Harlequin sign due to an upper thoracic paravertebral lesion. A systematic review of the literature.

INTRODUCTION: Harlequin syndrome (HS) is an uncommon condition affecting the sympathetic nervous system, characterized by asymmetrical flushing and sweating impairment, which can affect the face or half of the body. When the dysfunction results from external factors like damage or compression, it's referred to as Harlequin Sign. Our objective was to document an exceedingly rare presentation of Harlequin Sign caused by a T3-T4 paravertebral mass and conduct the first systematic literature review on this subject. METHODS: We conducted a systematic review of English-language studies using PubMed, Scopus, and Embase databases. We excluded abstracts, posters, congenital and idiopathic Harlequin Syndrome cases, as well as iatrogenic and secondary Harlequin Sign cases related to pathologies other than upper thoracic lesions. RESULTS: We employed the PRISMA protocol and reviewed 1,538 papers, identifying 8 single case reports describing the Harlequin sign resulting from upper thoracic paravertebral lesions. The mean age of the patients was 41.25 years, with 6 (75 %) being female. The average time from onset to presentation was 8 months, and all patients (100 %) exhibited hemifacial flushing, while 4 (50 %) also had hemifacial anhidrosis. Stress or exercise exacerbated these symptoms in 50 % of cases. Additionally, 3 patients (37.5 %) presented with associated Horner Syndrome. The most commonly used diagnostic tool was a CT scan (50 %), revealing an average tumor diameter of 3.95 cm, with 50 % of cases located at T2-T3. Diagnosis indicated 57 % of cases as schwannomas and 29 % as lung adenocarcinoma (Superior Sulcus). Unfortunately, surgical treatment resolved symptoms in only 25 % of patients. CONCLUSIONS: Hemifacial or hemibody autonomic symptoms should raise concern for paraspinal lesions in the thoracic spine. In addition to the first comprehensive review on this topic, we present a rare case of a T3/4 paraspinal schwannoma causing Harlequin Syndrome successfully managed with neurosurgical intervention.

Effects of hot bath therapy on cholinergic urticaria with hypohidrosis or anhidrosis.

Cholinergic urticaria with hypohidrosis or anhidrosis (CUHA) can impair quality of life due to itching, tingling, and reduced sweating. Current treatment options for CUHA include antihistamines, pulsed steroids, and sweat-promoting therapies such as exercise or hot baths. However, the efficacy of these therapies, particularly hot bath therapy, has yet to be established. We evaluated the efficacy of hot bath therapy in patients with CUHA. We enrolled eight patients who underwent hot bath therapy between January 2010 and August 2022. Patients had a half-body bath in a bathtub filled with hot water (40-43°C) for 30-60 minutes daily for 3-7 days. After treatment, pain improved in three (42.9%) patients, urticaria improved in four (50%) patients, and anhidrosis improved in five (62.5%) patients without any severe adverse events. Because hot bath therapy is easily performed, it should be considered a treatment option for patients with CUHA.

A Systematic Review of Congenital Insensitivity to Pain, a Rare Disease.

INTRODUCTION: Pain perception, far from being a pathological mechanism, is a crucial protective stimulus to prevent additional injuries. Any disturbance in this complex system poses significant risks to individuals, affecting their quality of life and even their survival. OBJECTIVE: This review aims to explore congenital insensitivity to pain, an extremely rare genetic disorder with an autosomal recessive pattern that results in the inability to perceive pain. We will focus on the well-known subtype, congenital insensitivity to pain with anhidrosis (CIPA). Our research seeks to update existing knowledge through a comprehensive literature review. METHODOLOGY: The review employs a systematic literature review, analyzing various sources and scientific documents, primarily emphasizing CIPA. The review follows the PROSPERO protocol, registered under CRD42023394489. The literature search was performed on the Scopus, PubMed, and Cinahl databases. RESULTS: Our review reveals secondary complications associated with CIPA, such as recurrent bone fractures, temperature insensitivity, self-mutilation, and, occasionally, intellectual disabilities. The limited available information underscores the need for expanding our knowledge. CONCLUSIONS: In summary, CIPA, particularly, presents a significant medical challenge with adverse impacts on quality of life. Early diagnosis, education for families and healthcare professionals, and appropriate nursing care are essential for effective management. This review highlights the necessity of further research and awareness to enhance support for those affected.

Improving the Quality of Life in Patients With Hypohidrotic Ectodermal Dysplasia: A Holistic Approach.

Hypohidrotic ectodermal dysplasia (HED), often referred to as Christ-Siemens-Touraine syndrome, is an uncommon inherited genetic disorder characterized by irregularities in structures derived from the ectoderm, such as skin, hair, nails, teeth, and sweat glands. Common manifestations include thin hair, absent teeth (hypodontia) often pointed in shape, and diminished ability to sweat (hypohidrosis). Changes in the ectodysplasin A (EDA) gene are associated with the development of HED. Addressing this condition requires an integrated, interdisciplinary strategy to ensure the best possible support for individuals impacted. This case highlights the significance of early detection, collaborative care, and targeted interventions in managing HED. Continued research is crucial for creating novel therapies and enhancing life quality for those living with this rare condition. Here, we discuss a 22-year-old male patient displaying features such as hypodontia, sparse hair (hypotrichosis), irregular beard growth, a nasal deformity, and an inability to sweat (anhidrosis), which is associated with increased body temperature.

Two onset types of achalasia and the long-term course to diagnosis.

BACKGROUND: Recently, the incidence of achalasia has been increasing, but its cause remains unknown. This study aimed to examine the initial symptoms and the course of symptoms and to find new insights into the cause and course of the disease. METHODS: Altogether, 136 patients diagnosed with achalasia by high-resolution manometry (HRM) were enrolled. Questionnaires and chart reviews were conducted to investigate the initial symptoms, time from onset to diagnosis, and comorbidities, as well as the relationship between HRM results, time to diagnosis, and symptom severity. RESULTS: In total, 67 of 136 patients responded to the questionnaire. The median ages of onset and diagnosis were 42 and 58 years, respectively. The median time from onset to diagnosis was 78.6 months, with 25 cases (37.3%) taking > 10 years to be diagnosed. The symptom onset was gradual and sudden in 52 (77.6%) and 11 (16.4%) patients, respectively. Of the 11 patients with acute onset, three (27.3%) developed anhidrosis at the same time. There was no correlation between the time from onset to diagnosis and esophageal dilatation, resting LES pressure, or mean integrated relaxation pressure (IRP). No correlation was also found between the degree of symptoms and resting LES pressure or IRP. CONCLUSION: Esophageal achalasia can have acute or insidious onsets. This finding may help to elucidate the cause of achalasia.

Effects of two external cooling strategies on physiological and perceptual responses of athletes with tetraplegia during and after exercise in the heat.

Athletes with tetraplegia may experience marked hyperthermia while exercising under environmental heat stress due to their limited ability to dissipate heat through evaporative means. This study investigated the effectiveness of two external cooling strategies (i.e., spraying water onto the body surface or using a cooling vest) on physiological and perceptual variables in tetraplegic athletes during and after an aerobic exercise session in a hot environment. Nine male wheelchair rugby players performed an incremental test to determine their maximum aerobic power output. After that, they were subjected to three experimental trials in a counter-balanced order: control (CON, no body cooling), cooling vest (CV), and water spraying (WS). During these trials, they performed 30 min of a submaximal exercise (at 65% of their maximum aerobic power) inside an environmental chamber set to maintain the dry-bulb temperature at 32 °C. The following variables were recorded at regular intervals during the exercise and for an additional 30 min following the exertion (i.e., post-exercise recovery) with the participants also exposed to 32 °C: body core temperature (TCORE), skin temperature (TSKIN), heart rate (HR), rating of perceived exertion (RPE), thermal comfort (TC), and thermal sensation (TS). While exercising in CON conditions, the tetraplegic athletes had the expected increases in TCORE, TSKIN, HR, RPE, and TC and TS scores. HR, TC, and TS decreased gradually toward pre-exercise values after the exercise, whereas TCORE and TSKIN remained stable at higher values. Using a cooling vest decreased the temperature measured only on the chest and reduced the scores of RPE, TC, and TS during and after exercise but did not influence the other physiological responses of the tetraplegic athletes. In contrast, spraying water onto the athletes' body surface attenuated the exercise-induced increase in TSKIN, led to lower HR values during recovery, and was also associated with better perception during and after exercise. We conclude that water spraying is more effective than the cooling vest in attenuating physiological strain induced by exercise-heat stress. However, although both external cooling strategies do not influence exercise hyperthermia, they improve the athletes' thermal perception and reduce perceived exertion.

Autonomic impairment in primary lateral sclerosis.

PURPOSE: Prior studies reported evidence of autonomic involvement in motor neuron disease and suggested more severe dysfunction in upper motor neuron predominant syndromes. Hence, we sought to characterize autonomic impairment in primary lateral sclerosis. METHODS: Neurological evaluations, thermoregulatory sweat tests, and autonomic reflex screens were analyzed retrospectively in 34 primary lateral sclerosis patients (28 definite and 6 probable). Patients with other potential causes of autonomic failure and patients with autonomic testing results compromised by artifact were excluded. RESULTS: A total of 17 patients reported autonomic symptoms. Orthostatic lightheadedness was most frequent (8 patients), followed by bladder (7), bowel (5), and erectile dysfunction (3). The autonomic reflex screens of 33 patients were reviewed; 20 patients had abnormal studies. The thermoregulatory sweat tests of 19 patients were reviewed; 11 patients had abnormal studies. Composite Autonomic Severity Score was calculated for 33 patients and found abnormal in 20/33 patients (60.6%): 15/20 patients (75%) had mild impairment, and 5/20 patients (25%) had moderate impairment. The frequencies of testing abnormalities were: sudomotor 18/20 (90%), cardiovagal 9/20 (45%), and adrenergic 6/20 (30%). Sweat loss pattern analysis showed global, regional, and mixed patterns to be more common than length-dependent and distal patterns. CONCLUSION: We found evidence of frequent autonomic dysfunction in primary lateral sclerosis, which is generally of modest severity akin to prior reports for amyotrophic lateral sclerosis, but more commonly in a pattern consistent with preganglionic/ganglionic localization. This suggests that primary lateral sclerosis, as with amyotrophic lateral sclerosis, is a multisystem disease that affects the autonomic nervous system.

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.

Multiple courses of steroid pulse therapy are required in treating acquired idiopathic generalized anhidrosis patients with a large anhidrotic area: A retrospective study of 28 cases.

Patients with acquired idiopathic generalized anhidrosis (AIGA) demonstrate a sudden loss of sweating function without neurological or endocrine abnormalities. The main treatment is steroid pulse therapy. However, the number of courses required for improvement has been unclear. This study aims to clarify the factors associated with AIGA disease severity and with AIGA patients' responses to steroid pulse therapy. We retrospectively analysed the clinical information of 28 patients with AIGA in our department from the last 10 years. Univariate analysis revealed that patients with a large anhidrotic area need multiple courses of steroid pulse therapy.

Efficacy of treatment of equine anhidrosis with acupuncture and Chinese herbs is low but higher in treated horses compared with placebo.

OBJECTIVE: To assess the therapeutic efficacy of acupuncture in combination with Chinese herbs for treatment of horses affected with anhidrosis. ANIMALS: 44 horses affected with anhidrosis for up to 3 years' duration were enrolled. Inclusion required both compatible clinical signs and results of a quantitative intradermal terbutaline sweat test. METHODS: Study horses were randomly allocated into 2 groups. Group 1 (n = 19) was treated with daily Chinese herbs and 4 weekly acupuncture sessions. Group 2 (n = 25) was given daily hay powder as a placebo and 4 weekly sham acupuncture sessions. Horses were tested by quantitative intradermal terbutaline sweat test within 2 days after treatment completion and again 4 weeks following treatment. RESULTS: Terbutaline-induced sweat responses (mg) were not different between groups within 2 days and 4 weeks after treatment. Two days after treatment, ratios of sweat responses (compared to baseline) were higher (P < .05) in the treatment group compared to the placebo group at terbutaline concentrations of 1.0, 100, and 1,000 µg/mL. The number of horses responding to treatment was higher in the treatment group (5/19 [26%]), compared to horses in the placebo group (1/25 [4%]) for 1 of 5 terbutaline concentrations 2 days (10 µg/mL) or 4 weeks (0.1 µg/mL) after treatment. CLINICAL RELEVANCE: Ratios of sweat responses were higher in treatment horses 2 days after treatment, compared to baseline, but not 4 weeks later. The efficacy of a traditional Chinese veterinary medicine protocol for anhidrosis treatment with acupuncture and Chinese herbs was low but higher in treated horses compared with placebo.

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.

Congenital Insensitivity to Pain with Anhidrosis: A Case Report.

Hereditary sensory and autonomic neuropathy type 4 (HSAN4), or congenital insensitivity to pain with anhidrosis (CIPA), is a rare autosomal recessive disorder caused by mutations in the NTRK1 gene, resulting in pain insensitivity, anhidrosis, and temperature dysregulation. This report focuses on oral manifestations in an 11-year-old girl with CIPA, highlighting the need for early intervention and comprehensive care. The patient had a history of recurrent oral injuries and an unexplained fever, with a confirmed HSAN4 diagnosis through genetic analysis. Clinical features included pain insensitivity, anhidrosis, and intellectual disability. Dental history revealed emergency care, suboptimal oral hygiene, early tooth loss, and infections. Extra-oral examination showed nail-biting and injuries, while intra-oral assessment revealed ulcers and scars. Radiographic evaluation indicated mandibular alveolar bone thinning and periapical lesions in the lower incisors. This case emphasizes the complex challenges of CIPA, including pain insensitivity, recurring fever episodes, and self-inflicted injuries. Early diagnosis and specific dental care are vital to prevent orofacial trauma, necessitating a proactive interdisciplinary approach for comprehensive care.

Hypohidrotic Ectodermal Dysplasia: A Case Report.

Ectodermal dysplasia (ED) is a rare genetic disorder that affects the developmental disturbance of ectoderm-derived tissues, organs, and accessory appendages, i.e. skin, hair, tooth, nail, and sweat glands. ED has two types hypohidrotic or anhidrotic ectodermal dysplasia and hidrotic ectodermal dysplasia. We report this case of classical hypohidrotic ectodermal dysplasia (HED) with clubbing. The association of clubbing with HED is still rare. This case report aims to discuss the etiology, clinical manifestations, and management of ectodermal dysplasia. A multidisciplinary approach is required including dentists, nutritionists, dermatologists, and physicians to manage ectodermal dysplasia.

From the Destruction of Two Lumbar Segments to Thoracic-Lumbar-Pelvic Fusion: A Case Caused by Congenital Insensitivity to Pain with Anhidrosis and Literature Review.

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) with Charcot arthropathy is a rare combination in orthopaedic clinical practice. The experience dealing with such patients is limited. Here with this case of approximately 10 years follow-up, we wish to shed light on the choices of strategies of surgeries and alerting clinicians with post-surgery complications. The possible underlying reasons for the recurrent Charcot arthropathies as well as strategies for peri-operative management for such surgical cases are also discussed. CASE PRESENTATION: The patient underwent a surgery to correct her severe kyphosis caused by CIPA-related Charcot spine. Multiple post-surgery complications occurred during her follow-up, including hardware migration, adjacent segment disease (ASD), and loosening pedicle screws. Five revision surgeries were conducted consequently. From the limited experience on the management of CIPA-related Charcot spine, surgical correction is still the first-line treatment. CONCLUSIONS: Of all the 16 cases reviewed (including our case), loosening pedicle screws, hardware migration, and ASDs are the common post-surgery complications. Large-scale removal of damaged vertebrae and subsequent reconstruction are not recommended, which might increase the risk of hardware migration. A 360° long-segment fusion might be of help to reduce the risk of ASDs. In the meantime, comprehensive management including careful nursing, proper rehabilitation exercises, and treatments targeting bone mineral metabolism is also critical.

A Small-for-Gestational-Age Infant with MIRAGE Syndrome Who Developed Heat Stroke and Rhabdomyolysis due to Severe Temperature Instability.

MIRAGE syndrome is characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. This report describes heat stroke and rhabdomyolysis caused by anhidrosis as a symptom of MIRAGE syndrome in a small-for-gestational-age (SGA) female neonate born at 32 weeks of gestation (birth weight, 911 g [-3.8 SD]). She developed severe temperature instability with anhidrosis, growth failure, mild developmental delay, hypothyroidism, and intractable enteropathy. On day 156, her temperature reached 42.0°C; her fever persisted for 2 h with prolonged irritability. Her serum creatine kinase level increased to a peak value of 12,716 (normal range, 43-321) IU/L. The clinical feature was diagnosed as rhabdomyolysis caused by heat stroke, which resulted from physical exertion with anhidrosis. Her SAMD9 variant was c.2945G>A, p. (Arg982His). Neonatologists should be aware of MIRAGE syndrome as a differential diagnosis of SGA with temperature instability.

Pharmacovigilance-based drug repurposing: searching for putative drugs with hypohidrosis or anhidrosis adverse events for use against hyperhidrosis.

BACKGROUND: Drug repurposing refers to the application of existing drugs to new therapeutic indications. As phenotypic indicators of human drug response, drug side effects may provide direct signals and unique opportunities for drug repurposing. OBJECTIVES: We aimed to identify drugs frequently associated with hypohidrosis or anhidrosis adverse reactions (that is, the opposite condition of hyperhidrosis) from the pharmacovigilance database, which could be potential candidates as anti-hyperhidrosis treatment agents. METHODS: In this observational, retrospective, pharmacovigilance study, adverse event reports of hypohidrosis or anhidrosis in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) were assessed between January 2004 and December 2021 using reporting odds ratio (ROR) estimates and categorized by the World Health Organization Anatomical Therapeutic Chemical (ATC) classification code. The onset time of drug-associated hypohidrosis or anhidrosis was also examined. RESULTS: There were 540 reports of 192 drugs with suspected drug-associated hypohidrosis or anhidrosis in the FAERS database, of which 39 drugs were found to have statistically significant signals. Nervous system drugs were most frequently reported (187 cases, 55.82%), followed by alimentary tract and metabolism drugs (35 cases, 10.45%), genitourinary system and sex hormones (28 cases, 8.36%), and dermatologicals (22 cases, 6.57%). The top 3 drug subclasses were antiepileptics, drugs for urinary frequency and incontinence, and antidepressants. Taking disproportionality signals, pharmacological characteristics of drugs and appropriate onset time into consideration, the main putative drugs for hyperhidrosis were glycopyrronium, solifenacin, oxybutynin, and botulinum toxin type A. Other drugs, such as topiramate, zonisamide, agalsidase beta, finasteride, metformin, lamotrigine, citalopram, ciprofloxacin, bupropion, duloxetine, aripiprazole, prednisolone, and risperidone need more investigation. CONCLUSIONS: Several candidate agents among hypohidrosis or anhidrosis-related drugs were identified that may be redirected for diminishing sweat production. There are affirmative data for some candidate drugs, and the remaining proposed candidate drugs without already known sweat reduction mechanisms of action should be further explored.

Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal Dysplasia.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene (EDA). Most affected males are hemizygous for EDA null mutations that lead to the absence or inactivity of the signalling protein ectodysplasin A1 (EDA1) and, thus, to the full-blown phenotype with inability to perspire and few if any teeth. There are currently no long-term treatment options for XLHED. ER004 represents a first-in-class protein replacement molecule designed for specific, high-affinity binding to the endogenous EDA1 receptor (EDAR). Its proposed mechanism of action is the replacement of missing EDA1 in yet unborn patients with XLHED. Once bound to EDAR, ER004 activates the EDA/NFκB signalling pathway, which triggers the transcription of genes involved in the normal development of multiple tissues. Following preclinical studies, named-patient use cases demonstrated significant potential of ER004 in affected males treated in utero during the late second and third trimesters of pregnancy. In order to confirm these results, we started the EDELIFE trial, a prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration as a prenatal treatment for male subjects with XLHED. This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls.