There is no age restriction; therefore, viable neonates may be included. This eligibility
screening protocol is intended for individuals meeting one or more of the following
criteria:
1. Personal or family history of a diagnosis of a syndrome being actively investigated
in one of the following CGB study protocol:
- - Protocol 000678: Medical history of neoplasia of an unusual type, pattern, or
number.
- - Protocol 11C0255: A personal history of adrenal cortical carcinoma or choroid
plexus carcinoma at any age, regardless of family history, or family or
personal medical history of neoplasia consistent with the diagnosis of LFS or
LFL.
- - Protocol 20C0107: Individuals with a clinical diagnosis of a RASopathy,
including Costello syndrome, Noonan syndrome, Noonan syndrome with multiple
lentigines, Cardiofaciocutaneous syndrome, Legius syndrome, capillary
arteriovenous malformation syndrome, or others, are eligible.
Published
clinical diagnostic criteria exist for most of the clinical RASopathy syndromes
and differ by syndrome. It will be uncommon for individuals to have a clinical
diagnosis and not have had molecular genetic testing. All individuals
considered by the study team to be at risk for a RASopathy who have not had
prior genetic testing will have this completed as part of the study. The rare
individuals with a clinical diagnosis of a RASopathy who are not found to carry
a corresponding pathogenic or likely pathogenic variant in a known RASopathy
gene will be considered for exome analysis for identification of potentially
novel RASopathy germline variation.
- - Protocol 11C0034: An individual with histologically-confirmed PPB and/or other
DICER1-related tumors.
- - Protocol 02C0052: 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.
- - Protocol 02C0211: Personal medical history of melanoma of an unusual type,
pattern, or number diagnosed at any age.
- - Protocol 78C0039: Family or personal medical history of neoplasia of an unusual
type, pattern, or number.
2. Personal or family history of medical condition, malignancy, and/or benign neoplasm
suggestive of hereditary cancer predisposition being actively investigated in the
following CGB study protocol:
- - Protocol 000678: Known or suspected factor(s) predisposing to neoplasia, either
genetic and/or congenital factors (birth defects, metabolic phenotype,
chromosomal anomalies or Mendelian traits associated with tumors),
environmental exposure (medications, occupation, radiation, diet, infectious
agents, etc.), or unusual demographic features (very young age of onset,
multiple tumors, etc.)
- Protocol 11C0255: An individual with a sarcoma diagnosed under the age of 45;
AND - At least one first-degree relative (parents, brothers, sisters and
children) with a cancer of any kind diagnosed under the age of 45; AND - A
third family member who is either a first- or second-degree relative (such as
grandparents, aunts, uncles, nieces, nephews, and grandchildren) with cancer
diagnosed under the age of 45 or having a sarcoma at any age.
- - Protocol 001109: On referral, persons >= 12 years with Fanconi Anemia (FA)
primarily from North America will be included.
An individual with FA who is 8
-11 years can also be included if they have a history of persistent oral
potentially malignant lesion (OPMLs), dysphagia, or other concerning symptoms.
Individuals with prior cancer diagnosis are eligible.
- - Protocol 11C0034: An individual from the general population with one or more of
the unique tumors of the types associated with DICER1 including (but not
exclusively), PPB, cystic nephroma, ovarian Sertoli-Leydig cell and other sex
cordstromal tumors, ocular medulloepithelioma, nasal chondromesenchymal
hamartoma, Wilms tumor, embryonal rhabdomyosarcoma, pineoblastoma, pituitary
blastoma, ovarian sarcoma, CNS sarcoma and/or thyroid cancer - regardless of
their family history.
Additional DICER1-related neoplasms may be identified in
the future, and they will be added to the protocol as needed.
- - Protocol 02C0052: Fanconi anemia: FA patients have relatively specific birth
defects, aplastic anemia, increased chromosome breakage in cells cultured with
a DNA crosslinking agent such as mitomycin C (MMC) or diepoxybutane (DEB),
pathogenic variant(s) in one of the cloned genes (six genes at this time), or
assignment to one of the 7 or more complementation groups.
Bone marrow failure
is NOT required for the diagnosis, and approximately 25% do not have birth
defects. FA has been diagnosed from birth to >50 years of age. FA Proven =
positive chromosome breakage result, and/or pathogenic variant(s) in a known
FANC gene. Patients in whom FA is suspected but whose chromosome breakage test
is negative will still be considered if they have sufficient findings that lead
the Principal Investigator to think they may be somatic mosaics and warrant
further evaluation. Diamond Blackfan anemia: DBA patients have pure red cell
aplasia with reticulocytopenia. Approximately 30% have physical abnormalities,
often involving malformations of the thumbs. Approximately 90% are diagnosed
within the first year of life. A pathogenic variant in a known DBA gene (RPS19
is currently the only known gene) is diagnostic, but lack of a pathogenic
variant does not rule out DBA, since the cloned gene is responsible for only
approximately 25% of the disease. Since many cases are sporadic or occur in
families with silent carriers, patients without a positive family history will
be included. Currently DBA is diagnosed by clinical findings after exclusion of
known causes of red cell aplasia. Approximately 90% have elevated red cell
adenosine deaminase levels, a finding which is supportive, but not diagnostic,
of DBA. Dyskeratosis congenita: DC patients develop dyskeratotic nails, lacy
hyperpigmentation of the skin and mucous membrane leukoplakia as they age (the
diagnostic clinical triad; two of the three are required for a firm diagnosis).
Findings in young patients may be very subtle, and diagnoses are usually made
in teenagers or young adults. More than 75% are male. DC patients are often
diagnosed without hematologic abnormalities by dermatologists; however, some
patients present with aplastic anemia prior to the evolution of the
syndrome-related physical features. A pathogenic variant in the DKC1 gene is
diagnostic, but normal DKC1 does not exclude DC. The diagnosis is often
clinical, after exclusion of FA and other IBMFS. Shwachman Diamond Syndrome:
SDS patients have neutropenia, malabsorption and failure to thrive due to
exocrine pancreatic insufficiency. The gene has not yet been cloned. Pancreatic
insufficiency is documented by direct measurement of pancreatic enzymes, low
serum immunoreactive trypsinogen, or elevated fecal fat levels. Neutropenia
requires an absolute neutrophil count of <1500/mm3 on multiple occasions. Other
causes of malabsorption such as cystic fibrosis, Pearson syndrome, and
Johansson-Blizzard syndrome must be excluded. Cystic fibrosis will be excluded
in patients who have a positive sweat test performed at an approved CF center.
Amegakaryocytic thrombocytopenia: These patients have early onset
thrombocytopenia (<150,000/mm3), usually within the first year of life, due to
absent, diminished, or abnormal bone marrow megakaryocytes, without
antiplatelet antibodies. Physical examination is often normal; in particular,
there are no abnormalities of the radial rays. Pathogenic variant(s) in the MPL
gene are diagnostic, but normal MPL does not exclude this diagnosis.
Thrombocytopenia absent radii: TAR patients have absent radii, usually
bilateral, with intact thumbs (in contrast with FA and trisomy 18, where thumbs
are absent if radii are absent), and thrombocytopenia at birth. Other radial
aplasia syndromes such as Holt-Oram syndrome or VATER syndrome must be
excluded. Severe Congenital Neutropenia: Patients with SCN have persistent and
noncyclic low absolute neutrophil counts, with more than 2 measurements
<200/mm3, and a history of pyogenic infections during the first year of life,
and bone marrow maturation arrest at the promyelocyte/myelocyte stage. They do
not have birth defects, and they usually have normal hemoglobin and platelet
counts. They are designated Kostmann Syndrome (KS) only if there is a pattern
of autosomal recessive inheritance. Pathogenic variant(s) in the neutrophil
elastase gene (ELA2) are supportive of the diagnosis of SCN, but do not
distinguish SCN patients from those with cyclic neutropenia, which is milder
and not preleukemic. Many of the cases of SCN have been shown to be due to
dominant pathogenic variant(s)s in ELA2. Pearson Syndrome: Pearson syndrome
consists of malabsorption, neutropenia, alone or with anemia and/or
thrombocytopenia, and metabolic acidosis. Onset is in infancy or early
childhood. The diagnosis is strongly suspected if bone marrow examination
reveals vacuoles in myeloid and erythroid progenitors, and ring sideroblasts.
Confirmation derives from detection of deletions in mitochondrial DNA, which
range from 2 to 8 kb in size, and include the respiratory enzymes. Absence of
reports to date of cancer or leukemia in this syndrome may derive from early
death due to the metabolic problems. Other bone marrow failure syndromes: There
are occasional patients with a pattern of hematologic abnormalities, physical
findings, malignancies, or family histories which are not characteristic of the
syndromes described above, but which nonetheless suggests that they have a
genetic bone marrow failure syndrome. There may be similar cases in the
literature, or in the experience of the investigator, which may ultimately lead
to assignment of these patients to a known or new syndrome. There are
additional bone marrow failure syndromes which are even more rare, such as
Revesz, WT, IVIC, radio-ulnar synostosis, ataxia-pancytopenia, etc. Syndromic
classification of extremely rare disorders is facilitated if they are collected
in one center. Since malignancy is often part of these syndromes, they will be
eligible for enrollment in this protocol.
- - Protocol 02C0211: Known or suspected factor(s) predisposing to melanoma, either
genetic or congenital factors (giant congenital nevi, dysplastic nevi, Spitzoid
tumors), or unusual demographic features (e.g., very young age of onset,
multiple melanomas, previous history of heritable retinoblastoma, Hodgkin's
disease, lymphoma, immunodeficiency syndrome, or organ transplant).
- - Protocol 10CN188: Diagnose with chordoma or related tumor at any age and any
primary site.
- - Protocol 78C0039: Known or suspected factor(s) predisposing to neoplasia,
either genetic and/or congenital factors (birth defects, metabolic phenotype,
chromosomal anomalies or Mendelian traits associated with tumors),
environmental exposure (medications, occupation, radiation, diet, infectious
agents, etc.), or unusual demographic features (very young age of onset,
multiple tumors, etc.).
Personal and family medical history must be verified
through questionnaires, interviews, and review of pathology slides and medical
records. For familial neoplasms, two or more living affected cases among family
members are required. The types of familial tumors that we are currently
actively accruing include Familial Cancers: bladder, brain, chordoma, lung,
nevoid basal cell carcinoma syndrome (NBCC) Familial Benign Neoplasms:
meningiomas, neurofibromatosis 2 (bilateral acoustic neurofibromatosis) The
types of familial tumors under active accrual and study are predominantly
investigator- and hypothesis-driven. This approach permits CGB investigators to
remain alert to the opportunities afforded by clusters of rare tumors in
families and individuals, and to be more responsive to the dynamic research
priorities in cancer genetics.
3. Personal or family history of a genetic variant in a hereditary cancer
predisposition being actively investigated in the following CGB study protocols:
- - Protocol 11C0255: A personal history of a germline TP53 mutation; or, - A first
or second- degree relative of a TP53 mutation carrier, regardless of mutation
status.
- - Protocol 20C0107: Individuals with a germline variant (P/LP or a variant of
uncertain significance but predicted bioinformatically to be damaging) in a
RASopathy-associated gene are eligible.
These include but are not limited to:
BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, MAP3K8, MRAS, NRAS, PPP1CB,
PTPN11, RAF1, RASA1, RASA2, RIT1, RRAS, SHOC2, SOS1, SPRED1. From herein, we
refer to 1) individuals with germline pathogenic variation in a RAS pathway
gene AND 2) individuals with a clinical RASopathy diagnosis but in whom a
genetic variant has not yet been identified as "carriers." The first member of
a family to be identified is termed a "proband."
- - Protocol 11C0034: An individual with a known or suspected DICER1 disease
associated variant.
- - Protocol 02C0052: An individual with a pathogenic variant(s) in a known FANC
gene.
Individual with Diamond Blackfan Anemia with a pathogenic variant in a
known DBA gene (RPS19). Individuals with Dyskeratosis congenita with a
pathogenic variant in the DKC1 gene. Individuals with Amegakaryocytic
thrombocytopenia with pathogenic variants) in the MPL gene. Individuals with
Severe Congenital Neutropenia with a pathogenic variant(s) in the neutrophil
elastase gene (ELA2).
EXCLUSION CRITERIA.While this protocol is intended to be used by those meeting the inclusion criteria above,
there are no explicit exclusion criteria for this study, since the initiative to complete
the eligibility screener survey is at the will of the participant or his or her
parent/guardian/LAR.
