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Lack of type VII collagen (C7) disrupts cellular proteostasis yet the mechanism remains undescribed. By studying the relationship between C7 and the extracellular matrix (ECM)-associated proteins thrombospondin-1 (TSP1), type XII collagen (C12) and tissue transglutaminase (TGM2) in primary human dermal fibroblasts from multiple donors with or without the genetic disease recessive dystrophic epidermolysis bullosa (RDEB) (n=31), we demonstrate that secretion of each of these proteins is increased in the presence of C7. In dermal fibroblasts isolated from patients with RDEB, where C7 is absent or defective, association with the COPII outer coat protein SEC31 and ultimately secretion of each of these ECM-associated proteins is reduced and intracellular levels are increased. In RDEB fibroblasts, overall collagen secretion (as determined by the levels of hydroxyproline in the media) is unchanged while traffic from the ER to Golgi of TSP1, C12 and TGM2 occurs in a type I collagen (C1) dependent manner. In normal fibroblasts association of TSP1, C12 and TGM2 with the ER exit site transmembrane protein Transport ANd Golgi Organization-1 (TANGO1) as determined by proximity ligation assays, requires C7. In the absence of wild-type C7, or when ECM-associated proteins are overexpressed, C1 proximity and intracellular levels increase resulting in elevated cellular stress responses and elevated TGFß signaling. Collectively, these data demonstrate a role for C7 in loading COPII vesicle cargo and provides a mechanism for disrupted proteostasis, elevated cellular stress and increased TGFß signaling in patients with RDEB. Furthermore, our data point to a threshold of cargo loading that can be exceeded with increased protein levels leading to pathological outcomes in otherwise normal cells.

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Introduction: Hematohidrosis and hemolacria are 2 conditions surrounded in religiousness, mysticism, and supernatural superstitions. While the mechanism is still unclear, these cases have amazed physicians for centuries. Methods: We performed a systematic review in PubMed from 2000 to mid-2021 accounting for 75 studies from which we included 60 cases in 53 articles which were described. Results: The median age of apparition was 24 years with the youngest case being 12 and the oldest 81. Some of the diseases were secondary to other causes such as hemangiomas and other neoplasias or epistaxis episodes. Most of the cases have been reported in India and the USA; most of them correspond to hemolacria alone (51.6%). Discussion: We have stated the basics of the substances involved in the coagulation process that have been described as genetically altered in some patients such as mucins, metalloproteinases, and fibrinogen, as well as propose a mechanism that can explain the signs of this particular entity and approach to its treatment as well as provide the first trichoscopy image of a patient with hemolacria.

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Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis caused by mutations in the gene coding for type VII collagen (COL7A1). More than 800 different pathogenic mutations in COL7A1 have been described to date; however, the ancestral origins of many of these mutations have not been precisely identified. In this study, 32 RDEB patient samples from the Southwestern United States, Mexico, Chile, and Colombia carrying common mutations in the COL7A1 gene were investigated to determine the origins of these mutations and the extent to which shared ancestry contributes to disease prevalence. The results demonstrate both shared European and American origins of RDEB mutations in distinct populations in the Americas and suggest the influence of Sephardic ancestry in at least some RDEB mutations of European origins. Knowledge of ancestry and relatedness among RDEB patient populations will be crucial for the development of future clinical trials and the advancement of novel therapeutics.

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Buschke-Fischer-Brauer (BFB) disease is a rare keratoderma characterized by multiple hyperkeratotic lesions on the palms and soles, with an autosomal dominant pattern. In several countries, some genetic alterations have been associated with this clinical entity. A 68-year-old Peruvian woman presenting with hyperkeratotic lesions on both her palms and soles was diagnosed with BFB keratoderma. After sequencing of the genes that had previously been related to this disease, a mutation (c.249C>G) that was predicted to generate a termination codon (Tyr83*) was found in the alpha and gamma adaptin binding protein P34 gene (AAGAB). After treatment with 30% urea plus 10% salicylic acid, the patient experienced an improvement in her condition. Here we report a novel mutation in the AAGAB gene of a patient diagnosed with BFB keratoderma and a treatment that improved her symptoms.

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BACKGROUND: Mycetoma is a chronic, localized infection caused by fungi and bacteria. It usually affects the skin, subcutaneous tissue, and bone of exposed areas with deformity of the affected limb, ulcers, and fistula; however, pain is not severe, therefore the patient comes late to hospital for care. OBJECTIVE: To establish the diagnosis of mycetoma in the foot by imaging and identify the principal radiological signs. MATERIALS AND METHODS: Six patients with foot mycetoma were evaluated with plain x-ray, ultrasound, and magnetic resonance (MR) after confirming the diagnosis by histopathology and culture. RESULTS: All patients presented the MR "dot-in-circle" sign; four presented "punched out" bone lesions on plain x-ray. The six patients had fistulas, ulceration, a seropurulent exudate, edema, and a foot deformity. Four patients had N. brasiliensis infection with positive anti-Nocardia IgG antibodies, and only half presented bone lesions. CONCLUSION: Characteristic findings were foot deformity, edema, bone lesions, ulcers, fistulas and the presence of the "dot-in-circle" sign. We recommend a comprehensive study of patients with plain x-ray and MR.

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OBJECTIVES: This study aims to describe salivary beta-2 microglobulin (sB2M) levels in our setting and to assess the performance of sB2M for the diagnosis of Sjögren's syndrome (SS). PATIENTS AND METHODS: This cross-sectional, comparative study included 192 SS patients (2 males, 190 females; mean age 53.1 years; range 23 to 84 years) and 64 healthy controls (1 male, 63 females; mean age 46.9 years; range 21 to 82 years). Patients were divided into three groups as those with primary SS, secondary SS, and sicca non-Sjögren's syndrome (snSS). sB2M was measured by enzyme-linked immunosorbent assay in whole unstimulated saliva (ng/mL). Differences in sB2M were evaluated using the Kruskal-Wallis test. Receiver operating curves were generated to determine the performance of sB2M for distinguishing between SS and non-autoimmune snSS groups, and between SS group and healthy controls. RESULTS: The primary SS and secondary SS groups had a significantly higher concentration of sB2M than the other two groups. There was no significant difference in the concentration of sB2M between primary SS and secondary SS groups, and neither between snSS group and healthy controls. The receiver operating curve analysis for distinguishing SS and snSS showed an area under the curve of 0.661 (95% confidence interval 0.590-0.728, p=0.0001) with an optimal cutoff value of 0.582 ng/mL. Sensitivity, specificity, positive predictive value, and negative predictive value were 68.7%, 59.3%, 20.2%, and 92.7%, respectively. The reported prevalence of SS in Mexico was considered when calculating the last two values. CONCLUSION: In our setting, sB2M effectively distinguished between SS patients and non-autoimmune sicca symptoms. Including sB2M in our conventional diagnostic arsenal may assist in the evaluation of patients in whom SS is suspected; however, further studies are needed to clarify this hypothesis.

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GAPO syndrome is a very rare genetic disorder characterized by growth retardation, alopecia, pseudoanodontia and progressive optic atrophy (GAPO). To date, only 30 cases have been described worldwide. Recently, gene alterations in the ANTXR1 gene have been reported to be causative of this disorder, and an autosomal recessive pattern has been observed. This gene encodes a matrix-interacting protein that works as an adhesion molecule. In this report, we describe 2 homozygous siblings diagnosed with GAPO syndrome carrying a new missense mutation. This mutation produces the substitution of a glutamine in position 137 for a leucine (c.410A>T, p.Q137L).

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Keratitis-ichthyosis-deafness syndrome is a well-characterized disease that has been related to mutations in the GJB6 gene. Clinical features such as erythrokeratoderma, palmoplantar keratoderma, alopecia, and progressive vascularizing keratitis, among others, are well known in this entity. In this report we describe a newborn female patient diagnosed with keratitis-ichthyosis-deafness syndrome with a lethal outcome due to sepsis. The patient harbored the mutation A88V that has been previously reported in lethal cases.

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OBJECTIVE: The purpose of this study was to assess esophageal damage in patients with recessive dystrophic epidermolysis bullosa (RDEB) with or without dysphagia. SUBJECTS AND METHODS: Fourteen patients with either severe generalized or another generalized form of RDEB recruited through a research and support foundation were evaluated for obstructive esophageal lesions by means of barium esophagography. RESULTS: All patients, even those without dysphagia, had at least one stenosis; five patients had two stenoses. Stenotic lesions occurred most often (74%) in the upper third of the esophagus. CONCLUSION: Esophageal stenosis is a common complication in patients with RDEB, even when they do not have dysphagia. We recommend regular esophagographic examinations of all patients with RDEB.

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Sjögren's syndrome is a chronic autoimmune disease whose main clinical manifestation is oral dryness (xerostomia) and ocular dryness (xerophthalmia). It is characterized by progressive mononuclear infiltration of the exocrine glands and can affect a variety of organ systems. The prevalence of primary Sjögren's syndrome varies from 0.01 up to 4.8%; this variability reflects differences in definition, application of diagnostic criteria, and geographic differences in age groups. The etiology of primary Sjögren's syndrome is unknown, but the interaction between genetic and environmental factors (viruses, hormones, vitamins, stress) is important. There are few reported cases of concordance in monozygotic twins, and it is common for patients with primary Sjögren's syndrome to have relatives with other autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, thyroid disease, psoriasis, and multiple sclerosis. Among the most common findings is hypergammaglobulinemia. Elevated levels of γ-globulins contain autoantibodies directed against nonspecific antigens such as rheumatoid factor, antinuclear antibodies, and cellular antigens SS-A/Ro and SS-B/La. Regarding diagnosis, there have been 11 different published criteria for Sjögren's syndrome since 1965; none have been approved by the American College of Rheumatology or the European League Against Rheumatism. The current criteria were published in 2012 jointly with the progressive advance in the knowledge of the human salivary proteome that has gained wide acceptance in Sjögren's syndrome, with the possibility of using saliva as a useful tool in both diagnosis and prognosis in this field because the analysis of salivary proteins may reflect the state of locally underlying disease of the salivary glands, which are the target organs in this disease.

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BACKGROUND: B-Raf is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. It has been shown that 50% of melanomas harbor activating BRAF mutations, with over 90% being the V600E mutation. OBJECTIVE: The goal of this research was to determine the prevalence of the BRAF V600E mutation in patients from Central Mexico diagnosed with primary melanoma. METHODS: Skin biopsies from 47 patients with melanoma were obtained from the dermatology department of the Hospital General 'Dr. Manuel Gea González' in Mexico City. For BRAF mutation determination, after DNA isolation, the gene region where the mutation occurs was amplified by PCR. Subsequently, the presence or absence of the V600E mutation was detected by Sanger sequencing performed at the private molecular diagnostic laboratory Vitagénesis in Monterrey, Mexico. RESULTS: Of the 47 patients sampled, 6.4% harbored the V600E mutation. No statistical significance was found between mutations and the type of tumor.

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The most common cause of death in blue rubber bleb nevus syndrome is gastrointestinal bleeding. Here we present a case of central nervous system bleeding that resulted in death.

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Coccidioidomycosis is a highly prevalent disease in the Western hemisphere. It is considered one of the most virulent primary fungal infections. Coccidioides species live in arid and semi-arid regions, causing mainly pulmonary infection through inhalation of arthroconidia although many other organs can be affected. Primary inoculation is rare. Since the first case of coccidioidomycosis was reported in 1892, the skin has been identified as an important target of this disease. Knowledge of cutaneous clinical forms of this infection is important and very useful for establishing prompt diagnosis and treatment. The purpose of this article is to provide a review of this infection, emphasizing its cutaneous manifestations, diagnostic methods and current treatment.

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AbstractCoccidioidomycosis is a highly prevalent disease in the Western hemisphere. It is considered one of the most virulent primary fungal infections. Coccidioides species live in arid and semi-arid regions, causing mainly pulmonary infection through inhalation of arthroconidia although many other organs can be affected. Primary inoculation is rare. Since the first case of coccidioidomycosis was reported in 1892, the skin has been identified as an important target of this disease. Knowledge of cutaneous clinical forms of this infection is important and very useful for establishing prompt diagnosis and treatment. The purpose of this article is to provide a review of this infection, emphasizing its cutaneous manifestations, diagnostic methods and current treatment.

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Recessive dystrophic epidermolysis bullosa (R-DEB) is caused by mutations in the COL7A1 gene. The most common mutation reported in Mexican families is the c.2470insG mutation, normally detected by DNA sequencing. We report a faster and more economical high-throughput genotyping method to detect the c.2470insG mutation using specific TaqMan probes in a real-time polymerase chain reaction (RT-PCR) that facilitates genotype analysis with allelic discrimination plots. Our new method correctly genotyped 45 samples that had previously been sequenced as 41 wild-type homozygous (-/-), 1 heterozygous (-/G) and three mutant homozygous (G/G) (100% specificity). This new method allows high-throughput screening and furthermore is economical ($3 US/sample), fast (2 h), and sensitive as it requires only 20 ng input DNA. We used the new test to genotype 89 individuals from 32 unrelated Mexican families with R-DEB. The observed genotypic frequencies were 93.3% for the homozygous wild-type and 6.7% for the heterozygous genotype. The homozygous mutant genotype was not found. In conclusion, the allelic discrimination assay by RT-PCR is a sensitive, specific and effective high-throughput test for detecting the c.2470insG mutation.

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A 2-month-old female infant was referred to DebRA Mexico from the Regional Children's Hospital because of a generalized dermatosis from birth characterized by multiple blisters and erosions on the trunk, face and limbs, associated with minor trauma. A skin biopsy showing subepidermal blisters associated with a dermal infiltrate of Giemsa-positive cells and CD117-positive antibody was consistent with the diagnosis of bullous mastocytosis. Treatment with oral antihistamines, topical steroids, and antibiotics was initiated, leading to a remission of the lesions.