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The article analyzes the most significant genodermatoses associated with a high risk of allergic reactions that may occur in the practice of a dermatologist and pediatrician, such as ichthyosis and ichthyosiform dermatoses, Netherton syndrome and other ichthyosiform erythroderma, peeling skin syndrome, SAM syndrome, as well as congenital bullous epidermolysis. The article also describes in detail the pathogenetic aspects of transcutaneous sensitization, the development of food allergies and the listed above genodermatoses, two illustrative clinical cases are given.

Desmoplakin (DSP) and Desmoglein 1 (DSG1) variants result in skin barrier defects leading to erythroderma, palmoplantar keratoderma and variable [AQ4] other features. Some DSG1 variant carriers present with SAM syndrome (Severe dermatitis, multiple Allergies, Metabolic wasting) and a SAM-like phenotype has been reported in 4 subjects with different heterozygous DSP variants. We report here a patient with a novel DSP spectrin region (SR) 6 variant c.1756C>T, p.(His586Tyr), novel features of brain lesions and severe recurrent mucocutaneous herpes simplex virus infections, with a favourable response to ustekinumab. Through a review of reported cases of heterozygous variants in DSP SR6 (n = 15) and homozygous or compound heterozygous variants in DSG1 (n = 12) and SAM-like phenotype, we highlight phenotypic variability. Woolly hair, nail abnormalities and cardiomyopathy characterize patients with DSP variants, while elevated immunoglobulin E and food allergies are frequent in patients with DSG1 variants. Clinicians should be aware of the diverse manifestations of desmosomopathies.

A single male Rottweiler dog with severe footpad hyperkeratosis starting at an age of eight weeks was investigated. The hyperkeratosis was initially restricted to the footpads. The footpad lesions caused severe discomfort to the dog and had to be trimmed under anesthesia every 8–10 weeks. Histologically, the epidermis showed papillated villous projections of dense keratin in the stratum corneum. Starting at eight months of age, the patient additionally developed signs consistent with atopic dermatitis and recurrent bacterial skin and ear infections. Crusted hyperkeratotic plaques developed at sites of infection. We sequenced the genome of the affected dog and compared the data to 655 control genomes. A search for variants in 32 candidate genes associated with human palmoplantar keratoderma (PPK) revealed a single private protein-changing variant in the affected dog. This was located in the DSG1 gene encoding desmoglein 1. Heterozygous monoallelic DSG1 variants have been reported in human patients with striate palmoplantar keratoderma I (SPPK1), while biallelic DSG1 loss of function variants in humans lead to a more pronounced condition termed severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome. The identified canine variant, DSG1:c.2541_2545delGGGCT, leads to a frameshift and truncates about 20% of the coding sequence. The affected dog was homozygous for the mutant allele. The comparative data on desmoglein 1 function in humans suggest that the identified DSG1 variant may have caused the footpad hyperkeratosis and predisposition for allergies and skin infections in the affected dog. [ABSTRACT FROM AUTHOR]

Desmoplakin (DSP) and Desmoglein 1 (DSG1) variants result in skin barrier defects leading to erythroderma, palmoplantar keratoderma and variable other features. Some DSG1 variant carriers present with SAM syndrome (Severe dermatitis, multiple Allergies, Metabolic wasting) and a SAM-like phenotype has been reported in 4 subjects with different heterozygous DSP variants. We report here a patient with a novel DSP spectrin region (SR) 6 variant c.1756C>T, p.(His586Tyr), novel features of brain lesions and severe recurrent mucocutaneous herpes simplex virus infections, with a favourable response to ustekinumab. Through a review of reported cases of heterozygous variants in DSP SR6 (n = 15) and homozygous or compound heterozygous variants in DSG1 (n = 12) and SAM-like phenotype, we highlight phenotypic variability. Woolly hair, nail abnormalities and cardiomyopathy characterize patients with DSP variants, while elevated immunoglobulin E and food allergies are frequent in patients with DSG1 variants. Clinicians should be aware of the diverse manifestations of desmosomopathies. [ABSTRACT FROM AUTHOR]

The presence of eczema and elevated IgE in pediatric patients does not always indicate atopic dermatitis. Rare genodermatoses may share this clinical presentation and should be considered in the differential diagnosis for patients with congenital immunodeficiency and severe refractory dermatitis. We describe a case of severe dermatitis, allergies, and metabolic wasting syndrome, due to a novel mutation in DSG1 gene, an additional example of this uncommon genetic disorder of desmosome function. [ABSTRACT FROM AUTHOR]

Abstract: Severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a rare life‐threatening inherited condition caused by bi‐allelic mutations in DSG1 encoding desmoglein 1. The disease was initially reported to manifest with severe erythroderma, failure to thrive, atopic manifestations, recurrent infections, hypotrichosis and palmoplantar keratoderma. We present 3 new cases of SAM syndrome in 2 families and review the cases published so far. Whole exome and direct sequencing were used to identify SAM syndrome‐causing mutations. Consistent with previous data, SAM syndrome was found in all 3 patients to result from homozygous mutations in DSG1 predicted to result in premature termination of translation. In contrast, as compared with patients previously reported, the present cases were found to display a wide range of clinical presentations of variable degrees of severity. The present data emphasize the fact that SAM syndrome is characterized by extensive phenotypic heterogeneity, suggesting the existence of potent modifier traits. [ABSTRACT FROM AUTHOR]

Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here, we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and, when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support human keratinocyte stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target. [Display omitted] • Desmosomal cadherin, desmoglein 1, requires the retromer for endosomal trafficking • The retromer is necessary for epidermal differentiation and stratification • Retromer chaperone enhances the function of Dsg1 and a disease-associated mutant • Retromer cargo GLUT1 is upregulated in Dsg1-deficient epidermis Hegazy et al. identify the endosomal trafficking complex, the retromer, as a regulator of epidermal development and homeostasis through its regulation of the important disease target, a desmosomal cadherin called desmoglein 1. Their work identifies the retromer as a possible therapeutic target for a systemic skin disorder. [ABSTRACT FROM AUTHOR]

Objective: To analyze in-hospital results of surgical treatment of patients with obstructive hypertrophic cardiomyopathy., Material and Methods: There were 15 patients (8 women and 6 men) with obstructive hypertrophic cardiomyopathy and severe mitral insufficiency for the period from November 2017 to March 2019. Mean age of patients was 55.9±7.1 years. All patients had chronic heart failure NYHA class III and secondary coronary insufficiency., Results: Surgical correction of LVOT obstruction and mitral valve repair with elimination of systolic anterior motion were technically successful in all cases. There was no need for mitral valve replacement in all patients. Heart failure NYHA class I-II in early postoperative period was observed in all cases., Conclusion: Careful preoperative planning with a comprehensive analysis of hemodynamic and anatomical features of LV and certain surgical experience are essential for adequate correction of LVOT obstruction without atrioventricular node injury and mitral valve repair.

Background: The immune abnormalities underlying the ichthyoses are poorly understood., Objective: To determine the immunophenotype of an ichthyosis resulting from mutations in the spectrin repeat 6 (SR6) domain of desmoplakin gene (DSP) and target therapy on the basis of molecular pathogenesis., Methods: Immunophenotyping was performed by using the blood and skin of a girl with SR6 region DSP mutations causing erythroderma/ichthyosis and cardiomyopathy., Results: On the basis of the discovery of T helper 1 and T helper 17/interleukin 23 skewing in the skin and T helper 17/interleukin 22 skewing in blood, ustekinumab therapy was initiated. Ustekinumab was also administered to a boy with an SR6 region DSP mutation and ichthyosis without cardiomyopathy. Both children responded despite previous poor responses to immunosuppressants and retinoids., Limitations: Small number of patients and immunophenotyping in only 1 patient., Conclusion: An understanding of the molecular basis of inflammation in rare cutaneous disorders can lead to targeted therapy, which promises to be more beneficial than broad immunosuppressants., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)