Background: Skin aging has long been considered only as a cosmetic problem. With the increase in lifespan, we are now more often experiencing a further dimension of skin aging, which is no longer only cosmetic, but also functional, in the sense that the skin has lost its protective mechanical function. Dermatoporosis is the name proposed to capture, in a holistic approach, all the aspects of this chronic cutaneous insufficiency/fragility syndrome. Observations: In this paper, we review the clinical aspects of dermatoporosis, its histological features and the current understanding of its etiological factors. The clinical manifestations of dermatoporosis comprise (i) morphologicalmarkers of fragility – rather trivial – such as senile purpura, stellate pseudoscars and skin atrophy, and (ii) functional expression of skin fragility resulting from minor traumas such as frequent skin laceration, delayed wound healing, nonhealing atrophic ulcers and subcutaneous bleeding with the formation of dissecting hematomas leading to large zones of necrosis. Dissecting hematomas bear significant morbidity needing hospitalization and urgent surgical procedures. Molecular mechanisms implying hyaluronate-CD44 pathways in the control and maintenance of epithelial growth and the viscoelastic properties of the extracellular matrix offer new opportunities for preventive intervention. Conclusion: We propose to group the different manifestations and implications of this syndrome under the umbrella term of ‘dermatoporosis’,because we think it will helpto capture the understanding of health professionals that, as osteoporosis, ‘dermatoporosis’should be prevented and treated to avoid complications. Dermatologists should be aware of this emerging syndrome and function as key players in prevention and therapy. Randomized clinical trials should demonstrate which intervention may best prevent and/or reverse dermatoporosis.

Skin atrophy is a common manifestation of aging and is frequently accompanied by ulceration and delayed wound healing. With an increasingly aging patient population, management of skin atrophy is becoming a major challenge in the clinic, particularly in light of the fact that there are no effective therapeutic options at present. Atrophic skin displays a decreased hyaluronate (HA) content and expression of the major cell-surface hyaluronate receptor, CD44. In an effort to develop a therapeutic strategy for skin atrophy, we addressed the effect of topical administration of defined-size HA fragments (HAF) on skin trophicity. Treatment of primary keratinocyte cultures with intermediate-size HAF (HAFi; 50,000–400,000 Da) but not with small-size HAF (HAFs; 400,000 Da) induced wild-type (wt) but not CD44-deficient (CD44^−/−) keratinocyte proliferation. Topical application of HAFi caused marked epidermal hyperplasia in wt but not in CD44^−/− mice, and significant skin thickening in patients with age- or corticosteroid-related skin atrophy. The effect of HAFi on keratinocyte proliferation was abrogated by antibodies against heparin-binding epidermal growth factor (HB-EGF) and its receptor, erbB1, which form a complex with a particular isoform of CD44 (CD44v3), and by tissue inhibitor of metalloproteinase-3 (TIMP-3). Our observations provide a novel CD44-dependent mechanism for HA oligosaccharide-induced keratinocyte proliferation and suggest that topical HAFi application may provide an attractive therapeutic option in human skin atrophy.

In recent weeks, several reports have emerged of skin lesions with different clinical presentations in COVID-19 cases. All dermatologists should be aware of these cutaneous lesions, which may be early clinical symptoms of infection. We reviewed the literature on cutaneous manifestations in the PubMed database from December 2019 and June 2020. From the cases described as case reports or series in 57 recent articles, it appears that skin lesions (i) are highly varied, (ii) may not be related to the severity of the condition and (iii) resolve spontaneously in a few days. The frequency of these lesions in COVID-19 patients varies between 1.8% and 20.4%. The major clinical forms described were maculopapular eruptions, acral areas of erythema with vesicles or pustules (pseudochilblain), urticarial lesions, other vesicular eruptions and livedo or necrosis. The lesions were mainly localized in the trunk and extremities. The majority of patients were male, aged between 4.5 and 89 years. A minority of the patients were children presenting with acral, chilblain-like lesions, papulo-vesicular eruptions or Kawasaki disease-like pediatric inflammatory multisystem syndrome. The mean duration of the lesions was a few days, but some lasting as little as 20 min and others as long as four weeks have been reported. The mean latency time in the majority of cases was between 1 and 14 days; however, in some patients, lesions appeared 2 to 5 days before the onset of COVID-19 symptoms. The histopathological features of these lesions also vary, corresponding to the diversity of clinical manifestations. These features underline the nature of epidermal and dermal vascular lesions—and in severe cases, microvascular injury and thrombosis—associated with COVID-19, and provide important clues to their pathological mechanisms.

We recently proposed the term “dermatoporosis” to define the various clinical manifestations and complications of chronic cutaneous insufficiency or fragility syndrome.^1-3 Dermatoporosis is an emerging problem of the aging population; the first clinical manifestations appear at around 60 years of age, and the signs of fully developed disease are seen at ages 70 to 90 years. The clinical presentations of this entity include the morphologic markers of fragility (eg, senile purpura, stellate pseudoscars, and skin atrophy) and functional expression of skin fragility (eg, frequent skin laceration resulting from minor traumas, delayed wound healing, and subcutaneous bleeding) with the formation of deep dissecting hematoma (DDH), potentially leading to large zones of necrosis.³ We have proposed 4 stages of dermatoporosis³: stage 1, the presence of extreme skin thinning, senile purpura, and pseudoscars; stage 2, the presence of some localized skin lacerations in addition to the lesions found in stage 1; stage 3, larger and more numerous skin lacerations with prominent delayed healing; and stage 4, DDH associated with any of the other 3 stages.

CD44 is a polymorphic proteoglycan and functions as the principal cell-surface receptor for hyaluronate (HA). Heparin-binding epidermal growth factor (HB-EGF) activation of keratinocyte erbB receptors has been proposed to mediate retinoid-induced epidermal hyperplasia. We have recently shown that intermediate size HA fragments (HAFi) reverse skin atrophy by a CD44-dependent mechanism. Treatment of primary mouse keratinocyte cultures with retinaldehyde (RAL) resulted in the most significant increase in keratinocyte proliferation when compared with other retinoids, retinoic acid, retinol or retinoyl palmitate. RAL and HAFi showed a more significant increase in keratinocyte proliferation than RAL or HAFi alone. No proliferation with RAL was observed in CD44^−/− keratinocytes. HA synthesis inhibitor, 4-methylumbelliferone inhibited the proliferative effect of RAL. HB-EGF, erbB1, and tissue inhibitor of MMP-3 blocking antibodies abrogated the RAL- or RAL- and HAFi-induced keratinocyte proliferation. Topical application of RAL or RAL and HAFi for 3 days caused a significant epidermal hyperplasia in the back skin of wild-type mice but not in CD44^−/− mice. Topical RAL and HAFi increased epidermal CD44 expression, and the epidermal and dermal HA. RAL induced the expression of active HB-EGF and erbB1. However, treatment with RAL and HAFi showed a more significant increase in pro-HB-EGF when compared to RAL or HAFi treatments alone. We then topically applied RAL and HAFi twice a day to the forearm skin of elderly dermatoporosis patients. After 1 month of treatment, we observed a significant clinical improvement. Our results indicate that (i) RAL-induced in vitro and in vivo keratinocyte proliferation is a CD44-dependent phenomenon and requires the presence of HA, HB-EGF, erbB1 and MMPs, (ii) RAL and HAFi show a synergy in vitro and in vivo in mouse skin, and (iii) the combination of RAL and HAFi seems to have an important therapeutic effect in dermatoporosis.