Abstract
The Hashimoto Research Group for Comprehensive Research of Gene Mutation-related Rare and
Intractable Diseases of the Skin is a contributor to the Project for Research on
Intractable Diseases of the Ministry of Health, Labor, and Welfare (MHLW) of Japan. Our
research group performs clinical research on 23 rare intractable genetic skin diseases
that are classified into eight disease groups. Among the 23 diseases, 17 are mainly
studied by our research group, and 6 diseases are studied in collaboration with other
research groups. Cockayne syndrome and familial chronic and benign pemphigus (also known
as Hailey-Hailey disease) are the designated intractable diseases that are mainly studied
by our research group. This review summarizes the activities of our research group for
these 23 intractable hereditary skin diseases, including the MHLW tasks for designated
intractable diseases, epidemiological studies using nationwide surveys, preparation of
patient registries, creation of repositories, development and publication of clinical
practice guidelines, clinical trials for novel treatments in collaboration with the
Japanese Agency for Medical Research and Development, help with genetic diagnosis,
applications for the listing of new designated intractable diseases, communication of
information to academic societies, medical professionals and patients, spreading awareness
of our activities to the public, supporting patient societies, and presentation and
publication of achievements. These studies are performed in collaboration with the
relevant academic societies, mainly the Japanese Dermatological Association.
Structure and Activities of the Hashimoto Research Group
The Hashimoto research group conducts research on rare and intractable skin diseases
related to genetic defects. It is one of the research groups that contributes to the Project
for Research on Intractable Disease of the Ministry of Health, Labor, and Welfare (MHLW) of
Japan. This group is supervised and represented by Takashi Hashimoto, a specially appointed
professor in Department of Dermatology, Graduate School of Medicine, Osaka Metropolitan
University. The group has nine research contributors and 38 research collaborators, who are
experts in the respective diseases of interest.
The aim of the Hashimoto group is to perform epidemiological studies and clinical research
on genetic mutation-related rare and intractable diseases of the skin. This work is
supported by a Health and Labor Science Research Grant from the MHLW. The details of the
diseases of interest (23 distinct diseases within eight disease groups) are provided in
Table 1. Group 1 includes Cockayne syndrome
(CS) [designated intractable disease (DID) notification number 192] (supervisor: Shinichi
Moriwaki), Group 2 includes familial benign chronic pemphigus (also known as Hailey-Hailey
disease; HHD) (DID #161) and Darier’s disease (DD) (supervisor: Hiroaki Iwata; previously
Minao Furumura), and Group 3 includes hidradenitis suppurativa (HS) and pyoderma gangrenosum
(PG) (supervisor: Koremasa Hayama). Group 4 contains various autoinflammatory diseases that
mainly affect the skin, including Weber-Christian syndrome (WCS), Sweet’s disease,
Schnitzler syndrome, and Granular C3 dermatosis (GCD) (supervisor: Nobuo Kanazawa). Another
five diseases that are primarily studied by the Nishikomori group (Kurume University School
of Medicine) are also included in Group 4: Nakajo-Nishimura syndrome (NNS) (DID #268),
cryopyrin-associated periodic fever syndrome (CAPS) (DID #106), Blau syndrome (BS) (DID
#110), pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome (DID #269),
and TNF receptor-associated periodic syndrome (TRAPS) (DIF #108). These diseases are also
studied by the Hashimoto group from a dermatological perspective (supervisor: Nobuo
Kanazawa). Group 5 contains various perforating skin diseases, including reactive
perforating dermatosis, Kirle disease, folliculitis perforans, and elastosis perforans
serpiginosa (supervisor: Tamihiro Kawakami). Group 5 also includes Sturge-Weber syndrome
(DID #157), which, as a neurological disorder, is primarily studied by the Inoue group
(National Center of Neurology and Psychiatry). The dermatological
manifestations of the disease are studied by the Hashimoto group (supervisor: Tamihiro
Kawakami).
Table 1Details of diseases, their causative genes, and chief investigators of 23 diseases
studied by the Hashimoto group
| Disease group |
Disease |
DID |
Causative genes |
Chief investigator |
| 1 Photosensitive skin disease |
1: Cockayne syndrome (CS) |
DID #192 |
ERCC6 (CSB),
ERCC8 (CSA), ERCC3
(XPB), ERCC2 (XPD),
ERCC5 (XPG) |
Shinichi Moriwaki |
| 2 Dyskeratotic skin diseases |
2: Familial benign chronic pemphigus, also known as
Hailey-Hailey disease (HHD) |
DID #161 |
ATP2C1
|
Hiroaki Iwata |
|
3: Darier’s disease (DD) |
|
ATP2A2
|
Hiroaki Iwata |
| 3 Inflammatory skin diseases |
4: Hidradenitis suppurativa (HS), including familial
HS |
|
NCSTN, PSEN1,
PSENEN, SOX9, KLF5 |
Koremasa Hayama |
|
5: Pyoderma gangrenosum (PG) |
|
NFkB1
|
Koremasa Hayama |
| 4 Autoinflammatory skin diseases |
6 Schnitzler syndrome |
|
Unknown |
Nobuo Kanazawa |
|
7 Sweet’s disease |
|
Unknown |
Nobuo Kanazawa |
|
8 Weber-Christian syndrome (WCS) |
|
Unknown |
Nobuo Kanazawa |
|
9 Granular C3 dermatosis (GCD) |
|
Unknown |
Nobuo Kanazawa |
|
10 Nakajo-Nishimura syndrome (NNS) |
DID #268 |
PSMB8, PSMA3,
PSMB4, PSMB9, POMP |
Nobuo Kanazawa |
|
11 Cryopyrin-associated periodic fever syndrome
(CAPS) |
DID #106 |
NLRP3
|
Nobuo Kanazawa |
|
12 Blau syndrome (BS) |
DID #110 |
NOD2
|
Nobuo Kanazawa |
|
13 Pyogenic sterile arthritis,
pyoderma
gangrenosum and acne (PAPA) syndrome |
DID #269 |
PSTPIP1
|
Nobuo Kanazawa |
|
14 TNF receptor-associated periodic syndrome
(TRAPS) |
DID #108 |
TNFRSF1A
|
Nobuo Kanazawa |
| 5 Perforating skin dermatoses |
15 Reactive perforating dermatosis |
|
Unknown |
Tamihiro Kawakami |
|
16 Kirle disease |
|
Unknown |
Tamihiro Kawakami |
|
17 Folliculitis perforans |
|
Unknown |
Tamihiro Kawakami |
|
18 Elastosis perforans serpiginosa |
|
Unknown |
Tamihiro Kawakami |
|
19 Sturge-Weber syndrome |
DID #157 |
GNAQ, GNA11 |
Tamihiro Kawakami |
| 6 Palmoplantar keratoderma group |
20 Palmoplantar keratoderma
including
pachyonychia congenita |
|
KRT1, KRT6A,
KRT6B, KRT6C, KRT9,
KRT16, KRT17, AQP5,
GJB2, AAGAB, SERPINB7,
SERPINA12, SLURP1, TRPV3,
DSP, DSG1 |
Toshifumi Nomura |
| 7 Familial cancer diseases of the skin |
21 Gorlin syndrome |
|
PTCH1, PTCH2, SUFU
|
Daisuke Tsuruta e |
|
22 Cowden syndrome |
|
PTEN
|
Daisuke Tsuruta e |
| 8 Epidermodysplasia verruciformis |
23 Epidermodysplasia verruciformis |
DID #65 |
EVER1, EVER2,
CIB1, RHOH, MST1
(STK4), DOCK8, CORO1A,
LCK, DCLRE1C, RASGRP1,
TPP |
Eijiro Akasaka f |
Group 6 covers various types of palmoplantar keratoderma (supervisor: Toshifumi Nomura;
previously Kozo Yoneda), and Group 7 includes Gorlin syndrome and Cowden syndrome
(supervisor: Daisuke Tsuruta; assisted by Chiharu Tateishi). Currently, Cowden syndrome is
not a designated intractable disease and is a topic of interest as a gastrointestinal tumor
prevalent disease. However, given that this condition also manifests as a dermatological
disorder, it is likely to be studied as part of a collaboration in the near future.
Group 8 includes epidermodysplasia verruciformis (DID #65), which is also studied as an
immunodeficiency syndrome in collaboration with the Morio group (Instituteof Science Tokyo).
However, because epidermodysplasia verruciformis manifests as cutaneous lesions, the main
research effort is delivered by the Hashimoto group (supervisor: Eijiro Akasaka; previously
Hajime Nakano) in collaboration with the Morio Group.
The research activities of the Hashimoto group started about 11 years ago with
investigations of other diseases, which have since discontinued. For example, we
investigated hereditary diseases of the hair (Yutaka Shimomura) and dermatitis herpetiformis
Duhring (Chica Ohata), but these studies were discontinued because of a lack of disease
severity and a lack of genetic background, respectively. The current interactions and
activities of the Hashimoto group are illustrated in Fig.
1.
Missions, Activities, and Achievements of the Hashimoto Research Group
The missions of the Hashimoto group are to contribute to MHLW policy areas by providing
medical information on genetic mutation-related rare and intractable diseases of the skin to
the personnel of the MHLW, medical personnel, and patient societies. The details of the
missions of our research group are described in Table
2.
Table 2The missions of the Hashimoto research group
| Mission |
Description |
| 1 |
Address the tasks related to the policy of the Ministry
of Health, Labor, and Welfare for designated intractable diseases |
| 2 |
Epidemiological surveys |
| 3 |
Preparation and update of patient registries |
| 4 |
Creation and expansion of repositories of patient
biological samples |
| 5 |
Preparation and publication of clinical practice
guidelines |
| 6 |
Development of new therapies in collaboration with the
Japanese Agency for Medical Research and Development |
| 7 |
Provide assistance for genetic diagnosis |
| 8 |
Organization and hosting of annual meetings |
| 9 |
Initiate applications for recognition of new designated
intractable diseases |
| 10 |
Communication of achievements to the general public |
| 11 |
Provide support for patient societies |
| 12 |
Presentations at meetings and publication of
results |
Contribute to MHLW policy
The first mission of the Hashimoto research group is to perform tasks that contribute to
the MHLW policy related to designated intractable diseases. Among the 23 diseases listed in
Table 1, this effort mainly relates to our
work on CS and familial benign chronic pemphigus.
Epidemiological surveys
We have performed and are performing a series of nationwide epidemiological surveys to
obtain detailed information on the number of patients and their status for the 23 diseases
in Japan. This task is particularly relevant for the future designation of intractable
diseases and those recently designated. Detailed nationwide surveys are now in progress for
HS, palmoplantar keratoderma, and perforating dermatoses, which were previously rejected as
designated intractable diseases. Nationwide surveys are also performed for other diseases,
including CS, familial benign chronic pemphigus, Cowden syndrome, and epidermodysplasia
verruciformis.
Patient registries
We have prepared and are preparing nationwide patient registries for some of the diseases
investigated by our research group. A unique and powerful strategy to build large patient
registries is through the use of the Research Electronic Data Capture (REDCap) system, which
we have implemented under the guidance of Ayumi Shintani and assistance from Keiko Ota and
Chiharu Tateishi. We have already prepared the frameworks for the registries for CS,
familial benign chronic pemphigus, Gorlin syndrome, Cowden syndrome, palmoplantar
keratoderma, and epidermodysplasia verruciformis. In future, we will prepare patient
registries using the REDCap system for all 23 diseases studied in our research group based
on patient data obtained from our epidemiological surveys.
Creation of sample repositories
We have created and are expanding the repositories of various biological samples from
patients, particularly DNA samples. These samples have been obtained during the course of
our studies on these diseases.
Clinical practice guidelines
Our research group is continuously developing and revising evidence-based clinical practice
guidelines, particularly for diagnostic criteria and severity classifications. Clinical
practice guidelines for HS, palmoplantar keratoderma,1)pyoderma
gangrenosum,2)perforating
dermatosis,3) and familial
benign chronic pemphigus have already been prepared in collaboration with the Japanese
Dermatological Association and have been published in both Japanese and English. The
clinical practice guidelines for DD and epidermodysplasia verruciformis are also being
prepared in collaboration with the Japanese Dermatological Association. Similarly, the
clinical practice guidelines for CS and Cowden’s syndrome are being prepared in
collaboration with the Japanese Dermatological Association and with the input of other
societies related to pediatrics. The clinical practice guidelines for Schnitzler syndrome
have been prepared in collaboration with the Japanese Rheumatology Association.
Development of new therapies
New therapies are being developed in collaboration with the Japanese Agency for Medical
Research and Development (AMED). Our research group has applied for AMED grants for the
treatment of Schnitzler syndrome with canakinumab and for the treatment of familial benign
chronic pemphigus with apremilast. The canakinumab treatment of Schnitzler syndrome has been
accepted (JP24ek0109582), and work has progressed to a physician-oriented randomized
clinical trial (jRCT2051220139) in collaboration with AMED to evaluate the therapeutic
effects on this disease.
Genetic diagnosis
Upon requests from clinicians and researchers at institutes affiliated with our research
group, some genetic diagnostic tests have been performed in undiagnosed cases to confirm
final diagnoses. Recently, with the help of experts in the respective genetic diseases, we
also introduced genetic diagnostic tests at the Kazusa DNA Research Institute (Kisarazu,
Japan).
Annual meetings
As the principal investigator, Takashi Hashimoto organizes and conducts annual meetings for
the members of our research group, which are typically held in late autumn. An additional
meeting is conducted in February for the researchers based in the Kansai region. A joint
meeting of the Hashimoto group, the Nishikomori group, and the Morio group was conducted for
the first time in October 2024.
New applications for designation as an intractable disease
In a typical year, our research group investigates four to six diseases that we consider
should be recognized as designated intractable diseases.
Communication of achievements to the public
The achievements of our research group in relation to intractable diseases are communicated
to the public through meetings of patients and meetings that are open to the public.
Support for patient societies
Our research group provides continuous support to the Cockayne Syndrome Patient Society. In
addition, with the support of our research group, a new patient society for palmoplantar
keratoderma was established in 2024.
Presentation and publication of achievements
The members of our research group continue to present the achievements of our studies at
various scientific and public meetings. In addition, these achievements are published as
scientific articles in various journals every year.
Activities of Hashimoto Research Group for Different Diseases
Group 1: Cockayne syndrome
To contribute to MHLW policy on designated intractable diseases, the Hashimoto group
continues to prepare and submit documentation for the management of CS. The clinical
practice guidelines for CS have already been prepared and are currently proceeding to
publication by obtaining approvals from the Japanese Dermatology Association and other
societies related to pediatrics. In addition, for the early definitive diagnosis of CS,
Shinichi Moriwaki, the research supervisor, is continuing diagnostic tests at the CS
Diagnostic Center by using patient specimens received from facilities nationwide. The CS
Diagnostic Center, which was set up under the leadership of Shinichi Moriwaki, continues to
support the CS family society.
Group 2: Dyskeratotic skin diseases
The Hashimoto group contributes to the management of HHD through various actions. The
clinical practice guideline for HHD has been published in collaboration with the Japanese
Dermatology Association. The clinical practice guideline includes the revised diagnostic
criteria, severity classification, the establishment of various treatments, and evidence for
implementation. An application for a clinician-initiated clinical trial for treatment of HHD
with apremilast was submitted for AMED grant funding, but the application was
unsuccessful.
The clinical practice guideline for DD is currently in preparation. We expect that the
guideline will be published soon after approval from the Japanese Dermatology Association.
After the guideline is published, we will prepare an application for DD to be recognized as
a designated intractable disease. Case reports for HHD and DD have been published in
dermatological journals.
Group 3: Inflammatory skin diseases
The Hashimoto group has conducted nationwide epidemiological surveys for HS through
questionnaires on the effects of daily life events on the disease and the quality of life
(QOL) of patients and family members. In addition, we have performed an epidemiological
survey by questionnaire for the presence or absence of skin rash in normal subjects to
investigate the true morbidity of HS patients in Japan. This study was carried out as an
international collaborative study with European researchers. The clinical practice guideline
for HS has been published in collaboration with the Japanese Dermatology Association. We
have applied for HS to be recognized as a designated intractable disease, but the
application was unsuccessful. We intend to submit a revised application after we have
obtained more detailed epidemiological information on HS.
For PG, a nationwide epidemiological survey has been conducted, and the clinical practice
guideline for diagnostic criteria, severity classification, and treatment has been published
in collaboration with the Japanese Dermatological Association. We will soon apply for PG to
be recognized as a designated intractable disease.
Group 4: Autoinflammatory diseases involving skin lesions
The group of autoinflammatory diseases studied by the Hashimoto group includes WCS, Sweet’s
disease, Schnitzler syndrome, and GCD. Our research group is conducting nationwide
epidemiological surveys on these diseases. The gathered information will allow us to prepare
clinical practice guidelines for these diseases, including revised diagnostic criteria,
severity classifications, and treatments.
A multicenter physician-initiated randomized clinical trial for canakinumab treatment of
Schnitzler syndrome (jRCT2051220139) has received AMED research funding (JP24ek0109582) and
is currently in progress (supervisor: Naotomo Kambe; assisted by Nobuo Kanazawa). Clinical
practice guideline for Schnitzler syndrome is in preparation, and we will soon apply for
Schnitzler syndrome to be recognized as a designated intractable disease.
A nationwide epidemiological survey was conducted for GCD (supervisor: Nobuo Kanazawa). In
addition, studies are in progress to investigate the complement activation mechanism and to
establish a disease concept in GCD (supervisor: Norimitsu Inoue). Various fresh specimens
from new GCD patients are being received from facilities nationwide.
The five systemic and cutaneous autoinflammatory diseases that are already accepted as
designated intractable diseases are NNS, TRAPS, CAPS, BS, and PAPA syndrome. Although these
diseases are mainly studied by the Nishikomori Group for the establishment of diagnostic
criteria, severity classification, and clinical guidelines, the Hashimoto group (supervisor:
Nobuo Kanazawa) is also studying the dermatological manifestations of these diseases.
Group 5: Perforating skin dermatosis and Sturge-Weber syndrome
For perforating dermatoses, we are continuing epidemiological survey studies on reactive
perforating dermatosis, Kirle disease, folliculitis perforans, and elastosis perforans
serpiginosa. The obtained data will be used to establish a patient registry through the
REDCap system. In addition, the clinical practice guideline for these diseases is being
updated in collaboration with the Japanese Dermatological Association, and we will apply for
this disease group to be added to the list of designated intractable diseases. Furthermore,
we are investigating the pathogenesis of the disease group, particularly the mechanism of
itch induction, for the development of a new treatment in the future.
With regards to Sturge-Weber syndrome, epidemiological surveys will be conducted in
collaboration with the Inoue group. This work will contribute toward the development,
revision, and verification of the clinical practice guidelines.
Group 6: Diseases of palmoplantar keratoderma
Epidemiological surveys for palmoplantar keratoderma are in progress to clarify the actual
status of the disease. The obtained data are under analysis for the construction of a
registry using the REDCap system. In addition, we have revised the clinical practice
guideline for palmoplantar keratoderma for diagnostic criteria, severity classification, and
treatment. We also intend to apply for palmoplantar keratoderma to be listed as a designated
intractable disease.
To promote international research, the Hashimoto group is collaborating with the European
and US patient societies for pachyonychia congenita and palmoplantar keratoderma. A new
patient society for palmoplantar keratoderma was recently established by patients in
collaboration with Toshifumi Nomura and Takashi Hashimoto. The homepage of this patient
society has been prepared and will be used promote awareness of this disease to patients and
the public.
Group 7: Familial cancer diseases of the skin
For Gorlin syndrome and Cowden syndrome, efforts are continuing toward nationwide
epidemiological surveys, construction of patient registries, and preparation of clinical
practice guidelines. Obtained data will be used to build a registry through the REDCap
system (Ayumi Shintani, Keiko Ota, and Chiharu Tateishi). The clinical practice guidelines
for Cowden syndrome will be constructed in collaboration with the research group for
gastrointestinal tumor prevalent disease by revising the draft of the diagnostic criteria,
severity classification, and treatment. Subsequently, we will apply for the disease to be
added to the list of designated intractable diseases.
Group 8: Epidermodysplasia verruciformis
Epidermodysplasia verruciformis is an extremely rare autosomal recessive genetic disorder
characterized by the generalized development of flat verrucous lesions caused by an
immunodeficiency against the human papillomavirus (HPV). Epidermodysplasia verruciformis is
highly susceptible to cutaneous malignancies such as squamous cell carcinoma in the exposed
areas. Early diagnosis and appropriate follow-up are important. Because it is a rare
disease, to first ascertain the exact number of patients in Japan, we are conducting
nationwide epidemiological surveys. We will use data from the surveys to establish a
registry by using the REDCap system. Then, we will collaborate with the Japanese
Dermatological Association to develop clinical practice guideline for epidermodysplasia
verruciformis. To clarify the pathogenesis of this disease, we will perform genetic tests
and analyze HPV expression in all patients.
The statistical analyses for the 23 diseases investigated by our research group were
conducted by Ayumi Shintani, with the assistance of Tamihiro Kawakami. The creation and
expansion of the registries by using the REDCap system were also performed by Ayumi
Shintani, with the assistance of Keio Ota and Chiharu Tateishi. Ultimately, the REDCap
system will be used to construct registries for all diseases studied by the Hashimoto
group.
Future Perspectives and Conclusions
The members of the Hashimoto research group have performed and continue to perform various
clinical studies on genetic mutation-related rare and intractable diseases of the skin (23
diseases in eight disease groups). This work aligns with the policies of the MHLW and occurs
under the supervision of Takashi Hashimoto as principal investigator with input from nine
research contributors and 38 research collaborators.
The Hashimoto group continues to implement nationwide epidemiological surveys, create
registries using the REDCap system, and establish and revise clinical practice guidelines.
This work has produced many significant findings that have been presented at medical
conferences and have been published in Japanese and international journals.
We will continue to provide medical information on the 23 rare intractable hereditary skin
diseases to personnel of the MHLW, to medical personnel, and to members of the public. We
also intend to organize meetings that are open to the public to communicate the achievements
of our research. We hope that the results of our research will be used to facilitate
improvements in medical care and improve the QOL of patients with these intractable
hereditary skin diseases, both in Japan and in other countries.
Acknowledgments
The work of the Hashimoto group is supported by a grant from the Ministry of Health, Labor,
and Welfare of Japan (Health and Labor Sciences Research Grant for Research on Intractable
Diseases: 23FC1036). The authors thank Ms. Yoko Mukaoku and Ms. Naomi Miyamoto (Osaka
Metropolitan University) for secretarial work.
Conflicts of Interest
The authors have declared that no conflict of interest exists.
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