Status of children and caregivers with Bloom syndrome and Rothmund–Thomson syndrome in Japan

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BS is characterized by short stature, sun-sensitive erythema, immunodeficiency, and a predisposition to various malignancies. RTS is characterized by poikiloderma, bone malformations, and a predisposition to osteosarcoma. In our previous studies, approximately 10 cases of each condition were reported in Japan; however, most of the reported cases involved adults. To elucidate the current state of children and caregivers of patients with BS and RTS in Japan, we conducted a questionnaire-based study. We received responses from four guardians of children with BS and five of those with RTS, all of whom were members of family association of BS or RTS in Japan. None of the children had been included in previous studies. All patients were low birth weight infants (under 2300 g), and one child with BS was classified as extremely low birth weight. With the exception of one child with BS, all received growth hormone replacement therapy; no children with RTS received growth hormone treatment. The height of children with BS tended to be shorter than those with RTS. Most children with BS or RTS visited the hospital once a month. Blood tests and ultrasonography were commonly used for malignancy surveillance. Three of the five RTS guardians did not recognize characteristic skin lesions such as poikiloderma. Although sun sensitivity was not prominent, nearly all children with RTS used sunscreen. One child with RTS developed osteosarcoma. BS was considered to impose a greater psychological burden on parents than RTS. This study clarified the needs and challenges faced by children with BS and RTS and their families in Japan. Understanding the true status and needs of these patients and their caregivers will help improve their quality of life. Bloom syndrome Rothmund–Thomson syndrome growth curve immunodeficiency surveillance caregiver concerns Figures Figure 1 Introduction Bloom syndrome (BS) and Rothmund–Thomson syndrome (RTS) are extremely rare autosomal recessive diseases. BS and RTS are caused by mutations in the BLM and RECQL4 genes, respectively, both belonging to the RecQ helicase family. Worldwide, the Bloom Syndrome Registry has documented at least 294 cases of BS ( 1 ). Since its original description by Auguste Rothmund in Austria in 1868, fewer than 500 individuals with RTS have been reported in the English literature ( 2 , 3 ). BS is characterized by short stature, sun-sensitive erythema, immunodeficiency, and a predisposition to various malignancies. Meanwhile, RTS is characterized by poikiloderma, bone malformation, and a predisposition to osteosarcoma. Both BS and RTS confer an increased risk for malignancy. In 2018, annual to biannual whole-body magnetic resonance imaging (MRI) was recommended for the early detection of lymphoma in patients with BS ( 4 , 5 ). However, owing to the lack of supporting evidence about early detection of lymphoma with MRI, the American Association for Cancer Research does not recommend routine whole-body MRI in children ( 6 ). It recommends at least annual clinical evaluation from the time of BS diagnosis and family education regarding the signs and symptoms of malignancies. For colorectal cancer risk, annual colonoscopy and immunochemical fecal occult blood testing every 6 months is recommended starting at age 10–12 years ( 6 ). Photoprotection, radiation avoidance, and annual skin examinations are also recommended to reduce the risk of skin cancer. The care and management of patients with BS require a multidisciplinary team, including specialists in genetics, endocrinology, immunology, nutrition, and oncology. Regarding RTS, given the high risk of osteosarcoma in individuals with pathogenetic variants in the RECQL4 gene, whole-body MRI from head to toe may be considered for surveillance. However, its risks and benefits should be carefully weighed and discussed with patients. The clinical benefit of detecting asymptomatic osteosarcoma remains uncertain. Therefore, it is important that both patients and caregivers recognize early signs and symptoms of osteosarcoma, such as bone pain and swelling. Avoiding sun exposure and using sun protection strategies are recommended to lower the risk of skin cancer ( 6 , 7 ) We have previously reported on BS and RTS surveillance in Japan ( 8 , 9 ). Our earlier study on BS included eight patients and showed that facial skin lesions are less prominent and life-threatening infections are uncommon, although a predisposition to neoplasia and possibly diabetes mellitus remained—findings consistent with earlier reports ( 10 ). Separate nationwide surveys on RTS were conducted in Japan in 2010 and 2020, including 10 and 8 patients, respectively. In both surveys, skin lesions such as poikiloderma, erythema, pigmentation, and abnormal scalp hair were observed in nearly all cases. Bone lesions were seen in four patients in each survey year. However, only two children with BS and two with a pathogenetic variant of the RECQL4 gene were included across all previous studies, leaving the status of pediatric patients with BS and RTS in Japan largely unknown. In this study, we conducted a survey to assess the height, weight, symptoms, timing of diagnosis, and malignancy surveillance strategies for Japanese children with BS or RTS. We also aimed to understand caregivers’ concerns and identify what type of examinations these children undergo for disease monitoring. Method The study was approved by the Ethical Review Committee of Gifu Prefectural General Medical Center (approval no. 911). By responding to the questionnaire, parents were considered to have provided consent to participate in the study. We requested that the BS and RTS patient associations distribute the questionnaires to families of children with BS and RTS. Four children (under 14 years old) with BS and five (under 14 years old) with RTS were registered in these groups, and the questionnaires were mailed to their guardians. Responses were received from all nine families. The questionnaire consisted of two parts. The first part covered medical and developmental information, including the child's sex and age (as of January 1, 2024), age at diagnosis, growth profile (gestational age, height, and weight until 6 years of age), growth hormone treatment, and various symptoms. These symptoms included skin manifestations (eczema), hair and eyebrow development, eyelashes, nail deformities, sun sensitivity, and bone abnormalities (e.g., missing thumb, absent radius, premature cranial fusion, scoliosis, ore other skeletal defects). Dental condition (e.g., cavities, delayed tooth eruption), susceptibility to infections (e.g., frequent fevers), eye conditions (e.g., cataracts or other ocular diseases), and the presence or absence of diabetes and tumor history were also recorded. Genetic testing was noted for RECQL4 or BLM , including whether pathogenetic variants were detected. In addition, sun exposure practices (avoidance or not) and sunscreen usage were documented. Information on bone surgeries, hospital visit frequency in the past year, departments visited, tumor screening frequency, and method of malignancy surveillance was also collected. Parents were also asked to select all applicable types of home medical care their child received from a provided list. The options included: 1) suction (e.g., for phlegm or saliva), 2) inhalation therapy (e.g., bronchodilators), 3) tracheal cannula management, 4) home oxygen therapy, 5) ventilator support, 6) total parenteral nutrition, 7) tube feeding (including gastrostomy nutrition), 8) continuous infusion, 9) bowel control, 10) colostomy management, 11) self-catheterization (or catheterization by a guardian), 12) intravesical catheter care, 13) wound care (including pressure ulcers), 14) blood glucose monitoring, 15) self-injection (or guardian-assisted injection), 16) other forms of care, and 17) no home medical care provided. The second part of the questionnaire addressed school life, caregiver concerns, and information access. This section was partially based on the 2023 Survey on the Lives of Children with Chronic Specific Pediatric Illnesses conducted by the Ministry of Health, Labour and Welfare of Japan ( 11 ). Parents were asked to provide information on the number of hospitalizations, total days their child was hospitalized, reasons for admission, and the surveillance methods used for malignancy detection. Additionally, the following items were included: (a) number of absences from school in the past year, (b) concerns or worries about having their child live at home, (c) specific types of concerns (multiple responses allowed), (d) people outside the family who were informed of the child’s illness (multiple responses allowed), (e) whether the child was unable to enroll in school, nursery, or other facilities due to illness (multiple responses allowed), (f) difficulties in obtaining medical or welfare service information (multiple responses allowed), and (g) methods used to obtain information on medical and welfare services (multiple responses allowed). Data was collected and analyzed. Height and weight were plotted on the Japanese growth curve. Statistical analysis was not performed due to the small number of subjects. Results Four children with BS and five with RTS were included in the questionnaire study at the time of conducting the study (Table I). None of the children had been included in previous studies of BS or RTS. All patients were low birth weight infants (under 2300 g), and one child with BS (BS4) was classified as an extremely low birth weight infant. With the exception of BS4, all BS patients received growth hormone therapy. None of those with RTS received growth hormone treatment. Children with BS tended to be shorter at birth than those with RTS. Three of five children with RTS did not show characteristic skin lesions such as poikiloderma. Although sun sensitivity was not prominent, nearly all children with RTS used sunscreen. Several children were reported to be prone to fever. One child with RTS developed osteosarcoma. Figure 1 presents growth curves by sex, showing that children with BS were consistently shorter and lighter than those with RTS. Most children visited the hospital once a month and underwent blood tests and ultrasound scans for malignancy surveillance (Table II). The average number of medical departments visited was four for BS patients and eight for RTS patients. According to the hospitalization questionnaire, children with RTS had been hospitalized for bone lesions. Regarding school attendance, eight of nine children were absent for no more than 5 days per month over the past year (Table IIIA). Parents of children with BS and RTS expressed concerns about growth and development, disease progression, and limited peer interaction opportunities (Table IIIB, C). Compared with BS families, RTS guardians were more likely to share their child's diagnosis with others. Some BS parents had not informed anyone outside the family about the condition (Table IIID). Some children with BS and RTS were unable to enroll in nursery or kindergarten programs owing to their condition (Table IIIE). Regarding difficulties in accessing information about medical and welfare services, parents reported not knowing who to consult and where to seek help (Table IIIF). BS and RTS guardians most often obtained information from websites, local government offices, and medical institutions (Table IIIG). Among RTS families, three guardians reported receiving information directly from other caregivers. Discussion We conducted this study to classify the status of Japanese children with BS or RTS and their caregivers. Participants were recruited through national BS or RTS patient organizations. Previous nationwide surveys were unable to enroll sufficient numbers of pediatric patients. This study is important because it provides insights into the experiences and characteristics of children with BS and RTS. Children with BS were generally shorter than those with RTS, consistent with previous findings ( 12 ). Importantly, the shorter stature observed in children with BS persisted despite growth hormone therapy. Many clinicians consider BS as a contraindication for growth hormone treatment owing to the potential cancer risk ( 13 ). The Pediatric Endocrine Society’s Drug and Therapeutics Committee has reviewed the evidence and concluded that current data are insufficient to determine whether growth hormone increases cancer risk in these patients ( 14 ). When considering growth hormone treatment in the patients with BS, the benefits of increased height and the risk of cancer should be carefully considered. The follow-up for malignancy surveillance in children receiving growth hormone should be continued. Notably, some RTS caregivers did not recognize hallmark skin lesions such as poikiloderma. This represents a limitation of the study, as the data were self-reported by guardians. Although poikiloderma is a central clinical feature of RTS, previous studies have documented patients without this manifestation ( 15 ). The importance of recognizing atypical presentations of RTS to allow for early awareness and surveillance for cancer was reported ( 16 ). In such cases, diagnosis may be difficult, and whole-exome sequencing may be necessary. Originally, immunodeficiency was not considered to be a characteristic feature of RTS. Recently the 2024 update of IUIS phenotype classification of human inborn errors of immunity has involved RTS as the feature of variable immunodeficiency ( 17 ). However, most of recruited RTS children showed no recurrent fever, which might suggest our cases have no susceptibility to infection. There were a few reports of RTS about immunodeficiency which described a wide variety of degrees of immunodeficiency including severe combined immunodeficiency and antibody deficiency ( 18 , 19 ). Further research should be continued to clarify the relationship between RTS and immunodeficiency. Most children of BS and RTS visited the hospital once a month and underwent blood tests and ultrasound scans for malignancy surveillance. One child with BS and one with RTS also received MRI screening. In the update on recommendations for cancer screening and surveillance in children with BS the importance of education about the symptoms of malignancies is emphasized ( 7 ). To detect the symptoms of malignancies and to start treatment at an early stage is important because treating malignancies in BS patients is challenging due to heightened sensitivity to DNA-damaging therapies, including alkylating agents and radiotherapy ( 20 ). Immunochemical fecal occult blood testing for the detection of colon cancer was not performed for children with recruited BS, likely because they were still young. As BS surveillance guidelines evolve every few years, it is necessary to stay updated with the latest recommendations. Compared with RTS families, BS families were less likely to disclose their child's condition to others. This tendency toward secrecy may be caused by the data that 29% of cancers occurred by age 18 and the median survival for all participants in the Bloom Syndrome Registry was 36.2 years ( 21 ). On the other hand, the lifespan of the patients with RTS was not altered, provided that the neoplastic disease was diagnosed and treated in time ( 2 ). The difference in prognosis between BS and RTS may have influenced the caregivers’ responses to the questionnaire. Some children with BS and RTS were unable to enroll in nursery school or kindergarten owing to their condition. There is a clear need to expand access to early childhood education for children with rare genetic diseases in Japan. Parents reported difficulties accessing information about medical and welfare services, often citing uncertainty about where to seek help or whom to consult. Government agencies should clearly identify centralized sources of information for families of children with serious illnesses. BS and RTS families obtained information primarily through websites, local government offices, and medical institutions. Notably, RTS families also benefited from peer support, as three guardians reported obtaining information from other caregivers. For rare diseases, patient associations were not only a place for patients with the same disease to interact with each other, but were also important in obtaining information from them. In conclusion, this study clarified the needs and challenges faced by children with BS and RTS and their families in Japan. Understanding the true status and needs of these patients and their caregivers will help improve their quality of life. Abbreviations BS Bloom syndrome RTS Rothmund–Thomson syndrome MRI Magnetic Resonance Imaging MHLW Ministry of Health,Labour and Welfare Declarations Ethics approval and consent to participate The requirement for informed consent was waived owing to the retrospective nature of the study. The study was approved by the Ethical Review Committee of Gifu Prefectural General Medical Center (911). This study was conducted in accordance with the Declaration of Helsinki. Patient consent for publication Not applicable Disclosure The authors declare that they have no competing interests. Use of artificial intelligence tools Not applicable. Funding information This work was supported by the Ministry of Health, Labour and Welfare (MHLW) of Japan (grant no. R6-nanchi-ippan- 24FC1013 [Yoshiro Maezawa]). The funding body had no role in the design of the study, data collection, analysis, or interpretation. Author Contribution H.K. and H.O. designed the study. H.K. and H.M. collected the data. H.K. and H.O. wrote the manuscript. H.K. and H.M. confirm the authenticity of all the raw data. All authors contributed to the intellectual content of this manuscript. All authors read and approved the final manuscript. Acknowledgments Not applicable. Availability of data and materials The data generated in the present study may be requested from the corresponding author. Use of artificial intelligence tools Not applicable. References Langer K, Cunniff CM and Kucine N: Bloom syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE and Amemiya A (eds). GeneReviews® [Internet]. University of Washington, Seattle; 1993–2025. Updated 2023 Oct 12. Larizza L, Roversi G and Volpi L: Rothmund-Thomson syndrome. Orphanet J Rare Dis 5: 2, 2010. Wang LL and Plon SE: Rothmund-Thomson syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE and Amemiya A (eds). GeneReviews® [Internet]. University of Washington, Seattle; 1993–2025. Updated 2020 Jun 4]. Walsh MF, Chang VY, Kohlmann WK, Scott HS, Cunniff C, Bourdeaut F, Molenaar JJ, Porter CC, Sandlund JT and Plon SE: Recommendations for childhood cancer screening and surveillance in DNA repair disorders. Clin Cancer Res 23: e23-e31, 2017. Cunniff C, Djavid AR, Carrubba S, Cohen B, Ellis NA, Levy CF, Jeong S, Lederman HM, Vogiatzi M and Walsh MF: Health supervision for people with Bloom syndrome. Am J Med Genet A 176: 1872-1881, 2018. Nakano Y, Kuiper RP, Nichols KE, Porter CC, Lesmana H, Meade J, Kratz CP, Godley LA, Maese LD, Achatz MI, et al: Update on recommendations for cancer screening and surveillance in children with genomic instability disorders. Clin Cancer Res 30: 5009–5020, 2024. Martins DJ, Di Lazzaro Filho R, Bertola DR and Hoch NC: Rothmund-Thomson syndrome, a disorder far from solved. Front Aging 4: 1296409, 2023. Kaneko H, Kawase C, Seki J, Ikawa Y, Yachie A and Funato M: Intellectual disability and abnormal cortical neuron phenotypes in patients with Bloom syndrome. J Hum Genet 68: 321–327, 2023. Kaneko H, Takemoto M, Murakami H, Ihara K, Kosaki R, Motegi SI, Taniguchi A, Matsuo M, Yamazaki N, Nishigori C, et al: Rothmund-Thomson syndrome investigated by two nationwide surveys in Japan. Pediatr Int 64: e15120, 2022. German J and Takebe H: Bloom's syndrome. XIV. The disorder in Japan. Clin Genet 35: 93–110, 1989. The Survey on the Lives of Children with Chronic Specific Pediatric Illnesses conducted by the Ministry of Health, Labour and Welfare of Japan https://www.mhlw.go.jp/content/001277467.pdf de Renty C and Ellis NA: Bloom's syndrome: Why not premature aging? A comparison of the BLM and WRN helicases. Ageing Res Rev 33: 36-51, 2017. Renes JS, Willemsen RH, Wagner A, Finken MJ and Hokken-Koelega AC: Bloom syndrome in short children born small for gestational age: A challenging diagnosis. J Clin Endocrinol Metab 98: 3932–3938, 2013. Raman S, Grimberg A, Waguespack SG, Miller BS, Sklar CA, Meacham LR and Patterson BC: Risk of neoplasia in pediatric patients receiving growth hormone therapy: A report from the Pediatric Endocrine Society Drug and Therapeutics Committee. J Clin Endocrinol Metab 100: 2192–2203, 2015. Teferedegn E, Izumi K, Ahrens-Nicklas R, Bhoj E, Rippert A: Rothmund-Thomson Syndrome Type 2 in an African American/Puerto Rican Child Demonstrates Diagnostic Challenges in Diverse Population. Am J Med Genet A. Jun 9:e64132. doi: 10.1002/ajmg.a.64132, 2025. Grossman LD, Baldino S, Zelley K, Balis F, Bagatell R, Kalish JM, MacFarland SP: Atypical presentations of RECQL4-related syndromes. Pediatr Blood Cancer. 71:e31315, 2024. Bousfiha AA, Jeddane L, Moundir A, Poli MC, Aksentijevich I, Cunningham-Rundles C, Hambleton S, Klein C, Morio T, Picard C, Puel A, Rezaei N, Seppänen MRJ, Somech R, Su HC, Sullivan KE, Torgerson TR, Tangye SG, Meyts I: The 2024 update of IUIS phenotypic classification of human inborn errors of immunity. J Hum Immun 1 (1): e20250002, 2025. Broom MA, Wang LL, Otta SK, Knutsen AP, Siegfried E, Batanian JR, Kelly ME, Shah M: Successful umbilical cord blood stem cell transplantation in a patient with Rothmund-Thomson syndrome and combined immunodeficiency. Clin Genet 69:337-343, 2006. De Somer L, Wouters C, Morren MA, De Vos R, Van Den Oord J, Devriendt K, Meyts I: Granulomatous skin lesions complicating Varicella infection in a patient with Rothmund-Thomson syndrome and immune deficiency: case report. Orphanet J Rare Dis. 8;5:37. doi: 10.1186/1750-1172-5-37, 2010. Pacaud C, Nazon C, Pages M, Rouger J, Berthet P, Winter S, Thebault É, Faure-Conter C, Berger C, Paillard C. Management of Paediatric Cancers Associated With Bloom Syndrome. Hum Mutat. 3;2025:7065233. doi: 10.1155/humu/7065233, 2025. Sugrañes TA, Flanagan M, Thomas C, Chang VY, Walsh M, Cunniff C: Age of first cancer diagnosis and survival in Bloom syndrome. Genet Med. 24:1476-1484, 2022. Tables Table I. Clinical characteristics of recruited children with BS or RTS BS1 BS2 BS3 BS4 RTS1 RTS2 RTS3 RTS4 RTS5 Current age 13y 11y 3y 4y 11y 7y 9y 13y 1y Age at diagnosis 12y 10y 1y 1y 8y 10y 2y 12y 3y Gestational age 37w 37w 37w 26w 36w 37w 38w 36w 38w Birth weight 1560g 1540g 1440g 470g 2060g 2000g 1850g 2060g 1710g GH replacement 2y~12y 2y~10y １y none none none none none none Skin lesion café-au-lait eczema none none none eczema none pigmentation, hyperkeratosis none Sun sensitivity yes unknown none none yes yes yes yes unknown Sunscreen yes yes none yes yes yes yes yes none Susceptibility to infections none none none yes none none none none yes Malignancy none none none none osteosarcoma 11y knee none none none none Table II. Number of visits to the hospitals and the methods of surveillance for malignancy BS1 BS2 BS3 BS4 RTS1 RTS2 RTS3 RTS4 RTS5 Number of visits once a month once a month once a month 2-3 times a month once a month once a month two or three times every six months once a week 2-3 times a month Surveillance for malignancy blood test, ultrasonography blood test, ultrasonography MRI blood test, ultrasonography blood test, MRI ultrasonography blood test, ultrasonography blood test X-ray not described Table III. Results of a survey of guardians of children with BS and RTS about their concerns regarding school life and where they obtain information about the disease a) Please tell us about your child's absences over the past year. Almost no absence: RTS2, Absence for about 2-3 days per month: BS3, RTS2, Absence for about 4-5 days per month: RTS1 Absence for about half the month: BS1, Almost always absence: N b) Do you have any worries or concerns about having your child live at home? Yes: BS3, RTS2, Somewhat Yes: RTS2, Somewhat No: RTS1, No: BS1 c) Please answer the questions that apply to your concerns or worries (multiple answers possible). Concerns about children's growth and development: BS4, RTS3, Concerns about the worsening of a child's illness: BS4, RTS4, Impact on other family members: RTS2 Financial insecurity at home: RTS1, Securing a place for children outside the home: RTS3, Opportunities for children to interact with peers of the same age: BS3, RTS2 I don't have time for myself: BS1, RTS1, Concerns about my employment and working style: BS1, Understanding from neighbors: N, I can't express my worries and concerns: N d) Who outside of your family do you tell about your child's illness? (multiple answers possible) Nursery/kindergarten teachers: BS2, School teacher: RTS4, Some of my children's friends: RTS2, All classmates: RTS1, Parents of children's friends: BS1, RTS3, My friends in the neighborhood: BS1, RTS2, I haven't told anyone: BS2 e) Has your child ever been unable to enroll in the school, nursery school or other facility of their choice due to an illness? (multiple answers possible) Nursery school: BS2, RTS1, Kindergarten: RTS2, Primary school: N, Junior high school: N, High school: N, Special Education School: RTS1, Visiting education: N f) Have you ever had trouble obtaining information on medical and welfare services? (multiple answers possible) I didn't know who to consult: BS2, RTS2, I couldn't get the information I needed: RTS1, I didn't know where to look: BS4, RTS4, The sources of information varied depending on the age of the children: RTS1, There is no institution nearby that I can consult with: RTS1, It wasn't particularly difficult: RTS1 g) How to obtain information about medical and welfare services for your child (multiple answers allowed) Websites created by government agencies, support groups. Excluding SNS: BS1, RTS1, Children's schools, daycare centers: RTS1, Announcements from local governments: N, Local government offices: BS1, Medical institutions: BS2, RTS4, Welfare facilities: N, Self-reliance support worker and other consultation supporters: N, Announcements from patient family associations: N, SNS: N, Books and magazines: N, Information exchanges between parents: RTS3, Home-visit nursing : BS1, I do not need information: N BS3 means that three BS guardians answered yes. N means that neither BS nor RTS guardians apply to the answer. The number of respondents was four for BS guardians and five for RTS. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7260291","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":498939429,"identity":"5e263b4c-1f38-4677-9ec1-e4be260afc89","order_by":0,"name":"HIDEO KANEKO","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBElEQVRIie3QsUrDQBzH8V8Q4nKm6/848RkSAqmCD5OQwSWtg0unkildrs7ZfAV9gxTBqeILCCYImTLYRaIU6rV2cUi4Ucp9ueOW+9xxB5hM/zBS00qB0EYIfIAGAMPv1CFWDuKpNtmOI7VxT3ris+dFlU8wdo7jxfvl9zm5xclTidPXTiLYOPbul7ixWR37o1tSxLlywepOcoYk4FW2iTJKAjGSNHXfmoDAHrvJoBl+VRkUuf4UF3J7C+snQh1uPexIYgu0GoTnjc/zpSKs9r15SsQLNnTDnrfQS+Kt5ATR3SyuynY9JUfdUq5k94/9zcp2i41IFpoE6z1Bq01MJpPp8PsBuDpRiFnFKSsAAAAASUVORK5CYII=","orcid":"","institution":"Gifu Prefectural General Medical Center","correspondingAuthor":true,"prefix":"","firstName":"HIDEO","middleName":"","lastName":"KANEKO","suffix":""},{"id":498939430,"identity":"d603d888-f5da-4ec5-a70e-96b538000436","order_by":1,"name":"HIROAKI MURAKAMI","email":"","orcid":"","institution":"Gifu Prefectural General Medical Center","correspondingAuthor":false,"prefix":"","firstName":"HIROAKI","middleName":"","lastName":"MURAKAMI","suffix":""},{"id":498939431,"identity":"99b450f7-e2c8-478e-93c3-1c36ff3ef008","order_by":2,"name":"HIDENORI OHNISHI","email":"","orcid":"","institution":"Gifu University","correspondingAuthor":false,"prefix":"","firstName":"HIDENORI","middleName":"","lastName":"OHNISHI","suffix":""}],"badges":[],"createdAt":"2025-07-31 09:08:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7260291/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7260291/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88957533,"identity":"bf2c5f9e-26d5-47ba-98bb-659c9a4528f7","added_by":"auto","created_at":"2025-08-13 07:25:44","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":192510,"visible":true,"origin":"","legend":"\u003cp\u003eGrowth charts of children with BS and RTS from birth to 6 years of age. The left panel represents boys; The right panel represents girls. Blue dots indicate BS, and red dots indicate RTS. Bold lines represent the average height and body weight for each group. Between ages 0 and 6, Children with BS had smaller body sizes than those with RTS.\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7260291/v1/b17c6c6cc21314085ab3ed0b.jpg"},{"id":90762032,"identity":"f27ca966-92dc-4c51-96ca-8cf3942fad3c","added_by":"auto","created_at":"2025-09-07 15:53:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1038344,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7260291/v1/341ff307-4993-46f8-b329-d5e8c81d1057.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Status of children and caregivers with Bloom syndrome and Rothmund–Thomson syndrome in Japan","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBloom syndrome (BS) and Rothmund–Thomson syndrome (RTS) are extremely rare autosomal recessive diseases. BS and RTS are caused by mutations in the \u003cem\u003eBLM\u003c/em\u003e and \u003cem\u003eRECQL4\u003c/em\u003e genes, respectively, both belonging to the RecQ helicase family. Worldwide, the Bloom Syndrome Registry has documented at least 294 cases of BS (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Since its original description by Auguste Rothmund in Austria in 1868, fewer than 500 individuals with RTS have been reported in the English literature (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). BS is characterized by short stature, sun-sensitive erythema, immunodeficiency, and a predisposition to various malignancies. Meanwhile, RTS is characterized by poikiloderma, bone malformation, and a predisposition to osteosarcoma.\u003c/p\u003e\u003cp\u003eBoth BS and RTS confer an increased risk for malignancy. In 2018, annual to biannual whole-body magnetic resonance imaging (MRI) was recommended for the early detection of lymphoma in patients with BS (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, owing to the lack of supporting evidence about early detection of lymphoma with MRI, the American Association for Cancer Research does not recommend routine whole-body MRI in children (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). It recommends at least annual clinical evaluation from the time of BS diagnosis and family education regarding the signs and symptoms of malignancies. For colorectal cancer risk, annual colonoscopy and immunochemical fecal occult blood testing every 6 months is recommended starting at age 10–12 years (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Photoprotection, radiation avoidance, and annual skin examinations are also recommended to reduce the risk of skin cancer. The care and management of patients with BS require a multidisciplinary team, including specialists in genetics, endocrinology, immunology, nutrition, and oncology.\u003c/p\u003e\u003cp\u003eRegarding RTS, given the high risk of osteosarcoma in individuals with pathogenetic variants in the \u003cem\u003eRECQL4\u003c/em\u003e gene, whole-body MRI from head to toe may be considered for surveillance. However, its risks and benefits should be carefully weighed and discussed with patients. The clinical benefit of detecting asymptomatic osteosarcoma remains uncertain. Therefore, it is important that both patients and caregivers recognize early signs and symptoms of osteosarcoma, such as bone pain and swelling. Avoiding sun exposure and using sun protection strategies are recommended to lower the risk of skin cancer (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eWe have previously reported on BS and RTS surveillance in Japan (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Our earlier study on BS included eight patients and showed that facial skin lesions are less prominent and life-threatening infections are uncommon, although a predisposition to neoplasia and possibly diabetes mellitus remained—findings consistent with earlier reports (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Separate nationwide surveys on RTS were conducted in Japan in 2010 and 2020, including 10 and 8 patients, respectively. In both surveys, skin lesions such as poikiloderma, erythema, pigmentation, and abnormal scalp hair were observed in nearly all cases. Bone lesions were seen in four patients in each survey year. However, only two children with BS and two with a pathogenetic variant of the \u003cem\u003eRECQL4\u003c/em\u003e gene were included across all previous studies, leaving the status of pediatric patients with BS and RTS in Japan largely unknown.\u003c/p\u003e\u003cp\u003eIn this study, we conducted a survey to assess the height, weight, symptoms, timing of diagnosis, and malignancy surveillance strategies for Japanese children with BS or RTS. We also aimed to understand caregivers’ concerns and identify what type of examinations these children undergo for disease monitoring.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003e The study was approved by the Ethical Review Committee of Gifu Prefectural General Medical Center (approval no. 911). By responding to the questionnaire, parents were considered to have provided consent to participate in the study. We requested that the BS and RTS patient associations distribute the questionnaires to families of children with BS and RTS. Four children (under 14 years old) with BS and five (under 14 years old) with RTS were registered in these groups, and the questionnaires were mailed to their guardians. Responses were received from all nine families.\u003c/p\u003e\u003cp\u003eThe questionnaire consisted of two parts. The first part covered medical and developmental information, including the child's sex and age (as of January 1, 2024), age at diagnosis, growth profile (gestational age, height, and weight until 6 years of age), growth hormone treatment, and various symptoms. These symptoms included skin manifestations (eczema), hair and eyebrow development, eyelashes, nail deformities, sun sensitivity, and bone abnormalities (e.g., missing thumb, absent radius, premature cranial fusion, scoliosis, ore other skeletal defects). Dental condition (e.g., cavities, delayed tooth eruption), susceptibility to infections (e.g., frequent fevers), eye conditions (e.g., cataracts or other ocular diseases), and the presence or absence of diabetes and tumor history were also recorded. Genetic testing was noted for \u003cem\u003eRECQL4\u003c/em\u003e or \u003cem\u003eBLM\u003c/em\u003e, including whether pathogenetic variants were detected. In addition, sun exposure practices (avoidance or not) and sunscreen usage were documented. Information on bone surgeries, hospital visit frequency in the past year, departments visited, tumor screening frequency, and method of malignancy surveillance was also collected.\u003c/p\u003e\u003cp\u003e Parents were also asked to select all applicable types of home medical care their child received from a provided list. The options included: 1) suction (e.g., for phlegm or saliva), 2) inhalation therapy (e.g., bronchodilators), 3) tracheal cannula management, 4) home oxygen therapy, 5) ventilator support, 6) total parenteral nutrition, 7) tube feeding (including gastrostomy nutrition), 8) continuous infusion, 9) bowel control, 10) colostomy management, 11) self-catheterization (or catheterization by a guardian), 12) intravesical catheter care, 13) wound care (including pressure ulcers), 14) blood glucose monitoring, 15) self-injection (or guardian-assisted injection), 16) other forms of care, and 17) no home medical care provided.\u003c/p\u003e\u003cp\u003eThe second part of the questionnaire addressed school life, caregiver concerns, and information access. This section was partially based on the 2023 Survey on the Lives of Children with Chronic Specific Pediatric Illnesses conducted by the Ministry of Health, Labour and Welfare of Japan (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Parents were asked to provide information on the number of hospitalizations, total days their child was hospitalized, reasons for admission, and the surveillance methods used for malignancy detection. Additionally, the following items were included: (a) number of absences from school in the past year, (b) concerns or worries about having their child live at home, (c) specific types of concerns (multiple responses allowed), (d) people outside the family who were informed of the child’s illness (multiple responses allowed), (e) whether the child was unable to enroll in school, nursery, or other facilities due to illness (multiple responses allowed), (f) difficulties in obtaining medical or welfare service information (multiple responses allowed), and (g) methods used to obtain information on medical and welfare services (multiple responses allowed).\u003c/p\u003e\u003cp\u003eData was collected and analyzed. Height and weight were plotted on the Japanese growth curve. Statistical analysis was not performed due to the small number of subjects.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFour children with BS and five with RTS were included in the questionnaire study at the time of conducting the study (Table I). None of the children had been included in previous studies of BS or RTS. All patients were low birth weight infants (under 2300 g), and one child with BS (BS4) was classified as an extremely low birth weight infant. With the exception of BS4, all BS patients received growth hormone therapy. None of those with RTS received growth hormone treatment. Children with BS tended to be shorter at birth than those with RTS. Three of five children with RTS did not show characteristic skin lesions such as poikiloderma. Although sun sensitivity was not prominent, nearly all children with RTS used sunscreen. Several children were reported to be prone to fever. One child with RTS developed osteosarcoma. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents growth curves by sex, showing that children with BS were consistently shorter and lighter than those with RTS. Most children visited the hospital once a month and underwent blood tests and ultrasound scans for malignancy surveillance (Table II).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe average number of medical departments visited was four for BS patients and eight for RTS patients. According to the hospitalization questionnaire, children with RTS had been hospitalized for bone lesions. Regarding school attendance, eight of nine children were absent for no more than 5 days per month over the past year (Table IIIA). Parents of children with BS and RTS expressed concerns about growth and development, disease progression, and limited peer interaction opportunities (Table IIIB, C). Compared with BS families, RTS guardians were more likely to share their child's diagnosis with others. Some BS parents had not informed anyone outside the family about the condition (Table IIID). Some children with BS and RTS were unable to enroll in nursery or kindergarten programs owing to their condition (Table IIIE). Regarding difficulties in accessing information about medical and welfare services, parents reported not knowing who to consult and where to seek help (Table IIIF). BS and RTS guardians most often obtained information from websites, local government offices, and medical institutions (Table IIIG). Among RTS families, three guardians reported receiving information directly from other caregivers.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe conducted this study to classify the status of Japanese children with BS or RTS and their caregivers. Participants were recruited through national BS or RTS patient organizations. Previous nationwide surveys were unable to enroll sufficient numbers of pediatric patients. This study is important because it provides insights into the experiences and characteristics of children with BS and RTS. Children with BS were generally shorter than those with RTS, consistent with previous findings (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Importantly, the shorter stature observed in children with BS persisted despite growth hormone therapy. Many clinicians consider BS as a contraindication for growth hormone treatment owing to the potential cancer risk (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The Pediatric Endocrine Society\u0026rsquo;s Drug and Therapeutics Committee has reviewed the evidence and concluded that current data are insufficient to determine whether growth hormone increases cancer risk in these patients (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). When considering growth hormone treatment in the patients with BS, the benefits of increased height and the risk of cancer should be carefully considered. The follow-up for malignancy surveillance in children receiving growth hormone should be continued.\u003c/p\u003e\u003cp\u003eNotably, some RTS caregivers did not recognize hallmark skin lesions such as poikiloderma. This represents a limitation of the study, as the data were self-reported by guardians. Although poikiloderma is a central clinical feature of RTS, previous studies have documented patients without this manifestation (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The importance of recognizing atypical presentations of RTS to allow for early awareness and surveillance for cancer was reported (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In such cases, diagnosis may be difficult, and whole-exome sequencing may be necessary.\u003c/p\u003e\u003cp\u003eOriginally, immunodeficiency was not considered to be a characteristic feature of RTS. Recently the 2024 update of IUIS phenotype classification of human inborn errors of immunity has involved RTS as the feature of variable immunodeficiency (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). However, most of recruited RTS children showed no recurrent fever, which might suggest our cases have no susceptibility to infection. There were a few reports of RTS about immunodeficiency which described a wide variety of degrees of immunodeficiency including severe combined immunodeficiency and antibody deficiency (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Further research should be continued to clarify the relationship between RTS and immunodeficiency.\u003c/p\u003e\u003cp\u003eMost children of BS and RTS visited the hospital once a month and underwent blood tests and ultrasound scans for malignancy surveillance. One child with BS and one with RTS also received MRI screening. In the update on recommendations for cancer screening and surveillance in children with BS the importance of education about the symptoms of malignancies is emphasized (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). To detect the symptoms of malignancies and to start treatment at an early stage is important because treating malignancies in BS patients is challenging due to heightened sensitivity to DNA-damaging therapies, including alkylating agents and radiotherapy (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Immunochemical fecal occult blood testing for the detection of colon cancer was not performed for children with recruited BS, likely because they were still young. As BS surveillance guidelines evolve every few years, it is necessary to stay updated with the latest recommendations.\u003c/p\u003e\u003cp\u003eCompared with RTS families, BS families were less likely to disclose their child's condition to others. This tendency toward secrecy may be caused by the data that 29% of cancers occurred by age 18 and the median survival for all participants in the Bloom Syndrome Registry was 36.2 years (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). On the other hand, the lifespan of the patients with RTS was not altered, provided that the neoplastic disease was diagnosed and treated in time (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The difference in prognosis between BS and RTS may have influenced the caregivers\u0026rsquo; responses to the questionnaire.\u003c/p\u003e\u003cp\u003eSome children with BS and RTS were unable to enroll in nursery school or kindergarten owing to their condition. There is a clear need to expand access to early childhood education for children with rare genetic diseases in Japan. Parents reported difficulties accessing information about medical and welfare services, often citing uncertainty about where to seek help or whom to consult. Government agencies should clearly identify centralized sources of information for families of children with serious illnesses. BS and RTS families obtained information primarily through websites, local government offices, and medical institutions. Notably, RTS families also benefited from peer support, as three guardians reported obtaining information from other caregivers. For rare diseases, patient associations were not only a place for patients with the same disease to interact with each other, but were also important in obtaining information from them.\u003c/p\u003e\u003cp\u003eIn conclusion, this study clarified the needs and challenges faced by children with BS and RTS and their families in Japan. Understanding the true status and needs of these patients and their caregivers will help improve their quality of life.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBloom syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRTS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRothmund\u0026ndash;Thomson syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMagnetic Resonance Imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMHLW\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMinistry of Health,Labour and Welfare\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\u003cp\u003e The requirement for informed consent was waived owing to the retrospective nature of the study. The study was approved by the Ethical Review Committee of Gifu Prefectural General Medical Center (911). This study was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003ePatient consent for publication\u003c/h2\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eDisclosure\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eUse of artificial intelligence tools\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding information\u003c/h2\u003e\u003cp\u003eThis work was supported by the Ministry of Health, Labour and Welfare (MHLW) of Japan (grant no. R6-nanchi-ippan- 24FC1013 [Yoshiro Maezawa]). The funding body had no role in the design of the study, data collection, analysis, or interpretation.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eH.K. and H.O. designed the study. H.K. and H.M. collected the data. H.K. and H.O. wrote the manuscript. H.K. and H.M. confirm the authenticity of all the raw data. All authors contributed to the intellectual content of this manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\u003cp\u003eThe data generated in the present study may be requested from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUse of artificial intelligence tools\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLanger K, Cunniff CM and Kucine N: Bloom syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE and Amemiya A (eds). GeneReviews\u0026reg; [Internet]. University of Washington, Seattle; 1993\u0026ndash;2025. Updated 2023 Oct 12.\u003c/li\u003e\n\u003cli\u003eLarizza L, Roversi G and Volpi L: Rothmund-Thomson syndrome. Orphanet J Rare Dis 5: 2, 2010.\u003c/li\u003e\n\u003cli\u003eWang LL and Plon SE: Rothmund-Thomson syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE and Amemiya A (eds). GeneReviews\u0026reg; [Internet]. University of Washington, Seattle; 1993\u0026ndash;2025. Updated 2020 Jun 4].\u003c/li\u003e\n\u003cli\u003eWalsh MF, Chang VY, Kohlmann WK, Scott HS, Cunniff C, Bourdeaut F, Molenaar JJ, Porter CC, Sandlund JT and Plon SE: Recommendations for childhood cancer screening and surveillance in DNA repair disorders. Clin Cancer Res 23: e23-e31, 2017.\u003c/li\u003e\n\u003cli\u003eCunniff C, Djavid AR, Carrubba S, Cohen B, Ellis NA, Levy CF, Jeong S, Lederman HM, Vogiatzi M and Walsh MF: Health supervision for people with Bloom syndrome. Am J Med Genet A 176: 1872-1881, 2018.\u003c/li\u003e\n\u003cli\u003eNakano Y, Kuiper RP, Nichols KE, Porter CC, Lesmana H, Meade J, Kratz CP, Godley LA, Maese LD, Achatz MI, et al: Update on recommendations for cancer screening and surveillance in children with genomic instability disorders. Clin Cancer Res 30: 5009\u0026ndash;5020, 2024.\u003c/li\u003e\n\u003cli\u003eMartins DJ, Di Lazzaro Filho R, Bertola DR and Hoch NC: Rothmund-Thomson syndrome, a disorder far from solved. Front Aging 4: 1296409, 2023.\u003c/li\u003e\n\u003cli\u003eKaneko H, Kawase C, Seki J, Ikawa Y, Yachie A and Funato M: Intellectual disability and abnormal cortical neuron phenotypes in patients with Bloom syndrome. J Hum Genet 68: 321\u0026ndash;327, 2023.\u003c/li\u003e\n\u003cli\u003eKaneko H, Takemoto M, Murakami H, Ihara K, Kosaki R, Motegi SI, Taniguchi A, Matsuo M, Yamazaki N, Nishigori C, et al: Rothmund-Thomson syndrome investigated by two nationwide surveys in Japan. Pediatr Int 64: e15120, 2022.\u003c/li\u003e\n\u003cli\u003eGerman J and Takebe H: Bloom\u0026apos;s syndrome. XIV. The disorder in Japan. Clin Genet 35: 93\u0026ndash;110, 1989.\u003c/li\u003e\n\u003cli\u003eThe Survey on the Lives of Children with Chronic Specific Pediatric Illnesses conducted by the Ministry of Health, Labour and Welfare of Japan https://www.mhlw.go.jp/content/001277467.pdf\u003c/li\u003e\n\u003cli\u003ede Renty C and Ellis NA: Bloom\u0026apos;s syndrome: Why not premature aging? A comparison of the BLM and WRN helicases. Ageing Res Rev 33: 36-51, 2017.\u003c/li\u003e\n\u003cli\u003eRenes JS, Willemsen RH, Wagner A, Finken MJ and Hokken-Koelega AC: Bloom syndrome in short children born small for gestational age: A challenging diagnosis. J Clin Endocrinol Metab 98: 3932\u0026ndash;3938, 2013.\u003c/li\u003e\n\u003cli\u003eRaman S, Grimberg A, Waguespack SG, Miller BS, Sklar CA, Meacham LR and Patterson BC: Risk of neoplasia in pediatric patients receiving growth hormone therapy: A report from the Pediatric Endocrine Society Drug and Therapeutics Committee. J Clin Endocrinol Metab 100: 2192\u0026ndash;2203, 2015.\u003c/li\u003e\n\u003cli\u003eTeferedegn E, Izumi K, Ahrens-Nicklas R, Bhoj E, Rippert A: Rothmund-Thomson Syndrome Type 2 in an African American/Puerto Rican Child Demonstrates Diagnostic Challenges in Diverse Population. Am J Med Genet A. Jun 9:e64132. doi: 10.1002/ajmg.a.64132, 2025.\u003c/li\u003e\n\u003cli\u003eGrossman LD, Baldino S, Zelley K, Balis F, Bagatell R, Kalish JM, MacFarland SP: Atypical presentations of RECQL4-related syndromes. Pediatr Blood Cancer. 71:e31315, 2024.\u003c/li\u003e\n\u003cli\u003eBousfiha AA, Jeddane L, Moundir A, Poli MC, Aksentijevich I, Cunningham-Rundles C, Hambleton S, Klein C, Morio T, Picard C, Puel A, Rezaei N, Sepp\u0026auml;nen MRJ, Somech R, Su HC, Sullivan KE, Torgerson TR, Tangye SG, Meyts I: The 2024 update of IUIS phenotypic classification of human inborn errors of immunity. J Hum Immun 1 (1): e20250002, 2025.\u003c/li\u003e\n\u003cli\u003eBroom MA, Wang LL, Otta SK, Knutsen AP, Siegfried E, Batanian JR, Kelly ME, Shah M: Successful umbilical cord blood stem cell transplantation in a patient with Rothmund-Thomson syndrome and combined immunodeficiency. Clin Genet 69:337-343, 2006. \u003c/li\u003e\n\u003cli\u003eDe Somer L, Wouters C, Morren MA, De Vos R, Van Den Oord J, Devriendt K, Meyts I: Granulomatous skin lesions complicating Varicella infection in a patient with Rothmund-Thomson syndrome and immune deficiency: case report. Orphanet J Rare Dis. 8;5:37. doi: 10.1186/1750-1172-5-37, 2010.\u003c/li\u003e\n\u003cli\u003ePacaud C, Nazon C, Pages M, Rouger J, Berthet P, Winter S, Thebault \u0026Eacute;, Faure-Conter C, Berger C, Paillard C. Management of Paediatric Cancers Associated With Bloom Syndrome. Hum Mutat. 3;2025:7065233. doi: 10.1155/humu/7065233, 2025.\u003c/li\u003e\n\u003cli\u003eSugra\u0026ntilde;es TA, Flanagan M, Thomas C, Chang VY, Walsh M, Cunniff C: Age of first cancer diagnosis and survival in Bloom syndrome. Genet Med. 24:1476-1484, 2022.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable I. Clinical characteristics of recruited children with BS or RTS\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBS1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBS2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBS3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBS4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCurrent age\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003e13y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003e11y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e3y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e4y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003e11y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003e7y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003e9y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003e13y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003e12y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003e10y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003e8y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003e10y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003e2y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003e12y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003e3y\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGestational age\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003e37w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003e37w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e37w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e26w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003e36w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003e37w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003e38w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003e36w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003e38w\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBirth weight\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003e1560g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003e1540g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e1440g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e470g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003e2060g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003e2000g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003e1850g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003e2060g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003e1710g\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGH replacement\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003e2y~12y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003e2y~10y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003e１y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSkin lesion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003ecaf\u0026eacute;-au-lait\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003eeczema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003eeczema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003epigmentation, hyperkeratosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSun sensitivity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003eunknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003eunknown\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSunscreen\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSusceptibility to infections\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.5507%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMalignancy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.69213%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.66591%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.95553%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4025%;\"\u003e\n \u003cp\u003eosteosarcoma 11y knee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.52566%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.06956%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8586%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.32383%;\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable II. Number of visits to the hospitals and the methods of surveillance for malignancy\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBS1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBS2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBS3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBS4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"35\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of visits\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eonce a month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eonce a month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003eonce a month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e2-3 times a month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eonce a month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eonce a month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003etwo or three times every six months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eonce \u0026nbsp; \u0026nbsp; a week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e2-3 times a month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"36\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd height=\"36\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurveillance for malignancy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eblood test, ultrasonography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eblood test, ultrasonography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eblood test, ultrasonography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eblood test, MRI ultrasonography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eblood test, ultrasonography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eblood test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eX-ray\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003enot described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"36\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd height=\"36\" style=\"width: 0px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable III. Results of a survey of guardians of children with BS and RTS about their concerns regarding school life and where they obtain information about the disease \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ea) Please tell us about your child\u0026apos;s absences over the past year.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eAlmost no absence: RTS2, Absence for about 2-3 days per month: BS3, RTS2, Absence for about 4-5 days per month: RTS1\u003c/p\u003e\n \u003cp\u003eAbsence for about half the month: BS1, Almost always absence: N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb) Do you have any worries or concerns about having your child live at home?\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eYes: BS3, RTS2, Somewhat Yes: RTS2, Somewhat No: RTS1, No: BS1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ec) Please answer the questions that apply to your concerns or worries (multiple answers possible).\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eConcerns about children\u0026apos;s growth and development: BS4, RTS3, Concerns about the worsening of a child\u0026apos;s illness: BS4, RTS4, Impact on other family members: RTS2\u003c/p\u003e\n \u003cp\u003eFinancial insecurity at home: RTS1, Securing a place for children outside the home: RTS3, Opportunities for children to interact with peers of the same age: BS3, RTS2\u003c/p\u003e\n \u003cp\u003eI don\u0026apos;t have time for myself: BS1, RTS1, Concerns about my employment and working style: BS1, Understanding from neighbors: N, \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eI can\u0026apos;t express my worries and concerns: N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ed) Who outside of your family do you tell about your child\u0026apos;s illness? (multiple answers possible)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eNursery/kindergarten teachers: BS2, School teacher: RTS4, Some of my children\u0026apos;s friends: RTS2, All classmates: RTS1, Parents of children\u0026apos;s friends: BS1, RTS3,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMy friends in the neighborhood: BS1, RTS2, I haven\u0026apos;t told anyone: BS2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ee) Has your child ever been unable to enroll in the school, nursery school or other facility of their choice due to an illness? (multiple answers possible)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eNursery school: BS2, RTS1, Kindergarten: RTS2, Primary school: N, Junior high school: N, High school: N, Special Education School: RTS1, Visiting education: N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ef) Have you ever had trouble obtaining information on medical and welfare services? (multiple answers possible)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eI didn\u0026apos;t know who to consult: BS2, RTS2, I couldn\u0026apos;t get the information I needed: RTS1, I didn\u0026apos;t know where to look: BS4, RTS4, The sources of information varied depending on the age of the children: RTS1, There is no institution nearby that I can consult with: RTS1, It wasn\u0026apos;t particularly difficult: RTS1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eg) How to obtain information about medical and welfare services for your child (multiple answers allowed)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eWebsites created by government agencies, support groups. Excluding SNS: BS1, RTS1, Children\u0026apos;s schools, daycare centers: RTS1, \u0026nbsp;Announcements from local governments: N, Local government offices: BS1, Medical institutions: BS2, RTS4, Welfare facilities: N, \u0026nbsp; \u0026nbsp; Self-reliance support worker and other consultation supporters: N, Announcements from patient family associations: N, SNS: N, Books and magazines: N, Information exchanges between parents: RTS3, Home-visit nursing : BS1, I do not need information: N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBS3 means that three BS guardians answered yes. N means that neither BS nor RTS guardians apply to the answer. The number of respondents was four for BS guardians and five for RTS.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Bloom syndrome, Rothmund–Thomson syndrome, growth curve, immunodeficiency, surveillance, caregiver concerns","lastPublishedDoi":"10.21203/rs.3.rs-7260291/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7260291/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBloom syndrome (BS) and Rothmund\u0026ndash;Thomson syndrome (RTS) are caused by pathogenetic variants in the \u003cem\u003eBLM\u003c/em\u003e and \u003cem\u003eRECQL4\u003c/em\u003e genes, which belong to the RecQ helicase family. BS is characterized by short stature, sun-sensitive erythema, immunodeficiency, and a predisposition to various malignancies. RTS is characterized by poikiloderma, bone malformations, and a predisposition to osteosarcoma. In our previous studies, approximately 10 cases of each condition were reported in Japan; however, most of the reported cases involved adults. To elucidate the current state of children and caregivers of patients with BS and RTS in Japan, we conducted a questionnaire-based study. We received responses from four guardians of children with BS and five of those with RTS, all of whom were members of family association of BS or RTS in Japan. None of the children had been included in previous studies. All patients were low birth weight infants (under 2300 g), and one child with BS was classified as extremely low birth weight. With the exception of one child with BS, all received growth hormone replacement therapy; no children with RTS received growth hormone treatment. The height of children with BS tended to be shorter than those with RTS. Most children with BS or RTS visited the hospital once a month. Blood tests and ultrasonography were commonly used for malignancy surveillance. Three of the five RTS guardians did not recognize characteristic skin lesions such as poikiloderma. Although sun sensitivity was not prominent, nearly all children with RTS used sunscreen. One child with RTS developed osteosarcoma. BS was considered to impose a greater psychological burden on parents than RTS. This study clarified the needs and challenges faced by children with BS and RTS and their families in Japan. Understanding the true status and needs of these patients and their caregivers will help improve their quality of life.\u003c/p\u003e","manuscriptTitle":"Status of children and caregivers with Bloom syndrome and Rothmund–Thomson syndrome in Japan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-13 07:25:40","doi":"10.21203/rs.3.rs-7260291/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b06b3ffd-2653-4de3-8b2a-91079d126330","owner":[],"postedDate":"August 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-09T10:23:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-13 07:25:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7260291","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7260291","identity":"rs-7260291","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}