Clinical and histological characterization of transient dermal pain triggered by sweating stimuli.

BACKGROUND: Tingling dermal pain triggered by sweating impairs the lives of patients with cholinergic urticaria and generalized anhidrosis. However, dermal pain evoked by sweating stimuli has been under investigated. METHODS: To clarify characteristics of tingling dermal pain on sweating, we retrospectively evaluated clinical and histopathological manifestations in 30 patients having the main problem of dermal pain on sweating, and the efficacy of treatments. RESULTS: Dermal pain upon sweating affected mostly young males. It accompanied eruptions upon sweating and/or hypohidrosis in 24 patients, while 6 patients had dermal pain independently of hypohidrosis or eruptions. Dermal pain appeared immediately upon exposure to sweating stimuli, and disappeared within mostly 30 or 10 min. Hypohidrosis was not necessarily generalized but localized or absent. Histological analysis revealed that dermal pain could occur even without morphological changes and inflammation of sweat glands. Hypersensitivity to sweat contents was found only in 26% of patients. Sweat histamine and increase of plasma histamine after thermal induction in patients were significantly higher than those in healthy subjects. Effectiveness of steroid pulse therapy was demonstrated for dermal pain with hypohidrosis. Medications acting on nervous systems and regular sweat-inducing activities for promoting perspiration were also effective. CONCLUSIONS: Short-lasting tingling dermal pain appears immediately upon exposure to sweating stimuli, regardless of developing eruptions and/or presence of hypohidrosis, but possibly in association with sweat and plasma histamine.

Acquired Idiopathic Generalized Anhidrosis (AIGA) and Its Complications: Implications for AIGA as an Autoimmune Disease.

Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder in which systemic anhidrosis/hypohidrosis occurs without causative dermatological, metabolic or neurological disorder. Most cases of AIGA have been reported in Asia, especially in Japan, but there have been only a few reports in Europe and the United States. Severe AIGA may result in heatstroke and can reduce quality of life due to restriction of exercise and outdoor works. AIGA is often accompanied by cholinergic urticaria (CholU), and it is thought that AIGA and CholU with anhidrosis/hypohidrosis belong to the same spectrum of the disease. However, the pathophysiology of AIGA has not yet been clarified. Decreased expression of cholinergic receptor M3 on the epithelial cells of eccrine sweat glands is often accompanied by T cell infiltration around eccrine apparatus, suggesting an immunological mechanism of disordered perspiration. AIGA is occasionally associated with various complications indicative of autoimmune disorders. The association of autoimmune complications further suggests that AIGA is an autoimmune disorder. Studies on complications may lead to a better understanding of the pathophysiology of AIGA.

Clinical, genomics and networking analyses of a high-altitude native American Ecuadorian patient with congenital insensitivity to pain with anhidrosis: a case report.

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). CASE PRESENTATION: Here, we present clinical and molecular findings in a 9-year-old girl with CIPA. The high-altitude indigenous Ecuadorian patient presented several health problems such as anhidrosis, bone fractures, self-mutilation, osteochondroma, intellectual disability and Riga-Fede disease. After the mutational analysis of NTRK1, the patient showed a clearly autosomal recessive inheritance pattern with the pathogenic mutation rs763758904 (Arg602*) and the second missense mutation rs80356677 (Asp674Tyr). Additionally, the genomic analysis showed 69 pathogenic and/or likely pathogenic variants in 46 genes possibly related to phenotypic heterogeneity, including the rs324420 variant in the FAAH gene. The gene ontology enrichment analysis showed 28 mutated genes involved in several biological processes. As a novel contribution, the protein-protein interaction network analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix involved in the response to stimulus and nervous system development. CONCLUSIONS: This is the first study that associates clinical, genomics and networking analyses in a Native American patient with consanguinity background in order to better understand CIPA pathogenesis.

The characterization of hypodontia, hypohidrosis, and hypotrichosis associated with X-linked hypohidrotic ectodermal dysplasia: A systematic review.

The objective of this study was to review the published literature on X-linked hypohidrotic ectodermal dysplasia (XLHED) for the prevalence and characteristics of three features of XLHED: hypodontia, hypohidrosis, and hypotrichosis. A systematic search of English-language articles was conducted in May 2019 to identify publications with information on any of the three features of XLHED. We excluded studies with five or fewer participants, that did not specify X-linked inheritance or an EDA mutation, and discussed only management of features. The weighted means for total missing teeth, location of missing teeth, prevalence of reduced and absent sweating ability, and sparse or absent hair were analyzed across all studies. Additional findings for hypodontia, hypohidrosis, and hypotrichosis were summarized qualitatively. Twenty publications (18 studies) were accepted. Reported findings for males tended to be more informative than for carrier females. The weighted mean for missing teeth for affected males was 22.4 (range: 10-28) and carrier females was 3.4 (range: 0-22). The most common conserved teeth for males were the canines. The most common missing teeth for females were the maxillary lateral incisors. The weighted mean prevalence of reduced or absent sweating ability was 95.7% for males and 71.6% for females. The weighted mean prevalence for hypotrichosis was 88.1% for males and 61.6% for females. This systematic review provides insight into the prevalence, characteristics, and variability of the three classic features of XLHED. These findings provide detailed natural history information for families with XLHED as well as key characteristics that can aid in diagnosis.

ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.

PURPOSE: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. METHODS: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. RESULTS: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. CONCLUSION: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

Quantification of sweat gland innervation in patients with Fabry disease: A case-control study.

INTRODUCTION: Hypohidrosis and heat intolerance, frequently reported by men and women with Fabry disease (FD), is thought to be related not only to the deposition of globotriaosylceramide (Gb3) in eccrine sweat glands, but also to reduced sweat gland sympathetic innervation. METHODS: We performed a case-control study to compare the density of sweat gland innervation between patients with FD and healthy controls by examining lower leg skin punch biopsies. We used a standardized grid of circles superimposed upon the immunofluorescent specimen to create a simple pattern of circles over the sweat gland. Nerve fibers that crossed within the circles were manually counted ("crossed circles"). Nerve fibers that touched the edge of the circle but did not enter were spared ("uncrossed circles"). The percentage of crossed circles from all circles was determined. RESULTS: Biopsy specimens were available of 37 FD patients (median age 44 years, 19-67; n = 18 men) and 16 controls (median age 48 years, 24-83, n = 7 men). Totally there were 153 sweat glands from FD patients and 63 from controls, in which innervation was quantified. While mean sweat gland innervation per biopsy did not differ between the entire FD cohort and controls, data stratification for the reported sweating phenotype revealed a stepwise lower innervation in women with FD and hypohidrosis (n.s.) and anhidrosis (p < .05) compared to women reporting normal sweating. CONCLUSION: Sweat gland innervation is reduced in women with FD and anhidrosis compared to female patients without sweating impairment. Loss of sweat gland innervation may play a role in FD associated anhidrosis, at least in women.

X-Linked Hypohidrotic Ectodermal Dysplasia: New Features and a Novel EDA Gene Mutation.

We described a 5-year-old male with hypodontia, hypohidrosis, and facial dysmorphisms characterized by a depressed nasal bridge, maxillary hypoplasia, and protuberant lips. Chromosomal analysis revealed a normal 46,XY male karyotype. Due to the presence of clinical features of hypohidrotic ectodermal dysplasia (HED), the EDA gene, located at Xq12q13.1, of the patient and his family was sequenced. Analysis of the proband's sequence revealed a missense mutation (T to A transversion) in hemizygosity state at nucleotide position 158 in exon 1 of the EDA gene, which changes codon 53 from leucine to histidine, while heterozygosity at this position was detected in the slightly affected mother; moreover, this mutation was not found in the publically available Human Gene Mutation Database. To date, our findings indicate that a novel mutation in EDA is associated with X-linked HED, adding it to the repertoire of EDA mutations.

Serum carcinoembryonic antigen specifically increases among various serum markers of adenocarcinoma in hypohidrosis or conditions related to hypohidrosis.

Anhidrosis/hypohidrosis are conditions presenting various level of sweating dysfunction. Among them, acquired idiopathic generalized anhidrosis (AIGA) presents inadequate decrease or loss of sweating without apparent neurological and dermatological symptoms except cholinergic urticaria. Recently, serum level of carcinoembryonic antigen (CEA), one of the most well-known tumor markers, has been proposed as a clinical marker reflecting activity of AIGA. This study was performed to verify the specificity and independence of serum CEA level from the other serum tumor markers especially related to adenocarcinoma. The expression of various tumor markers in the serum collected from three healthy control subjects, four AIGA cases, and a cholinergic urticaria (CU) case with elevation of serum CEA level and history of hyperthermia was analyzed using a membrane-based antibody array. In all AIGA and CU cases, the intensity of CEA was significantly increased (7.60-15.9 times compared with that of control), relatively well-reflecting the serum CEA level, and the mean intensity of CEA was 11.8 times higher than the control subjects (P = 0.0011). On the other hand, the ratio of carbohydrate antigen (CA)125 and CA19-9 was 1.93 and 0.23 times compared with the mean intensity of the control subjects, respectively, and there was no statistical significance. Immunohistochemistry on 10 AIGA cases showed increased expression of CEA but not CA19-9 and CA125 in the eccrine sweat glands. In conclusion, the elevation of serum CEA level was independent from the other tumor markers in hypohidrotic condition represented by AIGA.

Evaluation of the correlation between severity of acquired idiopathic generalized anhidrosis and quality of life scores.

Symptoms of acquired idiopathic generalized anhidrosis (AIGA) include heat retention and/or heat stroke due to the effects of the disorder on the perspiration ability of the whole body under thermal environmental changes or exercise. Additionally, cholinergic urticaria can also occur in these patients. AIGA has a major impact on everyday life. However, the effects of AIGA severity on the quality of life (QOL) of the patients have not been sufficiently defined. The objective of this study was to evaluate the correlation between AIGA severity and QOL. Study subjects comprised 44 patients diagnosed with AIGA at three registered institutions. AIGA severity assessment was conducted and the Dermatology Life Quality Index (DLQI) questionnaire was administered. Correlations between AIGA severity and DLQI, as well as severity by DLQI subscale, were assessed. We found a positive correlation between total score of AIGA severity criteria and DLQI total scores (R = 0.720, P = 0.001). The impairment increased with the increase in AIGA severity (P < 0.01). In relation to the DLQI subscales, leisure (social and sporting activities) impairment was significantly higher for patients with severe AIGA than those with mild AIGA (P < 0.01). Comparing QOL for AIGA patients with that of patients with other dermatological disorders, it is possible that QOL impairment for AIGA patients is as severe as that for patients with atopic dermatitis. AIGA severity and DLQI are correlated and AIGA patients experience disruption of everyday life more broadly than conventionally perceived.