Orthopedic Manifestations of Hereditary Sensory and Autonomic Neuropathy IV in a 10-Year-Old Patient.

Hereditary sensory and autonomic neuropathy type IV (HSAN) is a rare and debilitating disorder highlighted by congenital absence of pain and anhidrosis. Orthopedic sequelae include physeal fractures, Charcot joint development, excessive joint laxity, soft tissue infections and recurrent painless dislocations, all of which often present in a delayed fashion. While there is no accepted guideline on management of these patients, several case studies have highlighted the importance of early diagnosis and cautioned against surgical intervention in these patients due to their inability to perceive pain and comply with post-operative restriction. The purpose of this case report is to present the clinical course of a patient with HSAN IV and the unique orthopedic challenges it presented. While some of her orthopedic injuries healed appropriately following treatment, others have gone on to have devastating complications and progressive joint destruction. Level of Evidence: IV.

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.

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.

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.

Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing ß-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

The painless eye: Neurotrophic keratitis in a child suffering from hereditary sensory autonomic neuropathy type IV.

Hereditary sensory autonomic neuropathy (HSAN) is a group of inherited disorders (total 5 types) that are associated with sensory dysfunction and varying degrees of autonomic dysfunction. HSAN type IV (HSAN-IV) or congenital insensitivity to pain and anhidrosis (CIPA) is a rare genetic disorder inherited in an autosomal recessive manner. We report a case of this very rare genetic disease in a 3-year-old girl child, born to a family in north India with ocular features of neurotrophic keratitis. The diagnosis was made clinically based on the hallmark features of insensitivity to pain and temperature, anhidrosis, self-mutilating behavior with multiple recurrent oral ulcers, nasal bleeds, multiple trophic ulcers over joints, and decreased intellect.

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

BACKGROUND: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS: Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS: Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS: Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).

De novo pathogenic DNM1L variant in a patient diagnosed with atypical hereditary sensory and autonomic neuropathy.

BACKGROUND: Profiling the entire genome at base pair resolution in a single test offers novel insights into disease by means of dissection of genetic contributors to phenotypic features. METHODS: We performed genome sequencing for a patient who presented with atypical hereditary sensory and autonomic neuropathy, severe epileptic encephalopathy, global developmental delay, and growth hormone deficiency. RESULTS: Assessment of the variants detected by mapped sequencing reads followed by Sanger confirmation revealed that the proband is a compound heterozygote for rare variants within RETREG1 (FAM134B), a gene associated with a recessive form of hereditary sensory and autonomic neuropathy, but not with epileptic encephalopathy or global developmental delay. Further analysis of the data also revealed a heterozygous missense variant in DNM1L, a gene previously implicated in an autosomal dominant encephalopathy, epilepsy, and global developmental delay and confirmed by Sanger sequencing to be a de novo variant not present in parental genomes. CONCLUSIONS: Our findings emphasize the importance of genome-wide sequencing in patients with a well-characterized genetic disease with atypical presentation. This approach reduces the potential for misdiagnoses.

A Case of Congenital Insensitivity to Pain With Anhidrosis Comorbid With Attention Deficit Hyperactivity Disorder: Clinical Implications for Pathophysiology and Treatment.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disorder caused by a mutation in the neurotrophic tyrosine kinase receptor (NTRK1) gene. CIPA is accompanied by abnormal catecholamine metabolism and decreased blood concentration of dopamine and norepinephrine. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of heterogeneous etiology and presentation, and recent reports have suggested a pathophysiological role of neurotrophins in ADHD. Furthermore, dopamine and norepinephrine are known to play major roles in the pathophysiology of ADHD, and the imbalance of monoaminergic and cholinergic systems as an underlying cause of ADHD has recently been studied. Here, we report the case of an 11-year-old boy with CIPA and comorbid ADHD. Our observations have important clinical implications for patients with CIPA. Because of deficiencies in self-control, proper management of these patients necessitates a highly structured and monitored environment, made dually important by possible comorbidity of ADHD.

Hereditary Sensory and Autonomic Neuropathy Presenting With Mutilating Trophic Ulcers.

Two siblings, a 19-year-old woman and an 18-year-old man, born to apparently normal parents of second-degree consanguineous marriage, presented to the Department of Dermatology, Sawai Man Singh Medical College Hospital, Jaipur, India, with recurrent skin ulcers of the hands and feet since early childhood. The ulcers were spontaneous, slow to heal, and caused deformities. On initial examination, they were found to have distal sensory loss, predominantly to pain and temperature. The patients were diagnosed with hereditary sensory and autonomic neuropathy of ulceromutilating type (Type 2) based on clinical evidences, nerve studies, and neuropathology. Although clinical features were distinct, due to slow progression of the disease and lack of clinical suspicion, diagnosis was delayed until adulthood when complications developed leading to deformities. Through this report, the authors intend to familiarize readers with this rare disease that can present with trophic ulcers.

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.

Anesthetic management during adenotonsillectomy for twins with congenital insensitivity to pain with anhidrosis: two case reports.

BACKGROUND: Congenital insensitivity to pain with anhidrosis is a rare autosomal recessive disorder characterized by hyperpyrexia, anhidrosis, pain insensitivity, self-inflicted injuries, and intellectual disability. The anesthetic management of these patients is challenging owing to the high risk of perioperative complications resulting from their autonomic dysfunction, such as hyperthermia, hypotension, and bradycardia, which result from autonomic nervous system dysfunction. CASE PRESENTATION: Two 3-year-old Han Chinese identical male twins (weighing 13.5 kg and measuring 93 cm tall) were previously diagnosed as having congenital insensitivity to pain with anhidrosis based on clinical features and genetic screening. According to the presence of loud snoring and heavy breathing during sleep and neck radiograph findings, they were diagnosed as having tonsil and adenoid hypertrophy and needed adenotonsillectomy. Because of innate analgesia, some reports suggested that patients with congenital insensitivity to pain with anhidrosis do not require perioperative pain control. Accordingly, our patients did not receive opiates. We describe the general anesthetic management of these patients using sevoflurane and propofol, but without opiates, for adenotonsillectomy. Remarkable tachycardia and hypertension occurred during airway manipulation and when the surgical stimuli increased, and their temperatures increased from 36 °C and 36.8 °C to 37.8 °C and 38.5 °C, respectively. Patients with congenital insensitivity to pain with anhidrosis lack pain sensation, but they may have tactile hyperesthesia. Surgical noxious stimuli may therefore produce a stress response and unpleasant sensations, leading to hemodynamic fluctuation and temperature increase. CONCLUSIONS: On the basis of these findings, we suggest that careful intraoperative opiate titration may be justified to blunt the surgical stress response and promote hemodynamic and temperature stability in similar patients; we also recommend the preparation of warming and cooling devices and continuous temperature monitoring in these patients. Since anesthetic management of these patients is not simple, careful attention is required.