Autism spectrum disorder in a boy with congenital insensitivity to pain with anhidrosis: a case report.

BACKGROUND: In this case report, we described the past history, clinical manifestations, genetic characteristics and cognitive evaluation of a boy with congenital insensitivity to pain with anhidrosis (CIPA) who developed autism spectrum disorder (ASD). CASE PRESENTATION: The boy had an early onset of CIPA at the age of 48 months, and was later diagnosed with ASD at 5 years old. Developmental delays in communication, social skills and the presence of maladaptive behaviors were observed in the patient. Professional treatments significantly improved the developmental delays. CONCLUSIONS: This case demonstrated that ASD may develop in children with CIPA, and pediatricians should be aware that if they suspect or identify a child with CIPA that they should also be screened for ASD using similar examination and diagnostic tools as shown in the present report. Moreover, therapeutic interventions for ASD was helpful for the remission of both diseases.

Ocular manifestations of congenital insensitivity to pain: a long-term follow-up.

AIM: To describe ocular manifestations in children with congenital insensitivity to pain with and without anhidrosis (CIPA and CIP). METHODS: We reviewed records of eye examinations of 39 children diagnosed with CIPA or CIP. We collected clinical data, with particular attention to ocular surface findings. Corneal sensitivity was tested by presence of a blink reflex upon touching the cornea. Statistical analysis assessed differences in manifestations between the two conditions, and relationships among corneal sensitivity, presence of corneal opacities and visual acuity (VA). RESULTS: CIPA was diagnosed in 32 children and CIP in 7. The median follow-up periods were 50 months (CIPA group) and 94 months (CIP group). Corneal opacities were present in 23% of CIPA eyes and in 57% of CIP eyes. A blink reflex was positive in 52% of CIPA eyes and in 33% of CIP eyes. We recorded VA ≥20/25 in 36% of CIPA eyes, whereas all patients with CIP had VA ≤20/30. For the whole cohort, we found a negative correlation between a preserved blink reflex and the presence of corneal opacities, and a positive correlation between a preserved blink reflex and VA ≥20/25. CONCLUSION: Children with congenital insensitivity to pain are prone to develop corneal scarring. Patients with CIP tend to have more severe ocular surface disease than those with CIPA, probably due to more prevalent loss of corneal sensation. In both groups, a preserved blink reflex correlated with good vision. Affected children should have close follow-up to promptly treat ocular surface disease and prevent vision loss.

Congenital Insensitivity to Pain: A Case Report With Corneal Esthesiometry and In Vivo Confocal Microscopy.

PURPOSE: To report the findings of a comprehensive eye examination from an individual with congenital insensitivity to pain because of loss-of-function mutations in the SCN9A gene. METHODS: Ophthalmologic examination and confocal microscopy were performed on a patient with congenital insensitivity to pain. RESULTS: A 39-year-old man with compound heterozygous mutations in the SCN9A gene underwent examination. Cochet-Bonnet esthesiometry readings averaged 38 mm (SD 8 mm) in the right eye and 55 mm (SD 7 mm) in the left eye. Other corneal findings included mild conjunctival lissamine green staining, nonvisually significant corneal scars, mild anterior basement membrane dystrophy, and a tear breakup time of 3 seconds in each eye. In vivo confocal microscopy of the corneal subbasal nerve plexus revealed relatively normal corneal nerve morphology, but a reduction in corneal nerve fiber density. CONCLUSIONS: An individual with loss-of-function mutations in SCN9A had reduced corneal nerve fiber density but normal corneal mechanoreception.

Not Another Case Of Juvenile Idiopathic Arthritis: Congenital Insensitivity To Pain Presenting With Joint Problems.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare condition with protean manifestations. Occasionally, these diseases may present with musculoskeletal problems. Here we report a case of young child who presented with joint problems in our clinic. Since the child had a number of musculoskeletal manifestations her diagnosis was difficult and delayed. She was given supportive treatment and a team of doctors from different specialties was involved in her management.

Guided growth in the correction of knee deformity in patients with congenital insensitivity to pain.

BACKGROUND: Orthopedic manifestations of congenital insensitivity to pain (CIP) can be devastating if left untreated. Knee deformities are common in patients with CIP and might lead to joint destruction and loss of walking ability. The purpose of the present study was to report the results and complications of guided growth procedures around the knee in patients with CIP. METHODS: In a retrospective review, all patients with CIP who underwent guided growth procedures around the knee from 2009 to 2017 at a tertiary referral hospital were evaluated. Patients with secondary insensitivity to pain (e.g., syringomyelia), as well as patients with incomplete records, were excluded. Demographic data, clinical findings, correction rate, and complications were recorded. RESULTS: Ten knees in six patients fulfilled the inclusion criteria. The median age was 10 (range, 5-12), with a mean follow-up of 31 months (range, 16-56). Distal femoral tension-band hemiepiphysiodesis was the most common procedure, followed by proximal tibial hemiepiphysiodesis. The mean correction rate was 0.28°/month for femoral deformity. Staples were removed prematurely in one patient due to extrusion. No cases of infection or skin dehiscence were observed. None of the patients needed a reconstructive knee procedure during the study period. CONCLUSIONS: The findings of this study suggest that guided growth procedures might have a role in the correction of knee deformities in patients with CIP. However, the correction rate is lower than that of typically developing children, patients should be closely followed to prevent complications, and stringent patient selection criteria should be followed to ensure success.

Pediatric Use of Recombinant Human Nerve Growth Factor 20 µg/mL Eye Drops (Cenegermin) for Bilateral Neurotrophic Keratopathy in Congenital Corneal Anesthesia.

PURPOSE: This study aimed to present the efficacy and safety of cenegermin eye drop (Oxervate; Dompè Farmaceutici, Milan, Italy) treatment in a pediatric patient affected by neurotrophic keratopathy (NK) with Goldenhar syndrome. METHODS: This case reports an infant presenting ulceration and a small central opacity in the cornea of the right and left eyes, respectively. The NK bilaterally worsened despite the use of therapeutic contact lenses and temporary partial tarsorrhaphy. Magnetic resonance imaging showed absence and hypoplasia of the right and left trigeminal nerves, respectively. Cenegermin eye drops were administered 1 drop/each eye, 6 times daily for 8 weeks to promote corneal healing. RESULTS: Complete healing was achieved in both eyes after treatment. During the 16-month follow-up period, no epithelial defect, recurrence, or complications were noticed, whereas corneal opacities progressively became clearer, although insignificant improvements in corneal sensitivity or in the reflex tearing were observed. CONCLUSIONS: Cenegermin was effective in treating NK in an infant with Goldenhar syndrome.

Conservative Treatment or Surgical Treatment: A Case Report and Literature Review of Multiple Fractures of the Lower Extremities in a Child with Insensitivity to Pain.

Congenital pain insensitivity is a rare genetic disease and its clinical manifestations are many. In orthopaedics, common complications of this disease include painless fracture and Charcot's arthropathy. We followed up a case of multiple fractures of the lower extremity in two years, during which time he came to the clinic for five painless fractures of the lower extremity in a total of six parts. A mutation was found on the NTKRI gene (chr1:156813923(hg19), NM_001007792.1: c.1221938C > T). We have developed a combination of surgery and conservative treatments for his condition, focusing on the mental state of the child and considering comprehensive treatment to be the best option for this type of patient. Occult fractures caused by pain insensitivity are often treated only as fractures, however their complications require routine examination and cleaning, suitable protective shoes, splint fixation, stretching, guided exercise planning, and early treatment of injuries. Due to the risk of fracture in the future, it is important that parents pay attention to the behavior and psychology of the child, such as not letting the child participate in exercise with a risk of injury, protective measures while playing, engaging in psychological counseling, and inducing interest in mental activity. These interventions will play a very important role in preventing the recurrence of fracture.

Sensitivity to pain in autistic spectrum disorders: Its links with self-gressivity.

OBJECTIVES: To investigate the link between pain sensitivity in autism spectrum disorders (ASD) and self-aggressive behavior. METHODS: we performed a cross-sectional study which involved 50 children fulfilling DSM-V criteria for ASD; confirmed by the Autism Diagnostic Interview Revised. The severity of autism was determined using the Childhood Autism Rating Scale (CARS).The psycho-educational profile (PEP-R) was used to assess the age of development and perception.  Sensitivity to pain was assessed with item IX of the CARS. Self-aggressive behavior was assessed by the Behavior Problems Inventory. RESULTS: Pain sensitivity was lowered in 40% and elevated in 4% of children. In the univariate analysis, no statistically significant association was found between normal sensitivity or hyper sensitivity to pain and the presence of auto-aggressiveness. A significant association was found between the presence of hypo-sensitivity to pain and the following variables: auto-aggression (p = 0.007, OR = 5.8, 95% CI = 1.5-21) , frequency of self-aggression (p = 0.001), intensity of self-aggression (p = 0.05), location of auto-aggressiveness at head and (P = 0.007, OR = 7.6, 95% CI = 1.8-14), higher score at CARS, and lower perception score at PEP-R (p = 0.012). Multiple-varied analysis identified risk factors for hypo-sensitivity to pain: lower perceptual score (p = 0.003, adjusted OR = 4.3, 95% CI = 1.9-54) and location of self-aggression at head and hands (p = 0.001, adjusted OR = 1.09, 95% CI = 1.02-1.09). CONCLUSION: It would be interesting to develop tools allowing a fine and precise evaluation of the painful sensation.

[Congenital Analgesia: report of 2 cases]. / Analgesia congénita: reporte de dos casos.

Congenital analgesia is a rare condition, reporting in the international literature in rare cases since 1932, when it was first described. Its cause has been the subject of development of multiple theories and studies through the years. Currently various studies and experiments as its origin point mutation in the gene encoding SC9NA sodium channels, which have an important role in nociceptive transmission signals in the human body. The purpose of this study is to present two cases that were valued in the department of pediatric orthopedics at UMAE HTYOLV, patients whose insensitivity to pain has produced significant injuries that were once cause for valuation of the hospital.

La analgesia congénita es un padecimiento poco frecuente, en la literatura internacional se ha reportado en contados casos desde 1932, año en el que fue descrita por primera vez. Su causa ha sido motivo del desarrollo de múltiples teorías y numerosos estudios a través de los años. Actualmente diversos estudios y experimentos apuntan como origen la mutación en el gen SCN9A que codifica para los canales de sodio, los cuales tienen un papel muy importante en la transmisión de señales nociceptivas en el cuerpo humano. El motivo del presente estudio es dar a conocer dos casos que fueron valorados en el servicio de ortopedia pediátrica de la UMAE HTYOLV, pacientes en quienes la falta de sensibilidad al dolor ha producido lesiones importantes que fueron en su momento motivo de valoración por parte del hospital.

Midface toddler excoriation syndrome (MiTES) can be caused by autosomal recessive biallelic mutations in a gene for congenital insensitivity to pain, PRDM12.

BACKGROUND: Midface toddler excoriation syndrome (MiTES) is a condition recently reported in three unrelated children. Habitual scratching from the first year of life inflicted deep, chronic, scarring wounds around the nose and eyes. One child had a mild neurological deficit but there was no other evidence of insensitivity to pain. Bilateral distribution and localization to the midface distinguish MiTES from other causes of self-inflicted skin damage such as trigeminal trophic syndrome. An earlier study of five siblings from a consanguineous Irish family, with lesions corresponding to MiTES plus other sensory deficits, showed homozygous mutations in a gene for hereditary sensory and autonomic neuropathy type VIII (HSAN8), PRDM12. OBJECTIVES: To study further cases of MiTES, including analysis of PRDM12. METHODS: We describe five further children, from four families, with facial lesions typical of MiTES, in whom mutation analysis of PRDM12 was carried out. RESULTS: Homozygous or compound heterozygous pathogenic expansions of the PRDM12 polyalanine tract were found in four of five affected individuals, in three families. CONCLUSIONS: Our finding of autosomal recessive mutations in PRDM12 in four of five patients with MiTES extends the phenotypic spectrum of PRDM12 mutations, which usually cause HSAN8, characterized by mutilating self-inflicted wounds of the extremities, lips and tongue. By contrast, MiTES shows severe midfacial lesions with little if any evidence of generalized pain insensitivity. The condition is probably genetically heterogeneous, and other congenital insensitivity to pain and HSAN genes such as SCN11A may be implicated. This new understanding of the nature of MiTES, which can masquerade as factitious disease, will facilitate appropriate management.

Analgesia congénita: reporte de dos casos / Congenital Analgesia: report of 2 cases

Resumen: La analgesia congénita es un padecimiento poco frecuente, en la literatura internacional se ha reportado en contados casos desde 1932, año en el que fue descrita por primera vez. Su causa ha sido motivo del desarrollo de múltiples teorías y numerosos estudios a través de los años. Actualmente diversos estudios y experimentos apuntan como origen la mutación en el gen SCN9A que codifica para los canales de sodio, los cuales tienen un papel muy importante en la transmisión de señales nociceptivas en el cuerpo humano. El motivo del presente estudio es dar a conocer dos casos que fueron valorados en el servicio de ortopedia pediátrica de la UMAE HTYOLV, pacientes en quienes la falta de sensibilidad al dolor ha producido lesiones importantes que fueron en su momento motivo de valoración por parte del hospital.

Abstract: Congenital analgesia is a rare condition, reporting in the international literature in rare cases since 1932, when it was first described. Its cause has been the subject of development of multiple theories and studies through the years. Currently various studies and experiments as its origin point mutation in the gene encoding SC9NA sodium channels, which have an important role in nociceptive transmission signals in the human body. The purpose of this study is to present two cases that were valued in the department of pediatric orthopedics at UMAE HTYOLV, patients whose insensitivity to pain has produced significant injuries that were once cause for valuation of the hospital.

NGF-dependent neurons and neurobiology of emotions and feelings: Lessons from congenital insensitivity to pain with anhidrosis.

NGF is a well-studied neurotrophic factor, and TrkA is a receptor tyrosine kinase for NGF. The NGF-TrkA system supports the survival and maintenance of NGF-dependent neurons during development. Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder due to loss-of-function mutations in the NTRK1 gene encoding TrkA. Individuals with CIPA lack NGF-dependent neurons, including NGF-dependent primary afferents and sympathetic postganglionic neurons, in otherwise intact systems. Thus, the pathophysiology of CIPA can provide intriguing findings to elucidate the unique functions that NGF-dependent neurons serve in humans, which might be difficult to evaluate in animal studies. Preceding studies have shown that the NGF-TrkA system plays critical roles in pain, itching and inflammation. This review focuses on the clinical and neurobiological aspects of CIPA and explains that NGF-dependent neurons in the peripheral nervous system play pivotal roles in interoception and homeostasis of our body, as well as in the stress response. Furthermore, these NGF-dependent neurons are likely requisite for neurobiological processes of 'emotions and feelings' in our species.

Charcot spinal arthropathy in patients with congenital insensitivity to pain: a report of two cases and review of the literature.

Charcot spine, or neuropathic spinal arthropathy, involves the progressive destruction of the spinal joint due to the lack of normal protective sensations and proprioception. A rare cause of Charcot spine is congenital insensitivity to pain, which is an absent or abnormal response to painful stimuli. There are few case reports describing this condition, and long-term follow-up data are limited. The presentation and treatment of two patients with Charcot spine secondary to congenital insensitivity to pain are described. Both cases were characterized by lumbar involvement and were treated with circumferential decompression and an extended lumbo-pelvic fusion construct. The cases described here demonstrate stable neurological status at 1.5 and 5 years follow-up. Patient characteristics, pre- and post-operative imaging, operative approach, and outcomes are described. The literature regarding this rare condition is also reviewed, with an emphasis on operative management and outcomes. Surgical management is traditionally complicated by a high rate of hardware failure and adjacent segment degeneration. The current review highlights the importance of prompt and aggressive management following diagnosis of Charcot spine, as well as extended follow-up.

Congenital insensitivity to pain in one family.

Congenital insensitivity to pain (CIP) is a rare autosomal recessive genetic disease caused by mutation in several different genes. The diagnosis requires the combined skills and cooperation of pediatricians, neurologists, radiologists, pathologists, and orthopedic surgeons. Orthopedic manifestations of CIP include delayed diagnosis of fractures, nonunions, Charcot arthropathy, avascular necrosis, osteomyelitis, joint dislocations, and heterotopic ossifications. We present case reports of two brothers with CIP with various orthopedic manifestations and methods of surgical treatment with 10 years of follow-up.

Congenital insensitivity to pain: How should anesthesia be managed?

Özmete Ö, Sener M, Bali Ç, Çaliskan E, Aribogan A. Congenital insensitivity to pain: How should anesthesia be managed? Turk J Pediatr 2017; 59: 87-89. Congenital insensitivity to pain syndrome is a rare, sensorial and autonomic neuropathy characterized by unexplained fever, insensitivity to pain and anhidrosis. Patients may require anesthesia even for minor surgical procedures due to mental retardation and trauma arising from self- mutilating behavior. A child diagnosed with congenital insensitivity to pain syndrome was scheduled for gastric endoscopy under sedation due to suspected ingestion of a household cleaning disinfectant. Deep sedation was achieved, and spontaneous respiration was maintained. We did not encounter any complications. There is limited data regarding the safe anesthesia management in these patients because of the rarity of the disease. Therefore, we think that more clinical experience, case reports and studies are needed to establish the appropriate anesthesia management.

Anesthesia Procedure for Congenital Insensitivity to Pain in a Child with Anhidrosis Syndrome: A Rare Case.

Congenital insensitivity to pain with anhidrosis (CIPA) syndrome is a neuropathy characterized by insensitivity to pain, impaired thermoregulation, anhidrosis, and mental retardation. A 9-year old boy with CIPA syndrome, underwent 2 operations for a calcaneal ulcer. During the first operation standard monitorization was performed. In the second operation, Bispectral Index (BIS) monitoring was added and temperature was monitored with an esophageal probe. In the first operation, in which anesthesia induction was applied with ketamine and midazolam, extremity movements with surgical stimuli were seen. Despite pain insensitivity, as extremity movements were seen with surgical stimuli, propofol was administered in the second operation. Throughout the operation, the BIS values varied from 19-58 and body temperature was measured as 36.1°C-36.9°C. In conclusion, despite the absence of pain sensitivity in CIPA syndrome cases, there is an absolute need for the administration of anesthesia in surgical procedures because of tactile hyperesthesia.

Novel 9 amino acid in-frame deletion in the NTRK1 tyrosine kinase domain in a patient with congenital insensitivity to pain with anhydrosis.

Schematic presentation of NTRK1 protein structure. Variants identified in this study are shown in red and previously reported variants associated with CIPA are shown in black (LRM, leucine rich motif; Ig, immunoglobulin-like domain; TM, transmembrane domain; TK, tyrosine kinase domain).

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.