Update on Cancer and Central Nervous System Tumor Surveillance in Pediatric NF2-, SMARCB1-, and LZTR1-Related Schwannomatosis

doi:10.1158/1078-0432.CCR-24-3278

. 2025 Apr 14;31(8):1400-1406.

doi: 10.1158/1078-0432.CCR-24-3278.

Update on Cancer and Central Nervous System Tumor Surveillance in Pediatric NF2-, SMARCB1-, and LZTR1-Related Schwannomatosis

Melissa R Perrino¹, Marjolijn C J Jongmans^{2

3}, Gail E Tomlinson⁴, Mary-Louise C Greer^{5

6}, Sarah R Scollon⁷, Sarah G Mitchell⁸, Jordan R Hansford⁹, Kris Ann P Schultz¹⁰, Wendy K Kohlmann^{11

12}, Jennifer M Kalish^{13

14

15

16}, Suzanne P MacFarland¹⁷, Anirban Das¹⁸, Kara N Maxwell^{17

19}, Stefan M Pfister²⁰, Rosanna Weksberg²¹, Orli Michaeli²², Uri Tabori¹⁸, Gina M Ney²³, Philip J Lupo²⁴, Jack J Brzezinski¹⁸, Douglas R Stewart²³, Emma R Woodward^{25

26}, Christian P Kratz²⁷

Affiliations

¹ Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
² Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
³ Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
⁴ Division of Hematology-Oncology, Department of Pediatrics, UT Health San Antonio, Greehey Children's Cancer Research Institute, San Antonio, Texas.
⁵ Department of Diagnostic and Interventional Radiology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
⁶ Department of Medical Imaging, University of Toronto, Toronto, Canada.
⁷ Division of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Houston, Texas.
⁸ Department of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia.
⁹ Michael Rice Centre for Hematology and Oncology, South Australia Health and Medical Research Institute, South Australia ImmunoGENomics Cancer Institute, University of Adelaide, Adelaide, Australia.
¹⁰ Cancer and Blood Disorders, Children's Minnesota, Minneapolis, Minnesota.
¹¹ VA National TeleOncology Program, Durham, North Carolina.
¹² Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
¹³ Division of Human Genetics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
¹⁴ Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁵ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁶ Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
¹⁷ Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁸ Division of Paediatric Haematology and Oncology, Hospital for Sick Children, University of Toronto, Toronto, Canada.
¹⁹ Medicine Service, Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
²⁰ Hopp Children's Cancer Center Heidelberg (KiTZ), Division Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg University Hospital and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²¹ Division of Clinical and Metabolic Genetics, Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada.
²² Division of Hematology/Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
²³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
²⁴ Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
²⁵ Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
²⁶ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
²⁷ Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.

PMID: 39937237
PMCID: PMC12002630 (available on 2025-10-14)
DOI: 10.1158/1078-0432.CCR-24-3278

Update on Cancer and Central Nervous System Tumor Surveillance in Pediatric NF2-, SMARCB1-, and LZTR1-Related Schwannomatosis

Melissa R Perrino et al. Clin Cancer Res. 2025.

. 2025 Apr 14;31(8):1400-1406.

doi: 10.1158/1078-0432.CCR-24-3278.

Authors

Affiliations

¹ Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
² Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
³ Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
⁴ Division of Hematology-Oncology, Department of Pediatrics, UT Health San Antonio, Greehey Children's Cancer Research Institute, San Antonio, Texas.
⁵ Department of Diagnostic and Interventional Radiology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
⁶ Department of Medical Imaging, University of Toronto, Toronto, Canada.
⁷ Division of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Houston, Texas.
⁸ Department of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia.
⁹ Michael Rice Centre for Hematology and Oncology, South Australia Health and Medical Research Institute, South Australia ImmunoGENomics Cancer Institute, University of Adelaide, Adelaide, Australia.
¹⁰ Cancer and Blood Disorders, Children's Minnesota, Minneapolis, Minnesota.
¹¹ VA National TeleOncology Program, Durham, North Carolina.
¹² Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
¹³ Division of Human Genetics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
¹⁴ Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁵ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁶ Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
¹⁷ Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁸ Division of Paediatric Haematology and Oncology, Hospital for Sick Children, University of Toronto, Toronto, Canada.
¹⁹ Medicine Service, Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
²⁰ Hopp Children's Cancer Center Heidelberg (KiTZ), Division Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg University Hospital and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²¹ Division of Clinical and Metabolic Genetics, Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada.
²² Division of Hematology/Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
²³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
²⁴ Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
²⁵ Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
²⁶ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
²⁷ Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.

PMID: 39937237
PMCID: PMC12002630 (available on 2025-10-14)
DOI: 10.1158/1078-0432.CCR-24-3278

Abstract

Schwannomatosis (SWN) is a distinct cancer predisposition syndrome caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is a significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal, and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome, with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas, and less commonly, ependymoma. SMARCB1-related SWN is a familial SWN syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence of radiation. These individuals do not develop bilateral vestibular schwannomas. Finally, patients with LZTR1-related SWN typically present with peripheral schwannomas, and unilateral vestibular schwannomas have been reported. The following perspective is intended to highlight the clinical presentation and international tumor surveillance recommendations across these SWN syndromes.

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Conflict of interest statement

Conflicts of interest: MRP has received honoraria from Alexion unrelated to this work. JRH has received honoraria from Alexion and Bayer Pharmaceuticals, unrelated to this work, and is a member of the Servier International scientific advisory board. MCG serves as a research consultant for Alimentiv and holds an investigator-initiated grant from AbbVie unrelated to this work. The remaining authors have no disclosures or conflicts of interest to report.

Cited by

SMARCB1-related schwannomatosis and other SMARCB1-associated phenotypes: clinical spectrum and molecular pathogenesis.
Kehrer-Sawatzki H, Cooper DN. Kehrer-Sawatzki H, et al. Fam Cancer. 2025 Aug 12;24(3):64. doi: 10.1007/s10689-025-00486-4. Fam Cancer. 2025. PMID: 40794298 Free PMC article. Review.
Pediatric Cancer Predisposition and Surveillance Update: Summary Perspective and Future Directions.
Brodeur GM, Diller LR, Nichols KE, Plon SE, Porter CC, Malkin D. Brodeur GM, et al. Clin Cancer Res. 2025 Jul 1;31(13):2581-2588. doi: 10.1158/1078-0432.CCR-25-0423. Clin Cancer Res. 2025. PMID: 40327330 Review.

References

1. Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, et al. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genetics in Medicine 2022;24(9):1967–77 doi 10.1016/j.gim.2022.05.007. - DOI - PubMed
1. Evans DG, Hartley CL, Smith PT, King AT, Bowers NL, Tobi S, et al. Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing. Genetics in Medicine 2020;22(1):53–9 doi 10.1038/s41436-019-0598-7. - DOI - PubMed
1. Hadfield KD, Newman WG, Bowers NL, Wallace A, Bolger C, Colley A, et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J Med Genet 2008;45(6):332–9 doi 10.1136/jmg.2007.056499. - DOI - PubMed
1. Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 2007;80(4):805–10 doi 10.1086/513207. - DOI - PMC - PubMed
1. Carter JM, O’Hara C, Dundas G, Gilchrist D, Collins MS, Eaton K, et al. Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with “neuroblastoma-like” schwannomatosis and a novel germline SMARCB1 mutation. Am J Surg Pathol 2012;36(1):154–60 doi 10.1097/PAS.0b013e3182380802. - DOI - PMC - PubMed

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[1] Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, et al. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genetics in Medicine 2022;24(9):1967–77 doi 10.1016/j.gim.2022.05.007. - DOI - PubMed

[2] Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, et al. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genetics in Medicine 2022;24(9):1967–77 doi 10.1016/j.gim.2022.05.007. - DOI - PubMed

[3] Evans DG, Hartley CL, Smith PT, King AT, Bowers NL, Tobi S, et al. Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing. Genetics in Medicine 2020;22(1):53–9 doi 10.1038/s41436-019-0598-7. - DOI - PubMed

[4] Evans DG, Hartley CL, Smith PT, King AT, Bowers NL, Tobi S, et al. Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing. Genetics in Medicine 2020;22(1):53–9 doi 10.1038/s41436-019-0598-7. - DOI - PubMed

[5] Hadfield KD, Newman WG, Bowers NL, Wallace A, Bolger C, Colley A, et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J Med Genet 2008;45(6):332–9 doi 10.1136/jmg.2007.056499. - DOI - PubMed

[6] Hadfield KD, Newman WG, Bowers NL, Wallace A, Bolger C, Colley A, et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J Med Genet 2008;45(6):332–9 doi 10.1136/jmg.2007.056499. - DOI - PubMed

[7] Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 2007;80(4):805–10 doi 10.1086/513207. - DOI - PMC - PubMed

[8] Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 2007;80(4):805–10 doi 10.1086/513207. - DOI - PMC - PubMed

[9] Carter JM, O’Hara C, Dundas G, Gilchrist D, Collins MS, Eaton K, et al. Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with “neuroblastoma-like” schwannomatosis and a novel germline SMARCB1 mutation. Am J Surg Pathol 2012;36(1):154–60 doi 10.1097/PAS.0b013e3182380802. - DOI - PMC - PubMed

[10] Carter JM, O’Hara C, Dundas G, Gilchrist D, Collins MS, Eaton K, et al. Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with “neuroblastoma-like” schwannomatosis and a novel germline SMARCB1 mutation. Am J Surg Pathol 2012;36(1):154–60 doi 10.1097/PAS.0b013e3182380802. - DOI - PMC - PubMed

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Update on Cancer and Central Nervous System Tumor Surveillance in Pediatric NF2-, SMARCB1-, and LZTR1-Related Schwannomatosis

Affiliations

Update on Cancer and Central Nervous System Tumor Surveillance in Pediatric NF2-, SMARCB1-, and LZTR1-Related Schwannomatosis

Authors

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Conflict of interest statement

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