to pain [40,[45][46][47][48][49][50][51][52][53][54][55][56]. Self-tooth pulling in patients with congenital insensitivity to pain is a behavior that has yet to be fully explained. ...
... Acro-osteolysis leading to amputation of digits is common in patients with congenital insensitivity to pain [15,40,44,45,[49][50][51]. Acro-osteolysis has been reported to be associated with a number of genetic syndromes, including NOTCH2-associated Hajdu-Cheney syndrome (MIM 600275), CTSK-associated Pycnodysostosis (MIM 601105), CTSCassociated Haim-Munk syndrome (MIM 245010), IFIH1-associated Singleton-Merten syndrome 1 (MIM 182250), COL3A1-associated Ehlers-Danlos syndrome, vascular type (MIM 130050), PDGFRB-associated premature aging syndrome, Penttinen type (MIM 601812), DST-associated hereditary sensory and autonomic neuropathy, type VI (HSAN6; MIM 614653) [92], and WNK1-associated hereditary sensory and autonomic neuropathy, type II (MIM 201300) (https://omim.org: 8 January 2024). ...
Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the molecular etiology of congenital insensitivity to pain in two Thai patients. Clinical, radiographic, histopathologic, immunohistochemical, and molecular studies were performed. Patients were found to have congenital insensitivity to pain, self-mutilation, acro-osteolysis, cornea scars, reduced temperature sensation, tooth agenesis, root maldevelopment, and underdeveloped maxilla and mandible. The skin biopsies revealed fewer axons, decreased vimentin expression, and absent neurofilament expression, indicating lack of dermal nerves. Whole exome and Sanger sequencing identified a rare homozygous variant c.4039C>T; p.Arg1347Cys in the plakin domain of PLEC, a cytolinker protein. This p.Arg1347Cys variant is in the spectrin repeat 9 region of the plakin domain, a region not previously found to harbor pathogenic missense variants in other plectinopathies. The substitution with a cysteine is expected to decrease the stability of the spectrin repeat 9 unit of the plakin domain. Whole mount in situ hybridization and an immunohistochemical study suggested that PLEC is important for the development of maxilla and mandible, cornea, and distal phalanges. Additionally, the presence of dental anomalies in these patients further supports the potential involvement of PLEC in tooth development. This is the first report showing the association between the PLEC variant and congenital insensitivity to pain in humans.
... Frequent falls and trauma result in unnoticed fractures, poorly healing ulcers, joint deformities, septic arthritis and osteomyelitis. Less common presentations are recurrent corneal ulcers, avascular necrosis, heterotopic ossification and precocious loss of deciduous teeth [4][5][6]. Death before the age of 3 years owing to hyperpyrexia has been reported in up to 20% of cases [7]. ...
... The patient's profile aligns well with the classic presentation of CIPA, demonstrating self-inflicted injuries, developmental delays, and a history of recurrent fever episodes. Finger and nail biting is a common manifestation [14]. The oral findings of CIPA patients usually include an increased incidence of traumatic injuries. ...
Hereditary sensory and autonomic neuropathy type 4 (HSAN4), or congenital insensitivity to pain with anhidrosis (CIPA), is a rare autosomal recessive disorder caused by mutations in the NTRK1 gene, resulting in pain insensitivity, anhidrosis, and temperature dysregulation. This report focuses on oral manifestations in an 11-year-old girl with CIPA, highlighting the need for early intervention and comprehensive care. The patient had a history of recurrent oral injuries and an unexplained fever, with a confirmed HSAN4 diagnosis through genetic analysis. Clinical features included pain insensitivity, anhidrosis, and intellectual disability. Dental history revealed emergency care, suboptimal oral hygiene, early tooth loss, and infections. Extra-oral examination showed nail-biting and injuries, while intra-oral assessment revealed ulcers and scars. Radiographic evaluation indicated mandibular alveolar bone thinning and periapical lesions in the lower incisors. This case emphasizes the complex challenges of CIPA, including pain insensitivity, recurring fever episodes, and self-inflicted injuries. Early diagnosis and specific dental care are vital to prevent orofacial trauma, necessitating a proactive interdisciplinary approach for comprehensive care.
... A s a rare condition, only a few hundred cases of CIPA have been reported world-wide. 6,7 Here we present a case of a patient with typical clinical manifestations of Congenital Insensitivity to Pain with Anhidrosis (CIPA), ...
Background:
Congenital insensitivity to pain with anhidrosis (CIPA) with Charcot arthropathy is a rare combination in orthopaedic clinical practice. The experience dealing with such patients is limited. Here with this case of approximately 10 years follow-up, we wish to shed light on the choices of strategies of surgeries and alerting clinicians with post-surgery complications. The possible underlying reasons for the recurrent Charcot arthropathies as well as strategies for peri-operative management for such surgical cases are also discussed.
Case presentation:
The patient underwent a surgery to correct her severe kyphosis caused by CIPA-related Charcot spine. Multiple post-surgery complications occurred during her follow-up, including hardware migration, adjacent segment disease (ASD), and loosening pedicle screws. Five revision surgeries were conducted consequently. From the limited experience on the management of CIPA-related Charcot spine, surgical correction is still the first-line treatment.
Conclusions:
Of all the 16 cases reviewed (including our case), loosening pedicle screws, hardware migration, and ASDs are the common post-surgery complications. Large-scale removal of damaged vertebrae and subsequent reconstruction are not recommended, which might increase the risk of hardware migration. A 360° long-segment fusion might be of help to reduce the risk of ASDs. In the meantime, comprehensive management including careful nursing, proper rehabilitation exercises, and treatments targeting bone mineral metabolism is also critical.
... These findings are in agreement with observations of neurodevelopmental disorders in human patients bearing CDK13 mutation (Trinh et al., 2019). Connection between insufficient growth of craniofacial nerves leading to development of various craniofacial clefts has been already described (Rizos et al., 1998, Gao et al., 2013. Based on this evidence, we hypothesize that Cdk13-deficiency in mouse embryos could also lead to altered growth of craniofacial nerves which could lead to development of severe facial clefts which we observed in both hypomorph and knockout embryos (Nováková et al., 2019). ...
... On the contrary, based on other studies, Möbius syndrome is suggested to be caused by developmental defects of the entire rhombencephalon rather than just underdevelopment of craniofacial nerves (Verzijl et al., 2003). Another disorder of peripheral nervous system which leads to cleft palate and other facial defects, is known as hereditary sensory and autonomic neuropathy type IV (HSAN IV) (Gao et al., 2013). This disorder is associated with mutation in NTRK1, a gene encoding tyrosine kinase receptor (TRKA) for nerve growth factor (NGF) which is important also for craniofacial development (Louryan et al., 1995) and its mutation led to reduced neurite growth in vitro (Nakajima et al., 2020). ...
Congenital heart defects, facial dysmorphism and intellectual development disorder (CHDFIDD) is associated with mutations in CDK13 gene which encodes a transcription regulating Cyclin-dependent kinase 13 (CDK13). Here we analyzed early embryonic stages of CHDFIDD mouse models with hypomorphic mutation in Cdk13 gene with very similar phenotypic manifestations plus cleft lip/palate and knockout of Cdk13 which exhibits robust phenotype with midfacial cleft. Cdk13 is strongly expressed in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme. In vitro, CDK13 protein is located not only in nuclear region but also in the cellular protrusions in cultured mesenchymal cells and cells isolated from dorsal root ganglia. In Cdk13-deficient embryos, we found hypoplastic branches of the trigeminal nerve including maxillary branch and additionally we detected significant gene expression changes of molecules involved in neurogenesis (Mef2c, Pou4f1, Sod1, Cdk5rap2, Nrcam) within the developing palatal shelves. Key palate-associated molecules (Msx1 and Meis2) were downregulated during early craniofacial development in mutant embryos. These results demonstrate the role of CDK13 in regulation of facial morphogenesis and also growth of craniofacial peripheral nerves.
... Trka is implicated in cell migration in normal and pathological conditions (Wislet et al., 2018); and it is necessary for the formation of the dorsal root and sympathetic ganglia by the trunk NCC in mouse (Smeyne et al., 1994). In humans, mutations in the Trka gene produce congenital insensitivity to pain (CIP) with anhidrosis (CIPA), a neurocristopathy that results in a total loss of the C-fibres, lack of nociception, inability to sweat (hypotrophic sweat glands), lack of hair (bald patches in the scalp), poor thermoregulation, and oral and craniofacial manifestation including missing teeth and nasal malformations (Indo, 2009;Gao et al., 2013). Furthermore, CIPA patients seem to be unable to learn new fears and probably fail to exhibit a fight-or-flight response (Indo, 2009). ...
The Naked mole-rat (NMR) is becoming a prominent model organism due to its peculiar traits, such as eusociality, extreme longevity, cancer resistance, and reduced pain sensitivity. It belongs to the African mole-rats (AMR), a family of subterranean rodents that includes solitary, cooperative breeding and eusocial species. We identified and quantified the domestication syndrome (DS) across AMR, a set of morphological and behavioural traits significantly more common and pronounced amongst domesticated animals than in their wild counterparts. Surprisingly, the NMR shows apparent DS traits when compared to the solitary AMR. Animals can self-domesticate when a reduction of the fear response is naturally selected, such as in islands with no predators, or to improve the group’s harmony in cooperative breeding species. The DS may be caused by alterations in the physiology of the neural crest cells (NCC), a transient population of cells that generate a full range of tissues during development. The NCC contribute to organs responsible for transmitting the fear response and various other tissues, including craniofacial bones. Therefore, mutations affecting the NCC can manifest as behavioural and morphological alterations in many structures across the body, as seen in neurocristopathies. We observed that all social AMRs are chisel-tooth diggers, an adaption to hard soils that requires the flattening of the skull. We hypothesise that chisel-tooth digging could impose a selective pressure on the NCC that triggered the DS’s appearance, possibly facilitating the evolution of sociality. Finally, we discuss how DS traits are neutral or beneficial for the subterranean niche, strategies to test this hypothesis and report well-studied mutations in the NMR that are associated with the NCC physiology or with the control of the fear response. In conclusion, we argue that many of the NMR’s unconventional traits are compatible with the DS and provide a hypothesis about its origins. Our model proposes a novel avenue to enhance the understanding of the extraordinary biology of the NMR.
... In 1983, the first case of CIPA was reported in the Han population in China (Lin et al. 2010). CIPA patients have been reported in China for decades but are extremely rare (Gao et al. 2013;Geng et al. 2018;Wang et al. 2017). We previously recruited 41 patients with CIPA between January 2013 and February 2018 through hospital records, social networking platforms, and news reports ). ...
Background
Increasing evidence has shown that the occurrence and development of various human diseases are closely related to the gut microbiota. We compared the gut microbial communities of human subjects with congenital insensitivity to pain with anhidrosis (CIPA) and healthy controls (HCs) to assess whether fecal microbiota transplantation (FMT) into germ-free mice and mice in acute pain influenced the behaviors of the host.
Methods
We utilized 16 s rRNA analysis to compare the gut microbial communities of CIPA subjects and HCs and assessed whether FMT into germ-free mice and mice in acute pain influenced the behaviors of the host.
Results
In a 16 s RNA analysis, the CIPA group had significant decreases in the relative abundance of 11 bacteria, whereas 7 bacteria were significantly increased. In further animal experiments, the transplantation of fecal samples from CIPA patients to healthy mice significantly increased their scores on both the mechanical withdrawal test and the tail flick test; in an acute plantar incision model, scores were also significantly increased on the mechanical withdrawal test at 4 and 5 days after the operation. Moreover, pseudo-germ-free mice receiving fecal bacteria from patients with CIPA took significantly longer to escape and had a significantly longer path length on training days 1, 2, and 5 and also had fewer platform crossings and spent less time in the target quadrant in the probe trial.
Conclusions
Our results suggest that the gut microbiota in CIPA subjects plays a key role in behaviors. Therapeutic strategies for improving the gut microbiota might alleviate CIPA symptoms.
... Siragusa et al., 2013;Suhaib et al., 2017). Quando observada a população mais frequentemente acometida por automutilação oral, o grupo "crianças" apareceu em 21 estudos (AlSadhan & Al-Jobair, 2017b; Ashwin et al., 2015;Brissaud et al., 2016;El Khatib et al., 2013;Fantuzzo et al., 2014;Gao et al., 2013;Gaur et al., 2018;Gisbert de la Cuadra et al., 2016b;Kwon et al., 2015;Labib et al., 2011;L. N. Mistry et al., 2017;Mowafy et al., 2017a;Navya et al., 2019;Olczak-Kowalczyk et al., 2011;Romero Maroto et al., 2014;Siragusa et al., 2013;Soussou et al., 2019;Suhaib et al., 2017;Wadenya et al., 2011;Williams, 2015), enquanto que os "adolescentes", em 11 estudos (Ashwin et al., 2015;Carra et al., 2013;Elhennawy et al., 2017;Gantha et al., 2017;Gisbert de la Cuadra et al., 2016b;Herrera & Pollock, 2014;Olczak-Kowalczyk et al., 2011;Panek et al., 2012;Rangeeth et al., 2011;Siragusa et al., 2013;Topouzelis et al., 2010). ...
... Transtorno psiquiátrico (Herrera, Pollock, 2014); Transtorno do Espectro Autista -TEA (Suhaib et al., 2017;El Khatib et al., 2013;Gao et al., 2013). ...
... Insensibilidade congênita à dor (Navya et al. 2019;Soussou et al., 2019;Elhennawy et al., 2017;Ashwin et al., 2015;Gaur et al., 2018;Gao et al., 2013;Labib et al., 2011); Síndrome de Prader-Willi -PWS (Olczak-Kowalczyk et al., 2011); Sindrome de Lesch-Nyhan la Cuadra et al., 2016;Romero Maroto et al., 2014); Síndrome de Kabuki (Wadenya et al., 2011); Síndrome de Joubert Plus (Mowafy, Wahba, Sharaf, 2017). ...
Introdução: O comportamento autolesivo é definido como um ato dirigido a si mesmo que resulta em um dano tecidual. As estruturas orais podem ser traumatizadas por esse tipo de comportamento e sua incidência vem aumentando entre as crianças. Objetivo: Apresentar os fatores associados à automutilação oral em crianças e adolescentes, atentando para o diagnóstico diferencial das lesões orais. Metodologia: Foi realizada uma revisão integrativa da literatura a partir de pesquisa nas bases de dados Medline (PubMed), entre 2010 e 2020. Foram selecionados 27 artigos, sendo 5 caso-controle, 1 transversal e 21 relatos de caso. Resultados: Os estudos avaliados foram desenvolvidos em diversos países, em hospitais, ambulatórios, institutos, universidades, escolas e orfanato. Nos estudos observacionais as amostras variaram entre 30 e 303 participantes. A automutilação oral foi relacionada aos fatores sociais, hereditários, neurológicos e psiquiátricos. Observou-se também o envolvimento de indivíduos sem comorbidades em casos de automutilação oral. Nesses estudos houve mais crianças que adolescentes envolvidos em quadros de automutilação oral. Conclusão: Fatores hereditários, neurológicos, psiquiátricos e sociais são apontados como fatores associados aos quadros de automutilação oral em crianças e adolescentes. Entretanto, a literatura ainda é escassa em padronização de protocolo para diagnóstico de automutilação oral, assim outros estudos são necessários para determinação de quais fatores podem ser pertinentes a esses casos quando envolvem crianças e adolescentes.
... Microneurography is suggestive of abnormal activity of somatic A-delta and C fibers in the dermal nerves. [9] Proposed therapeutic interventions include counseling parents and school authorities about the risk of severe self-mutilation and the importance of protected environment, especially temperature. Early management of malignant hyperthermia and hypothermia, orthopedic, dental, and ophthalmic problems are essential. ...
Hereditary sensory and autonomic neuropathy is a rare syndrome characterized by congenital insensitivity to pain, temperature changes, and an autonomic nerve formation disorder. We report an 8-year-old boy who presented with late-onset of self-mutilating behavior, insensitivity to pain, temperature, and anhidrosis with compensatory hyperhidrosis. Exome sequencing revealed a mutation of the SCN9A gene at chromosome 2 with nucleotide change c. G554A/p. Arg185His at exon 5 along with HSPB1 mutation at chromosome 5.
... Regarding the Oro-dental findings, missing teeth was the most commonly seen in our study, followed by the self-inflicted soft tissue injuries. Missing teeth is a frequent finding in CIPA patients (10)(11)(12)(13)(14)(15)(16)(17) . The teeth are usually lost either by auto extraction or by prophylactic extraction in order to avoid further trauma. ...
