This study will establish a cohort (a group of people followed over time) of patients and families affected by an inherited bone marrow failure syndrome (IBMFS) that may predispose them to leukemia or other cancers. These syndromes include Fanconi's anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Pearson's syndrome, amegakaryocytic thrombocytopenia, thrombocytopenia absent radii, dyskeratosis congenita, and others. The study will try to identify the types of cancer the patient may be at risk for; measure the rates at which these cancers develop; look for early indicators of cancer; determine what distinguishes family members who develop cancer from those who do not; try to identify new genes that may be involved in causing IBMFS; compare the biology of cancers in patients and family member with IBMFS with the same cancers in people without IBMFS; evaluate the medical condition of affected family members and offer recommendations for future health care and cancer risk reduction; and evaluate whether carriers of just one abnormal gene develop significant health problems. (A carrier is someone who has only one altered gene for a disease that requires two altered genes to cause illness.) This study does not involve treatment.

Patients with an IBMFS and their family members are eligible for this study. Participants must provide written permission for the study investigators to 1) obtain medical records and pathology material (tissue samples) from hospitals or clinics where the patient has been treated for blood diseases, tumors, cancer, birth defects, or other illnesses; and 2) obtain medical records and pathology materials from deceased relatives for whom the patient or family member is the legally authorized representative. Participants will complete a family history questionnaire and individual information questionnaire at the start of the study and provide updates annually. In addition, the following tissue samples may be requested: blood or cheek cells, tissue from a scheduled bone marrow procedure, and tumor tissue from prior biopsies or cancer surgeries. Instructions for sending specimens will be provided. Additional samples for research may be requested over time as tests or surgeries are done as part of the patient's standard medical care.

Patients who agree to participate in a second part of this study will travel to the NIH Clinical Center for a comprehensive clinical and laboratory evaluation and screening for cancer or pre-cancerous conditions. The evaluation will include a detailed medical history, complete physical examination, cancer screening, and routine tests that are part of the standard medical management of persons with, or at risk of, the particular disorder. These include blood drawing, bone marrow aspirate and biopsy, urinalysis, stool examination, diagnostic X-rays and scans, and biopsies of tumors or pre-cancerous sites. In addition, special consultations may be requested depending on the individual's medical condition. These may include audiology, cardiology, social work, dentistry, dermatology, endocrinology, gastroenterology, gynecology, hematology, nephrology (kidney), neurology, ophthalmology, otorhinolaryngology (ear, nose and throat), physiatry, radiology and nuclear medicine and urology.

Finally, patients and family members may choose to participate in a part of the study to identify the specific genetic alteration (mutation) responsible for the IBMFS affecting them in order to learn whether knowing the mutation makes it possible to predict 1) the severity of disease or 2) which medical problems that can arise with the disorder are likely to affect a given patient. Genetic testing will be done on tissue samples already provided for the study, and confirmed on new samples. Patients and family members who want to learn the results of the genetic tests will receive face-to-face genetic counseling either at the NIH Clinical Center or from a counselor in their home community.

Condition
Fanconi's Anemia Anemia, Diamond-Blackfan Dyskeratosis Congenital Thrombocytopenia Neutropenia

This project will identify Inherited Bone Marrow Failure Syndromes (IBMFS) families for studies of mechanisms of human carcinogenesis, and for investigation of the pathogenesis of neoplastic complications of these diseases. These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer. The prototype disorder is Fanconi's Anemia (FA); other IBMFS will also be studied.

Hypothesis 1: A prospective cohort of IBMFS families will provide new information regarding cancer rates and types in these disorders.

Hypothesis 2: Mutations in IBMFS genes are relevant to carcinogenesis in sporadic cancers.

Hypothesis 3: Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer.

Hypothesis 4: Carriers of IBMFS gene mutations (i.e. heterozygotes) are at increased risk of cancer.

The primary objectives are to:

1) determine the types and incidence of specific cancers in IBMFS;

2) investigate the relevance of IBMFS gene mutations in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers;

3) identify risk factors for IBMFS-related cancers in addition to the primary germline mutations;

4) determine the risk of cancer in IBMFS carriers [heterozygotes].

The secondary objectives are to:

1) identify a large North American cohort with confirmed IBMFS;

2) collect cancer risk factor information;

3) perform clinical and laboratory evaluations and cancer screening of family members;

4) to verify diagnoses from medical records and laboratory tests including genotyping where available;

5) to provide the results of germline mutation testing of the IBMFS genes to study participants who desire such information.

6) compare tumor specimens from patients with cancers in the same tissues from the general population;

7) compare myelodysplastic syndrome (MDS) in IBMFS patients with sporadic MDS;

8) examine germline and tumor specimen DNAs for IBMFS mutations from individuals not previously diagnosed with a IBMFS if they have atypical tumors, without usual risk factors;

9) identify exposures in IBMFS patients with cancer that differ from those without cancer;

10) compare genotypes and phenotypes of those with and without cancer;

11) assess the epidemiologic profile of cancer in family members;

12) investigate the behavioral and psychosocial consequences of living in a family affected by IBMFS; and

13) employ new cellular and molecular technologies to achieve these objectives.

The study population will comprise all interested North American patients with IBMFS. This is a natural history study, involving clinical evaluations, clinical and research laboratory tests, cancer surveillance, and questionnaires. The 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 myelodysplastic syndrome or cytogenetic clones.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA - PATIENTS:
Fanconi's anemia.
Diamond-Blackfan anemia.
Dyskeratosis congenita.
Shwachman-Diamond Syndrome.
Amegakaryocytic thrombocytopenia.
Thrombocytopenia absent radii.
Severe congenital neutropenia.
Pearson's Syndrome.
Other bone marrow failure syndromes.
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, specifically for Hypothesis 4.
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).
INCLUSION CRITERIA - UNAFFECTED SIBLING STUDY:
Eligibility for this amendment will be assessed only after the subject has been deemed eligible for the parent protocol.
Abiliy to read, write, and speak in English.
Between the ages of 11 & 21.
Informant has at least one biologically related, living sibling (full or half) who has FA.
EXCLUSION CRITERIA - PARENT PROTOCOL:
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 physical findings to other syndromes or causes that are not part of the IBMFS disease spectrum.
Inability or unwillingness to complete the questionnaires or permit access to medical records and pathology specimens.
There are no other exclusion parameters not related to the primary disease.
EXCLUSION CRITERIA - UNAFFECTED SIBLING STUDY:
Diagnosis of FA or any other chronic illness.
Cognitive impairment or inability to express feelings or experiences verbally or inability to provide informed consent.
Emotional distress at the time of the interview.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  020052; 02-C-0052
Record last reviewed:  November 1, 2003
Last Updated:  November 1, 2003
Record first received:  November 29, 2001
ClinicalTrials.gov Identifier:  NCT00027274
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-10-29