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.

Christ-Siemens-Touraine Syndrome: A Report of a Rare Pediatric Case.

Anhidrotic ectodermal dysplasia (AED), or Christ-Siemens-Touraine syndrome, is an X-linked recessive dermatosis. Rare in incidence, it affects 1 in 100,000 births, mostly boys. Through this observation, we detail the clinical signs that led us to suspect the diagnosis, how this pathology was confirmed, and the therapeutic management we carried out. We present a case of a 10-month-old boy presenting with altered manifestations affecting almost all the ectodermal structures like skin, hair, nails, teeth, sebaceous glands, sweat glands, and tear glands. He also had complete anodontia and a dry mouth. A multidisciplinary treatment was given to the patient with the collaboration of various health professionals. Although Christ-Siemens-Touraine syndrome is a rare condition, it is vital to recognize it early to improve care and prognosis for these patients, while mitigating the psychological impact of the condition on both children and parents.

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.

HELIX Syndrome, a Claudinopathy with Relevant Dermatological Manifestations: Report of Two New Cases.

HELIX syndrome (Hypohidrosis-Electrolyte disturbances-hypoLacrimia-Ichthyosis-Xerostomia) (MIM#617671) (ORPHA:528105), described in 2017, is due to an abnormal claudin 10 b protein, secondary to pathogenic CLDN10 variants. So far, only ten families have been described. We aim to describe the phenotype in the first Spanish family identified, highlight the skin anomalies as an important clue, and expand the genotypic spectrum. Two adult brothers from consanguineous parents with suspected ectodermal dysplasia (ED) since early childhood were re-evaluated. A comprehensive phenotypic exam and an aCGH + SNP4 × 180 K microarray followed by Sanger sequencing of the CLDN10 gene were performed. They presented hypohidrosis, xerosis, mild ichthyosis, plantar keratosis, palm hyperlinearity, alacrima, and xerostomia. In adulthood, they also developed a salt-losing nephropathy with hypokalemia and hypermagnesemia. The molecular study in both patients revealed a novel pathogenic homozygous deletion of 8 nucleotides in exon 2 of the CLDN10 gene [CLDN10 (NM_0006984.4): c.322_329delGGCTCCGA, p.Gly108fs*] leading to a premature truncation of the protein. Both parents were heterozygous carriers. Hypohidrosis, ichthyosis, and plantar keratosis associated with alacrima and xerostomia should raise suspicion for HELIX syndrome, which also includes nephropathy and electrolyte disturbances in adults. Given the potential for ED misdiagnosis in infancy, it is important to include the CLDN10 gene in a specific genodermatosis next-generation sequencing (NGS) panel to provide early diagnosis, accurate management, and genetic counseling.

Altered Sweat Composition Due to Changes in Tight Junction Expression of Sweat Glands in Cholinergic Urticaria Patients.

In cholinergic urticaria (CholU), small, itchy wheals are induced by exercise or passive warming and reduced sweating has been reported. Despite the described reduced muscarinic receptor expression, sweat duct obstruction, or sweat allergy, the underlying pathomechanisms are not well understood. To gain further insights, we collected skin biopsies before and after pulse-controlled ergometry and sweat after sauna provocation from CholU patients as well as healthy controls. CholU patients displayed partially severely reduced local sweating, yet total sweat volume was unaltered. However, sweat electrolyte composition was altered, with increased K+ concentration in CholU patients. Formalin-fixed, paraffin-embedded biopsies were stained to explore sweat leakage and tight junction protein expression. Dermcidin staining was not found outside the sweat glands. In the secretory coils of sweat glands, the distribution of claudin-3 and -10b as well as occludin was altered, but the zonula occludens-1 location was unchanged. In all, dermcidin and tight junction protein staining suggests an intact barrier with reduced sweat production capability in CholU patients. For future studies, an ex vivo skin model for quantification of sweat secretion was established, in which sweat secretion could be pharmacologically stimulated or blocked. This ex vivo model will be used to further investigate sweat gland function in CholU patients and decipher the underlying pathomechanism(s).

Unexplained Fever in Infancy: Report of a Rare Case of Hypohidrotic Ectodermal Dysplasia in an Infant.

Hypohidrotic ectodermal dysplasia (HED) is a genetic condition that affects structures derived from the ectoderm during embryonic development. These structures include the outermost layer of the primary germ layers, which give rise to various body parts such as the ears, eyes, lips, and mucous membranes of the nose and mouth. Due to the impact on these structures, hypohidrotic ectodermal dysplasia can manifest differently in various age groups. However, the three primary characteristics typically associated with this condition are hypotrichosis, hypohidrosis, and hypodontia or anodontia. Here, we present a case of a male infant, aged 2 months, who was brought to our attention due to symptoms of unexplained fever and irritability. The child's family history was noteworthy, as an older sibling had distinctive features of ectodermal dysplasia. This information led us to consider the possibility of this diagnosis. This case report aims to highlight the distinctive features of such cases that facilitate the identification of this condition and its related complications. By sharing this case, we intend to raise awareness and encourage timely detection, diagnosis, and proper treatment of patients with this condition.

Concurrence of Hyperhidrosis and Hypohidrosis in Ross Syndrome.

Ross Syndrome is a rare disorder characterized by tonic pupils, hyporeflexia, and abnormal segmental sweating. The pathophysiology of the disease remains unclear, with either hypohidrosis or hyperhidrosis reported in individual patients. We present the case of a man, aged 57 years, who presented with hyperhidrosis in his right extremities, anhidrosis in the left extremities, and changes in his pupils. The disease was not associated with markers of autoimmune disease, which supports recent research findings on the role of neurodegeneration. The patient's son was exhibiting similar symptoms, which implicates genetic inheritance in the process. A multidisciplinary approach is crucial for the diagnosis and ultimate management of patients with Ross Syndrome.

Long-term dupilumab therapy in Netherton syndrome with severe atopic manifestations: Case report and review of the literature.

We herein present a unique patient of Netherton syndrome (NS) with ichthyosis linearis circumflexa (ILC) lesions associated with severe atopic manifestations since infancy, showing different responses of atopic and ILC lesions to a 2-year dupilumab therapy. The atopic eczematous lesions and pruritus healed remarkably, dramatically improving the patient's quality of life, whilst the scalp hair showed a clinical and light microscopic improvement. The additional recovery in axillary/pubic/extremity hair growth, sweating and nail growth in the presented case was not previously reported in NS patients treated with dupilumab. However, dupilumab had no therapeutic effect on ILC lesions which were not pruritic and showed a treatment-independent wax and waned course.

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.

The Swedish COG6-CDG experience and a comprehensive literature review.

Here, we present the first two Swedish cases of Conserved Oligomeric Golgi complex subunit 6-congenital disorders of glycosylation (COG6-CDG). Their clinical symptoms include intellectual disability, Attention Deficit/Hyperactivity Disorder (ADHD), delayed brain myelinization, progressive microcephaly, joint laxity, hyperkeratosis, frequent infections, and enamel hypoplasia. In one family, compound heterozygous variants in COG6 were identified, where one (c.785A>G; p.Tyr262Cys) has previously been described in patients of Moroccan descent, whereas the other (c.238G>A; p.Glu80Lys) is undescribed. On the other hand, a previously undescribed homozygous duplication (c.1793_1795dup) was deemed the cause of the disease. To confirm the pathogenicity of the variants, we treated patient and control fibroblasts with the ER-Golgi transport inhibitor Brefeldin-A and show that patient cells manifest a significantly slower anterograde and retrograde ER-Golgi transport.

Focal hypohidrosis in lesional skin in a probable case of confluent and reticulated papillomatosis: A case report with insight into the pathomechanism of recurrence.

Confluent and reticulated papillomatosis (CRP) is a rare skin disorder that develops in young adults and presents as persistent brown papules and plaques predominantly affecting the intertriginous areas, however, its etiopathogenesis remains elusive. Herein, we report a probable case of CRP with lesional hypohidrosis as detected by sweat test and provide insight into the pathomechanism. A 23-year-old man presented with nine-months history of painful sensation on his trunk without any skin change. The result of sweat test was compatible with acquired idiopathic generalized anhidrosis. Topical heparinoid and physical exercise improved the symptoms. However, he started to notice asymptomatic brownish reticulated macules on the trunk. Intriguingly, focal hypohidrosis, as detected by sweat test was evident on the macules. In histology, the lesional skin demonstrated hyperkeratosis, acanthosis, basal melanosis, mild papillomatosis, and obstruction of the sweat duct in the upper dermis, which were not observed in the peri-lesional skin. Accumulation of the sweat in the luminal aspect of the secretory portion and dilation of the sweat duct in the deeper dermis was detected in the lesional skin, as highlighted by anti-dermcidin staining. Aquaporin 5 expression in the secretory portion was more confined to the cell membrane in the lesional skin. Both brownish macules and lesional hypohidrosis simultaneously improved in summer and exacerbated in winter. Literature review found nine reports on recurrent CRP, and obesity was thought to be a major comorbidity in recurrent CRP cases. Obesity is often associated with sweat dysregulation. This, together with the findings in our case, implied the possible contribution of focal sweating abnormality in the pathogenesis of reticulated skin lesion in our case.

Appearance Says It All; A Rare Case Of Hypohidrotic Ectodermal Dysplasia.

Ectodermal Dysplasia (ED) is a rare genetic condition characterized by the involvement of ectoderm derivatives such as hair, nail, sweat glands, and teeth. It has many variants, but the two most common ones are hypohidrotic/anhidrotic ectodermal dysplasia and hidrotic ectodermal dysplasia. Herein, we present a case of a 20-year-old female with hypohidrotic ectodermal dysplasia who had anodontia, hypohidrosis, and hypotrichosis, and her condition went unrecognized until she was seen for gastroenteritis at a tertiary care center. This case report will help spread education and awareness regarding such a rare and under-recognized condition. Early diagnosis and intervention help improve the quality of life.

Impaired sweating in patients with cholinergic urticaria is linked to low expression of acetylcholine receptor CHRM3 and acetylcholine esterase in sweat glands.

Background: Cholinergic urticaria (CholU), a frequent form of chronic inducible urticaria, is characterized by itchy wheals and angioedema in response to sweating. As of now, the rate and pathophysiological relevance of impaired sweating in patients with CholU are ill-defined. Aim: To assess in CholU patients the rate and extent of impaired sweating and its links to clinical and pathophysiological features of CholU. Patients and methods: We assessed sweating in patients with CholU (n = 13) subjected to pulse-controlled ergometry (PCE) provocation testing. Pre- and post-PCE biopsies of lesional (L) and non-lesional (NL) skin were analyzed for the expression of acetylcholine receptor M3 (CHRM3) and acetylcholine esterase (ACh-E) by quantitative histomorphometry and compared to those of healthy control subjects (HCs). CholU patients were assessed for disease duration and severity as well as other clinical features. Results: Of the 13 patients with CholU, 10 showed reduced sweating in response to PCE provocation, and 3 had severely reduced sweating. Reduced sweating was linked to long disease duration and high disease severity. CholU patients with impaired sweating responses showed reduced sweat gland epithelial expression of CHRM3 and ACh-E. Conclusion: Reduced sweating is common in CholU patients, especially in those with long-standing and severe disease, and it can be severe. Reduced expression of CHRM3 and ACh-E may be the cause or consequence of CholU in patients with impaired sweating, and this should be explored by further studies.

Anhidrosis accompanied by cholinergic urticaria-like rash and dermal pain in a patient with Sjögren's syndrome.

Cholinergic urticaria (CholU)-like rash and dermal pain on sweating occur in patients with acquired idiopathic generalized anhidrosis (AIGA). However, it is unclear whether these are symptoms specific to AIGA among the various types of acquired generalized anhidrosis/hypohidrosis (AGAH). Moreover, the pathogenesis underlying CholU-like rash and dermal pain observed with anhidrosis remains to be clarified. A 20-year-old Japanese man with Sjögren's syndrome (SS) presented with anhidrosis. Transient stinging pain on the skin and pinpoint wheals were observed when his body temperature increased. Thermoregulatory sweat testing revealed anhidrotic areas covering 69% of the body surface area with a symmetrical distribution. A high concentration of histamine was detected (506 ng/mL) in the sweat. A skin biopsy specimen from the anhidrotic area showed the inflamed secretory portion of eccrine glands. This suggested inflammation-mediated damage to sweat glands, consistent with AGAH related to SS. Furthermore, immunohistochemical analysis revealed an ectopic distribution of dermcidin, a sweat-specific peptide, in the dermal tissue surrounding the secretory portion of eccrine glands. The expression of claudin-3, a tight junction (TJ) component of sweat glands, decreased or distributed in a mottled manner in the secretory portion. No decreased expression of muscarinic cholinergic receptor M3 was detected. These results suggested that sweat had leaked into the dermis in association with impaired TJ in the secretory portion, along with the damage to inflamed sweat glands related to SS. Collectively, CholU-like rash and dermal pain on sweating were observed in an AGAH patient with SS. The sweat leakage into the dermis may contribute to the development of the rash and pain.

Beneficial screening of Fabry disease in patients with hypohidrosis.

Fabry disease (FD), which is a lysosomal storage disease resulting from a deficiency of α-galactosidase A, leads to the accumulation of globotriaosylceramide in various tissues and multiorgan impairment. Early diagnosis is important to improve long-term prognosis. Early clinical manifestations of FD include neuropathic pain, vascular skin lesions, and sweating abnormalities. Hypohidorosis is one of the clinical findings in the early stage of FD. However, there have been no studies on prospective screening of FD in patients with definitive diagnosis of hypohidrosis. We examined α-galactosidase A activity in white blood cells in 17 (one female and 16 male) patients with generalized hypohidorosis. Among 17 patients, one male patient (approximately 5.8%) had significantly reduced α-galactosidase A activity. He presented with a history of hypohidrosis with heat intolerance and neuropathic tingling pain in a warm environment from 6 years ago. He had a few angiokeratoma on the trunk and extremities. Ultrastructural examination of skin biopsy from the angiokeratoma revealed lamellar inclusions in endothelial cells. Kidney biopsy revealed swollen podocytes and Gb3 deposition in the glomerulus, and urinalysis revealed mulberry bodies. He was finally diagnosed with FD and started on enzyme replacement therapy with agalsidase alpha in the early stage. In addition, his family screening led to find the patients of four additional FD. Screening for FD in patients with hypohidrosis may lead to efficient early detection of FD.

The phenotypic characteristics of patients with athelia and tooth agenesis.

BACKGROUND: Although athelia, which is a congenital aplastic deformity of the nipple, is seldom reported in tooth agenesis patients, we observed athelia in 2 hypodontia patients. This study aimed to summarize the phenotypic characteristics of patients with athelia and tooth agenesis. METHODS: A database search was conducted for publications reporting on patients with athelia and tooth agenesis, and the phenotypes of such patients were recorded. Athelia-related syndromes were identified in the Online Mendelian Inheritance in Man (OMIM) database. The common symptoms and the causative genes were documented. Potential interactions between athelia-related genes and tooth agenesis-related genes were analyzed in the Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. RESULTS: We summarized the phenotypic characteristics of 8 previously reported patients. Deformities in hair, skin, and sweat glands were common in these patients. There were 23 nipple deformity-related syndromes reported. The most common symptoms included abnormalities of the head and neck, cardiovascular, genitourinary, and skeletal systems, and the skin, nails, and hair. Hypodontia was noted in association with 10 syndromes. A total of 16 genes were related to them, including TP63, KCTD1, and IKBKG. The interaction found in the study suggests that nipple deformity-related genes potentially interact with tooth agenesis-related genes. CONCLUSIONS: These results indicated that athelia might be related to hypodontia. Additional molecular genetics research is needed to fully elucidate the underlying relationship between athelia and tooth agenesis.

Genetic analysis and prenatal diagnosis in a Chinese with growth retardation, abnormal liver function, and microcephaly.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a genetically heterogeneous group of disorders caused by defects in the synthesis and processing of glycoproteins. COG6-CDG is a kind of disorder caused by conserved oligomeric golgi complex 6 (COG6) deficiency. To date, only 19 patients with COG6-CDG have been reported. METHODS: We report a girl in a Chinese family with developmental delay, growth retardation, microcephaly, abnormal liver function, and hypohidrosis. Trio whole-exome sequencing was performed for this patient and her parents, and the variants identified were validated by Sanger sequencing. Prenatal diagnosis was done for this family during a subsequent pregnancy. The literature review on these patients was performed by reviewing articles published in English and Chinese. RESULTS: Genetic sequencing identified two novel heterozygous mutations: c.428G>T (p.S143I) and c.1843C>T (p.Q615X) in the COG6 gene, inherited from her healthy parents, respectively. A total of 11 different mutations in COG6 have been reported previously, and mutations potentially affecting splicing are the most common. The main clinical features included development delay, facial dysmorphism, growth retardation, skin abnormalities (hypohidrosis), microcephaly, abnormal brain structure, liver involvement, and recurrent infections. CONCLUSION: Our work broadens the mutation spectrum of COG6 gene and states the importance of whole-exome sequencing in facilitating the definitive diagnosis of this disorder and prenatal diagnosis in a subsequent pregnancy.

A novel claudin-10 mutation with a unique mechanism in two unrelated families with HELIX syndrome.

HELIX syndrome, characterized by hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia due to claudin-10 (CLDN10) mutations, was recognized in 2017. Here we describe two unrelated Saudi families with this syndrome due to a novel CLDN10 mutation with a unique mechanism of CLDN10 inactivation. The two consanguineous families include 12 affected individuals (three siblings in family 1 and nine members in family 2). They presented with hypokalemia and the above-mentioned features of HELIX syndrome. The underlying mutation was detected by whole exome sequencing, confirmed by Sanger sequencing and functionally indicated by RT-PCR, electrophysiological studies and immunohistochemical staining of transfected HEK293 and MDCK C7 cells, and skin and kidney biopsy tissues. A novel biallelic single nucleotide deletion was identified in exon 5 of CLDN10 (NM_182848.3: c.647delC, p.P216Lfs∗19 for CLDN10a or NM_006984.4: c.653delC, p.P218Lfs∗21 for CLDN10b). The mutation led to frameshift and extension of the original termination codon by nine amino acids with loss of the C-terminus pdz-binding motif. Functional studies showed mRNA degradation and protein retention in intracellular compartments and that the pdz-binding motif is crucial for proper localization of claudin-10 in tight junctions. In the kidney, claudin-10 was replaced by translocation of claudin-2 (proximal tubule) and claudin-19 (thick ascending limb), and in the sweat gland by claudin-3 and occludin. However, these claudins did not functionally compensate for loss of claudin-10. Thus, this novel CLDN10 mutation identified in these two families disrupted the C-terminus pdz-binding motif of claudin-10 causing HELIX syndrome.