bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023‒01‒22
thirteen papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. A case report of biallelic CHEK2 heterozygous variant presenting with breast cancer.
  2. PMS2 Pathogenic Variant in Lynch Syndrome-Associated Colorectal Cancer with Polyps.
  3. Current Understanding of DDX41 Mutations in Myeloid Neoplasms.
  4. Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study.
  5. Occurrence of variants of unknown clinical significance in genetic testing for hereditary breast and ovarian cancer syndrome and Lynch syndrome: a literature review and analytical observational retrospective cohort study.
  6. Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review.
  7. Relative Risk of Bladder and Kidney Cancer in Lynch Syndrome: Systematic Review and Meta-Analysis.
  8. Comments on <The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients>.
  9. Characterization of myeloproliferative neoplasms in the paediatric and young adult population.
  10. Germline study points to sarcoma pathways.
  11. Guideline-Based, Multi-Gene Panel Germline Genetic Testing for at-Risk Patients with Breast Cancer.
  12. The Contribution of Germline Pathogenic Variants in Breast Cancer Genes to Contralateral Breast Cancer Risk in BRCA1/BRCA2/PALB2-Negative Women.
  13. Development and early-stage evaluation of a patient portal to enhance familial communication about hereditary cancer susceptibility testing: A patient-driven approach.
  1. Clin Case Rep. 2023 Jan;11(1): e6820
    A case report of biallelic CHEK2 heterozygous variant presenting with breast cancer.
    Tahereh Soleimani, Corrie Bourdon, Jacquelyn Davis, Thais Fortes.
      Pathogenic germline variants in the CHEK2 gene have been shown to cause a moderate increased risk of breast cancer. Here, we present a striking CHEK2 family with a biallelic carrier of two frameshift pathogenic variants, to draw attention and to encourage a comprehensive genetic and cancer risk education for biallelic carriers of CHEK2 pathogenic variants.
    Keywords:  CHEK2; biallelic; breast cancer; checkpoint kinase 2; familial; genetic; heterozygous
    DOI:  https://doi.org/10.1002/ccr3.6820
  2. Glob Med Genet. 2023 Jan;10(1): 1-5
    PMS2 Pathogenic Variant in Lynch Syndrome-Associated Colorectal Cancer with Polyps.
    Henriette Poaty, Lauria Batamba Bouya, Aimé Lumaka, Arnaud Mongo-Onkouo, Deby Gassaye.
      Background  Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1 , MSH2 , MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. Patients and Methods  The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. Results  The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected. Conclusion  Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age.
    Keywords:  PMS2 deficiency ; colorectal cancer; lynch syndrome; mismatch repair gene
    DOI:  https://doi.org/10.1055/s-0042-1759888
  3. Cancers (Basel). 2023 Jan 05. pii: 344. [Epub ahead of print]15(2):
    Current Understanding of DDX41 Mutations in Myeloid Neoplasms.
    Kunhwa Kim, Faustine Ong, Koji Sasaki.
      The DEAD-box RNA helicase 41 gene, DDX41, is frequently mutated in hereditary myeloid neoplasms, identified in 2% of entire patients with AML/MDS. The pathogenesis of DDX41 mutation is related to the defect in the gene's normal functions of RNA and innate immunity. About 80% of patients with germline DDX41 mutations have somatic mutations in another allele, resulting in the biallelic DDX41 mutation. Patients with the disease with DDX41 mutations reportedly often present with the higher-grade disease, but there are conflicting reports about its impact on survival outcomes. Recent studies using larger cohorts reported a favorable outcome with a better response to standard therapies in patients with DDX41 mutations to patients without DDX41 mutations. For stem-cell transplantation, it is important for patients with DDX41 germline mutations to identify family donors early to improve outcomes. Still, there is a gap in knowledge on whether germline DDX41 mutations and its pathology features can be targetable for treatment, and what constitutes an appropriate screening/surveillance strategy for identified carriers. This article reviews our current understanding of DDX41 mutations in myeloid neoplasms in pathologic and clinical features and their clinical implications.
    Keywords:  DDX41 mutations; acute myeloid leukemia; hereditary myeloid neoplasms; myelodysplastic syndrome
    DOI:  https://doi.org/10.3390/cancers15020344
  4. Genes (Basel). 2022 Dec 29. pii: 106. [Epub ahead of print]14(1):
    Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study.
    Auhood Nassar, Abdel-Rahman N Zekri, Mahmoud M Kamel, Mostafa H Elberry, Mai M Lotfy, Mohamed G Seadawy, Zeinab K Hassan, Hany K Soliman, Ahmed M Lymona, Amira Salah El-Din Youssef.
      BACKGROUND: Precision oncology has been increasingly used in clinical practice and rapidly evolving in the oncology field. Thus, this study was performed to assess the frequency of germline mutations in early and late onset familial breast cancer (BC) Egyptian patients using multi-gene panel sequencing to better understand the contribution of the inherited germline mutations in BC predisposition. Moreover, to determine the actionable deleterious mutations associated with familial BC that might be used as biomarker for early cancer detection.METHODS: Whole blood samples were collected from 101 Egyptian patients selected for BC family history, in addition to 50 age-matched healthy controls. A QIAseq targeted DNA panel (human BC panel) was used to assess the frequency of germline mutations.
    RESULTS: A total of 58 patients (57.4%) out of 101 were found to have 27 deleterious germline mutations in 11 cancer susceptibility genes. Of them, 32 (31.6%) patients carried more than one pathogenic mutation and each one carried at least one pathogenic mutation. The major genes harboring the pathogenic mutations were: ATM, BRCA2, BRCA1, VHL, MSH6, APC, CHEK2, MSH2, MEN1, PALB2, and MUTYH. Thirty-one patients (30.6%) had BRCA2 mutations and twenty (19.8%) had BRCA1 mutations. Our results showed that exon 10 and exon 11 harbored 3 and 5 mutations, respectively, in BRCA1 and BRCA2 genes. Our analysis also revealed that the VHL gene significantly co-occurred with each of the BRCA2 gene (p = 0.003, event ratio 11/21), the MSH2 gene (p = 0.01, 4/10), the CHEK2 gene (p = 0.02, 4/11), and the MSH6 gene (p = 0.04, 4/12). In addition, the APC gene significantly co-occurred with the MSH2 gene (p = 0.01, 3/7). Furthermore, there was a significant mutually exclusive event between the APC gene and the ATM gene (p = 0.04, 1/36). Interestingly, we identified population specific germline mutations in genes showing potentials for targeted therapy to meet the need for incorporating precision oncology into clinical practice. For example, the mutations identified in the ATM, APC, and MSH2 genes.
    CONCLUSIONS: Multi-gene panel sequencing was used to detect the deleterious mutations associated with familial BC, which in turns mitigate the essential need for implementing next generation sequencing technologies in precision oncology to identify cancer predisposing genes. Moreover, identifying DNA repair gene mutations, with focus on non-BRCA genes, might serve as candidates for targeted therapy and will be increasingly used in precision oncology.
    Keywords:  BRCA1; BRCA2; familial breast cancer; germline mutations; multi-gene panel sequencing; precision oncology
    DOI:  https://doi.org/10.3390/genes14010106
  5. BMC Med Genomics. 2023 Jan 16. 16(1): 7
    Occurrence of variants of unknown clinical significance in genetic testing for hereditary breast and ovarian cancer syndrome and Lynch syndrome: a literature review and analytical observational retrospective cohort study.
    Felicia Adam, Muriel Fluri, Amina Scherz, Manuela Rabaglio.
      BACKGROUND AND PURPOSE: Over the last decade, the implementation of multigene panels for hereditary tumor syndrome has increased at our institution (Inselspital, University Hospital Berne, Switzerland). The aim of this study was to determine the prevalence of variants of unknown significance (VUS) in patients with suspected Lynch syndrome and suspected hereditary breast and ovarian cancer syndrome, the latter in connection with the trend toward ordering larger gene panels.RESULTS: Retrospectively collected data from 1057 patients at our institution showed at least one VUS in 126 different cases (11.9%). In patients undergoing genetic testing for BRCA1/2, the prevalence of VUS was 6%. When < 10 additional genes were tested in addition to BRCA1/2, the prevalence increased to 13.8%, and 31.8% for > 10 additional genes, respectively. The gene most frequently affected with a VUS was ATM. 6% of our patients who were tested for Lynch syndrome had a VUS result in either MLH1, MSH2 or MSH6.
    CONCLUSIONS: Our data demonstrate that panel testing statistically significantly increases VUS rates due to variants in non-BRCA genes. Good genetic counseling before and after obtaining results is therefore particularly important when conducting multigene panels to minimize patient uncertainty due to VUS results.
    Keywords:  BRCA1; BRCA2; Hereditary breast and ovarian cancer; Lynch syndrome; MMR genes; Multigene panel; VUS
    DOI:  https://doi.org/10.1186/s12920-023-01437-7
  6. BMC Med Genomics. 2023 Jan 16. 16(1): 6
    Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review.
    Shumpei Onishi, Fumiyuki Yamasaki, Kazuya Kuraoka, Akira Taguchi, Takeshi Takayasu, Kiwamu Akagi, Takao Hinoi.
      BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) results from a biallelic germline pathogenic variant in a mismatch repair (MMR) gene. The most common CMMRD-associated malignancies are brain tumors; an accurate diagnosis is challenging when a malignant brain tumor is the only tumor at presentation. We describe two cases of glioblastoma as the initial CMMRD malignancy and discuss current diagnostic and therapeutic challenges.CASE PRESENTATION: Two children with brain tumors without remarkable family history had biallelic pathogenic germline variants in PMS2. Patient 1: A 6-year-old girl presented biallelic PMS2 germline pathogenic variants. Glioblastomas at the left frontal lobe and right temporal lobe were resistant to immune-checkpoint inhibitor, temozolomide, and bevacizumab. Patient 2: A 10-year-old boy presented biallelic PMS2 germline variants. His glioblastoma with primitive neuroectodermal tumor-like features responded to chemoradiotherapy, but he developed advanced colon cancer and acute lymphocytic leukemia. In both patients, only a monoallelic PMS2 germline variant was detected by conventional gene tests. PMS2 immunohistochemistry showed lack of staining at both the tumors and normal tissue as vascular endothelial cells. Further gene tests revealed large genomic deletion including the entire PMS2 gene, confirming biallelic PMS2 germline variants.
    CONCLUSION: Conventional multi-gene panel tests are insufficient for detecting large deletions of MMR genes, resulting in misdiagnoses of CMMRD as Lynch syndrome. PMS2 variants have low cancer penetrance; family histories may thus be absent. Long-range gene analyses or immunohistochemical staining of MMR proteins in normal tissue should be considered for pediatric brain tumors with a single allele MMR variant when CMMRD is suspected.
    Keywords:  Acute lymphocytic leukemia; CMMRD; Colon cancer; Constitutional mismatch repair deficiency; Genetic testing; Glioblastoma; Immune-checkpoint inhibitor; Large deletion; Lynch syndrome; PMS2
    DOI:  https://doi.org/10.1186/s12920-022-01403-9
  7. Cancers (Basel). 2023 Jan 13. pii: 506. [Epub ahead of print]15(2):
    Relative Risk of Bladder and Kidney Cancer in Lynch Syndrome: Systematic Review and Meta-Analysis.
    Anthony-Joe Nassour, Anika Jain, Nicholas Hui, George Siopis, James Symons, Henry Woo.
      BACKGROUND: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population.METHODS: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane's tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE.
    RESULTS: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p &lt; 0.01). The quality of the evidence was assessed as "low" due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias.
    CONCLUSION: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS.
    Keywords:  DNA; extra-colonic; genetic predisposition; genetics; genome; hereditary nonpolyposis colorectal cancer; inherited cancer risk; malignancy; malignant; mutated gene; oncology; tumour; urinary tract; urology
    DOI:  https://doi.org/10.3390/cancers15020506
  8. Int J Cancer. 2023 Jan 16.
    Comments on <The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients>.
    Christian P Kratz, D Gareth Evans.
      
    Keywords:  CHEK2; cancer predisposition; childhood cancer
    DOI:  https://doi.org/10.1002/ijc.34432
  9. Br J Haematol. 2023 Jan 16.
    Characterization of myeloproliferative neoplasms in the paediatric and young adult population.
    Zoey Harris, Hannah Kaizer, Aria Wei, Theodoros Karantanos, Donna M Williams, Shruti Chaturvedi, Tania Jain, Linda Resar, Alison R Moliterno, Evan M Braunstein.
      The aim of this study was to compare the genomic features and clinical outcomes between paediatric and young adult patients (PAYA, <40 years) and older adults (OA, ≥40 years) with myeloproliferative neoplasms (MPN) to gain insight into pathogenesis, disease prognosis and management. Of 630 MPN patients, 171 (27%) were PAYA with an average age at diagnosis of 31 years. Females were more prevalent in PAYA than OA (71% vs 58%; p = 0.002), and PAYA more frequently presented with essential thrombocytosis (ET) at diagnosis (67% vs 39%; p < 0.001). The presence of a JAK2 somatic mutation was higher in OA (80.4% vs 64.3%; p < 0.001), while a CALR mutation or lack of any traditional driver mutation was more common in PAYA (20.5% vs 10.5%; p = 0.001, 8.8% vs 3.7%; p = 0.01 respectively). Venous thrombosis was more common in PAYA compared to OA (19.8% vs 10.7%; p = 0.002). PAYA had a higher prevalence of familial MPN and familial cancer predisposition, and two PAYA patients harboured pathogenic germline JAK2 lesions. PAYA demonstrated longer survival from diagnosis than OA (median not reached vs 13 years), while disease transformation was less frequent (19.3% vs 37.9%).
    Keywords:  essential thrombocythaemia; genetic analysis; myelofibrosis; myeloproliferative disease; paediatric oncology; polycythaemia vera
    DOI:  https://doi.org/10.1111/bjh.18650
  10. Science. 2023 Jan 20. 379(6629): 238-239
    Germline study points to sarcoma pathways.
    Diana Mandelker, Marc Ladanyi.
      Pathogenic variants related to mitosis and telomere integrity are enriched in sarcoma patients.
    DOI:  https://doi.org/10.1126/science.adf8572
  11. Breast Cancer (Dove Med Press). 2023 ;15 1-10
    Guideline-Based, Multi-Gene Panel Germline Genetic Testing for at-Risk Patients with Breast Cancer.
    Hikmat Abdel-Razeq, Lama Abujamous, Khansa Al-Azzam, Hala Abu-Fares, Hira Bani Hani, Mais Alkyam, Baha' Sharaf, Shatha Elemian, Faris Tamimi, Fawzi Abuhijla, Sarah Edaily, Osama Salama, Hazem Abdulelah, Rand Daoud, Mohammad Abubaker, Areej Al-Atary.
      Background: Genetic testing for at-risk patients with breast cancer should be routinely offered. Knowledge generated may influence both treatment decisions and cancer prevention strategies among the patients themselves and their relatives. In this study, we report on the prevalence and patterns of germline mutations, using commercially available next-generation sequencing (NGS)-based multi-gene panels (MGP).Patients and Methods: Consecutive at-risk breast cancer patients, as determined by international guidelines, were offered germline genetic testing using a 20-gene NGS-based panel at a reference lab. Samples of peripheral blood were obtained for DNA extraction and genetic variants were classified as benign/likely benign (negative), pathogenic/likely pathogenic (positive) or variants of uncertain significance (VUS).
    Results: A total of 1310 patients, median age (range) 43 (19-82) years, were enrolled. Age ≤45 years (n = 800, 61.1%) was the most common indication for testing. Positive family history of breast, ovarian, pancreatic or prostate cancers, and triple-negative disease were among the common indications. Among the whole group, 184 (14.0%) patients had pathogenic/likely pathogenic variants; only 90 (48.9%) were in BRCA1 or BRCA2, while 94 (51.9%) others had pathogenic variants in other genes; mostly in APC, TP53, CHEK2 and PALB2. Mutation rates were significantly higher among patients with positive family history (p = 0.009); especially if they were 50 years or younger at the time of breast cancer diagnosis (p < 0.001). Patients with triple-negative disease had relatively higher rate (17.5%), and mostly in BRCA1/2 genes (71.4%). Variants of uncertain significance (VUS) were reported in 559 (42.7%) patients; majority (90.7%) were in genes other than BRCA1 or BRCA2.
    Conclusion: Pathogenic mutations in genes other than BRCA1/2 are relatively common and could have been missed if genetic testing was restricted to BRCA1/2. The significantly high rate of VUS associated with multi-gene panel testing can be disturbing.
    Keywords:  BRCA1; BRCA2; breast cancer; hereditary breast cancer; multigene panel; next generation sequencing
    DOI:  https://doi.org/10.2147/BCTT.S394092
  12. Cancers (Basel). 2023 Jan 08. pii: 415. [Epub ahead of print]15(2):
    The Contribution of Germline Pathogenic Variants in Breast Cancer Genes to Contralateral Breast Cancer Risk in BRCA1/BRCA2/PALB2-Negative Women.
    Alexey Larionov, Eleanor Fewings, James Redman, Mae Goldgraben, Graeme Clark, John Boice, Patrick Concannon, Jonine Bernstein, David V Conti, The Wecare Study Collaborative Group, Marc Tischkowitz.
      BACKGROUND: Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as BRCA1, BRCA2 and PALB2. However, data regarding genetic factors predisposing to CBC among younger women who are BRCA1/2/PALB2-negative remain limited.METHODS: In this nested case-control study, participants negative for BRCA1/2/PALB2 PGVs were selected from the WECARE Study. The burden of PGVs in established breast cancer risk genes was compared in 357 cases with CBC and 366 matched controls with unilateral breast cancer (UBC). The samples were sequenced in two phases. Whole exome sequencing was used in Group 1, 162 CBC and 172 UBC (mean age at diagnosis: 42 years). A targeted panel of genes was used in Group 2, 195 CBC and 194 UBC (mean age at diagnosis: 50 years). Comparisons of PGVs burdens between CBC and UBC were made in these groups, and additional stratified sub-analysis was performed within each group according to the age at diagnosis and the time from first breast cancer (BC).
    RESULTS: The PGVs burden in Group 1 was significantly higher in CBC than in UBC (p = 0.002, OR = 2.5, 95CI: 1.2-5.6), driven mainly by variants in CHEK2 and ATM. The proportions of PGVs carriers in CBC and UBC in this group were 14.8% and 5.8%, respectively. There was no significant difference in PGVs burden between CBC and UBC in Group 2 (p = 0.4, OR = 1.4, 95CI: 0.7-2.8), with proportions of carriers being 8.7% and 8.2%, respectively. There was a significant association of PGVs in CBC with younger age. Metanalysis combining both groups confirmed the significant association between the burden of PGVs and the risk of CBC (p = 0.006) with the significance driven by the younger cases (Group 1).
    CONCLUSION: In younger BRCA1/BRCA2/PALB2-negative women, the aggregated burden of PGVs in breast cancer risk genes was associated with the increased risk of CBC and was inversely proportional to the age at onset.
    Keywords:  contralateral breast cancer; exome sequencing; genomics; hereditary breast cancer
    DOI:  https://doi.org/10.3390/cancers15020415
  13. Health Expect. 2023 Jan 20.
    Development and early-stage evaluation of a patient portal to enhance familial communication about hereditary cancer susceptibility testing: A patient-driven approach.
    Samantha Pollard, Deirdre Weymann, Rosalie Loewen, Jennifer Nuk, Sophie Sun, Kasmintan A Schrader, Chiquita Hessels, Dean A Regier.
      INTRODUCTION: Genetic testing for hereditary cancer syndromes (HCSs) can improve health outcomes through cancer risk mitigation strategies. Effective communication between tested individuals and their family members is key to reducing the hereditary cancer burden. Our objective was to develop a patient portal to improve familial communication for patients undergoing HCS genetic testing, followed by an early-phase evaluation.METHODS: The portal was developed following the completion of 25 semistructured interviews with individuals having undergone HCS susceptibility testing at BC Cancer. Following initial development, we recruited patients and healthcare providers to provide critical feedback informing portal refinement. Quantitative feedback was summarized using descriptive statistics, and qualitative feedback was synthesized by two reviewers who engaged in iterative discussion within the research team to prioritize recommendations for integration.
    RESULTS: The patient portal includes four key components consisting of (a) targeted educational information about hereditary cancer and HBOC syndrome associated risks and testing process overview, (b) a general frequently asked questions 'FAQ' page informed by the qualitative interviews, patient partner feedback, and consultation with the HCP, (c) guidance to support familial communication including a video developed with a patient partner describing their lived experience navigating the communication process and (d) a series of lay summaries of genetic test findings to support information transfer among family members. Thirteen healthcare providers and seven patients participated in user testing. Domains within which participant recommendations were provided included presentation, educational content and process clarification.
    CONCLUSIONS: This investigation demonstrates the value of continual integration of patient and provider preferences through the development of tools endeavouring to assist with complex genomics-informed decision-making. Our work aims to broaden the population-wide impact of HCS testing programs by improving communication processes between probands and their potentially affected family members.
    PATIENT OR PUBLIC CONTRIBUTION: This work involved a patient partner who was actively engaged in all aspects of the research investigation including protocol development, review and editing of all study documentation (including that of the previously published qualitative investigation), interpretation of results, as well as reviewing and editing the manuscript. Patient partners and healthcare professionals were recruited as research participants to provide critical feedback on the patient portal.
    Keywords:  decision making; familial cancer; genetic testing; hereditary cancer syndromes; patient education
    DOI:  https://doi.org/10.1111/hex.13702
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