2025 Volume 74 Issue 1 Pages 1-3
There are a large number of genetic and hereditary diseases of the skin with various disease types, and a significant number of them are rare and intractable diseases. These skin diseases impose a heavy burden on each patient during their lifetime. Causative genes have been identified in most genetic skin diseases, which makes diagnosis easier and has helped in elucidation of the pathogenesis. However, causative genes have not been identified in some genetic skin diseases, and the pathogenesis in these diseases remains poorly understood. In addition, safe and effective therapeutic methods are yet to be established for most genetic skin diseases.
To clarify the current situations of various rare and intractable diseases and to support patients with these diseases in Japan, the Ministry of Health, Labor, and Welfare of Japan (MHLW) has long executed the Project for Research on Intractable Disease. In this project, a number of different research groups are currently working on 441 rare and intractable diseases in various fields. There are currently six dermatology-related research groups in the Project for Research on Intractable Disease. Because genetic diseases are usually rare and intractable, most of the dermatology-related research groups are studying various genetic skin diseases.
Of the six dermatology-related research groups, five of them are investigating genetic skin diseases. These five groups are: the research group for comprehensive research of gene mutation-related rare and intractable diseases of the skin (led by Takashi Hashimoto), which conducts various clinical and political research for 23 distinct genetic skin diseases; the research group for rare and intractable skin diseases (led by Masashi Akiyama), which works on various skin diseases including 6 genetic diseases; the neurocutaneous syndrome policy research group (led by Akihiko Asahina, previously Chikako Nishigori), which works on 4 genetic skin diseases [neurofibromatosis, tuberous sclerosis complex (TSC), xeroderma pigmentosum, and porphyria]; the research group for treatment strategies and epidemiological studies for rare and intractable diseases with abnormal sweating (led by Hiroyuki Murota), which works on genetic diseases that show abnormal sweating; and the research group for severe erythema exudative multiforme (led by Riichiro Abe, previously Hideo Asada), which works on four drug-induced skin diseases that involve a genetic predisposition. The sixth dermatology-related research group (led by Yoshihide Asano) studies systemic sclerosis, which is not a genetic disease. The Hashimoto group previously conducted research on hereditary hair diseases (with Yutaka Shimomura as a research contributor).
In this special issue, we have collected eight articles that describe researches on various genetic skin diseases. In particular, this special issue focuses on the missions, activities, and achievements of the three research groups (Hashimoto group, Akiyama group, and Asahina/Nishigori group) that participate in the Project for Research on Intractable Diseases of the MHLW.
In addition, two articles were submitted by a group with ties to the Pachyonychia Congenita Project (PC Project), an international patient advocacy organization for pachyonychia congenita (PC) patients, that coordinates PC research in Europe and the USA. The PC Project conducts both clinical/political work and basic research on PC and PC-related diseases including palmoplantar keratoderma, which is a disease studied by the Hashimoto group in Japan. In the two papers by the members of the PC Project, current advances in research on PC and palmoplantar keratoderma are described from the scientific viewpoint by McCarthy et al.1 and from the perspective of the patient society by Schwartz et al.2
This special issue was originally proposed and has been facilitated by the Editor-in-Chief of Keio Journal of Medicine, Kenjiro Kosaki, Professor of the Center for Medical Genetics, Keio University School of Medicine. Professor Kosaki also leads a research group for the collection and reconnection of natural history data on congenital anomaly syndromes based on two-way collaboration with patients (Kosaki group) within the MHLW. He is a leader of the Initiative on Rare and Undiagnosed Diseases (IRUD) within the Japanese Agency for Medical Research and Development (AMED).
In this special issue, Hashimoto et al.3 describe the mission, activities, and achievements of the research group for comprehensive research of gene mutation-related rare and intractable diseases of the skin (Hashimoto group) within the Project for Research on Intractable Diseases of the MHLW. The Hashimoto group conducts clinical and political research on 23 rare intractable genetic skin diseases within eight disease groups. Among the 23 diseases, Cockayne syndrome and familial chronic benign pemphigus (Hailey–Hailey disease) are designated intractable diseases. The Hashimoto group researchers continue to work toward ten mission areas: tasks related to the policy of the MHLW for designated intractable diseases, epidemiological studies, creation and maintenance of patient registries using the REDCap system, creation of patient sample repositories, development of clinical practice guidelines, clinical trials in collaboration with AMED, genetic diagnosis, applications for recognition of new designated intractable diseases, raising awareness within the general population and the scientific community, and support of patient societies. These studies are performed in collaboration with the relevant academic societies, mainly the Japanese Dermatological Association. The prepared clinical practice guidelines and the achievements of the Hashimoto group are published in many English and Japanese journals.
Akiyama et al.4 describe the aims, activities, and achievements of the research group for rare and intractable skin diseases (Akiyama group) within the Project for Research on Intractable Diseases of the MHLW. The Akiyama group is conducting research on a number of skin diseases, including six genetic diseases: epidermolysis bullosa, congenital ichthyosis, oculocutaneous albinism, pseudoxanthoma elasticum, hereditary angioedema, and generalized pustular psoriasis. In particular, the causative genes of these genetic diseases are described in detail.
Goto et al.5 describe studies on two familial cancer syndromes with cutaneous tumors, Gorlin syndrome and Cowden syndrome, which are studied within the Hashimoto group by Daisuke Tsuruta as the research contributor with assistance from Hiroyuki Goto and Chiharu Tateishi. They describe the symptoms, diagnostic methods, and treatments for both diseases and then discuss the clinical and political studies of these two diseases within the Hashimoto group, mainly in relation to epidemiological studies and creation of registries using the REDCap system.
Shimomura6 describes work on genetic diseases that show hair abnormality, including woolly hair, monilethrix, Marie-Unna hereditary hypotrichosis, and hypotrichosis simplex as non-syndromic forms of hereditary hair diseases, as well as 12 syndromic forms of hereditary hair diseases. Yutaka Shimomura previously worked on these genetic skin diseases as a research contributor within the Hashimoto group. In his article, Shimomura6 explains the hair structure and the clinical features of these genetic hair diseases, provides in-depth information on the currently known causative genes, and presents a schematic representation of the functional relationships among the causative genes/molecules.
Yoshida7 discusses neurofibromatosis 1 (also known as von Recklinghausen disease), which is studied by the Asahina group as part of the Project for Research on Intractable Diseases of the MHLW. Yoshida7 describes the diagnosis, clinical symptoms, treatments, and severity classification for neurofibromatosis 1 and emphasizes that clinicians should be aware of possible malignant transformation of plexiform neurofibromas into malignant peripheral nerve sheath tumors.
Wataya-Kaneda8 describes tuberous sclerosis complex (TSC) (also known as Bourneville-Pringle disease), which is also studied by the Asahina group. Wataya-Kaneda8 describes the history, epidemiology, diagnostic methods, and treatments, including recently developed therapies, for TSC. In-depth information is provided on the pathogenic molecular mechanisms of the disease. Wataya-Kaneda8 also describes the role and activities of the neurocutaneous syndrome policy research group within the Project for Research on Intractable Diseases of the MHLW.
McCarthy et al.1 describe pachyonychia congenita (PC) and other PC-related skin diseases, including palmoplantar keratoderma. Because palmoplantar keratoderma is one of the 23 skin diseases studied by the Hashimoto group (with Toshiyuki Nomura as a research contributor), members of the Hashimoto group are collaborating with members of the PC Project in Europe and the USA and facilitate communication between family societies for this disease in Japan and Europe/USA. McCarthy et al.1 describe the classification, clinical manifestations, various burdens and loss of quality of life, differential diagnoses, causative genes, genetic counselling, and current and future management options for PC and various PC-related skin diseases, including palmoplantar keratoderma.
Schwartz et al.2 describe the missions and activities of the PC Project, which is an international patient advocacy organization for patients with PC (and PC-related skin diseases) and their families. The PC Project achieves its missions via two pivotal foundational programs: the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR). Schwartz et al.2 describe the structures and activities of the IPCC and IPCRR, and they discuss the importance of these agencies in achieving correct diagnoses, providing education and awareness, conducting research and drug development, and providing patient support for these intractable hereditary skin diseases.
The eight articles published in this special issue on genetic rare and intractable skin diseases are: mainly based on studies within the Project for Research on Intractable Diseases of the MHLW. The aims of this project are: to increase awareness of these rare diseases among the general public, including scientific communities and patient societies; to identify disease phenotypes and disease severity, including disease burden and loss of quality of life; to improve diagnosis by developing genetic tests for newly identified causative genes; to understand disease pathogenesis; and to develop new effective and safe treatments. I expect that readers will find the articles in this special issue to be informative and engaging.
The author declares that no conflict of interest exists.
