Analysis of genetic variation for a child affected with congenital insensitivity to pain with anhidrosis and albinism by whole genome sequencing / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic variation of a Chinese family affected with congenital insensitivity to pain with anhidrosis and albinism.@*METHODS@#Whole exome sequencing (WES) was carried out to screen potential variants within genomic DNA extracted from the proband and his parents. Whole genome sequencing (WGS) was applied when variants were not found completely. Suspected variants were validated by Sanger sequencing.@*RESULTS@#WES has identified a heterozygous c.1729G>C (p.G577R) variant of NTRK1 gene and two heterozygous variants of OCA2 gene, namely c.1363A>G (p.R455G) and c.1182+1G>A. WGS has identified two additional heterozygous variants c.(851-798C>T; 851-794C>G) in deep intronic regions of the NTRK1 gene.@*CONCLUSION@#The compound heterozygous variants of the NTRK1 gene probably underlay the congenital insensitivity to pain with anhidrosis. And the compound heterozygous variants of the OCA2 gene probably underlay the albinism in the proband. In the case where no variant is detected by WES in the coding region, WGS should be considered to screen potential variants in the whole genome.

Congenital Insensitivity to Pain with Anhidrosis: Five-Year-Old Girl with a Neglected Distal Femur Fracture / 대한정형외과학회잡지

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disease that affects the sensory and autonomic nervous system. The patients do not have the ability to sense different sensations, such as pain, which tends to lead to different injuries. In addition, the patients suffer from fluctuations in body temperature due to autonomic involvement. The present case was a five-year-old girl with a neglected distal femur fracture. X-rays taken during the follow-up showed marked callus formation and pseudarthrosis of the distal femur. She had biting injuries of the tongue, auto-amputation of the fingers, some developmental delay and a history of recurrent fever with an unknown origin. The electrodiagnostic study was normal. The quantitative sudomotor axon reflex test revealed markedly reduced postganglionic sudomotor axonal responses at all sites recorded on the left. She was diagnosed with CIPA. As the initial presentation of CIPA involves the musculoskeletal system, orthopedic surgeons should have a high index of suspicion.

Dental Management in a Patient with Congenital Insensitivity to Pain with Anhidrosis : A Case Report / 대한소아치과학회지

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare, autosomal recessive disorder; affected patients are characterized by inability to feel pain and to sweat over the entire body, as well as by mental retardation. Because, in the oral examination, no specific findings on soft or hard tissue may be found except possible lesions due to self-mutilation, early recognition and diagnosis are essential for these patients. Pediatric dentists must be aware of the clinical manifestations and treatment considerations related to uncontrolled body temperature, tactile hyperesthesia and lack of pain reflex. In this case report, dental management of CIPA was suggested by presenting a 6-year follow-up of young patient.

Funcionamiento Cognitivo Global y Conducta Adaptativa en dos Niñas con Neuropatía Sensitiva Autonómica Hereditaria Tipo IV / Global cognitive and adaptive functioning in two girls with hereditary sensory and autonomic neuropathy type IV

La neuropatía sensitiva autonómica hereditaria tipo IV (HSAN-IV) es una condición neurológica de origen genético extremadamente rara que puede cursar con discapacidad intelectual, sin embargo, hay escasas publicaciones sobre las características del funcionamiento cognitivo global y la conducta adaptativa de los afectados. En este estudio se describe la capacidad cognitiva global y el funcionamiento adaptativo de dos niñas de 12 y 14 años diagnosticadas con HSANIV, incluyendo una caracterización de los procesos de comprensión verbal, razonamiento perceptual, memoria de trabajo y velocidad de procesamiento. Las menores fueron evaluadas mediante la Escala de Inteligencia para niños de Wechsler cuarta edición (WISC-IV) encontrándose en ambos casos un bajo índice de comprensión verbal, una medida del desarrollo cognitivo alcanzado a través de la historia de aprendizaje de las niñas; así como un bajo índice de razonamiento perceptivo, indicador de su capacidad para adaptarse y afrontar situaciones nuevas de forma flexible. Esto se acompaña de dificultad en la manipulación de información en la memoria para la resolución de problemas y enlentecimiento en la velocidad de procesamiento de la información. Adicionalmente, se evaluó su funcionamiento adaptativo mediante el sistema de evaluación de la conducta adaptativa ABAS-II, el cual se caracterizó por fortalezas en habilidades comunicativas, uso de recursos comunitarios y vida en el hogar; con limitaciones en habilidades académicas y de autocuidado. En conclusión, la HSAN-IV es una condición que cursa con discapacidad intelectual con necesidades de apoyo variables en intensidad. En los casos estudiados se encontró discapacidad intelectual con necesidad de apoyo limitado, es decir, los apoyos se requieren de forma regular durante un periodo de tiempo corto pero definido.

Hereditary sensory autonomic neuropathy type IV (HSAN-IV) is a neurological condition of extremely rare genetic origin that may be associated with intellectual disability; however, there are few publications about the characteristics of global cognitive functioning and adaptive behaviour of these patients. In this study we describe the global cognitive function and the adaptive behavior of two girls aged 12 and 14 diagnosed with HSAN-IV, including a characterization of the processes of verbal comprehension, perceptual reasoning, working memory and processing speed. The children were assessed using the Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV), finding in both cases a low level of verbal comprehension, a measure of cognitive development achieved through the girls' learning history; as well as a low rate of perceptual reasoning, indicator of their ability to adapt and face new situations in a flexible way. This is accompanied by difficulty in manipulating information in the memory to solve problems and slow down the speed of information processing. Additionally, its adaptive functioning was evaluated through the Adaptive Behavior Assessment System ABAS-II, which was characterized by strengths in communication skills, use of community resources and life at home; with limitations in academic and self-care skills. In conclusion, HSAN-IV is a condition related with intellectual disability with varying support needs in intensity. In the cases studied, intellectual disability was found with limited need for support, that is, supports are required on a regular basis for a short but defined period.

A novel mutation in the DNMT1 gene in a patient presenting with pure cerebellar ataxia

Mutations in the DNA methyltransferase 1 gene (DNMT1) were reported to cause two phenotypes: OMIM 604121 and OMIM 614116. The first phenotype includes autosomal dominant cerebellar ataxia, deafness, and narcolepsy, which were reported to be caused by mutations in exon 21. The second phenotype includes hereditary sensory and autonomic neuropathy type 1E, which was suggested to be caused by mutations in exon 20 and 21. In this article, we report a novel heterozygous missense variant c.898A>C, p.(Lys300Gln) in exon 12 of DNMT1 in a young woman who presented with pure cerebellar ataxia. This report indicates that a mutation in exon 12 may lead to pure cerebellar ataxia. Another possibility is that the patient is currently in an early stage of the disease, and as the disease progresses, she will have more manifestations. To confirm or exclude this possibility, a subsequent follow-up study reporting the disease progression in this patient may be needed. Further reports of cases with the same mutation are needed to confirm the phenotype of this mutation.

Mutation analysis of NTRK1 gene in a family affected with congenital insensitivity to pain with anhidrosis / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To screen for mutations of NTRK1 gene in a Chinese family affected with congenital insensitivity to pain with anhidrosis (CIPA).</p><p><b>METHODS</b>Genomic DNA was extracted from the proband and her family members. All of the 17 exons and intron-exon boundaries of the NTRK1 gene were analyzed by direct Sanger sequencing. For the deletional mutation, the PCR products were subjected to T-A cloning and sequencing to verify the mutation.</p><p><b>RESULTS</b>NTRK1 gene analysis revealed that proband has carried a c.1786C>T (p.Arg596*) nonsense mutation inherited from her mother and a novel deletional mutation c.1928-2028+23del from her father. Her elder brother only carried the deletional mutation.</p><p><b>CONCLUSION</b>The diagnosis of CIPA relied on typical clinical symptoms of no pain, anhidrosis and intellectual disability and detection of the biallelic NTRK1 mutations. The novel deletional mutation has enriched the spectrum of NTRK1 mutations.</p>

Insensibilidad congénita al dolor con anhidrosis. Diagnóstico clínico, evolución y complicaciones: reporte de un caso / Congenital insensitivity to pain with anhidrosis. Clinical diagnosis, evolution and complications: case report

La insensibilidad congénita al dolor con anhidrosis es una enfermedad autosómica recesiva infrecuente, que se produce por mutaciones en el gen NTRK1 (neurotrophic tyrosine receptor kinase 1), localizado en el cromosoma 1q21-22, que codifica el dominio tirosinasa del receptor de alta afinidad del factor de crecimiento nervioso. Se caracteriza por anhidrosis, insensibilidad a los estímulos dolorosos y retraso mental. Dada su baja prevalencia y los pocos casos reportados, es importante conocer sus principales características para considerarlo entre los diagnósticos diferenciales en la práctica pediátrica. Realizamos la descripción del diagnóstico clínico, complicaciones, secuelas y tratamiento sintomático administrado en una niña de 3 años y 6 meses en el Hospital Asdrúbal de la Torre, Cotacachi, Ecuador.

The congenital insensitivity to pain with anhidrosis is a rare autosomal recessive disease caused by mutations in NTRK1 gene (neurotrophic tyrosine kinase receptor 1) located in chromosome 1q21-22, encoding the tyrosinase domain receptor high affinity nerve growth factor. It is characterized by anhidrosis, insensitivity to painful stimuli and mental retardation. Given their low prevalence and the few reported cases, it is important to know its main features to be considered in the differential diagnosis in pediatric practice. We describe the clinical diagnosis, complications, sequelae and symptomatic treatment administered to a 3 years and 6 months old girl in the Hospital Asdrubal de la Torre, Cotacachi, Ecuador.

Neuropatía autonómica sensorial hereditaria / Hereditary sensory and autonomic neuropathy

La insensibilidad congénita al dolor es una patología infantil poco frecuente. Existen cinco diferentes tipos de neuropatía sensorial y autonómica descritas hasta la fecha, cada una de ellas con hallazgos clínicos diversos. A continuación se reporta el caso de un niño de 10 años, con el diagnóstico de neuropatía autonómica sensorial hereditaria tipo IV, condición que presenta una herencia autosómica recesiva. Esta patología se caracteriza por la pérdida de la sensibilidad al dolor y temperatura, anhidrosis, automutilación y retardo mental. La anhidrosis lleva a trastornos de la termorregulación, que pueden causar episodios de fiebre y la pérdida de sensibilidad, se asocia con fracturas y traumas articulares recurrentes...

Clinical and neurophysiologic characterization of an European family with hereditary sensory neuropathy, paroxysmal cough and gastroesophageal reflux / Caracterização clínica e neurofisiológica de uma família europeia com neuropatia sensitiva hereditária, tosse paroxística e refluxo gastroesofágico

In 2002, Spring et al reported a family with an autosomal dominant form of hereditary sensory neuropathy; patients also presented adult onset of gastroesophageal reflux and cough. Since then, no further families have been described. Objective: To study a new Portuguese family with these characteristics. Method: To describe the clinical and neurophysiologic characteristics of one family with features of sensory neuropathy associated with cough and gastroesophageal erflux. Results: Three of five siblings presented a similar history of paroxysmal cough (5th decade). About a decade later they experienced numbness and paraesthesia in the feets and in all cases there was evidence of an axonal sensory neuropathy. A history of gastroesophageal reflux of variable severity and age of onset was also present. Discussion: Molecular genetic studies have demonstrated genetic heterogeneity between the hereditary sensory neuropathy type 1 subtypes. The identification of these families is of major importance because further work is required to identify the underlying genetic defect. .

Em 2002, Spring et al descreveram uma família com uma combinação de polineuropatia sensitiva hereditária, doença do refluxo gastroesofágico e tosse paroxística. Desde então não foram descritos outros casos. Objectivo: Estudar uma nova família portuguesa com essas características. Método: Caracterização clínica e neurofisiológica de uma família com a referida combinação de patologias. Resultados: Três, de cinco irmãos, apresentam uma história semelhante de tosse paroxística com início na 5a década. Cerca de uma década mais tarde iniciam quadro de parestesias em ambos os pés, com evidência de neuropatia sensitiva axonal. Todos os casos apresentam também uma história de doença do refluxo gastroesofágico de gravidade variável. Discussão: Nos últimos anos, os estudos de genética molecular permitiram evidenciar a heterogeneidade genética dos vários subtipos de polineuropatia sensitiva hereditária tipo 1. A identificação das famílias afectadas reveste-se de grande importância, nomeadamente na tentativa de caracterização da alteração genética deste subtipo. .

Seropositive rheumatoid arthritis in a female patient with sensory neuropathy

No abstract available.

A novel mutation of NTRK1 gene in a family with congenital insensitivity to pain with anhidrosis / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To screen for mutations in the neurotrophic tyrosine kinase receptor type 1 (NTRK1) gene in a Chinese family affected with congenital insensitivity to pain with anhidrosis (CIPA).</p><p><b>METHODS</b>With informed consent obtained, peripheral blood samples were obtained from the patient and his family members. Seventeen coding exons and intron-exon boundaries of the NTRK1 gene were amplified with PCR and analyzed by direct sequencing.</p><p><b>RESULTS</b>A novel mutation c.2086_2087insC (p.Arg696 fsx) was identified in exon 16 of the NTRK1 gene in the proband. This insertion has caused open reading frame shifting and a premature termination has occurred just one codon downstream. Truncation of 72 amino acids at the C terminus has wiped out part of the tyrosine kinase domain (TKD) of the protein. Both of the proband's parents and two grandmothers have carried the c.2086_2087insC (p.Arg696 fsx) mutation. No mutation was found in the NTRK1 gene of other siblings.</p><p><b>CONCLUSION</b>Mutation analysis of the NTRK1 gene has been carried out in a Chinese family affected with CIPA, and a novel NTRK1 gene mutation was identified.</p>

Neuropatía sensitiva y autonómica hereditaria tipo II / Hereditary sensory and autonomic neuropathy type II

Las neuropatías sensitivas y autonómicas hereditarias (NSAH) son un grupo de enfermedades caracterizadas por una serie de trastornos hereditarios degenerativos del sistema nervioso periférico. Asocian disfunción sensorial (táctil, térmica y nociceptiva) con diveros grados de alteración autonómica (reflujo gastroesofágico, hipotensión postural, e hiper o anhidrosis). El compromiso motor es leve o nulo. La clasificación en cinco tipos principales se basa en los patrones de herencia, las características clínicas y el grado de disfunción sensitiva y autonómica. Sin embargo, entidades adicionales siguen siendo descriptas, por lo que la clasificación está aún en revisión. En este trabajo se presentan dos nuevos casos de NSAH de tipo II. Motiva esta publicación la baja frecuencia de esta enfermedad, cuyo diagnóstico y enfoque multidisciplinario constituyen un desafío para prevenir o retrasar la aparición de secuelas irreversibles...

Hereditary sensory and autonomic neuropathies (HSANs) are a group of diseases characterized by a series of degenerative hereditary disorders of the peripheral nervous system. They are associated with sensory dysfunction (tactile, thermal, and nociceptive) and varying degrees of autonomic failure (gastroesophageal reflux, postural hypotension, hyperhidrosis or anhidrosis), with none or slight motor involvement. The classification into five main types is based on patterns of inheritance, clinical features, and the degree of sensory and autonomic dysfunction. However, additional entities continue to be described, so the classification is ongoing. Two new cases of HSAN II are herein presented. This paper has been motivated by the rarity of this disorder which early diagnosis and multidisciplinary approach constitute a challenge to prevent or delay the appearance of irreversible sequelae...

Emissões otoacústicas em um grupo de crianças com o espectro da neuropatia auditiva: estudo retrospectivo / Otoacoustic emissions in a group ofchildren with auditory neuropathy spectrum disorder: retrospective study

Introdução:O Espectro da Neuropatia Auditiva é uma desordem auditiva com alteração na condução dos impulsos nervosos nas células ciliadas internas e/ou no nervo auditivo com função coclear preservada. Verifi ca-se ausência ou alteração do Potencial Evocado Auditivo de Tronco Encefálico com presença das Emissões Otoacústicas e do microfonismo coclear. O objetivo deste estudo foi analisar a ocorrência ou não do registro das Emissões Otoacústicas em um grupo de crianças com o Espectro da Neuropatia Auditiva, considerando idade, grau da perda auditiva e etiologia. Material e Método: Estudo retrospectivo com levantamento de prontuários dos pacientes atendidos em uma clínica-escola nos últimos 5 anos. Resultados: Obedeceram aos critérios de inclusão os prontuários de 15 crianças, 67 do sexo feminino e 33 do sexo masculino, entre 2 e 17 anos de idade. Foi possível observar que, tanto no grupo com Emissões Otoacústicas presentes, quanto no grupo com ausência de Emissões Otoacústicas, as idades foram semelhantes. A maior porcentagem de ausência de Emissões Otoacústicas foi observada na etiologia hiperbilirrubinemia, com uma menor ocorrência deste fenômeno nos casos de origem genética e ausência deste fenômeno nos casos hereditários e idiopáticos. Conclusões: A ausência das Emissões Otoacústicas não teve relação direta com a idade nem com o grau da perda auditiva e uma maior ocorrência de casos com ausência das Emissões Otoacústicas pôde ser observada nas crianças cuja etiologia do Espectro da Neuropatia Auditiva foi a hiperbilirrubinemia.

Introduction: Auditory Neuropathy Spectrum Disorder is a hearing disorder with altered auditory nerve impulses conduction in the inner hair cells and / or the auditory nerve with cochlear function preserved. There is absence or alteration of the Auditory Evoked Potential Brain Stem with presence of Otoacoustic Emissions and cochlear microphonics. The aim of this study was to analyze the occurrence or nonoccurrence of Otoacoustic Emissions in a group of children with Auditory Neuropathy Spectrum Disorder, considering factors such as age, degree of hearing loss and etiology. Material and Method: Retrospective study of medical chart survey from patients in a university clinic in the last five years. Results: There were 15 dossiers that fi t the inclusion criteria, 67 females and 33 males, with ages between 2 and 17 years old. It was observed that in both groups, with present Otoacoustic Emissions and with absent Otoacoustic Emissions, the ages were similar. The highest percentage of absent Otoacoustic Emissions was observed in the etiology of hyperbilirubinemia, with a lower occurrence of this phenomenon in cases of genetic origin and absence of this phenomenon in hereditary and idiopathic cases. Conclusions: The absence of Otoacoustic Emissions had no direct relationship with the age of the children neither with the degree of hearing loss, and a higher incidence of cases with absence of Otoacoustic Emissions was observed in children whose etiology of Auditory neuropathy spectrum disorder was hyperbilirubinemia.

Introducción: El Espectro de Neuropatía Auditiva es un trastorno auditivo con alteración en la conducción del impulso nervioso en las células ciliadas internas y/o en el nervio auditivo con la función coclear conservada. Tiene ausencia o alteración del Potencial Auditivo Evocados de Tronco Encefálico con presencia de Emisiones Otoacústicas y de la microfonía coclear. El objetivo de este estudio fue analizar la ocurrencia o no de la Emisiones Otoacústicas en un grupo de niños con el Espectro de Neuropatía Auditiva , teniendo en cuenta edad, grado de la perdida auditiva y etiología. Material y Método: Estudio retrospectivo de los archivos de los pacientes atendidos en una clínica-escuela en los últimos cinco años. Resultados: atendieron a los criterios de inclusión los registros de 15 niños, 67 mujeres y 33 hombres, entre 2 y 17 años de edad. Se observó que tanto el grupo con Emisiones Otoacústicas presente, como en el grupo con Emisiones Otoacústicas ausente, las edades fueron semejantes. El mayor porcentaje de ausencia de Emisiones Otoacústicas se observó en la etiología de hiperbilirrubinemia, con una menor incidencia de este fenómeno en los casos de origen genético y la ausencia de este fenómeno en los casos hereditarios e idiopáticos Conclusiones: La ausencia de Emisiones Otoacústicas no tubo relación directa con la edad ni con el grado de pérdida auditiva y una mayor incidencia de casos con ausencia de Emisiones Otoacústicas se pudo observar en los niños cuya etiología del Espectro de la Neuropatía Auditiva fue la hiperbilirrubinemia.

Anesthetic management of patient with congenital insensitivity to pain with anhidrosis (CIPA) by using BIS monitor: A case report

Congenital insensitivity to pain with anhidrosis (CIPA, or hereditary sensory and autonomic neuropathy type IV) is a rare, autosomal recessive disease, is characterized by inability to sweat, insensitivity to pain, recurrent episodes of hyperpyrexia, self-mutilation and mental retardation. Because of lacking autonomic response to painful stimuli, it is difficult to determine adequate depth of anesthesia in patients with CIPA. We report an anesthetic experience for child with CIPA who had undergone an orthopedic operation. Anesthesia was induced by propofol and maintained by Sevoflurane with 50% nitrous oxide and anesthetic depth was monitored by using bispectral index (BIS). Throughout the operation, anesthesia was maintained with low end-tidal Sevoflurane concentrations (<1.5 vol%), BIS was within 28-62 and vital signs were stable. After operation, he did not remember anything about the surgery. The BIS monitor may be a useful tool to guide the adequate depth of anesthesia for the patient with CIPA.

Cardiac arrest after anesthetic management in a patient with hereditary sensory autonomic neuropathy type IV

Hereditary sensory autonomic neuropathy type IV is a rare disorder with an autosomal recessive transmission and characterized by self-mutilation due to a lack in pain and heat sensation. Recurrent hyperpyrexia and anhydrosis are seen in patients as a result of a lack of sweat gland innervation. Self-mutilation and insensitivity to pain result in orthopedic complications and patients undergone recurrent surgical interventions with anesthesia. However, these patients are prone to perioperative complications such as hyperthermia, hypothermia, and cardiac complications like bradycardia and hypotension. We report a 5-year-old boy with hereditary sensory autonomic neuropathy type IV, developing hyperpyrexia and cardiac arrest after anesthesia

Congenital Insensitivity to Pain and Anhidrosis Masquerading as a Chronic Osteomyelitis of the Talus: A Case Report / 대한족부족관절학회지

We experienced a case of congenital insensitivity to pain with anhidrosis mimicking a chronic osteomyelitis of the talus, with recurrent ankle swelling and intermittent fever. He was misdiagnosed as low virulence osteomyelitis at other hospital in annual recurrence for 3 years. A Charcot joint in children is a very rare condition and diagnosis should be made in a careful approach.

Genetics of Hereditary Peripheral Neuropathies

Hereditary peripheral neuropathies can be categorized as hereditary motor and sensory neuropathies (HMSN), hereditary motor neuropathies (HMN), and hereditary sensory neuropathies (HSN). HMSN, HMN, and HSN are further subdivided into several subtypes. Here, we review the most recent findings in the molecular diagnosis and therapeutic strategy for hereditary peripheral neuropathies. The products of genes associated with hereditary peripheral neuropathy phenotypes are important for neuronal structure maintenance, axonal transport, nerve signal transduction, and functions related to the cellular integrity. Identifying the molecular basis of hereditary peripheral neuropathy and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, as well as the processes involved in the normal development and function of the peripheral nervous system. These advances and the better understanding of the pathogenesis of peripheral neuropathies represent a challenge for the diagnoses and managements of hereditary peripheral neuropathy patients in developing future supportive and curative therapies.

Anesthetic Management for a Patient with Congenital Insensitivity to Pain with Anhidrosis (CIPA): A case report / 대한마취과학회지

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare, autosomal-recessive disorder characterized by the clinical triad of indifference of pain, anhidrosis and heat intolerance.Because of their lack of autonomic response to noxious stimuli, the determination of adequate depth of anesthesia in the CIPA patient undergoing surgery is a major challenge.We experienced a patient with CIPA who had minor procedures three times under the general anesthesia, in which bispectral index (BIS) was maintained at 40-50 by adjusting sevoflurane concentrations with 50% nitrous oxide.The low end-tidal sevoflurane concentrations (<1.2 vol%) were required to keep the target BIS while vital signs remained stable throughout the surgery in each operation.BIS monitor may be a valuable tool to guide the depth of anesthesia in patients with CIPA.