Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

Considerations for lactation with Ehlers-Danlos syndrome: a narrative review

Background Ehlers-Danlos syndrome (EDS) is a rare genetic connective tissue condition that is poorly understood in relation to lactation. As diagnostic methods improve, prevalence has increased. EDS, a disorder that impacts connective tissue, is characterized by skin extensibility, joint hypermobility, and fragile tissue which can affect every organ and body system leading to complications during pregnancy, delivery, and the postpartum period. Traits of this disease can cause mild to severe physiologic and functional obstacles during lactation. Unfortunately, there is little clinical evidence and minimal guidance for lactation management, and providers may feel uncomfortable and hesitant to address these concerns with patients due to a lack of readily available resources on the subject and inexperience with such patients. This narrative review describes and discusses the types of EDS, identifying symptoms, considerations, and precautions for care providers to implement during lactation and breastfeeding. Methods An electronic search of relevant citations was conducted using the databases Cochrane, PubMed, and Google Scholar from 1 January 2000 to 1 November 2021. Search terms used were Ehlers-Danlos syndrome, Hypermobility Syndrome, breastfeeding, lactation, breastmilk expression, breastmilk collection, human milk expression, human milk collection, and infant feeding. The search of these databases yielded zero results. As no research articles on EDS were directly related to lactation, this narrative review includes articles found that related to the health of mothers relevant to maternal function during lactation. Discussion For the healthcare provider, identifying characteristics of EDS can improve the management of lactation challenges. Mothers may experience generalized symptoms from gastrointestinal distress to fatigue or chronic pain, while they also may suffer from more specific joint complaints and injuries, such as dislocations / subluxations, or skin fragility. Such obstacles can generate impediments to breastfeeding and create unique challenges for breastfeeding mothers with EDS. Unfortunately, new mothers with these symptoms may have them overlooked or not addressed, impacting a mother’s ability to meet her breastfeeding intentions. While there are some published research manuscripts on EDS and pregnancy, there is a lack of information regarding breastfeeding and lactation. Additional research is needed to help guide EDS mothers to achieve their breastfeeding intentions.

Biallelic Missense Mutations in the Integrin Alpha 3 Gene Causes Skin Fragility Without Structural Defects in Lungs and Kidneys

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A single dose of Ultraviolet-A induces proteome remodeling and senescence in primary human keratinocytes

Epidermal photoaging contributes to skin fragility over time and it is a risk factor for skin cancer. Photoaging has been associated for a long time with exposure to Ultraviolet-A (UVA) light, the predominant component of the solar ultraviolet radiation. While the cellular mechanisms underlying UVA-induced photoaging in the dermis have been well characterized, UVA’s action on the epidermis remains elusive. Here, proteomic analysis was conducted to derive the cellular responses induced by an environmentally relevant dose of UVA in primary human keratinocytes. We also investigated the effects of UVA on non-transformed immortalized keratinocytes (HaCaT cells), bearing potentially oncogenic mutations. We showed that UVA induces proteome remodeling and senescence in primary keratinocytes, eliciting potent antioxidant and pro-inflammatory responses. Additionally, we showed that UVA modulates the secretory phenotype of these cells to the extent of inducing paracrine oxidative stress and immune system activation in pre-malignant keratinocytes. These observations offer insights into the cellular mechanisms by which UVA drives photoaging in the skin.

Plectin in Skin Fragility Disorders

Plectin is a multi-faceted, 500 kDa-large protein, which due to its expression in different isoforms and distinct organs acts diversely as a cytoskeletal crosslinker and signaling scaffold. It functions as a mediator of keratinocyte mechanical stability in the skin, primarily through linking intermediate filaments to hemidesmosomes. Skin fragility may occur through the presence of mutations in the gene encoding for plectin, PLEC, or through the presence of autoantibodies against the molecule. Below, we review the cutaneous manifestations of plectinopathies as well as their systemic involvement in specific disease subtypes. We summarize the known roles of plectin in keratinocytes and fibroblasts and provide an outlook on future perspectives for plectin-associated skin disorders.

Multifocal periapical cement dysplasia in Ehlers-Danlos Typ VIII combined with leukoencephalopathy in de novo-mutation of c.890G>A, G297D [pEDS]

Periodontal Ehlers-Danlos syndrome type VIII (pEDS) is rare and caused by mutation in complement 1 subunit. Lack of attached gingiva, pretibial plaques, joint mobility, skin fragility, and easy bruising consolidate the diagnosis. We describe a case of de novo-mutation of pEDS with generalized periapical cemento dysplasia (PCD) and leukoencephalopathy.

Bullous Pemphigoid and Other Pemphigoid Dermatoses

The pemphigoid family of dermatoses is characterized by autoimmune subepidermal blistering. The classic paradigm for pemphigoid, and the most common member, is bullous pemphigoid. Its variable clinical presentation, with or without frank bullae, is linked by significant pruritus afflicting the elderly. Mucous membrane pemphigoid is an umbrella term for a group of subepidermal blistering dermatoses that favor the mucosal membranes and can scar. Epidermolysis bullosa acquisita is a chronic blistering disorder characterized by skin fragility, sensitivity to trauma, and its treatment-refractory nature. Clinicians that encounter these pemphigoid disorders may benefit from an overview of their clinical presentation, diagnostic work-up, and therapeutic management, with an emphasis on the most frequently encountered pemphigoid disease, bullous pemphigoid.

A Familial Form of Epidermolysis Bullosa Simplex Associated with a Pathogenic Variant in KRT5

Epidermolysis bullosa simplex is a disease that belongs to a group of genodermatoses characterised by the formation of superficial bullous lesions caused by minor mechanical trauma to the skin. The skin fragility observed in the EBS is mainly caused by pathogenic variants in the KRT5 and KRT14 genes that compromise the mechanical stability of epithelial cells. By performing DNA sequencing in a female patient with EBS, we found the pathogenic variant c.967G>A (p.Val323Met) in the KRT5 gene. This variant co-segregated with EBS in the family pedigree and was transmitted in an autosomal dominant inheritance manner. This is the first report showing a familial form of EBS due to this pathogenic variant.

IMPLEMENTATION OF ADVANCED SOCIAL PRACTICES BASED ON INNOVATIVE GERONTOTECHNOLOGIES IN THE SYSTEM OF LONG-TERM CARE FOR ELDERLY AND SENILE PATIENTS

В рамках развития типовой модели системы долговременного ухода и внедрения инновационных геронтотехнологий в качестве передовых социальных практик для дальнейшей оптимизации социально-медицинского обслуживания пациентов пожилого и старческого возраста с 2017 г. по настоящее время на территории Ленинградской обл. реализуется научно-практический проект «Применение дерматопротекторов для повышения качества жизни пациентов гериатрического профиля с возраст-ассоциированным ксерозом» (ВАК). В статье представлены результаты сравнительного анализа эффективности применения эмолентов дерматопротекторного действия для повышения качества жизни, профилактики и коррекции ВАК, изучены клинические проявления данного заболевания до и после применения дерматопротекторов. В когорту обследованных вошли женщины - пациентки гериатрического профиля со старческой астенией семи учреждений социальной защиты населения Ленинградской обл. В зарубежной литературе таких пациентов называют «хрупкими» (frailty). Полученные данные свидетельствуют о том, что ВАК как проявление «хрупкости» кожи при старении может рассматриваться в качестве составной части гериатрического синдрома старческой астении у пациентов старших возрастных групп. Развитие «хрупкости» кожи существенно снижает качество жизни пациентов гериатрического профиля и требует своевременной профилактики и коррекции адекватно подобранными дерматопротекторами. From 2017 to the present a scientific project «The use of dermatoprotectors to improve the quality of life of geriatric patients with age-associated xerosis (AAX)» has been realized as part of a typical model of a long-term care system in order to introduce the innovative gerontotechnologies as advanced social practices in further optimization of social and medical care for elderly and senile patients in Leningrad Region. The article presents the results of a comparative analysis of the effectiveness of the dermatoprotectors application in the improvement of the quality of life, prevention and correction of AAX. The AAX clinical manifestations have been studied before and after the emollients use. The cohort under study has included geriatric patients with senile asthenia from seven institutions of social protection of the Leningrad Region. In the foreign literature, such patients are called «fragile». The data thus obtained indicate that AAX as a manifestation of skin «fragility» during aging can be considered as a component of the geriatric syndrome of senile asthenia in patients of older age groups. The development of skin «fragility» significantly reduces the quality of life of geriatric patients and requires timely prevention and correction with adequately selected dermatoprotectors.

Recalibrated Scales: The Use of Low-dose Isotretinoin in a Case of Epidermolytic Ichthyosis-NPS1 in a Filipino Child

Epidermolytic Ichthyosis (EI) is a rare non-syndromic keratinopathic ichthyosis without definitive treatment. This is a case of EI in a 5-year-old Filipino female who presented with hyperkeratotic scales sparing the palms and soles. Histopathology revealed epidermolytic hyperkeratosis. A trial of treatment with isotretinoin 0.3 mg/kg/day, together with keratolytic agents, urea lotion and lactic acid lotion, resulted in a marked decrease in the thickness of the scales and odor. Interestingly, rebound effects were noted at 0.6 mg/kg/day. Taking into account that EI presents with more skin fragility compared to non-EHK ichthyosis, the authors surmise that there may be a smaller treatment window for patients with EI, which is notably lower than recommended for ichthyosis in general.