Advances in understanding of Netherton syndrome and therapeutic implications

Abstract

Introduction: Netherton syndrome (NS) is a rare and severe ichthyosis characterized by superficial scaling, skin inflammation, a specific hair shaft defect, severe atopic manifestations and multisystemic complications. It is an orphan disease with currently no satisfactory treatment. NS is caused by loss-offunction mutations in SPINK5 encoding the serine protease inhibitor LEKTI. NS patients present with ichthyosiform erythroderma or ichthyosis linearis circumflexa and show considerable clinical variability. Areas covered: Uncontrolled serine protease activity leads to a profound skin barrier defect and the release of pro-inflammatory and pro-allergic mediators by keratinocytes and immune cells. Improved understanding of NS pathogenesis has led to the successful use of repurposed biologics such as intravenous immunoglobulins and anti-IL-17A blockers. Between April 1, 2020 and November 18, 2020, authors searched for NS-relevant information in the following databases: MEDLINE, DrugBank, ClinicalTrials.gov, and patent datasets accessed through lens.org. Expert opinion: Specific KLK5 and/or KLK7 inhibitors represent the most promising disease-modifying treatments. They are currently being developed by several companies. Comprehension of the determinants of NS variability, flares and modification over time will be the foundation for precision medicine. While improved knowledge of the inflammatory and allergic pathways involved is still needed, clinical trials using repurposed biologics have already begun.

Analysis of the structure and function of the epidermal barrier in patients with ichthyoses—clinical and electron microscopical investigations

“…NTS showed the highest undulation in our study, with a significant difference to the undulation of ARCI. This resembles the strong epidermal barrier damage of NTS, also reflected by the low nICLL and often described in literature 7,19 . The pathogenetic reason for the variable expression of the corneocyte membrane undulation in barrier defects has not yet been investigated.…”

“…NTS is characterized by a triad of ichthyosiform erythroderma with typical serpiginous lesions (ichthyosis linearis circumflexa), hair shaft abnormalities and an atopic predisposition. NTS is typically associated with a severe clinical picture, 7 prone to hypernatremic dehydration, hypothermia and sepsis 9,19 …”

“…NTS is typically associated with a severe clinical picture, 7 prone to hypernatremic dehydration, hypothermia and sepsis. 9,19 The therapy of ichthyoses aims to restore skin hydration and improves skin lesions. 1,20 Basic therapy includes daily baths to remove scales and rehydrate the SC as well as the application of lipid-containing externa to keep the moisturization of the skin.…”

New developments in the molecular treatment of ichthyosis: review of the literature

“…This obstructs stratum corneum cohesion and therefore leads to detachment of the stratum corneum, causing a severe permeability barrier defect. Furthermore, KLK5 and KLK14 activation results in the activation of proteinase-activated receptor 2 (PAR-2), which leads to synthesis of pro-inflammatory factors in keratinocytes [ 1 , 28 – 30 ].…”

Outcomes of Systemic Treatment in Children and Adults With Netherton Syndrome: A Systematic Review

“…Although lifelong treatment is required, there are no registered treatments and treatment guidelines available for patients with NS. First-step treatment options include topical corticosteroids ( 34 ). Also topical calcineurin inhibitors and narrowband ultraviolet B phototherapy have been reported in NS patients ( 35 , 36 ).…”