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.

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.

Gorlin syndrome and Cowden syndrome are hereditary diseases that are characterized by multiple malignancies, cutaneous symptoms, and various other abnormalities. Both disorders are caused by a mutation of the gene that regulates cell proliferation and growth, resulting in tumorigenesis. Representative mutations are mutation in the patched 1 gene (PTCH1) in Gorlin syndrome and mutation in the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) gene in Cowden syndrome. Making a diagnosis of these diseases in the early years of life is important because detection of malignancies at an early stage is linked to improved prognosis. Both Gorlin syndrome and Cowden syndrome have cutaneous findings in the early phase in childhood, and the role of dermatologists is therefore important. These diseases are generally diagnosed by clinical criteria, but some patients who do not meet the criteria need genetic examinations including a genetic diagnostic panel and next-generation sequencing. The most important treatment and management are detection and resection of malignancies in the early stage, and targeted therapies have recently been used for treatment of tumors and other symptoms in these diseases. Although evidence of the effectiveness of targeted therapies has been limited, they are promising therapeutic options and further clinical trials are needed in the future.

The hair follicle is an appendage of the skin that undergoes hair cycles throughout life. Recently, numerous genes expressed in the hair follicles have been identified, and variants in some of these genes are now known to underlie hereditary hair diseases in humans. Hereditary hair diseases are classified into non-syndromic and syndromic forms. In the Japanese population, the non-syndromic form of autosomal recessive woolly hair, which is caused by founder pathogenic variants in the lipase H (LIPH) gene, is the most prevalent hereditary hair disease. In addition, other types of hereditary hair diseases are known in Japan, such as Marie-Unna hereditary hypotrichosis, hypohidrotic ectodermal dysplasia, and tricho–rhino–phalangeal syndrome. To ensure correct diagnoses and appropriate patient care, dermatologists must understand the characteristics of each hair disorder. Elucidation of the molecular basis of hereditary hair diseases can directly tell us which genes are crucial for morphogenesis and development of hair follicles in humans. Therefore, continuation of “wet laboratory” research for these diseases remains important. To date, several syndromic forms of hereditary hair diseases have been approved as designated intractable diseases in Japan. As part of our efforts in the Project for Research on Intractable Diseases through the Ministry of Health, Labour, and Welfare of Japan, we anticipate that more hereditary hair diseases be recognized as designated intractable diseases in the future, which will be to the benefit of the affected individuals.

Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease characterized by systemic hamartomas, neuropsychiatric symptoms known as TAND (TSC-associated neuropsychiatric disorders), and vitiligo. These symptoms are attributed to the constant activation of mechanistic target of rapamycin complex 1 (mTORC1) caused by genetic mutations in the causative genes TSC1 or TSC2. The elucidation of the pathogenesis of this disease and advances in diagnostic technologies have led to dramatic changes in the diagnosis and treatment of TSC. Diagnostic criteria have been created at a global level, and mTORC1 inhibitors have emerged as therapeutic agents for this disease. Previously, the treatment strategy was limited to symptomatic treatments such as surgery. Inhibitors of mTORC1 are effective against all symptoms of TSC, but they also have systemic side effects. Therefore, the need for a cross-disciplinary, collaborative medical care system has increased, resulting in the establishment of a practice structure known as the “TSC Board.” Furthermore, to reduce the side effects of systemic administration of mTORC1 inhibitors, a topical formulation of mTORC1 inhibitor was developed in Japan for the treatment of skin lesions caused by TSC. This report summarizes the pathogenesis and current status of TSC and the contribution of the Neurocutaneous Syndrome Policy Research Group to the policies of the Ministry of Health, Labor, and Welfare with respect to this rare, intractable disease.

Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy. It can be debilitating, causing significantly impaired mobility. PC is diagnosed clinically alongside identification of a heterozygous pathogenic mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Each keratin gene mutation is associated with a distinct clinical phenotype, with variable age of onset and additional features, which has allowed classification by genotype. Additional features include pilosebaceous cysts, follicular hyperkeratosis, natal teeth, oral leukokeratosis, hidradenitis suppurativa, itching, and neurovascular structures. Although classed as rare, the prevalence of PC is likely to be underestimated. There is no cure or specific treatment for PC at present. Current treatments are limited to conservative measures to reduce plantar friction and trauma, mechanical debridement, topical treatments, and treatments for associated features or complications, most commonly infection. However, through active research in collaboration with PC Project, a patient-advocacy group, and the International PC Research Registry, a global registry of PC patients, there are now many new potential therapeutic options on the horizon. This review summarizes the clinical features associated with PC and highlights the current and future treatment of its manifestations.

Pachyonychia Congenita Project (PC Project) is an international patient advocacy organization dedicated to patients who suffer from pachyonychia congenita (PC). This condition is a painful and debilitating skin disorder caused by a mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16,or KRT17. Through two primary programs, namely the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR), PC Project provides comprehensive patient support and diagnostics while uniting patients, researchers, physicians, and industry partners on a global level to advance research and drug development for meaningful treatments and, ultimately, a cure for PC.

Chimeric Antigen Receptor (CAR) T-cell immunotherapy has revolutionized the treatment of hematological malignancies. However, its application to solid tumors has been hindered by poor specificity and potential toxicity to healthy tissues. To address these limitations, we developed an integrated approach combining a high-throughput robotic platform with mathematical modeling to systematically evaluate and optimize T-cell function. This novel approach enabled us to uncover previously unknown signaling crosstalk within CAR T-cells, leading to the development of an optimized CAR design. Our enhanced CAR T-cell platform demonstrates significantly improved anti-tumor activity while minimizing toxicity to healthy tissues. These findings highlight the power of computational modeling in simulating immune cell behaviors and provide a robust framework for designing more precise and effective cancer immunotherapies.

(Presented at the 2015th Meeting, December 6th, 2024)