Summary
Background
Peeling skin syndrome type 1 (PSS1) is a rare and severe autosomal recessive form of congenital ichthyosis. Patients are affected by pronounced erythroderma accompanied by pruritus ...and superficial generalized peeling of the skin. The disease is caused by nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). PSS1 severely impairs quality of life and therapeutic approaches are totally unsatisfactory.
Objectives
The objective of this study was to develop the first steps towards a specific protein replacement therapy for CDSN deficiency. Using this approach, we aimed to restore the lack of CDSN and improve cell–cell cohesion in the transition area of the stratum granulosum (SG) to the stratum corneum.
Methods
Human CDSN was recombinantly expressed in Escherichia coli. A liposome‐based carrier system, prepared with a cationic lipopeptide to mediate the transport to the outer membrane of keratinocytes, was developed. This formulation was chosen for CDSN delivery into the skin. The liposomal carrier system was characterized with respect to size, stability and toxicity. Furthermore, the interaction with primary keratinocytes and human epidermal equivalents was investigated.
Results
The liposomes showed an accumulation at the membranes of keratinocytes. CDSN‐deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG. Finally, the penetration assay and histological examinations revealed an improved epidermal integrity for CDSN‐deficient epidermal equivalents, if they were treated with liposomal encapsulated CDSN.
Conclusions
This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1.
What is already known about this topic?
Peeling skin syndrome type 1 (PSS1) refers to Mendelian disorders of cornification and is characterized by pruritus, pronounced erythroderma with skin abnormalities and lifelong patchy peeling of the skin.
The disease is caused by autosomal recessive nonsense mutations in the gene encoding corneodesmosin (CDSN). Histopathologically, the absence of CDSN is characterized by subcorneal splitting and enhanced detachment of corneocytes.
What does this study add?
We present a liposomal formulation, which can be used for topical delivery of recombinant CDSN.
Our in vitro study shows that the impaired barrier of CDSN‐deficient human epidermal equivalents can be improved when treated with liposomal human CDSN.
What is the translational message?
This study presents, for the first time, preclinical in vitro experiments for a specific protein replacement therapy in patients with PSS1.
Linked Comment: Schmuth. Br J Dermatol 2021; 184:998–999.
Background
Autosomal‐recessive congenital ichthyosis (ARCI) is a heterogeneous group of ichthyoses presenting at birth. Self‐improving congenital ichthyosis (SICI) is a subtype of ARCI and is ...diagnosed when skin condition improves remarkably (within years) after birth. So far, there are sparse data on SICI and quality of life (QoL) in this ARCI subtype. This study aims to further delineate the clinical spectrum of SICI as a rather unique subtype of ARCI.
Objectives
This prospective study included 78 patients (median age: 15 years) with ARCI who were subdivided in SICI (n = 18) and non‐SICI patients (nSICI, n = 60) by their ARCI phenotype.
Methods
Quality of life (QoL) was assessed using the (Children’s) Dermatology Life Quality Index. Statistical analysis was performed with chi‐squared and t‐Tests.
Results
The genetically confirmed SICI patients presented causative mutations in the following genes: ALOXE3 (8/16; 50.0%), ALOX12B (6/16; 37.5%), PNPLA1 (1/16; 6.3%) and CYP4F22 (1/16; 6.3%). Hypo‐/anhidrosis and insufficient vitamin D levels (<30 ng/mL) were often seen in SICI patients. Brachydactyly (a shortening of the 4th and 5th fingers) was statistically more frequent in SICI (P = 0.023) than in nSICI patients. A kink of the ear’s helix was seen in half of the SICI patients and tends to occur more frequently in patients with ALOX12B mutations (P = 0.005). QoL was less impaired in patients under the age of 16, regardless of ARCI type.
Conclusions
SICI is an underestimated, milder clinical variant of ARCI including distinct features such as brachydactyly and kinking of the ears. Clinical experts should be aware of these features when seeing neonates with a collodion membrane. SICI patients should be regularly checked for clinical parameters such as hypo‐/anhidrosis or vitamin D levels and monitored for changes in quality of life.
Summary
Background
Transglutaminase (TG)1 plays a key role in the formation of the cornified envelope and thus in the maintenance of the epidermal barrier. Patients with Netherton syndrome (LEKTI ...deficiency) have increased activity of both TG1 and serin proteases.
Objectives
To determine whether there is a functional biochemical link between TG1 and LEKTI and whether LEKTI domains could possibly serve as substrates for TG1.
Methods
We analysed the protein sequence of LEKTI for possible TG1 recognition sites using bioinformatics. Synthetic peptides and recombinant LEKTI domains D6, D7 and D8+9 were examined in vitro and in situ for possible substrate specificity. The recombinant LEKTI domains were studied for inhibitory activity in a kallikrein (KLK)5 activity test.
Results
We identified possible TG1 consensus sequences in LEKTI domains D6, D7 and D8+9, pointing to a novel biological link between these two proteins. Indeed, synthesized short peptides from these consensus sequences were incorporated into the TG1 activity zone of the epidermis. In vitro the entire recombinant domains of LEKTI showed substrate specificity for TG1, which was again confirmed in situ. The inhibitory activity of the recombinant LEKTI domains was confirmed by a KLK5 inhibition test. The strongest inhibition was observed for domains D8+9.
Conclusions
There are specific domains of LEKTI that are recognized and processed by TG1. LEKTI domains D6, D7 and D8+9 contribute to the formation and protection of the cornified envelope. These results impact the development of protein replacement therapy approaches for Netherton syndrome.
What's already known about this topic?
LEKTI and transglutaminase (TG)1 are key proteins involved in the terminal differentiation of the epidermis.
Lack of LEKTI causes Netherton syndrome; TG1 deficiency causes lamellar ichthyosis.
The serine protease inhibitor LEKTI is processed into different functional units.
Among different target proteases, kallikrein (KLK)5 appears to be a key player in disease pathology.
It has been demonstrated that LEKTI domain 6 inhibits KLK5 and KLK7; LEKTI domains 8–11 also inhibit KLK14.
What does this study add?
The single LEKTI domains 6, 7 and the functional unit of domains 8 and 9 contain recognition motifs for TG1.
We show that these domains and unit are crosslinked into the epidermis by TG1.
Functional analyses of the recombinant LEKTI domains revealed that LEKTI D8+9 has the strongest inhibitory effect on KLK5.
What is the translational message?
The novel functional link between LEKTI and TG1 should be taken into account when considering the development of a targeted topical protein therapy for Netherton syndrome.
The unit of domains D8+9 may be sufficient for this purpose.
Respond to this article
Summary
These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an ...expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert‐based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.
What's already known about this topic?
Various symptomatic treatment options exist for congenital ichthyoses, but there are no European guidelines.
What does this study add?
These European guidelines for the management of congenital ichthyosis may help to improve outcomes and quality of life for patients.
Linked Comment: Akiyama. Br J Dermatol 2019; 180:449–450.
Plain language summary available online
Summary
These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an ...expert conference held in Toulouse in 2016 and a consensus on the discussions. They summarize evidence and expert‐based recommendations and are intended to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part one, covering topical therapies, systemic therapies, psychosocial management, communicating the diagnosis and genetic counselling.
Linked Comment: Levy. Br J Dermatol 2019; 180:253.
Patients with inherited ichthyosis suffer from scaling due to mutations affecting the epidermal barrier. Symptomatic treatment with ointments, bathing and mechanical scale removal can alleviate the ...disease, but therapy is time and cost intensive.
We investigated costs, time and disease burden of ichthyoses. The study addresses difficulties of the healthcare situation for patients with ichthyoses and reveals potential improvements.
We developed a questionnaire addressing time and financial effort for the treatment. Additionally, we collected data of the Dermatology Life Quality Index (DLQI) and the Pruritus Life Quality (5PLQ) questionnaires to determine the impact of ichthyosis and associated pruritus on quality of life (QoL).
We recruited 144 patients with ichthyosis (median age: 23; 53.5% female) from the Department of Dermatology in Muenster (Germany) and the German patient support group including common, rare and syndromic subtypes. Eighty-seven percent reported applying topical therapeutics at least once per day, 66.4% several times with an overall median duration of 15 min. Highest single expenditure of time was due to balneotherapy (n = 115; median bathing time: 40 min). In 81.9%, the health insurance did not completely cover the costs for topical treatment causing additional financial burden to the patient with a median of 71 € per quarter, herein creams being the largest cost factor (50 €). Patients with Netherton syndrome showed the highest median expenditure (170 €). The QoL impairment under treatment was moderate (median DLQI: 8.5 points). Pruritus was prevalent in 79.9% and showed a distinct impact on QoL (median 5PLQ: 7.5 points) without any significant difference between the subtypes (p = 0.37).
Patients suffering from ichthyoses have a large and lifelong overall burden in mild and severe subtypes. Since continuous topical treatment is required, financial and psychosocial support needs to be considered beyond dermatological care.
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