Recent Advances in Clinical Research on Rare Intractable Hereditary Skin Diseases in Japan

Abstract

Our Research Group for Rare and Intractable Skin Diseases operates within the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare of Japan and is conducting research on eight rare intractable skin diseases. Five of these are monogenic disorders (epidermolysis bullosa, congenital ichthyoses, oculocutaneous albinism, pseudoxanthoma elasticum, and hereditary angioedema), and for a sixth [generalized pustular psoriasis (GPP)], genetic predisposing factors are important. This review introduces our activities for raising public awareness of these six intractable hereditary skin diseases and summarizes our recent achievements in clarifying the situation of medical treatments for these diseases in Japan. We note our current progress in elucidating the pathogeneses of these diseases and in developing new treatment methods, and we discuss our progress in establishing clinical practice guidelines. A nationwide survey on epidermolysis bullosa and a clinical survey on congenital ichthyoses are progressing. The Angioedema Activity Score and the Angioedema Quality-of-Life Questionnaire, the latter of which is a quality-of-life evaluation tool, have been established for hereditary angioedema. Registries of patients with oculocutaneous albinism and pseudoxanthoma elasticum have been created, and the registry for the latter has achieved its target of 170 cases. For GPP, the results of our survey on clinical practice were published in 2021. Information regarding all six of these hereditary skin diseases has been disseminated to academic societies, medical professionals, patients, and the general public.

Introduction

Our group, the Research Group for Rare and Intractable Skin Diseases, operates across multiple institutions under the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare of Japan. The research group collects scientific evidence from national surveys on rare intractable skin diseases, promotes the creation and revision of evidence-based clinical practice guidelines, and seeks to improve the quality of medical care by disseminating medical information and promoting social enlightenment activities. Other purposes of the group are to improve the quality of research and to promote the return of research results to the public (Fig. 1). Our group conducts research on eight rare intractable skin diseases: pemphigus, pemphigoid, pustular psoriasis, epidermolysis bullosa, congenital ichthyoses, pseudoxanthoma elasticum, oculocutaneous albinism, and hereditary angioedema. Five of these diseases are monogenic skin diseases (epidermolysis bullosa, congenital ichthyoses, oculocutaneous albinism, pseudoxanthoma elasticum, and hereditary angioedema), and a sixth [generalized pustular psoriasis (GPP)] involves important genetic predisposing factors (Table 1).

Fig. 1.

Aims, research methods, and expected effects of research on intractable hereditary skin diseases by our Research Group for Rare and Intractable Skin Diseases under the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare of Japan.

Table 1. Hereditary skin diseases investigated by our research group

Disease
Epidermolysis bullosa
Congenital ichthyoses
Oculocutaneous albinism
Pseudoxanthoma elasticum
Hereditary angioedema
Generalized pustular psoriasis

Our research group seeks to work closely with the Japanese Dermatological Association and related societies to create and revise high-quality clinical practice guidelines and to disseminate information globally. At the same time, we aim to conduct clinical research on treatment methods for optimizing guidelines and improving diagnostic accuracy. Furthermore, we aim to comprehensively analyze the epidemiological trends of each disease and to solidify the foundation of a nationwide patient registry. We continue to provide medical information and to contribute to social enlightenment by supporting patient associations. The present review introduces our activities for raising public awareness of these intractable hereditary skin diseases and summarizes our recent achievements in clarifying the current status of medical treatments for these diseases in Japan. In addition, we discuss our current progress in elucidating the pathogeneses of these diseases, the development of new treatment methods for them, and our progress in creating and revising the clinical practice guidelines.

Achievements of Our Research Group on Hereditary Skin Diseases

For all six of the hereditary skin diseases, smooth progress is being made in the use of national epidemiological surveys and quality-of-life (QOL) surveys and in the creation of registries for the establishment and revision of clinical practice guidelines. Progress in these areas has been largely achieved as planned. In addition, in light of the COVID-19 pandemic, we have been able to quickly provide information to doctors treating patients who have pustular psoriasis and are undergoing immunosuppressive therapy (URL: http://kinan.info/covid19.html). Given that pandemic restrictions remain, our public lectures for patients, educational lectures for doctors, and collaborations with patient associations have been delayed for some diseases. However, we plan to proceed with our clinical research as much as possible by making effective use of online exchanges of information, while paying close attention to the spread of COVID-19.

In efforts to address congenital ichthyoses, a collaboration was established with the Japan Agency for Medical Research and Development (AMED) through the research project titled “Development of a treatment method for epidermolytic ichthyosis using cultured epidermal sheets derived from mosaic healthy skin due to somatic revertant mutations.” To raise awareness of pustular psoriasis, congenital ichthyoses, and hereditary angioedema, we have given educational lectures for physicians at a number of society meetings, including the 120th Annual Meeting of the Japanese Dermatological Association and the 70th Annual Meeting of the Japanese Society of Allergology (2021).

Our research group also presented an online seminar for the general public on three diseases: epidermolysis bullosa, congenital ichthyoses, and hereditary angioedema. Based on the many questions we received from members of the public who attended and from the results of a post-event questionnaire, we believe that the seminar was meaningful for those in attendance. The activities of our research group have significantly contributed to improving the level of medical care and educating citizens about the six intractable hereditary skin diseases. For each disease, our group will continue to provide medical information through integrated analyses of epidemiological trends from nationwide surveys, expand the nationwide patient registry, and support related academic societies and patient associations.

Summary of Recent Advances in Our Research on the Six Genetic Skin Diseases

The following discussion describes our recent research advances for each of the six rare intractable hereditary skin diseases under investigation.

Epidermolysis bullosa

Epidermolysis bullosa is a disease in which the skin is genetically fragile, and blisters and erosions form on the entire body or on localized areas from even slight external force, particularly at sites susceptible to mechanical stimulation. Epidermolysis bullosa consists of a number of genetically heterogeneous diseases and is divided into four major types: epidermolysis bullosa simplex, junctional epidermolysis bullosa, dystrophic epidermolysis bullosa, and Kindler syndrome (Table 2).¹

Table 2. Classification and genetic causes of inherited epidermolysis bullosa

EB type	Inheritance	Causative mutated genes
EB simplex	Autosomal dominant	KRT5, KRT14, PLEC, KLHL24
	Autosomal recessive	KRT5, KRT14, DST, EXPH5 (SLAC2B), PLEC, CD151 (TSPAN24)
Junctional EB	Autosomal recessive	LAMA3, LAMB3, LAMC2, COL17A1, ITGA6, ITGB4, ITGA3
Dystrophic EB	Autosomal dominant	COL7A1
	Autosomal recessive	COL7A1
Kindler EB	Autosomal recessive	FERMT1 (KIND1)

EB, epidermolysis bullosa.

Modified from Has et al.¹

We completed our nationwide epidemiological survey for epidermolysis bullosa by analyzing data that had been collected by 2021, and additional analyses will be conducted as necessary. In addition, we conducted seasonal QOL surveys in spring, summer, autumn, and winter for 50 patients registered through the Web. After an interim analysis, we are proceeding with an analysis that focuses on intra-individual variability (unpublished). Concerning clinical practice guidelines, revisions are under way for completion in 2023. In addition, our group has been able to collaborate with the main patient association in Japan and we have shared the latest information on pathogenetic mechanisms, diagnosis, and treatments for epidermolysis bullosa.

Our group is proceeding with the AMED research project “Development of a minimally invasive and highly efficient gene therapy for dystrophic epidermolysis bullosa,” with the aim of developing such gene therapy. As part of the activities of our research group, in collaboration with the patient associations Epidermolysis Bullosa Tomo-no-Kai (DebRa Japan) (https://debra-japan.com) and Asebi-Kai (http://www.asebikai.com), we explained the latest results of QOL surveys and introduced the advances in AMED gene therapy research.

Yoshida et al.² reported a case of recessive dystrophic epidermolysis bullosa that resulted from a truncating mutation and a missense or in-frame mutation in COL7A1. The case was finally diagnosed from the mutation data as intermediate recessive dystrophic epidermolysis bullosa, despite LH7.2 staining being negative in the basement membrane zone. This case suggests that precise diagnosis of epidermolysis bullosa, requires a combination of immunohistological, ultrastructural, and genetic testing.² Mori et al.³ reported the successful extensive transplantation of a cultured epidermal autograft product called JACE (Japan Tissue Engineering, Gamagori, Japan) in a case of severe recessive dystrophic epidermolysis bullosa. It was suggested that JACE is useful for managing severe cases of epidermolysis bullosa in patients with extensive skin defects.³ Fujita et al.⁴ conducted a phase 1/2 open-label study of intravenous allogeneic multilineage-differentiating stress-enduring (Muse) cells for adult patients with dystrophic epidermolysis bullosa. From the results, they suggested that the administration of CL2020, a clinical-grade Muse cell product (Life Science Institute, Tokyo, Japan) is a potentially effective regenerative therapy for adult patients with severe dystrophic epidermolysis bullosa. Recently, Takaki et al.⁵ established a murine model for recessive dystrophic epidermolysis bullosa that carries patient-derived compound heterozygous mutations. This model is expected to facilitate research on innovative therapies for recessive dystrophic epidermolysis bullosa.

Congenital ichthyoses

Ichthyoses are a group of genetically heterogeneous diseases in which abnormalities in the cornification and exfoliation mechanisms of the stratum corneum cause skin barrier defects that result in rough, dry, hyperkeratotic, scaly skin over large areas of the body or over the entire body. Patients with congenital ichthyoses show ichthyotic skin symptoms at birth or during the neonatal period and often have severe phenotypes. Non-syndromic congenital ichthyoses include autosomal dominant keratinopathic ichthyosis and autosomal recessive congenital ichthyosis (Table 3).^6,7 Syndromic types of congenital ichthyoses include a large number of rare syndromes.⁸

Table 3. Major types and genetic causes of non-syndromic congenital ichthyoses

Type	Major subtypes	Inheritance	Causative mutated genes
Keratinopathic ichthyosis	Epidermolytic ichthyosis	Autosomal dominant	KRT1, KRT10
		Autosomal recessive	KRT10
	Superficial epidermolytic ichthyosis	Autosomal dominant	KRT2
Autosomal recessive congenital ichthyosis	Harlequin ichthyosis	Autosomal recessive	ABCA12
	Congenital ichthyosiform erythroderma	Autosomal recessive	TGM1, NIPAL4, ABCA12, ALOX12B, ALOXE3
	Lamellar ichthyosis	Autosomal recessive	TGM1, NIPAL4, ALOX12B, ALOXE3, CYP4F22, ABCA12, SDR9C7, PNPLA1, CERS3
	Pleomorphic ichthyosis	Autosomal recessive	TGM1, NIPAL4, ALOX12B, ALOXE3, SLC27A4, CYP4F22

Modified from Vahlquist et al.⁶ and Akiyama.⁷

In 2018, our research group published the results of our nationwide cross-sectional clinical survey on disease severity and QOL for patients with harlequin ichthyosis and ichthyosis syndromes in Japan.⁹ In addition, we published the results of our nationwide epidemiological survey on autosomal recessive ichthyosis and ichthyosis syndromes in Japan.¹⁰ We are now working on a clinical survey that focuses on the therapeutic effects and safety of drugs for the establishment of clinical practice guidelines for congenital ichthyosis. The survey is proceeding as planned, and the collection of a secondary questionnaire is expected to be completed in the near future.

In 2020, we clarified that SDR9C7, one of the causative molecules of lamellar ichthyosis, plays an important role in the formation of the corneocyte lipid envelope, which is essential for skin barrier function.¹¹ In addition, we reported that dupilumab, an anti-IL-4 receptor α monoclonal antibody, is effective not only against the atopic features of Netherton syndrome, but also against its ichthyotic features.¹²

To raise awareness of this disease, an educational lecture on genetic disorders of keratinization was delivered to dermatologists at the 120th Annual Meeting of the Japanese Dermatological Association (Web hybrid meeting in Yokohama, Japan, June 10, 2021). Furthermore, an open lecture for the general public was held as a Science Talk at the Aichi Science Festival 2022 (Zoom webinars, October 17, 2022). The symposium “Skin Barrier Defects and Inflammation” was held for clinicians at the 52nd Annual Meeting of the Japanese Society of Skin Immunology and Allergy (Web hybrid meeting in Nagoya, Japan, December 18, 2022). We published a comprehensive review paper on the international updated classification, diagnostic criteria, and current treatments for ichthyosis, which has led to international improvements in the level of medical care for congenital ichthyoses.⁸ We plan to establish updated diagnostic criteria and a revised classification of disease types as global standards.

Oculocutaneous albinism

In oculocutaneous albinism, a disease that shows autosomal recessive inheritance, melanin is decreased or absent in the skin, hair, and eyes from birth because of genetic abnormalities in the melanin production and transport pathways. Patients frequently suffer from photosensitivity and nystagmus. Oculocutaneous albinism includes a group of genetically heterogeneous diseases (Table 4).^13,14 They are divided into non-syndromic and syndromic types.

Table 4. Types and genetic causes of oculocutaneous albinism

OCA type	Causative mutated gene
Non-syndromic OCA
OCA1 (OCA1A, OCA1B)	TYR
OCA2	OCA2
OCA3	TYRP1
OCA4	SLC45A2
OCA5	Unknown (chromosome 4q24)
OCA6	SLC24A5
OCA7	LRMDA (C10orf11)
OCA8	DCT
Syndromic OCA
Hermansky–Pudlak syndrome (HPS)
HPS1	HPS1
HS2	AP3B1
PS3	HPS3
HS4	HPS4
HS5	HPS5
HS6	HPS6
HS7	DTNBP1
HPS8	BLOC1S3
HPS9	BLOC1S6
HPS10	AP3D1
PS11	BLOC1S5
Chediak–Higashi syndrome	LYST

OCA, oculocutaneous albinism.

Modified from Okamura and Suzuki.¹

The clinical practice guidelines for oculocutaneous albinism were established in 2014 (in Japanese) with an addendum in 2017. To disseminate the guidelines and raise awareness of their availability, we have conducted nationwide Web seminars and have held local seminars for medical professionals in various locations in Japan. Although plans were in place to deliver lectures to patient associations in various cities in Japan, opportunities to deliver lectures were limited by the pandemic. In efforts to create a registry of oculocutaneous albinism patients, we have collected the details of 234 cases of oculocutaneous albinism from throughout Japan.

We have established a next-generation sequencing-based targeted sequencing system to comprehensively identify causative gene variants in albinism patients.¹⁵ We identified two novel causative variants in HPS5 in a Japanese patient with Hermansky–Pudlak syndrome type 5.¹⁶ We also analyzed and reported a case of oculocutaneous albinism type 6, which is a rare subtype in Japan.¹⁷

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum is a disease in which multiple yellowish papules occur on the neck and armpits because of variants in ABCC6. In the skin lesions, elastorrhexis and progressive ectopic mineralization are typically observed. In patients with pseudoxanthoma elasticum, laxity of the skin is observed with aging, and ocular symptoms and vascular lesions are also observed. We recently published an English version of clinical practice guidelines for pseudoxanthoma elasticum in Japan.¹⁸ Currently, we are working to spread awareness amongst clinicians that genetic testing for causative ABCC6 variants is essential for a precise diagnosis of pseudoxanthoma elasticum.¹⁹

The exact pathomechanisms of the formation of mineralization lesions, including in the skin, have not been clarified. We are planning to analyze clinical data to develop measures to prevent the disease and to improve the prognosis of patients. We believe that further advances in transcriptome analysis will be necessary to discover means of preventing pseudoxanthoma elasticum and improving its prognosis. To elucidate the pathological mechanism by transcriptome analysis, we are currently identifying genes other than ABCC6 that are suspected of being involved in pathological conditions. We will accumulate cases and verify the results of our analysis. In efforts toward creating a registry of patients with pseudoxanthoma elasticum, we have collected information on 170 cases to date.

Hereditary angioedema

Hereditary angioedema is a disease in which angioedema recurs from the teenage years onwards because of various triggers, such as trauma and mental stress. According to the updated version of the international World Allergy Organization/European Academy of Allergy and Clinical Immunology (WAO/EAACI) guidelines for managing hereditary angioedema,²⁰ nine forms of hereditary angioedema are recognized (Table 5).

Table 5. Types and genetic causes of hereditary angioedema

HAE type	C1-INH level	Causative mutated gene
Type 1 HAE	Deficient	SERPING1
Type 2 HAE	Defective	SERPING1
HAE with normal C1-INH gene
HAE-FXII	Normal	F12
HAE-PLG	Normal	PLG
HAE-KNG1	Normal	KNG1
HAE-HS3ST6	Normal	HS3ST6
HAE-ANGPT1	Normal	ANGPT1
HAE-MYOF	Normal	MYOF
HAE-UNK	Normal	Unknown

HAE, hereditary angioedema.

Modified from Maurer et al.²⁰

The Angioedema Control Test (AECT), an internationally used tool for assessing disease control in hereditary angioedema, and the Angioedema Quality of Life Questionnaire (AE-QoL), a tool for assessing QOL, have been established.^21,22 Both scores are now widely known to clinicians, including dermatologists, and are used to assess patient disease status and QOL impairment at many medical institutions in Japan. In 2021, our research group published a report on the validation of the AE-QoL and the Angioedema Activity Score.²³

Currently, our group is translating the 2018 International Guidelines for Hereditary Angioedema²⁴ into Japanese. In the future, our group will also work on a Japanese translation of the 2021 version of the International Guidelines for Hereditary Angioedema that were published in 2022.²⁰

In efforts toward establishing a registry of patients with hereditary angioedema, our group continues to collect patient data, and a large number of cases have been registered. Based on the latest findings, we continue to raise awareness among physicians involved in medical care by presenting lectures to public audiences and by publishing columns in academic journals that explain terms associated with hereditary angioedema.^25,26,27,28

Generalized pustular psoriasis

Pustular psoriasis is an autoinflammatory keratinization disease (AiKD)²⁹ in which sterile pustules occur over the entire body (GPP) or on parts of the body (localized pustular psoriasis) in recurrent episodes.³⁰ Variants in several genes, such as IL36RN and CARD14, have attracted attention as predisposing factors for GPP.³⁰ All pustular psoriasis subtypes are considered to be AiKDs, and, among them, GPP is a representative AiKD.³⁰ In cases of GPP, most early-onset GPP patients without psoriasis vulgaris have IL36RN variants as genetic predisposing factors.^31,32

Our research group conducted a survey on clinical practice for GPP, and the results were published in 2021.³³ The survey data suggested that Japanese GPP patients are often treated at large hospitals and that many of them are restricted to mild symptoms because of the introduction of biological agents. As part of efforts to revise the GPP clinical practice guidelines of the Japanese Dermatological Association,³⁴ our research group has conducted a preliminary survey on clinical practice for GPP and a survey on patient conditions.³⁵ Our analysis found that although the guidelines have achieved good prevalence, the severity scoring system is underused, and there may be regional differences in the actual treatment of GPP. In addition, our survey confirmed that many patients use biologics. Furthermore, the severity of skin lesions was retrospectively studied in patients with GPP alone and in patients with GPP plus psoriatic arthritis.³⁶ GPP skin lesions were found to be milder in patients with GPP plus psoriatic arthritis than in patients with only GPP.³⁶

Our research group is currently preparing a questionnaire-based epidemiological study to further investigate any regional differences in GPP care. To raise awareness of GPP, the data obtained to date by our research group were presented in lectures to clinicians and at patient meetings.

In regard to the genetic causative or predisposing factors for GPP, in addition to IL36RN and CARD14, three other genes (AP1S3, MPO, and SERPINA3) have been identified as being associated with pustular psoriasis (Table 6).³⁰ In regard to GPP in particular, we identified a pathogenic variant in MPO, which encodes myeloperoxidase (MPO).³⁷ This was the first case in which an MPO variant was found in a Japanese pustular psoriasis patient.

Table 6. Genetic predisposing factors for generalized pustular psoriasis

Disease-related gene (molecule)	Variant
IL36RN (IL-36 receptor antagonist)	Loss-of-function variants
CARD14 (caspase recruitment domain family member 14; CARD14)	Gain-of-function variants
AP1S3 (adaptor-related protein complex 1, sigma-3 subunit; AP1S3)	Loss-of-function variants
MPO (myeloperoxidase; MPO)	Loss-of-function variants
SERPINA3 (serine protease inhibitor A3; SERPINA3)	Loss-of-function variants

Modified from Akiyama.³⁰

Future Perspectives and Conclusions

Regarding epidermolysis bullosa, our research group will continue to analyze the secondary data from the National Epidemiological Survey on Epidermolysis Bullosa. In the QOL survey of epidermolysis bullosa patients, the RUDY Japan network system (https://rudy.hosp.med.osaka-u.ac.jp), which allows participation in clinical trials via the Web, will be used to investigate the QOL of epidermolysis bullosa patients in each season. Clinical practice guidelines for epidermolysis bullosa, including information on new treatments, will be completed in the near future.

Our work on congenital ichthyoses will continue through a clinical survey focusing on the therapeutic efficacy and safety of treatments, based on patients’ disease phenotypes and genotypes. Our novel comprehensive data will be integrated with clinical data obtained in previous studies. We aim to formulate clinical practice guidelines that will incorporate appropriate treatment guidelines for congenital ichthyoses.

Advances in addressing oculocutaneous albinism will continue with further promotion of the already-published treatment guidelines and through plans to expand and enhance the registry that has been built to date. In addition, our group will disseminate accurate knowledge to patient associations and will respond to individual consultations. We are planning to issue a questionnaire-based clinical survey on QOL for patients and their families that will enlist the cooperation of patient associations.

For pseudoxanthoma elasticum, we aim to standardize diagnosis and treatment by broadening awareness of the disease among doctors in Japan. In addition, by conducting transcriptome analysis and constructing a signaling network via ABCC6, we aim to identify severity predictors and prognostic factors and to develop new treatment methods.

Progress in addressing hereditary angioedema continues via the construction of a patient registry from clinical questionnaire data to understand patient QOL. This work uses the online registry system RUDY Japan (https://rudy.hosp.med.osaka-u.ac.jp) and is conducted in collaboration with the Biomedical Ethics and Public Policy Lab, Department of Social Medicine, Graduate School of Medicine, Osaka University, with the aim to develop novel treatments to improve symptoms and to prevent disease attacks.

For further work on GPP, our group will analyze the five genes reported to cause this disease using the genomic DNA from Japanese patients, and we will try to identify additional causative genes. We will analyze our obtained genotype information for associations between genotypes and patient clinical information, including medical history (presence or absence of psoriasis vulgaris, age of onset), disease severity, drug administration, and response to treatments.

Our research group will continue to pursue research that will help to improve the level of medical care for patients with these intractable hereditary skin diseases, not only in Japan but worldwide. In applying the results, we aim to improve the QOL of patients. Furthermore, we propose that the achievements of our research group be used by the Japanese government for policy decisions.

Acknowledgments

The work of the authors was supported by a grant from the Ministry of Health, Labour, and Welfare of Japan (Health and Labour Sciences Research Grant for Research on Intractable Diseases: 20FC1052).

Conflicts of Interest

The authors have declared that no conflict of interest exists.

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