Cancer in Inherited Bone Marrow Failure Syndromes

Background: A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders. Pathogenic variant(s) in IBMFS genes are relevant to carcinogenesis in sporadic cancers. Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer. These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer. Carriers of IBMFS pathogenic variant(s) are at increased risk of cancer. The prototype disorder is Fanconi's Anemia (FA); other IBMFS will also be studied. Objectives: To determine the types and incidence of specific cancers in patients with an IBMFS. To investigate the relevance of IBMFS pathogenic variant(s) in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers. To identify risk factors for IBMFS-related cancers in addition to the primary germline pathogenic variant(s). To determine the risk of cancer in IBMFS carriers. Eligibility: North American families with a proband with an IBMFS. IBMFS suspected by phenotype, confirmed by pathogenic variant(s) in an IBMFS gene, or by clinical diagnostic test. Fanconi's anemia: birth defects, marrow failure, early onset malignancy; positive chromosome breakage result. Diamond-Blackfan anemia: pure red cell aplasia; elevated red cell adenosine deaminase. Dyskeratosis congenita: dysplastic nails, lacey pigmentation, leukoplakia; marrow failure. Shwachman-Diamond Syndrome: malabsorption; neutropenia. Amegakaryocytic thrombocytopenia: early onset thrombocytopenia. Thrombocytopenia absent radii: absent radii; early onset thrombocytopenia. Severe Congenital Neutropenia: neutropenia, pyogenic infections, bone marrow maturation arrest. Pearson's Syndrome: malabsorption, neutropenia, marrow failure, metabolic acidosis; ringed sideroblasts. Other bone marrow failure syndromes: e.g. Revesz Syndrome, WT, IVIC, radio-ulnar synostosis, ataxia-pancytopenia. First degree relatives of IBMFS-affected subjects as defined here, i.e. siblings (half or full), biologic parents, and children. Grandparents of IBMFS-affected subjects. Patients in the general population with sporadic tumors of the types seen in the IBMFS (head and neck, gastrointestinal, and anogenital cancer), with none of the usual risk factors (e.g. smoking, drinking, HPV). Design: Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory test, review of medical records, cancer surveillance. Primary endpoints are all cancers, solid tumors, and cancers specific to each type of IBMFS. Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

Sex

All

Minimum age

1 Day

Maximum age

100 Years

* INCLUSION CRITERIA:

The participants will be affected by an IBMFS, or be members of a family with an IBMFS, and be at risk of being affected or carriers of the syndrome. Except for the rare X-linked recessive disorder (e.g. some dyskeratosis congenita patients), there should be equal numbers of male and female probands and family members. These IBMFS have been reported in most racial and ethnic groups, and thus all such groups will be included. The age range will be from birth to old age (grandparents of probands). The majority of the probands will be children (10-20% will be adults), and their parents and grandparents will be adults. All racial/ethnic groups are eligible.

INCLUSION CRITERIA for Patients:

* Fanconi s anemia.
* Diamond Blackfan anemia.
* Dyskeratosis congenita.
* Shwachman Diamond Syndrome.
* Amegakaryocytic thrombocytopenia.
* Thrombocytopenia absent radii.
* Severe Congenital Neutropenia.
* Pearson Syndrome.
* Other bone marrow failure syndromes.

Family Members of IBMFS - Affected Subjects:

-Family members include first degree relatives of IBMFS-affected subjects as defined here, i.e. siblings (half or full), biologic parents, and children. Grandparents of IBMFS-affected subjects are also included, specifically for Hypothesis 4. The age range will be from birth to old age (grandparents of probands).

Patients in the general population:

-Patients in the general population with sporadic tumors of the types seen in the IBMFS (head and neck, gastrointestinal, and anogenital cancer), with none of the usual risk factors for those tumors (e.g. smoking, drinking, HPV). These patients will be further evaluated for an IBMFS by the referring physician under the guidance of the study investigators and if diagnosed with an IBMFS or if not diagnosed but highly suspicious for an IBMFS, would be eligible for inclusion in the Field and Clinic Center cohorts.

EXCLUSION CRITERIA:

-Affected: An individual who meets any of the following criteria will be excluded from participation in this study:

* Evidence that the hematologic disorder is acquired rather than genetic. Such evidence includes temporal relation of the aplastic anemia to known marrow suppressant drugs, chemicals, toxins, or viruses (in the absence of evidence indicative of an inherited marrow failure disorder).
* Known causes of cytopenias such as autoantibodies to red cells, platelets, or neutrophils, viruses (especially hepatitis), micronutrient deficiencies, transient erythroblastopenia of childhood, and cyclic neutropenia.
* Assignment of the patient s physical findings to other syndromes or causes that are not part of the IBMFS disease spectrum.
* Inability of the participant or LAR to understand and be willing to sign a written informed consent document.
* Unwillingness to permit access to medical records and pathology specimens.

There are no other exclusion parameters not related to the primary disease.

-Unaffected/Family Members: An individual who meets any of the following criteria will be excluded from participation in this study:

* If there is no affected individual in the family who meets the inclusion criteria
* Inability of the participant or LAR to understand and be willing to sign a written informed consent document.
* Unwillingness to permit access to medical records and pathology specimens.

• BACKGROUNDVlachos A, Rosenberg PS, Atsidaftos E, Alter BP, Lipton JM. Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood. 2012 Apr 19;119(16):3815-9. doi: 10.1182/blood-2011-08-375972. Epub 2012 Feb 23. PMID 22362038
• BACKGROUNDAlter BP, Rosenberg PS, Giri N, Baerlocher GM, Lansdorp PM, Savage SA. Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica. 2012 Mar;97(3):353-9. doi: 10.3324/haematol.2011.055269. Epub 2011 Nov 4. PMID 22058220
• BACKGROUNDAlter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018 Jan;103(1):30-39. doi: 10.3324/haematol.2017.178111. Epub 2017 Oct 19. PMID 29051281
• DERIVEDNiknafs AM, Giri N, Niewisch MR, Savage SA. Avascular Necrosis and Minimal Trauma Fractures in Telomere Biology Disorders. Clin Genet. 2026 Feb;109(2):286-293. doi: 10.1111/cge.70038. Epub 2025 Aug 5. PMID 40762130
• DERIVEDThompson AS, Niewisch MR, Giri N, McReynolds LJ, Savage SA. Germline RTEL1 Variants in Telomere Biology Disorders. Am J Med Genet A. 2025 Feb;197(2):e63882. doi: 10.1002/ajmg.a.63882. Epub 2024 Sep 16. PMID 39279436
• DERIVEDRaj HA, Lai TP, Niewisch MR, Giri N, Wang Y, Spellman SR, Aviv A, Gadalla SM, Savage SA. The distribution and accumulation of the shortest telomeres in telomere biology disorders. Br J Haematol. 2023 Dec;203(5):820-828. doi: 10.1111/bjh.18945. Epub 2023 Jun 24. PMID 37354000
• DERIVEDBourke G, Wilks D, Kinsey S, Feltbower RG, Giri N, Alter BP. The incidence and spectrum of congenital hand differences in patients with Fanconi anaemia: analysis of 48 patients. J Hand Surg Eur Vol. 2022 Jul;47(7):711-715. doi: 10.1177/17531934221087521. Epub 2022 Mar 31.