[Progress in the diagnosis and treatment of Congenital insensitivity to pain with anhidrosis].

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disease which mainly affects infants, children and adolescents. As an autosomal recessive disorder, CIPA is also known as familial autonomic dysfunction type 2. The diagnosis of CIPA mainly relies on clinical observation and genetic testing. Currently there is lack of effective treatment, and it is mainly treated by cooling, anti-inflammatory and strengthened guardianization. This article has reviewed the literature and summarized the research on CIPA and progress made in its diagnosis and treatment, with an aim to improve the understanding of this disorder.

Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain.

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.

A rare case of congenital insensitivity to pain with anhidrosis.

A 22-month-old girl of consanguineous parents was admitted with a high-grade fever. She was found to have insensitivity to painful stimuli and an absence of perspiration. She also displayed self-mutilating behaviour and was insensitive to cold/hot water on her body. On examination, there was loss of the tip of the tongue, missing teeth, generalised xerosis, and several ulcers at sites of minor trauma. She also had dysplastic nails and digital ulcers. Sensory examination demonstrated a complete lack of awareness of pain and temperature, vibration and fine touch were intact and lacrimation was normal. Differential diagnoses of hereditary sensory and autonomic neuropathy (HSAN), Lesch-Nyhan syndrome, hypohidrotic ectodermal dysplasia and leprosy were considered. Results of routine blood investigations including serum uric acid were normal. On performing clinical exome sequencing, the diagnosis of congenital insensitivity to pain with anhidrosis (CIPA) of autosomal recessive inheritance was confirmed. A novel, predicted to be pathogenic variant detected at exon 16 of the NTRK1 gene resulting in congenital insensitivity to pain with anhidrosis is reported.Abbreviations: CIPA: congenital Insensitivity to pain with anhidrosis; HSAN: hereditary sensory and autonomic neuropathy; NGF: nerve growth factor; NTRK1: neurotrophic tyrosine kinase receptor 1 gene; TrKA: tropomyosin receptor kinase A.

Clinical and genetic characteristics of three patients with congenital insensitivity to pain with anhidrosis: Case reports and a review of the literature.

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self-mutilating behavior, and intellectual disability. METHODS: Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing. RESULTS: CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3-8 years). Two patients exhibited self-mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851-33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574-156_850+1113del (exons 5-7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851-33T>A (p.?) mutations and compound heterozygous for c.851-33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574-156_850+1113del (exons 5-7 del) displayed a late onset and milder clinical manifestation. CONCLUSION: All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.

Bilateral Total Knee Arthroplasties in a Patient with Bilateral Below-Knee Amputations and Osseointegration Limb Replacements: A Case Report.

CASE: A 38-year-old man with congenital pain insensitivity underwent bilateral below-knee amputations. After his subsequent bilateral osseointegration (OI) limb replacements, he rapidly developed severe bilateral knee arthritis and varus deformity. In lieu of performing bilateral above-knee amputations, he underwent bilateral staged total knee arthroplasties (TKA) with excellent clinical and radiographic evaluation at 1-year follow-up. CONCLUSION: To address both the limited bone stock and OI implant stem location, TKA after OI limb replacement in congenital pain insensitivity patients can be successfully achieved with a nonkeeled cementless tibial component and augmentation with a tibial cone.

Transient binocular vision loss and pain insensitivity in Klippel-Feil syndrome: a case report.

BACKGROUND: Klippel-Feil syndrome is a rare congenital bone disorder characterized by an abnormal fusion of two or more cervical spine vertebrae. Individuals with Klippel-Feil syndrome exhibit diverse clinical manifestations, including skeletal irregularities, visual and hearing impairments, orofacial anomalies, and anomalies in various internal organs, such as the heart, kidneys, genitourinary system, and nervous system. CASE PRESENTATION: This case report describes a 12-year-old Pashtun female patient who presented with acute bilateral visual loss. The patient had Klippel-Feil syndrome, with the typical clinical triad symptoms of Klippel-Feil syndrome, along with Sprengel's deformity. She also exhibited generalized hypoalgesia, which had previously resulted in widespread burn-related injuries. Upon examination, bilateral optic disc swelling was observed, but intracranial pressure was found to be normal. Extensive investigations yielded normal results, except for hypocalcemia and low vitamin D levels, while parathyroid function remained within the normal range. Visual acuity improved following 2 months of calcium and vitamin D supplementation, suggesting that the visual loss and optic nerve swelling were attributed to hypocalcemia. Given the normal parathyroid function, it is possible that hypocalcemia resulted from low vitamin D levels, which can occur after severe burn scarring. Furthermore, the patient received a provisional diagnosis of congenital insensitivity to pain on the basis of the detailed medical history and the findings of severe and widespread loss of the ability to perceive painful stimuli, as well as impaired temperature sensation. However, due to limitations in genetic testing, confirmation of the congenital insensitivity to pain diagnosis could not be obtained. CONCLUSION: This case highlights a rare presentation of transient binocular vision loss and pain insensitivity in a patient with Klippel-Feil syndrome, emphasizing the importance of considering unusual associations in symptom interpretation.

Phenotypes of a toddler with hereditary sensory and autonomic neuropathy type IV: comparing with normal: A case report.

RATIONALE: Hereditary sensory and autonomic neuropathy type IV (HSAN IV) may be misdiagnosed because of low awareness among clinical professionals and overlap with other subtypes of congenital insensitivity to pain (CIP). PATIENT: The patient was a 1-year-and-5-months-old boy whose main symptoms were delayed psychomotor development and recurrent fever. Whole-exome sequencing (WES) revealed a compound heterozygous mutation (c. 1927C > T, c. 851-33T > A) in the NTRK1 gene of the child. Pathological analysis showed decreased autonomic small nerve fibers, sparse hair follicles, and atrophy of the sweat glands. Sweat glands lack innervating nerve fibers. Brain magnetic resonance imaging (MRI) of the patient showed delayed myelination in the brain, slightly enlarged bilateral lateral ventricles, and patchy abnormal signals in the brain. DIAGNOSIS: hereditary sensory and autonomic neuropathy type IV (HSAN IV). INTERVENTION: Inform parents about the illness and take good care of the child. OUTCOMES: The children had less self-harming behavior and no painless fractures during follow-up at 2 years. LESSONS: This report describes the pathological and imaging features and clinical manifestations of a child with HSAN IV in early life to provide a reference for the early diagnosis of the disease. Early diagnosis can help avoid self-mutilation and painless injury and reduce wound infection.

A novel mutation in the SCN9A gene associated with congenital insensitivity to pain, anhidrosis, and mild cognitive impairment.

Congenital insensitivity to pain (CIP) is a rare phenotype characterized by the inability to perceive pain stimuli with subsequent self-injuries, whereas CIP associated with anhidrosis (CIPA) is an overlapping phenotype mainly characterized by insensitivity to noxious stimuli and anhidrosis. CIP is primarily associated with pathogenetic variants in the SCN9A gene while CIPA is associated with pathogenetic variants in NGF and NRTK genes. However, in recent years, a significant overlap between these two disorders has been observed highlighting the presence of anhidrosis in SCN9A variants. We report the cases of two siblings (age 4 and 6 years) born from consanguineous parents presenting with a previously undescribed phenotype due to a novel pathogenic variant in SCN9A clinically characterized by congenital insensitivity to pain, anhidrosis, and mild cognitive impairment.

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.

Novel SCN9A variant associated with congenital insensitivity to pain.

BACKGROUND: Congenital insensitivity to pain (CIP) is a rare autosomal recessive syndrome characterized by lack of pain perception and a wide spectrum of clinical signs such as anosmia and hyposmia. Variants in SCN9A gene are associated with CIP. We here report on a Lebanese family with three CIP patients referred for genetic investigations. METHODS AND RESULTS: Whole exome sequencing analysis revealed the presence of a novel nonsense, homozygous SCN9A pathogenic variant: SCN9A (NM_001365536.1): c.4633G > T, p.(Glu1545*) in exon 26. CONCLUSION: Our three Lebanese patients had CIP, urinary incontinence and normal olfactory function while two of them also presented with osteoporosis and osteoarthritis; this association of features has not been previously reported in the literature. We hope that this report would contribute to a better delineation of the phenotypic spectrum associated with SCN9A pathogenic variants.

Identification of founder and novel mutations that cause congenital insensitivity to pain (CIP) in palestinian patients.

BACKGROUND: Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder characterized primarily by an inability to perceive physical pain from birth, resulting in the accumulation of bruising, inflammation, and fractures that affect patient's life expectancy. CIP has different forms including CIP and CIPA. CIP with Anhidrosis (CIPA) is the most common type of CIP, which is caused mainly by mutations in NTRK1 and NGF genes, and is characterized by mental retardation and the inability to sweat (Anhidrosis). Because of high consanguinity rates in Palestine, this rare disease appears to have a higher frequency than in other communities. However, there were no systematic studies to address the genetic factors that cause CIP in the Palestinian community. METHODS: In our study, we used Sanger and Whole exome sequencing to genotype members of five CIP-affected Palestinian families. RESULTS: Our results confirm the presence of the founder c.1860-1861insT mutation in the NTRK1 gene of Palestinian Bedouin CIPA patients. Furthermore, one CIPA family carried a missense c.2170 G > A (G724 S) mutation in exon 16 of the NTRK1 gene. Finally, a novel nonsense c.901 A > T mutation (K301*) was detected in exon 7 of the SCN9A gene in CIP without anhidrosis family. CONCLUSIONS: Our study revealed three mutations that cause CIP and CIPA in the Palestinian community, which can help in improving the process of diagnosis and genetic counseling and establishing protocols for the diagnosis and follow-up for the affected individuals. This is especially important given that early diagnosis and medical care interference can prevent unpleasant CIP and CIPA complications.

SCN9A variant in a family of mixed breed dogs with congenital insensitivity to pain.

BACKGROUND: Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSANs) are a rare group of genetic disorders causing inability to feel pain. Three different associated variants have been identified in dogs: 1 in Border Collies, 1 in mixed breed dogs, and 1 in Spaniels and Pointers. OBJECTIVES: To clinically and genetically characterize CIP in a family of mixed breed dogs. ANIMALS: Two mixed breed dogs from the same litter were independently presented: 1 for evaluation of painless fractures, and the other for chronic thermal skin injuries. METHODS: Physical, neurological, and histopathological evaluations were performed. Whole genome sequencing of 1 affected dog was used to identify homozygous protein-changing variants that were not present in 926 control genomes from diverse dog breeds. RESULTS: Physical and neurological examinations showed the absence of superficial and deep pain perception in the entire body. Histopathological evaluations of the brain, spinal cord and sensory ganglia were normal. Whole genome sequencing identified a homozygous missense variant in SCN9A, XM_038584713.1:c.2761C>T or XP_038440641.1:(p.Arg921Cys). Both affected dogs were homozygous for the mutant allele, which was not detected in 926 dogs of different breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: We confirmed the diagnosis of CIP in a family of mixed breed dogs and identified a likely pathogenic variant in the SCN9A gene. The clinical signs observed in these dogs mimic those reported in humans with pathogenic SCN9A variants causing CIP. This report is the first of a spontaneous pathogenic SCN9A variant in domestic animals.

Ocular manifestations among patients with congenital insensitivity to pain due to variants in PRDM12 and SCN9A genes.

Congenital insensitivity to pain (CIP) is a group of rare genetic disorders with a common characteristic of absent sensation to nociceptive pain. Here we present a series of six patients; three had a novel variant in the PRDM12 gene (group A), and three had a missense variant in the SCN9A gene (group B). We compared the ocular manifestations between the two groups. Records of these patients from 2009 through 2018 were reviewed. The retrieved data included demographics, genetic analysis results, ocular history and ophthalmic findings including visual acuity, corneal sensitivity, tear production, ocular surface findings, cycloplegic refraction, and fundoscopy. We found that patients with PRDM12 variant had more severe manifestations of ocular surface disease, with more prevalent corneal opacities and worse visual acuity, compared to patients with SCN9A variant.

Destructive Spondyloarthropathy due to Congenital Insensitivity to Pain with Anhidrosis: A Case Report of Long-Term Follow-Up.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal-recessive hereditary neuropathy causing congenital loss of pain sensation, thermoception, and perspiration. CIPA sometimes causes destructive spondyloarthropathy, the so-called Charcot spine, because of insensitivity to pain stimuli. Herein, we report a case of CIPA with severe spinal destruction treated by multiple spinal reconstructive surgeries and over 15 years of follow-up. A 15-year-old male patient who had been diagnosed with CIPA at the age of 17 months presented to his previous spine clinic with gait disturbance due to muscle weakness in his lower extremities. Imaging studies revealed that collapsed L3 and L4 vertebral bodies involved the spinal canal, and it was treated by L3-L4 instrumented posterior fusion. Fourteen years after surgery, the patient became unable to walk again due to spinal canal stenosis at the proximal fusion segment. An L2-L3 posterior interbody fusion alleviated his gait ability for 2 years; however, he became unable to stand again because of the collapsed fusion segment that caused severe lumbar kyphosis. Subsequently, a two-staged posterior and anterior fusion surgery from the lower thoracic spine to the pelvis was performed, and spinal fusion and neurological recovery were achieved 3 years after surgery. A kyphotic deformity in patients with CIPA-associated Charcot spine could be favorably treated by a long spinal fusion in combination with a reconstruction of an anterior spinal column. This case report provides a significant lesson for a treatment of CIPA-associated Charcot spine.

[Marsili syndrome manifested by fever: a case report and literature review].

Objective: To describe the clinical features, genetic characteristics, and diagnosis of Marsili syndrome, an extremely rare disease which should be differentiated from other fever disorders. Methods: The clinical data and diagnostic process of a case with Marsili syndrome, hospitalized in the Department of Respiratory and Critical Care Medicine, the Eighth Medical Center of Chinese PLA General Hospital in February 2021, were summarized. The exon regions of 20, 000 genes of peripheral blood were detected in the patient and her parents. Using key words of"Marsili syndrome"and"ZFHX2 gene mutation", the related literatures were searched in Wanfang and PubMed databases from January, 2000 to November, 2021. In addition, the literatures of congenital insensitivity to pain and anhidrosis were retrieved in Wanfang domestic database from the same period. Results: A 23-year-old female patient had suffered from recurrent fever for more than two years, accompanied by anhidrosis, insensitive to pain and weakened corneal reflex. The effect of non-steroidal anti-inflammatory drugs for fever was minimal. The ZFHX2 gene mutation was positive in the patient and her mother, while NTRK1 gene mutation specific to congenital insensitivity to pain with anhidrosis (CIPA) was negative. The ZFHX2 gene mutation was negative in her father. A total of 2 literatures of Marsili syndrome were retrieved and a total of 6 cases of Marsili syndrome in one family were reported worldwide up to now. These patients had a group of similar symptoms including fever, little or no sweating, and insensitivity to pain caused by skin burn and bone fracture. However, there was no abnormality in headache and visceral pain, and female patients' childbirth pain as well as tactile sensation in these cases. The corneal reflex was decreased or negative. They had less sensitivity to stimulus of capsaicin. The ZFHX2 gene mutation was positive, but NTRK1 gene was not detected in all patients. A total of 4 literatures were retrieved and a total of 34 cases of CIPA were reported in China. Though Marsili syndrome and CIPA exhibited a number of similar clinical manifestations, they were distinct diseases and had obviously different outcome. Conclusions: Marsili syndrome is an autosomal dominant genetic disease. It is extremely rare worldwide. In clinical practice, when a patient presents with unexplained recurrent fever and poor effect of non-steroidal anti-inflammatory drugs, especially with the symptoms of no sweating and insensitivity to pain, the possibility of Marsili syndrome should be considered and the ZFHX2 gene should be determined. Marsili syndrome appears to be a benign disease with a good prognosis. A definitive diagnosis can avoid ineffective treatment and its adverse effects. To our knowledge, there is currently no effective genetic therapy for this disease.

A case report: Anesthetic management for open-heart surgery in a child with congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disease also known as hereditary sensory and autonomic neuropathy. CIPA is characterized by a lack of pain sensitivity and impaired development of sweat glands. Surgery is required for patients with self-mutilation and skeletal developmental disorders. Due to the disease's rarity and intricacy, anesthesia poses its challenges. Although there have been a few cases of CIPA patients receiving surgery and anesthesia, the number is very limited. Here, we report a case of a child with CIPA who underwent open-heart surgery and discuss the anesthetic considerations. We conclude that patients with CIPA undergoing open-heart surgery require some opioids, that muscle relaxants and volatile anesthetics should be used with extreme caution, and that airway management and temperature control require special attention.

Genetic pain loss disorders.

Genetic pain loss includes congenital insensitivity to pain (CIP), hereditary sensory neuropathies and, if autonomic nerves are involved, hereditary sensory and autonomic neuropathy (HSAN). This heterogeneous group of disorders highlights the essential role of nociception in protecting against tissue damage. Patients with genetic pain loss have recurrent injuries, burns and poorly healing wounds as disease hallmarks. CIP and HSAN are caused by pathogenic genetic variants in >20 genes that lead to developmental defects, neurodegeneration or altered neuronal excitability of peripheral damage-sensing neurons. These genetic variants lead to hyperactivity of sodium channels, disturbed haem metabolism, altered clathrin-mediated transport and impaired gene regulatory mechanisms affecting epigenetic marks, long non-coding RNAs and repetitive elements. Therapies for pain loss disorders are mainly symptomatic but the first targeted therapies are being tested. Conversely, chronic pain remains one of the greatest unresolved medical challenges, and the genes and mechanisms associated with pain loss offer new targets for analgesics. Given the progress that has been made, the coming years are promising both in terms of targeted treatments for pain loss disorders and the development of innovative pain medicines based on knowledge of these genetic diseases.