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Concise Handbook of Familial Cancer Susceptibility
Second Edition
Noralane M. Lindor, Mary L. McMaster, Carl J. Lindor, Mark H. Greene TABLE







1. Ataxia Telangiectasia (includes Ataxia Telangiectasia
Complementation Groups A, C, D, E, Louis–Barr
2. Basal Cell Nevus Syndrome, Nevoid Basal Cell
Carcinoma Syndrome, or Gorlin Syndrome
3. Beckwith–Wiedemann Syndrome
(Exomphalos–Macroglossia–Gigantism Syndrome)
4. Birt–Hogg–Dubé Syndrome
5. Bloom Syndrome
6. Breast/Ovarian Cancer, Hereditary (BRCA1)
7. Breast/Ovarian Cancer, Hereditary (BRCA2)
8. Carney Complex, Types I and II (formerly known as
NAME Syndrome [Nevi, Atrial Myxoma, Myxoid
Neurofibromata, and Ephelides] and LAMB Syndrome
[Lentigines, Atrial Myxomata, Mucocutaneous Myxoma,
Blue Nevi])
9. Chordoma, Familial
10. Colon Cancer, Hereditary Nonpolyposis–Lynch
Syndrome (includes Lynch Syndrome, Hereditary
Mismatch Repair Deficiency Syndrome, Muir–Torre
Syndrome, and a subset of Turcot Syndrome)
11. Costello Syndrome; Facio–Cutaneous–Skeletal Syndrome 12. Cowden Syndrome (Multiple Hamartoma Syndrome;
PTEN Hamartoma Tumor Syndrome)
13. Dyskeratosis Congenita
14. Esophageal Cancer, Tylosis with; Keratosis Palmaris
et Plantaris with Esophageal Cancer; Howel–Evans
15. Exostosis, Hereditary Multiple (includes Type 1,
Type 2, Type 3, and Multiple Osteochondromas
16. Fanconi Anemia
17. Gastric Cancer, Hereditary Diffuse
18. Gastrointestinal Stromal Tumor; also Multiple
Gastrointestinal Autonomic Nerve Tumors
19. Hyperparathyroidism, Familial (includes Familial Isolated Hyperparathyroidism and Familial Hyperparathyroidism
with Multiple Ossifying Jaw Fibromas (aka Hereditary
Hyperparathyroidism-Jaw Tumor Syndrome); Familial
Cystic Parathyroid Adenomatosis)
20. Leukemia, Acute Myeloid, Familial
21. Leukemia, Chronic Lymphocytic, Familial
22. Li–Fraumeni Syndrome, including Li-Fraumeni-Like


Journal of the National Cancer Institute Monographs, No. 38, 2008







23. Lymphoma, Hodgkin, Familial
24. Lymphoma, Non-Hodgkin, Familial
25. Melanoma, Hereditary Multiple (includes Dysplastic
Nevus Syndrome, Familial Atypical Mole–Malignant
Melanoma Syndrome, Melanoma–Pancreatic Carcinoma
Syndrome, Melanoma–Astrocytoma Syndrome, Familial
Uveal Melanoma)
26. Mosaic Variegated Aneuploidy
27. Multiple Endocrine Neoplasia Type 1 (MEN1; Wermer
Syndrome; includes Zollinger–Ellison [Z–E]
Syndrome; also Multiple Endocrine Neoplasia Type 1B
[MEN 1B] noted)
28. Multiple Endocrine Neoplasia Type 2A, 2B
(Sipple Syndrome), and Familial Medullary Thyroid
29. Multiple Myeloma, Familial
30. Neuroblastoma, Hereditary
31. Neurofibromatosis Type 1 (NF1; includes von
Recklinghausen Disease)
32. Neurofibromatosis Type 2 (sometimes called
Central Neurofibromatosis or Bilateral Acoustic
33. Nijmegen Breakage Syndrome (formerly called
Ataxia Telangiectasia Variant or AT-V1; includes
Berlin Breakage Syndrome, formerly called AT-V2)
34. Pancreatic Cancer, Hereditary
35. Paraganglioma, Hereditary
36. Peutz–Jeghers Syndrome
37. Polyposis, Familial Adenomatous (includes
Gardner Syndrome, Familial Multicentric Fibromatosis
and/or Hereditary Desmoid Disease, and a subset of
Turcot Syndrome)
38. Polyposis, Familial Juvenile (includes Hereditary
Mixed Polyposis Types 1 and 2)
39. Polyposis, MYH-Associated (MAP)
40. Prostate Cancer, Hereditary








Affiliations of authors: Department of Medical Genetics, Mayo Clinic, Rochester, MN (NML); Genetic Epidemiology Branch (MLM) and Clinical Genetics Branch (MHG), Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Correspondence to: Noralane M. Lindor, MD, Mayo E7B, Department of Medical Genetics, Mayo Clinic, Rochester, MN 55902 (e-mail: [email protected] edu).
See “Funding” and “Notes” following “References.” DOI: 10.1093/jncimonographs/lgn001
© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected]


41. Renal Cell Carcinoma, Hereditary, with
Multiple Cutaneous and Uterine Leiomyomas (HLRCC;
Reed Syndrome)
42. Renal Cell Carcinoma, Hereditary (used here to
apply only to Familial Nonpapillary, Clear Cell or
Conventional Cell, or Clear Cell Adenocarcinoma
of the Kidney)
43. Renal Cell Carcinoma, Hereditary Papillary
44. Retinoblastoma, Hereditary
45. Rhabdoid Predisposition Syndrome (includes Brain
Tumors in Infancy, Familial Posterior Fossa Tumors,
and Renal Rhabdoid Tumors)
46. Rothmund–Thomson Syndrome
47. Simpson–Golabi–Behmel Syndrome (SGBS)
48. Testicular Germ Cell Tumor, Familial






49. Thyroid Carcinoma, Familial Non-medullary (includes
Papillary Thyroid Carcinoma with Papillary Renal
50. Tuberous Sclerosis Complex
51. von Hippel–Lindau Syndrome
52. Waldenström Macroglobulinemia, Familial
53. Werner Syndrome (includes Adult Progeria)
54. Wilms Tumor, Familial (excludes Beckwith–
Weidemann Syndrome and Other Overgrowth
55. Xeroderma Pigmentosum (DeSanctis–Cacchione
Syndrome; includes Complementation Groups A–G
and XP Variant)
Appendix 1





Journal of the National Cancer Institute Monographs, No. 38, 2008

More than 10 years have passed since we first attempted to develop a clinically accessible catalog of recognizable family cancer syndromes (1). Our sense at that time was that we were on the brink of an avalanche of information regarding the inherited basis of human neoplasia and that the clinical consequences of these novel molecular insights threatened to overwhelm both health-care providers and their patients. We attempted to distill currently available data related to the most common genetically determined cancer susceptibility syndromes into a format that would make this arcane knowledge more readily accessible to busy clinicians who only occasionally needed this information. It seemed inevitable that, as the number of disorders for which germline mutation testing for cancer susceptibility increased, the need for a better understanding of how to approach these challenging clinical problems would follow.

And so it has. It is now increasingly routine to undertake a cancer genetics risk assessment, which includes the option of germline mutation testing for one or more relevant genes, for an astonishing array of disorders.

Experience over the past several decades has demonstrated,
unequivocally, that the study of rare familial clusters is a remarkably productive scientific and clinical enterprise. These data have identified multiple new susceptibility genes, defined the clinical phenotype of specific disorders more precisely, and have informed our understanding of the pathogenesis of hereditary and nonhereditary cancers at the individual, population, and laboratory levels. For example, recognition of the Li– Fraumeni syndrome provides a vivid illustration of how the

identification of familial clusters of childhood sarcomas and breast cancer ultimately led to the identification of germline mutations in the p53 tumor suppressor gene as the genetic basis for this disorder, thereby providing seminal insights from clinical cancer genetics to the molecular biology of both inherited and sporadic cancers (2–6).

Progress begets new challenges. Previously unfamiliar concepts related to clinical genetics are now being integrated into the information base used by diverse health-care providers, most of whom have no formal training in genetics. The need has

never been greater for clinicians to be well grounded in the biological and molecular bases of the diseases which they encounter and to become familiar with related new clinical issues, including predictive risk assessment, genetic counseling, germline mutation testing for clinical decision making, the duty to warn at-risk relatives vs their high-risk patients’ right to privacy and confidentiality and, most importantly, the need for evidencebased, safe, and effective management recommendations for high-risk individuals. Proposed elements of informed consent related to testing for inherited cancer susceptibility are set forth in Table 1.

The advent of syndrome-specific germline mutation testing
represents a major advance in the care of cancer-prone individuals. But, in the process of focusing on the molecular biology of human cancer susceptibility, the importance of taking a thoughtful family history cannot be emphasized sufficiently. Because the pace, complexity, and sophistication of medical practice have Journal of the National Cancer Institute Monographs, No. 38, 2008

Table 1. Basic elements of informed consent for cancer
susceptibility testing (7)
1. Information on the specific genetic test being performed. 2. Implications of a positive and negative result.
3. Possibility that the test will not be informative.
4. Options for risk estimation without genetic testing.
5. Risk of passing a mutation to children.
6. Technical accuracy of the test.
7. Fees involved in testing and counseling.
8. Psychological implications of test results (benefits and risks). 9. Risks of insurance or employer discrimination.
10. Confidentiality issues.
11. Options and limitations of medical cancer risk management and strategies for prevention following testing.
12. Importance of sharing genetic test results with at-risk relatives so that they may benefit from this information in making their own health-care decisions.

accelerated, the decidedly low-tech but nonetheless invaluable family history often receives short shrift, depriving both the patient and the health-care provider of information that might have a substantial impact on clinical decisions and patient outcome. In one survey of 100 unselected colorectal cancer patients, the medical record contained a family history in only 46% of subjects and, of those, only 80% were accurate (8). Taking an appropriately focused family history must receive increased emphasis in the course of daily practice. The Family History Public Health Initiative of the US Center for Disease Control and Prevention ( recognizes and promotes this need (9).

Learning the clinical features that suggest the possibility of an underlying genetic predisposition to cancer is another, easily mastered diagnostic tool (Table 2). These guidelines are not infallible but, when used to guide the collection of family history data, they have been proven to be clinically useful.

Because much of our risk assessment and clinical decision making rests on empirical studies of self-reported, unverified family history, a brief comment regarding these data is warranted.
Diagnosis accuracy varies considerably, depending on the age, gender, and cancer status of the respondent, the primary site of cancer origin, the degree of relatedness between the respondent and the relative of interest, the vital status of the affected relative, and the recentness of the reported cancer diagnosis (11,12). In general, reported breast and colorectal cancer diagnoses are quite accurate, whereas cancer “sites” that are vaguely defined (eg, organs in the female pelvis) or which represent tissues commonly involved with metastatic disease (eg, brain, liver, bone, and lung) are often incorrect (13). The predictive value of a negative cancer report (eg, “my mother did NOT have cancer”) is very high. The accuracy of reports from first-degree relatives is substantially better than for second-degree relatives; information from more distant relatives is of such poor quality that it is of questionable value in routine practice.

Genetic risk assessment in the context of childhood cancer represents another specific setting in which a meticulous clinical evaluation often provides essential information upon which to base a syndromic diagnosis. An elegant and detailed evaluation of the prevalence and patterns of morphological abnormalities in nearly 3

Table 2. Features that suggest the presence of a hereditary cancer predisposition [modified from Weber et al. (10)] In the individual patient

In the patient’s family

• One first-degree relative with the same or a related tumor and one of the individual features listed
• ≥ two first-degree relatives with tumors of the same site • ≥ two first-degree relatives with tumor types belonging to a known familial cancer syndrome
• ≥ two first-degree relatives with rare tumors
• ≥ two relatives in two generations with tumors of the same site or etiologically related sites

Multiple primary tumors in the same organ
Multiple primary tumors in different organs
Bilateral primary tumors in paired organs
Multifocality within a single organ
Younger-than-usual age at tumor diagnosis
Rare histology
In the sex not usually affected
Associated with other genetic traits
Associated with congenital defects
Associated with an inherited precursor lesion
Associated with another rare disease
Associated with cutaneous lesions known to be related to
cancer susceptibility disorders (eg, the genodermatoses)

1100 consecutive pediatric cancer patients resulted in the identification of confirmed cancer susceptibility syndromes in 42 (3.9%) patients and suspected syndromes in an additional 35 (3.3%). Half of the proven disorders had been missed before the study-related physical examination, leading the authors to recommend that all children with cancer should be examined by either a clinical geneticist or a pediatrician skilled in the clinical dysmorphology examination (14,15). Thus, even in this postgenomic world, the need for input from a skilled clinician remains essential to the cancer risk assessment enterprise. Much of the data that form the basis of our understanding of hereditary cancer syndromes are derived from evaluation of highly selected families. The inability to characterize the population from which such families are ascertained imposes major constraints on one’s ability to generalize these observations, particularly in estimating cancer risk. Alternatively, population-based analyses may produce results that are generalizable to the population that was studied, as well as being large enough to produce statistically reliable risk estimates, even for relatively rare cancers. Populationbased registries are particularly useful in assessing magnitude of familial risk, as opposed to risks associated with specific hereditary cancer syndromes, and for most patients with a “family history of cancer,” these risks are most relevant in clinical decision making. Single-gene hereditary syndromes account for only a small fraction of familial clustering on a population basis. The Utah Population Database (16) and the Swedish Family-Cancer Registry (17) have been explored systematically in an effort to improve the level of evidence related to the magnitude of familial cancer risk. A sample of the data available from these two registries is shown in Table 3, which summarizes the familial relative risk (FRR) of selected cancers among first-degree relatives of probands with a specified malignancy. The pattern of risks by site is similar between the Utah and the Swedish data, with FRRs in the range of

The Utah data were analyzed by age at cancer diagnosis in
the proband, and they show substantially increased FRRs among relatives of probands with early-onset cancer, consistent with the clinical clues to an inherited cancer susceptibility disorder. For example, the FRR for breast cancer is 1.8 overall but

3.7 among the relatives of women whose breast cancer was
diagnosed at age younger than 50 (Table 3). The Swedish

Family-Cancer Registry has generated data regarding the population-attributable fraction (PAF) related to site-specific familial cancer susceptibility in Sweden (see the final column in Table 3) (19). The PAF is the proportion of cases that is exposed to the risk factor of interest (here, positive family history of a particular cancer), and it represents that fraction of cases that could be prevented if the risk factor were completely eliminated. These data provide substantial support for the claim that familial and inherited factors account for a relatively small proportion of any specific malignancy. For most sites, the PAF is between

Table 3. Familial relative risks and population attributable fraction of the same cancer among first-degree relatives of cancer
probands by primary cancer site [modified from Risch (18)]a
Utah (16)

Sweden (17,19)

(total) onset) (child) (sibling) PAF (%)

Urinary bladder
Non-Hodgkin lymphoma
Brain and/or CNS
Multiple myeloma
Hodgkin lymphoma
Soft tissue sarcoma
Total, mean
Total, median

















= familial relative risk; PAF = population attributable risk; CNS = central nervous system. Cancers listed in order of decreasing population prevalence in Utah.


onset: age G allele (10). It
has been suggested that, while individual variants in specific DNA repair-related genes (ATM, BRCA1, and BRCA2) may be associated with undetectable levels of breast cancer risk even in adequately powered studies, increasing total numbers of SNPs in these genes might, in the aggregate, make a substantial contribution to cancer risk (Ptrend = 0.0004; OR for ≥3 SNPs = 3.2, P = 0.001) (11). Cancer risk management: There is no proven cancer reduction strategy for those with AT. The role of intensive mammographic surveillance for breast cancer in heterozygotes is unclear, in light of the demonstrated clinical sensitivity to ionizing radiation in this disorder. Breast MRI offers a theoretically attractive alternative screening strategy in this setting, but there are no data yet available to support its use.

Comments: AT patients are unusually sensitive to ionizing
radiation and some radiomimetic chemotherapy agents. Treatment of cancer with conventional doses of radiation can be fatal. References
1. Sun X, Becker-Catania SG, Chun HH, et al. Early diagnosis of ataxiatelangiectasia using radiosensitivity testing. J Pediatr. 2002;140(6):724–731. 2. Koksal Y, Caliskan U, Yurtcu M, Artac H, Ilerisoy-Yakut Z, Reisli, I. Dysgerminoma in a child with ataxia-telangiectasia. Pediatr Hematol Oncol. 2007;24:431–436.

3. Taylor AM, Byrd PJ. Molecular pathology of ataxia telangiectasia. J Clin Pathol. 2005;58(10):1009–1015.
4. Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med. 1987;316(21): 1289–1294.
5. Olsen JH, Hahnemann JM, Borresen-Dale AL, et al. Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br J Cancer. 2005;93(2):260–265. 6. Thompson D, Duedal S, Kirner J, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005;97(11): 813–822.

7. Liberzon E, Avigad S, Stark B, et al. Germ-line ATM gene alterations are associated with susceptibility to sporadic T-cell acute lymphoblastic leukemia in children. Genes Chromosomes Cancer. 2004;39(2):161–166. 8. Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxiatelangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006; 38(8):873–875.

9. Pylkas K, Tommiska J, Syrjakoski K, et al. Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer. Carcinogenesis. 2007;28(5):1040–1045.

10. Bernstein JL, Teraoka S, Southey MC, et al. Population-based estimates of breast cancer risk associated with ATM variants c.7271T>G and c.10666T>G from the Breast Cancer Family Registry. Hum Mutat. 2006; 27(11):1122–1128.

11. Johnson N, Fletcher O, Palles C, et al. Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet. 2007;16(9):1051–1057.

2. Basal Cell Nevus Syndrome, Nevoid Basal Cell
Carcinoma Syndrome, or Gorlin Syndrome
OMIM number: 109400; 601309.
Inheritance pattern: Autosomal dominant.
Gene and chromosomal location: Basal cell nevus syndrome
(BCNS) is caused by mutations in PTCH at 9q22.3.
Mutations: Multiple unique PTCH mutations have been
reported, but no clinically significant genotype–phenotype correlations were noted. Mutations are detected in 60%–85% of individuals meeting diagnostic criteria. Twenty to forty percent of 18

cases represent de novo germline mutations. Rarely, cytogenetically detectable deletions of chromosome 9q have been reported. Incidence: Incidence is estimated at one in 40 000–57 000 live births. In children diagnosed with basal cell skin cancer (BCC) younger than age 19 years, 26% had features of BCNS. Among

BCC cases diagnosed younger than age 45, at least 2% have
unequivocal BCNS. Among individuals with more than one odontogenic keratocyst, a minimum estimate is that 2.5% have BCNS. Diagnosis: Evans et al. (1) provided diagnostic criteria for BCNS (Table 7). Note that a full orthopantogram of the jaw, chest, and skull radiographs are required to adequately evaluate for BCNS, and pelvic ultrasound seeking ovarian fibromas may also be helpful. Ectopic calcification of the falx cerebri is seen in more than 90% of patients older than age 20. More than 50% of patients with BCNS manifest enlarged occipitofrontal circumference, mild ocular hypertelorism, palmar and/or plantar pits, calcified ovarian cysts, rib anomalies (splayed, fused, partially missing, bifid, etc), spina bifida occulta of cervical or thoracic vertebrae, calcified diaphragma sellae, or hyperpneumatization of paranasal sinuses. A recent report suggests that the occurrence of discrete patches of unusually long pigmented hair on the skin may represent a novel physical sign associated with BCNS (3).

Laboratory features: No specific findings.
Associated malignant neoplasms: Multiple BCCs usually
appear in the third decade, but have been reported as young as age 2 years, with a median age at diagnosis of 25 years. Only 40% of African Americans with BCNS manifest BCC and, even when present, the number of lesions may be small. Ten percent of gene mutation carriers may never develop BCC. Up to 5% of children develop medulloblastoma (a type of primitive neuroectodermal tumor) with a peak incidence around age 2 years, compared with 7 years in sporadic medulloblastomas (4). Ovarian fibrosarcoma may develop. Associated benign neoplasms: Odontogenic keratocysts of

the jaw (mean number = 5) in over 90% of individuals with BCNS, often developing in the second decade, and epidermal cysts and palmoplantar pits reportedly occur in the majority of cases. In a minority of cases, meningioma or ovarian fibromas (20%) and cardiac fibromas (2%) may occur. Fetal rhabdomyomas have been Table 7. Diagnostic criteria for basal cell nevus syndrome (1)a Diagnosis is established if two major or one major and two minor criteria are met.

Major criteria:
• Multiple (>2) basal cell carcinomas or one 10 basal
cell nevi.
• Any odontogenic keratocyst (proven on histology) or polyostotic bone cyst.
• Palmar or plantar pits (≥3).
• Ectopic calcification; lamellar or early (97th centile, with frontal bossing. • Cardiac or ovarian fibroma.
• Medulloblastoma (PNET, most often of desmoplastic histology) (2). • Lymphomesenteric or pleural cysts.
• Congenital malformation: cleft lip and/or palate, polydactyly, eye anomaly (cataract, coloboma, microphthalmia).

= basal cell nevus syndrome; PNET = primitive neuroectodermal tumor.

Journal of the National Cancer Institute Monographs, No. 38, 2008

reported now in five cases. More than 100 other manifestations have been recorded in BNCN (5). Radiographic features were
studied in new series of 82 patients (6).
Cancer risk management: The risks and benefits of cancer
screening in patients with BCNS have not been established.
Affected individuals should be carefully instructed on how to minimize sun exposure of the skin throughout life. In infancy, head circumference should be monitored for rapid enlargement that could indicate developing hydrocephalus. A jaw radiograph has been advised in individuals older than age 8, and every 12–18 months thereafter, because keratocysts usually require surgical excision. Skin examination by a dermatologist experienced with BCNS should be conducted every 4–12 months, from adolescence onward. BCC has been reported before puberty, albeit rarely. Surgical excision, laser therapy, and use of systemic retinoid are among the options now available for management of BCC. Careful annual gynecologic examination in adulthood is advised, and periodic ovarian ultrasound may be useful. If excision of large or symptomatic ovarian fibroma is required, attempts should be made to preserve ovarian tissue (and fertility), as malignant degeneration is uncommon. Echocardiogram in the first year of life has been suggested, and if fibromas are present but asymptomatic, regular evaluation by a cardiologist is suggested. Although there is a risk of medulloblastoma, no evidence exists to support routine brain imaging as a screening strategy. Exposure to radiation should be avoided in this condition when possible, based upon reports of thousands of BCCs developing within the radiation field of those receiving therapeutic radiation (7). A recent report suggests that BCNS patients are at risk of radiation-induced brain tumors (8). References

1. Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker N, Farndon PA. Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet. 1993;30(6):460–464. 2. Amlashi SF, Riffaud L, Brassier G, Morandi X. Nevoid basal cell carcinoma syndrome: relation with desmoplastic medulloblastoma in infancy. A population-based study and review of the literature. Cancer. 2003; 98(3):618–624.

3. Wilson KC, Ajayi-Obe E, Bernhard B, Maas SM. Patched mutations and hairy skin patches: a new sign in Gorlin syndrome. Am J Med Genet A. 2006;140(23):2625–2630.
4. Cowan R, Hoban P, Kelsey A, Birch JM, Gattamaneni R, Evans DGR. The gene for the naevoid basal cell carcinoma syndrome acts as a tumoursuppressor gene in medulloblastoma. Br J Canc. 1997;76(2):141–145. 5. Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med. 2004;6(6):530–539.

6. Kimonis VE, Mehta SG, Digiovanna JJ, Bale SJ, Pastakia B. Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome. Genet Med. 2004;6(6):495–502.
7. High A, Zedan W. Basal cell nevus syndrome. Curr Opin Oncol. 2005; 17(2):160–166.
8. Choudry Q, Patel HC, Gurusinghe NT, Evans DG. Radiation-induced brain tumors in the nevoid basal cell carcinoma syndrome—implications for treatment and surveillance. Childs Nerv Syst. 2007;23(1):133–136.

3. Beckwith–Wiedemann Syndrome (Exomphalos–
Macroglossia–Gigantism Syndrome)
OMIM number: 130650.
Inheritance pattern: Autosomal dominant pattern seen in
15% of cases. Of individuals with Beckwith–Wiedemann Syndrome (BWS), 85% have no family history of BWS.
Journal of the National Cancer Institute Monographs, No. 38, 2008

Genes and chromosomal location: A variety of genetic alterations are reported in BWS. Most are epigenetic in nature, involving a differentially imprinted region of chromosomal band 11p15. The molecular basis of this enormously complex disorder is

described and diagramed clearly by Weksberg et al. (1).
Mutations: Paternal segmental isodisomy or isodisomy of the
whole chromosome [92% vs 8%, respectively (2)], sometimes with somatic mosaicism, for a region including chromosomal band
11p15 is found in 10%–20% of all cases; at least five different genes in this region have been implicated in the etiology of BWS. IGF2 is normally paternally expressed. Disruption of IGF2
imprinting resulting in biallelic expression of this gene has been found in some BWS patients. H19 is a maternally expressed gene. Imprinting of IGF2 and H19 is controlled by the imprinting center locus (IC1) at 11p15.5. This is a methylation-sensitive chromatin insulator that binds zinc-finger protein, CTCF, in a parent-of-origin–specific manner. Microdeletions of the CTCF target sites of IC1 are associated with BWS by disrupting normal imprinting of the IGF2 and H19 loci (3). Rarely, changes in H19 expression have been reported in BWS. p57KIP2 (CDKN1C) has

preferential maternal expression (incomplete paternal imprinting), and 5%–10% of BWS cases have p57KIP2 mutations; these are
found more commonly in cases with a positive BWS family history, omphalocele, and cleft palate. KVLQT1 is maternally expressed. Loss of imprinting of an antisense transcript
(LIT1;KCNQ1OT1) that is expressed by the paternal allele and lies within the KVLQT1 gene has been reported in some BWS cases,
and maternally derived deletions of LIT1 can also cause BWS. Less than 1% of BWS cases have a cytogenetically visible abnormality involving the 11p15 region (4,5). Incidence: One in 13 700 live births.

Diagnosis: No consensus criteria exist, but it has been suggested that a diagnosis requires the presence of three findings (at least two major and one minor). Major findings include previously diagnosed family members, height and/or weight greater than 97th percentile, anterior linear ear lobe creases or posterior helical ear pits, macroglossia, omphalocele, visceromegaly involving one or more intra-abdominal organ (liver, spleen, kidneys, adrenals, pancreas), embryonal tumor in childhood, hemihyperplasia, adrenocortical cytomegaly, renal abnormalities, and cleft palate (rarely). Minor findings include polyhydramnios, prematurity, neonatal hypoglycemia, facial nevus flammeus, hemangioma, characteristic facies (midfacial hypoplasia, infraorbital creases), cardiomegaly or structural cardiac lesions, diastasis recti, advanced bone age, and monozygotic twinning (usually female and discordant for BWS). Associated malignant neoplasms: Children with BWS have

a 7.5% risk of tumors (all sites combined) in the first 8 years of life; development of cancer above that age is uncommon (6). The most common is Wilms tumor (60% of malignancies in BWS;
conversely, about 1%–2% of all Wilms tumors arise in the context of BWS). Mean age at Wilms tumor diagnosis in BWS is 28
months, with 89% of cases diagnosed younger than age 5 years. The contralateral kidney is also affected in 21% of BWS-related Wilms tumor. Other BWS-associated tumors include hepatoblastoma, neuroblastoma, adrenocortical carcinoma, rhabdomyosarcoma, and gonadoblastoma. Patients with uniparental disomy or 19

mutations in imprinting center 1 of the BWS region (involving the IGF2 and H19 genes) may be more likely to develop cancer than those with mutations elsewhere in the gene. Patients with mutations in imprinting center 2 (involves LIT1 and p57KIP2) generally do not develop Wilms tumor but are at risk of other BWS-related embryonal neoplasms (6), whereas loss of H19 gene imprinting, including that associated with uniparental disomy involving chromosome band 11p15, is associated with increased cancer risk, particularly for Wilms tumor (7). Associated benign neoplasms: Pancreatic islet cell hyperplasia (leading to neonatal hypoglycemia), adrenal cytomegaly (which may or may not result in adrenal overactivity), hyperplasia of pituitary, hamartomas, adenomas, myxomas, ganglioneuromas, and fibroadenomas.

Cancer risk management: Surveillance for neoplasia includes
ultrasound abdominal imaging to screen for embryonal tumors and is recommended every 3–4 months until age 8 years. Serum alphafetoprotein every 6 months may also be reasonable. Periodic chest radiograph and urinary screening for neuroblastoma have been suggested but are not often used in screening protocols because evidence of efficacy is lacking (8). For specific recommendations related to screening for Wilms tumor in BWS, see “Wilms Tumor.”

Comments: A multidisciplinary team is required to address
issues such as neonatal hypoglycemia, correction of omphalocele, management of hemihypertrophy, and more. Several recent
reports suggest increased risk of BWS and Angelman Syndrome in pregnancies conceived using assisted reproductive technology, raising the possibility that genomic imprinting can be altered by the process of in vitro fertilization (9). However, Doornbos et al. (10) present evidence that the increased risk of these syndromes is related to parental infertility rather than the assisted reproductive technology itself. Surgical correction of macroglossia is technically challenging because patients often fail to achieve completely normal tongue function and appearance as adults (11).

1. Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syndrome. [review]. Am J Med Genet. 2005;137(1):12–23.
2. Cooper WN, Curley R, Macdonald F, Maher ER. Mitotic recombination and uniparental disomy in Beckwith-Wiedemann syndrome. Genomics. 2007;89(5):613–617.
3. Sparago A, Russo S, Cerrato F, et al. Mechanisms causing imprinting defects in familial Beckwith-Wiedemann syndrome with Wilms tumour. Hum Mol Genet. 2007;16(3):254–264.
4. Li M, Squire J, Shuman C, et al. Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations.
Genomics. 2001;74(3):370–376.
5. Weksberg R, Nishikawa J, Caluseriu O, et al. Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet. 2001;10(26):2989–3000.

6. Cytrynbaum CS, Smith AC, Rubin T, Weksberg R. Advances in overgrowth syndromes: clinical classification to molecular delineation in Soto’s syndrome and Beckwith-Wiedemann syndrome. Curr Opin Pediatr. 2005;17(6):740–746.

7. Rump P, Zeegers MP, van Essen AJ. Tumor risk in Beckwith-Wiedemann syndrome: a review and meta-analysis. Am J Med Genet A. 2005;136(1): 95–1043.
8. Scott RH, Walker L, Olsen OE, et al. Surveillance for Wilms tumor in at-risk children: pragmatic recommendations for best practice. Arch Dis Child. 2006;91(12):995–999.

9. Maher ER, Brueton LA, Bowdin SC, et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet. 2003;40(1):62–64.
10. Doornbos ME, Maas SM, McDonnell J, Vermeiden JPW, Hennekam RCM. Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study. Hum Reprod. 2007:22(9):2476–2480. 11. Tomlinson JK, Morse SA, Bernard SP, Greensmith AL, Meara JG. Longterm outcomes of surgical tongue reduction in Beckwith-Wiedemann syndrome. Plast Reconstr Surg. 2007;119(3):992–1002.

4. Birt–Hogg–Dubé Syndrome
OMIM number: 135150; 607273.
Inheritance pattern: Autosomal dominant.
Gene and chromosomal location: FLCN (folliculin) at
17p11.2, encoding a novel protein of the same name. It is involved in AMPK and mTOR signaling (1).
Mutations: About 50% of mutations involve an insertion/
deletion of a C-8 hypermutable tract in exon 11; other mutations are found throughout the gene—10 of 61 families studied to date have no identifiable mutation (2). Overall, FLCN sequence analysis has an 84% detection rate in Birt–Hogg–Dubé Syndrome

Incidence: Unknown.
Diagnosis: The BHDS is first manifest by the cutaneous triad of multiple fibrofolliculomas (FFs), trichodiscomas (TD; both of which are fibroepithelial hamartomas of the hair follicle), and acrochordons (skin tags) appearing in the third to fourth decade of life. These asymptomatic lesions primarily appear on the head, face, neck, upper chest, back, arms, and inner thighs. In addition to various cutaneous manifestations, affected individuals are at risk of pulmonary cysts, spontaneous pneumothorax, and kidney tumors, and diagnostic evaluation includes screening for these skin, lung, and kidney features. The development of renal tumors may lead to syndrome recognition, particularly if they present with chromophobe or oncocytic histology, both of which are uncommon in the general population but typical for BHDS. A family history of multiple FFs may indicate BHDS. Ninety percent of BHDS patients studied in a familial kidney cancer program have pulmonary cysts, and pneumothorax develops in 20%. Pneumothorax has been

reported as the presenting sign in a BHDS family (3). In contrast, families ascertained through a dermatology genetics unit seemed to have lower risks of both kidney cancer and pneumothorax (4). Laboratory features: No specific laboratory findings. Skin biopsy is required to confirm the diagnosis of FF. Collins et al. (5) studied the histology of BHDS-related FFs and TDs and found

them to be similar to their sporadic counterparts.
Associated malignant neoplasms: BHDS is associated with
multiple bilateral renal tumors of various types, including oncocytoma, chromophobe renal cell carcinoma, clear cell carcinoma, and papillary renal carcinoma, as well as hybrid oncocytic neoplasms. Zbar et al. (6) demonstrated that BHDS patients were 6.9 times more likely to develop renal tumors compared with unaffected family members. Pavlovich et al. (7) reviewed 130 solid renal tumors resected from 30 patients with BHDS in 19 different families. Preoperative computed tomography (CT) scans showed a mean of 5.3 tumors per patient (range = 1–28 tumors), the largest averaging 5.7 centimeters in diameter. Multifocal tumors were noted at a mean age of 50.7 years and consisted of chromophobe Journal of the National Cancer Institute Monographs, No. 38, 2008

renal cell carcinomas (34%) or of hybrid oncocytic neoplasms with areas suggestive of chromophobe renal cell carcinoma and oncocytoma (50%). Nine percent were clear cell renal carcinomas. Microscopic oncocytosis was found in the renal parenchyma of most patients, including five patients with clear cell renal cell carcinoma. This suggests that microscopic oncocytic lesions may be precursors of hybrid oncocytic tumors, chromophobe renal cell carcinomas, and perhaps clear cell renal cell carcinomas in BHDS. Nonrenal malignancies are not known to be part of this

Associated benign neoplasms: Benign tumors of the hair follicle, including FFs, perifollicular fibromas (PFFs), TDs, and acrochordons. Several findings suggest that FF and TD represent a spectrum of a single process. The diagnosis of FF and TD may depend merely on the topographic location of the hair follicle within the biopsy specimen. Most likely, PFFs represent a part of the spectrum from FF to TD. Other features of BHDS include pulmonary cysts and, rarely, deforming lipomas and collagenomas (8). Colonic polyps have been noted in a number of case reports on BHDS; however, Zbar et al. (6) showed no increased prevalence of colonic polyps in BHDS families. They examined 83 BHD family members by colonoscopy. While eight of the 45 BHDS-affected

individuals (18%) had colon polyps, seven of the 38 non-BHDS individuals (18%) did as well. Others have reported parotid oncocytoma, multinodular goiter, meningioma, and neurothekeoma occurring in individuals with BHDS; it is unclear if they are syndrome related or not. Cancer risk management: No surveillance is indicated for the skin lesions because they are not precancerous. Annual imaging of the kidneys by magnetic resonance imaging (MRI) is suggested (avoiding radiation exposure on general principles), starting around age 35 or 10 years younger than the youngest case of renal tumor identified in that family. Abnormalities identified by MRI should be further evaluated by CT scan. Because BHD-related kidney

cancer is often bilateral, renal-sparing surgery should be attempted if possible; given the multifocal nature of these tumors, surgery is generally reserved for masses greater than 3 cm in diameter (9). Comment: Familial oncocytoma has been reported as a distinct entity. Some of the originally reported kindreds were later shown to have FLCN mutations, but other families may have a discrete new entity (gene unknown) [summarized by Cohen and Zhou (10)]. Individuals with BHDS should be counseled regarding the potential for spontaneous pneumothorax (which can occur as early as adolescence), and they should be made aware of pneumothorax-associated symptoms so as not to delay diagnosis, but no screening tests to detect cystic changes in the lungs seem indicated at this time. References

1. Baba M, Hong SB, Sharma N, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci USA. 2006;103(42): 15552–15557.

2. Schmidt LS, Nickerson ML, Warren MB, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with BirtHogg-Dubé syndrome. Am J Hum Genet. 2005;76(6):1023–1033. 3. Toro JR, Pautler SE, Stewart L, et al. Lung cysts, spontaneous pneumothorax and genetic associations in 89 families with Birt-Hogg-Dubé. Am J Respir Crit Care Med. 2007;175(10):1044–1053.

Journal of the National Cancer Institute Monographs, No. 38, 2008

4. Leter EM, Koopmans AK, Gille JJP, et al. Birt-Hogg-Dube syndrome: clinical and genetic studies of 20 families. J Invest Dermatol. 2008; 128(1):45–49.
5. Collins GL, Somach S, Morgan MB. Histomorphologic and immunophenotypic analysis of fibrofolliculomas and trichodiscomas in Birt-HoggDubé syndrome and sporadic disease. J Cutan Pathol. 2002;29(9):529. 6. Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé Syndrome. Cancer Epidemiol Biomarkers Prev. 2002;11(4):393–400.

7. Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the BirtHogg-Dubé syndrome. Am J Surg Pathol. 2002;26(12):1542–1552. 8. Toro JR, Glenn G, Duray P, et al. Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol. 1999;135(10):1195–1202. 9. Pavlovich CP, Grubb RL 3rd, Hurley K, et al. Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. J Urol. 2005;173(5):1482–1486.

10. Cohen D, Zhou M. Molecular genetics of familial renal cell carcinoma syndromes. Clin Lab Med. 2005;25(2):259–277.

5. Bloom Syndrome
OMIM number: 210900.
Inheritance pattern: Autosomal recessive.
Gene and chromosomal location: BLM at 15q26.1, a RecQlike DNA helicase. Mutations: Multiple mutations identified including missense, nonsense, frameshift, exon skipping, and exonic deletions (1). In a registry-based study, 64 different mutations (54 truncating and 10 missense) were identified in 125 affected subjects (2). Seventy-five subjects were homozygous for their mutation; 15 were compound heterozygotes. A founder mutation in Ashkenazi Jews is designated BLMash, a 6 bp deletion/7 bp insertion. Overall, 19 different recurring (founder) mutations were reported. Incidence: Actual incidence is unknown in general population. Among Ashkenazi Jews, Bloom syndrome (BS) is seen in one in

48 000 live births and is most common in those of Ukrainian or Polish ancestry. The Bloom Syndrome Registry represents the
majority of people in the world diagnosed with BS between l960 and 2006. Currently, there are 238 persons in the registry.
Approximately 30% report Ashkenazi ancestry. The reported frequency of the Ashkenazi founder mutation is 1/231 heterozygotes among New York Ashkenazim and 1/101 among Polish
Diagnosis: BS is characterized by growth deficiency (preand postnatal), with normal body proportion except for mild microcephaly, a sun-sensitive erythema or telangiectasia generally on the face and dorsa of the hands and forearms, and characteristic facies: malar hypoplasia, nasal prominence, small mandible, and dolichocephalic skull. Males are sterile and

females, although sometimes fertile, have reduced fertility and a shortened reproductive span. An increased susceptibility to
infection, with recurrent bronchitis and bronchiectasis; frequent occurrence of diabetes; infantile diarrhea and vomiting; café-aulait or hypopigmented macules; and high-pitched voice are all reportedly syndrome related. Learning disabilities are frequent, but overall intellect is usually normal.

Specific diagnostic testing involves demonstration of increased frequency of sister chromatid exchange (SCE) in cultured peripheral blood lymphocytes; demonstration of this feature requires special analytic techniques and cannot be detected by routine chromosomal 21

analysis. Limited clinical genetic testing for founder mutations is now available.
Laboratory features: Strikingly elevated (10-fold greater
than normal) SCE rate in all cell types examined. Other somatic hyperrecombination mutations that give rise to chromosomal
quadraradials and excess breakage are also seen, all of which may lead to loss of heterozygosity due to homologous recombination, duplications, and deletions from unequal SCEs between repetitive elements or syntenic members of gene families. BS is the only disorder with evidence of hyperrecombination of this type. Associated malignant neoplasms: Cancers show increased

frequency at all ages, with acute leukemia, lymphoid neoplasms, and Wilms tumor predominating before the age of 25; after age 20, carcinomas of the tongue, larynx, lung, esophagus, colon, skin, breast, and cervix are most frequent (summarized in Table 8), with the age at diagnosis often 20 or more years younger than that generally expected for each tumor type. German (1) reported that the two oldest persons known to have BS both died of cancer, one at age 46 and the other at 49.

Somatic mutations in BS cells are not inherited through the
germline but are far more likely to arise spontaneously compared with cells in healthy individuals. In BS patients, every cell in the body capable of further division is at high risk of neoplastic transformation. The spectrum of BS-related malignancies is very heterogeneous, a pattern quite distinct from the usual cancer susceptibility disorder, in which cancer risk is generally restricted to one or a limited number of cancers.

Until recently, obligatory heterozygotes have been said to lack any increased cancer risk. Gruber et al. (4) have now reported that Ashkenazi Jews with colorectal cancer were more than twice as likely to carry the BLM founder mutation than Ashkenazi

Jewish controls without colorectal cancer. This was true in both an Israeli population and a New York City cohort. On the other hand, the founder mutation was not overrepresented among
Ashkenazim with cancers of the breast, prostate, ovary, uterus, or in lymphomas.

Table 8. Malignancies reported by the Bloom Syndrome Registry through 2005 [adapted from Sanz and German (3)]

Persons under cancer risk management
Lower enteric
Upper enteric or respiratory
Genitals or urinary tract
Lower respiratory
Acute lymphocytic leukemia
Other acute leukemia
Germ cell
Other—Wilms tumor


Age at
y (range)






4 (1–8)

Associated benign neoplasms: Multiple adenomatous colon
polyps have been reported in one individual with BS.
Cancer risk management: The risks and benefits of cancer
screening in BS have not been established. In infancy, one could consider offering semiannual ultrasonographic screening through age 8 years for Wilms tumor. As colorectal cancer is the single most common carcinoma, we suggest colonoscopy every 3–5

years, starting in late adolescence. Meticulous annual physical examination is suggested from age 18 onward, with initiation of upper gastrointestinal endoscopic and mammographic surveillance beginning in early adulthood. Before adulthood, hematologic malignancies predominate, and no screening for these beyond a careful history and physical examination is specifically suggested.

1. German J, Ellis NA. Bloom syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Metabolic & Molecular Basis of Inherited Disease. New York: McGraw-Hill; 2001:733–752.
2. German J, Sanz MM, Ciocci S, Ye TZ, Ellis NA. Syndrome-causing mutations of the BLM gene in persons from the Bloom’s Syndrome Registry. Hum Mutat. 2007;28(8):743–753.
3. Sanz MM, German J. Bloom’s syndrome. Gene Reviews. www.genetests. org. Accessed January 2008.
4. Gruber SB, Ellis NA, Rennert G, Offit K. BLM heterozygosity and the risk of colorectal cancer. Science. 2002;297:2013. 10.1126/science.1074399.

6. Breast/Ovarian Cancer, Hereditary (BRCA1)
OMIM number: 113705.
Inheritance pattern: Autosomal dominant.
Gene and chromosomal location: BRCA1, a tumor suppressor gene at 17q21, is central to the maintenance of genome stability. It is a multifunction E3 ubiquitin ligase involved in DNA damage signaling, DNA repair (homologous recombination repair of double-stranded DNA breaks), chromatin remodeling and transcription (1). It is not homologous to BRCA2; each has its own distinctive mechanisms of action. Mutations in other genes that also play a role in protecting genomic integrity, for example, CHEK2, ATM, NBS1, RAD51, BRIP1, and PALB2 are all associated with approximately twofold increases in sporadic breast cancer risk (2). These genetic variants are relatively uncommon. The international CIMBA (Consortium of Investigators of Modifiers of BRCA1/2) collaboration is systematically searching for genetic modifiers of BRCA-related breast cancer, having assembled a cohort of more than 10 000 mutation carriers. To date, they have corroborated the reported increase in BRCA2-related breast cancer risk observed with a functional promoter variant in the RAD51 gene (3) and published definitive negative reports of the putative associations with the AIB1 polyglutamine repeat (4) and F31I variant of AURKA (5). A functional promoter SNP in the MDM2 gene has been reported to accelerate the rate of breast and ovarian carcinogenesis in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers (6).

Mutations: More than 1643 distinct mutations, polymorphisms, and variants have been identified (Breast Cancer Information Core: The diagnostic accuracy of various methods for detecting mutations in BRCA1/2 has been reviewed (7).

Journal of the National Cancer Institute Monographs, No. 38, 2008

Incidence: Overall, BRCA1 and BRCA2 account for a small
proportion of all breast cancers, a fraction that varies according to the population; most studies have been limited to early-onset cancer. The Anglican Breast Cancer Study Group (8) reported mutations in either BRCA1 or BRCA2 in 2% of women in ...

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191170 1912 1917 192 1920 192090 1925 1927 1933 195 1958 196 197 1971 1973 1979 198 1984 1985 1986 1987 1991 1992 1993 1994 1995 1996 1997 1998 1999 19p 1b 1p36 1q23 1q24 1q25 1q42.1 1q42.2 2 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 20 20.5 200 2000 2001 2002 2003 2004 2005 2006 2007 2008 201 2013 202300 203 2037 204 2043 206 2072 2078 2080 2083 20q13 20s 21 210 210900 211 213 214 215400 218 218040 219 21q22.3 22 221 2213 2216 223 224230 225 2256 2262 227 227645 227646 228 2281 2284 229 22q12.1 23 23.2 230 232 233 236 2360 2372 2375 238 2384 2387 2396 2397 24 2406 2417 2425 246 2465 2473 2476 2480 25 250 254 255 2554 2559 257 2587 259 2595 26 260 261 262 2624 2625 2630 2631 264 265 267 2677 2679 268 2680 268130 2685 269 27 2701 2712 272 273 2735 2743 275 2751 276 2763 276300 277 279 28 2807 2816 284 2869 2876 29 290 2905 2907 293 2938 294 2943 295 296 2961 2967 297 298 2989 299 2a 2b 2nd 2p16 2p16.1 2p21 2q21.2 2q31 3 3.0 3.2 3.3 3.4 3.5 3.6 3.7 3.75 3.8 3.9 30 300 3000 300126 300147 300240 300514 300515 3035 3037 3046 305000 306 3071 3075 308 30b 31 312 314 315 316 318 319 32 321 322 3233 325 33 331 332 3326 333 334 335 336 3387 3389 339 3392 3393 34 3409 341 3414 344 345 348 34g 35 350 352 353 354 3542 3544 355 356 357 358 36 361 362 367 37 370 3728 3732 376 3773 3779 379 38 3831 3836 387 39 390 393 397 3985 3990 3a 3b 3p 3p14.2 3p21.3 3p25.3 3q21 3rd 4 4.1 4.2 4.3 4.4 4.5 4.6 4.9 40 400 401 402 4034 4038 404 4041 4046 405 406 40s 41 41.7 410 411 413 416 4198 42 42.5 420 4205 424 425 427 428 4288 429 43 430 4306 431 4310 433 434 436 437 44 440 441 442 446 447 448 4486 449 4494 45 450 454 457 46 460 461 4635 464 4641 467 468 47 47.5 476 48 483 487 49 490 491 495 498 4q12 5 5.0 5.1 5.2 5.3 5.6 5.7 5.9 50 50.7 500 5000 501 502 507 509 51 511 515 518 52 52.3 523 524 525 5256 526 529 53 530 533 534 5382insc 5386 539 54 540 541 55 557 5583 55902 5591 56 561 566 57 57.9 572 574 577 579 58 583 5832 585 589 59 594 595 599 5p15.33 5q11 6 6.1 6.4 6.8 6.9 60 600185 600209 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allel allinson almost alon along alonso alpha alphafetoprotein also alter altern although alvarez alvord alway ambigu america american amezian amino aml amlashi amo among ampk amplifi ampullari amri amsterdam amsterdam-i anaemia analog analys analysi analyt analyz anastamosi ancestr ancestri and/or andersen andrea andrew andrologia anemia aneuploidi angelman angioleiomyoma angiomat anglican anisocytosi ankl ann annual anomali anoth anterior anti anti-inflammatori anticip antigen antisens antoniou aoki aoper apicella aplasia aplast appar appear appendix appli approach appropri approxim apt ar arber arcan arch ardern ardern-jon area aretz arg462gln aris arm armanio arnold aromatas around array arrest art artac arteri arterioven arthriti as-yet-unidentifi asab ascertain asco asher ashkenazi ashkenazim asian aspect asperen aspir aspirin assay assembl assess assist associ astonish astrocytoma asymmetri asymptomat at-risk at-v1 at-v2 ataxia ataxia-telangiectasia ataxiatelangiectasia atchley 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brodi brohet bromley bronchiectasi bronchiti brose brother brown brownstein brr brueton bruis bryant bs bs-relat bse bt buccal buley bunyan burgart burk burnel burrow bursztyn busi butler butzow bws bws-associ bws-relat byrd c c-kit c-t c-to-t c.10666t c.7271t ca ca125 cacchion cadherin cafe cafe-au-lait café café-au-lait café-aulait caféau caféau-lait cag cag-trinucleotid cajal calcif calcifi calcium calcium-depend calcifi calcific calcul calda calendar caliskan call callahan calo caluseriu calzon canada canadian canc cancer cancer-pron cancer-specific candid cannot canthi cap capabl capb capell caporaso capsul carcinogenesi carcinoma carcinomatosi cardiac cardio cardio-facio-cutan cardiofaciocutan cardiologist cardiomegali cardiomyopathi care careen carl carmona carneiro carney carney-strataki carri carrier carson carta carter cartilag cartilagin carvaj carvajal-carmona casadei cascia case case-control case-famili casey castel castellvi castellvi-bel cataldo catalog catalyz catania cataract catecholamin catlin catovski caucasian caus causal causat caution cavaco cbfa2/runx1 ccg cdh1 cdh1/ecadherin cdhi cdk4 cdkn1c cederquist celecoxib cell cell-cycl cellular cementifi center centil centimet central cerebellar cerebr cerebri cerrato cervic cervix cetani cfc cg challeng chang channel chapell chappui chapter character characterist chase cheadl chek2 chemoprevent chemotherapeut chemotherapi chemotherapyrel chen cheson chest chetrit chief child childbear childhood children china chines chmiel choic chompret chondroma chondrosarcoma chordoma choudri chromatid chromatin chromoendoscop chromoendoscopi chromophob chromosom chronic chun ci cimba ciocci circumfer circumst cite citi cj cl claim clarifi clark class classic classifi classific clastogen claus clavel clavicl clear cleari cleft clenden clin clinic clinic-bas clinicbas clinician clinicoradiolog cll clonal clone close clue cluster cm cnc cnc-relat cnc1 cnc2 cns coars coat cobbleston cobblestone-lik codon cogan 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easi easili easton eb ebersold eccrin echocardiogram echocardiographi econom ectop ectopia ed edema edit editori edu educ edward eel eerola effect effort efficaci eg eh eight either ej ek el elac2 elbow eleg element elev eleven elimin elli ellison elsewher em emanuelsson embrac embryon emerg emmerson emphas emphasi empir employ enchondroma enchondromatosi encod encompass encount end endocr endocrin endocrinol endocrinopathi endometri endometrium endoredupl endosc endoscop endoscopi energi eng engel engl england enhanc enlarg ennek enorm enough enter enterpris enthusiast entir entiti entri environment enzym enzymat ependymoma ephelid epicanth epidemiol epidemiolog epiderm epidermolyt epigenet epitheli epithelioid epithelioma epithelium er erkko erlichman erratum error erythema erythroleukemia es esophag esophagus especi essen essenti essop establish estep estim estrogen et etc ethnic etiolog eu eur europ european euthyroid evalu evan even event everi evid evidencebas evolv ew ewcm examin exampl exceed except excess exchang excis exclud exclus excresc exempt exert exfoli exhibit exist exomphalo exon exostos exostosi exostot expans expect experi experienc expert explain explan explor expos exposur express ext1 ext1-related ext2 ext3 extend extens extensor extern extra extra-adren extracolon extraordinari extrapol extrem exud eye eyelid eyler f f31i fa fa-n fa-rel fac face faci facial facio fact factor fade fail failur fallopian fals false-posit falx fam famili familiar family-canc fanc fanc-c fanc-d1 fanc-n fanca fancb fancb/faap95 fancc fancd1 fancd1/brca2 fancd2 fancf fancg fancg/xrcc9 fanci/kiaa1794 fancj/bach1/brip1 fancl/phf9/faap43/pog fancm/faap250/hef fancn fancn/palb2 fanconi fap far farhadi farndon farrington fast fast-flow fat fat-suppress fatal father fdp/aml fe featur fee feed feet fel felbert felton femal femur feng fentiman ferla ferreira fertil fetal ff ffs fh fibroblast fibrocyst fibroid fibroma fibromatosi fibrous field fifti fifty-six fihpt final finch find finland finnish first first-degre fish fitzgibbon five fj fk flcn fletcher flow flow-fish fnip1 focal foci focus fold follicl follicular folliculin follow follow-up followup fontain foot foramina forc fordyc forearm forehead form formal format former forth forti fossa foulk found foundat founder four fourfold fourquet fourth fp fpd fpd/aml fq fr fraction frameshift framp franc frank frankel franken fraser fraumeni frebourg fredriksson free freedman french french-canadian frequenc frequent frere friebel friedman frontal frr frrb frrs fu fujikawa full full-dos full-term fulfill fumar function fund fundic fuse futur g g12a g12s ga gadzicki gail galectin gallardo gallbladd gangliocytomatosi ganglioneuroblastoma ganglioneuroma gap gardner gastointestin gastrectomi gastric gastro gastroenterol gastroenterolog gastroesophag gastrointest gastrointestin gastroscopi gattamaneni gb gd ge gender gene gene-carri genealog genepoor genepso general generaliz generat genet genetic/familial geneticist geneticsa genit genitourinari genodermatos genom genome-wid genomewid genotyp genotype-phenotyp geo geo-hebon geograph gerhardus germ germ-lin german germlin gestalt gh gh-produc ghadirian ghia gi giatzaki giedion gigant gilchrist gill gilpin gimm gingiva girdl giri gist giusti give given gl glan gland glandular glenn glial glioblastoma glioma glogowski gls/pdf/colorectal_screening.pdf gluckman glucocorticosteroid glucos gly12 gly12-to-ala gly12-to-ser glycosylas gm gn gnidec godwin goergen goiter golabi goldgar goldin goldstein golovleva gonad gonadoblastoma gonadotropin gonadotropin-releas gong gordon gorlin gorski gosheg gosselaar gr grade graft graham grana grandmoth grandpar granul granulosa great greater greatest green greensmith greydanus griness gripp gronberg gronwald ground group grow growth grubb gruber gruener gs gu gub gudbjartsson guid guidelin guidlin guney gurtan gurusingh gustafson gut gynecol gynecolog gynecomastia h h/aca h19 h2ax ha hadley haematol hahnemann hair hairi half hallek hallmark hamartoma hamartoma-tumor hamartomat hamlin hampel hamper hand handbook handley hanenbernmjg hanna haploinsuffici haplotyp harbor harri hartg hartmann haven hayden hb hc hd hdgc head headach health health-car healthi heart hebbr hebon heel height heijboer heim heinrich helic helicas help hemangioma hemangiomata hematol hematolog hematopoiet hemihyperplasia hemihypertrophi hemminki hendrik hennekam hepat hepatobiliari hepatoblastoma hepatocellular hepatol her2/neu hereaft hereditari hermsen heterogen heterozyg heterozygos heterozygot hf hfa hh hietala high high-dens high-pitch high-risk highdens higher highest hill hippel hirsch hirsh hirsh-yechezkel hispan histolog histomorpholog histopatholog histor histori hit hj hl hlrcc hlrcc-associ hme hn hnpcc hnpcc-associ hnpcc-relat hnpccassoci hoars hoban hobb hochain hodgkin hodgson hogg hoggdubé hollema homolog homozyg homozygos homozygot hong honrado hope hopkin hormon horsburgh horsesho hortobagyi horvath horwitz hosey host hotspot houlston howel howel-evan howev howlett hoyera hoyeraal-hreidarsson hpc hpc2 hpc20 hpcx hprt2 hpt hpt-jt hptjt hras hrcc hreidarsson hrpt2 hruban hruska hs ht htr/terc hu huang huckl hudson huffman hum human humerus hundr hunter huntsman hurley hurthl hutson huzarski hy hyalin hybrid hydratas hydrocephalus hypercalcemia hyperhidrosi hyperkeratos hyperkeratosi hyperkeratot hyperlipidemia hypermut hyperparathyroid hyperparathyroidism-jaw hyperpigment hyperplasia hyperplast hyperpneumat hyperrecombin hyperreflexia hypersensit hypertelor hypertroph hypertrophi hypocalciur hypocellular hypoecho hypoglycemia hypogonad hypopig hypoplasia hypothesi hypothyroid hypotonia hysterectomi hysteroscop hysteroscopi ia ibcc ibm ic1 icc iceland icg icg-hnpcc id ideal ident identifi identifi identific idiopath ie igclc igf igf1 igf2 ihc ii ik ileorect ilerisoy ilerisoy-yakut illustr im imag immunodefici immunohistochemistri immunophenotyp immunostain impact implic import impos impress imprint improv inabl inactiv inborn incid includ incomplet inconsist incorpor incorrect increas incur independ index indic indistinguish individu indol induc inevit inexpens infal infanc infantil infect infertil inform infraorbit inher inherit inhibit initi inner inou input insensit insert insight inst instabl instanc institut institute-work instruct insuffici insul insur int intact integr integument intellect intens interact interest intern interphas interpret intersect interstiti interstrand interv intervent intestin intoler intra intra-abdomin intraabdomin intraduct intradur intraepitheli intragen intramedullari intramucos intramuscular intraor intrins introduc introduct invalu invas invert invest investig invit involv infiltrat inflammatori influenc ioniz ip iq ir iran irradi ishib islet isodisomi isol isra issu itin iversen ivs4 iwcll j ja jager jama januari jarai jarvinen jaussent jaw jb jbb jc jd je jegher jellema jenkin jew jewish jewish-ashkenazi jf jg jh ji jj jj-l jjp jk jl jm jn joenj john johnson joint jone journal [email protected] jp jpw jq jr jt judg juliao justifi juvenil jv jønsson k ka kahn kamino kannengiess kapori kapusta karlan karyotyp kathleen katki kauff kaurah kawam kb kc kcnq1ot1 kea kelley kelsey keratin keratoacanthoma keratocyst keratoderma keratos keratosi kerr kf kh khan kidney kilic kim kimoni kin kin-cohort kinas kind kindr king kingdom kirner kirschner kirwan kirwin kit kitneg kiuru kj kl kleibeuk klf6 klose km knee knight know knowledg known koksal kone koopman korczak kordish kote kote-jarai kotsopoulo kramer kras krauss kremer krieg kroiss kruger kuhner kum kuperstein kurian kusumi kvlqt1 kw kwast l l960 l998 la lab laboratori lacey lachlan lack ladusan laghmani lago lahad laiho lait lamb lambda lamellar lancet langan langer lansdorp larg larger largest larsson laryngoscop larynx laser late later latter launonen laurent laurent-puig lawrenc lax laxiti lc lccsct lccsts ld ldd lddb le lead lead-tim learn least lecuru led lee leeuw legius lehmann lehtonen lehtovirta lei leigh leiomoma leiomyoma leiomyomata leiomyomatosi leiomyosarcoma leminen lench lender length lengthen lent lentigin lentiginos leon leontovich leopard lesion less leter lethal leuk leukaemia leukemia leukemia-suscept leukocyt leukopenia leukoplakia level levi levitus levy-lahad lewi leydig lfl lfs lfs-relat lg lh lhermitt lhermitte-duclo li li-fraumeni-lik liaw liberzon lichtman liddl lie lied life lifeextend lifestyl lifetim ligas ligat light like likelihood liloglou limb limit lin lindau lindner lindor line lineag linear liniti link linkag linxian lip lip/palate lipoblastoma lipoma lipomatosi liposarcoma lipton list lit1 literatur liu live liver liverpool lj lm lobe lobular local locat location-specific loci lock locus log london long long-term longer longterm longton loni loos lord loss loss-of-funct loui low low-cost low-penetr low-risk low-set low-tech lower lowest lp lr ls lubin lubinski lucassen lumin lunetta lung lupelescu lymph lymphoblast lymphoblastoid lymphocyt lymphocytosi lymphoid lymphoma lymphomesenter lymphoprolif lymphoreticular lynch lynchassoci m m-c m-h ma maa macdonald macmillan macrocephali macrocytosi macroglobulinemia macroglossia macronodular macul made maffucci magnet magnitud maher mail maillef main maintain mainten major make malalign malar malat male male-to-mal malform malign mamir mammari mammogram mammograph mammographi man manag mandibl mandibular mani manifest mankin manley manner map margin mari mark marker marmo marron marrow marsh marti martin martinelli masada masciari maserati mason mass massiv mastectomi master mastocytosi matern mathemat matloff matthew matur matyakhina maxillari may maynard mayo mb mc mccaul mcconnel mcdonnel mcgarriti mcgaughran mcgraw mcgraw-hil mcguffog mcguir mclaughlin mcmaster mcniff mcreynold mcronald mcul mcwhinney md mdm2 mean meara measur mechan mecklin med medeiro medhurst median medic medullari medulloblastoma meera meet meetei megalencephali mehregan mehta meijer meijers-heijbo meitz mek1 melanoma melanot member men men1 mendelian meningioma menna menon mensdorff mensdorff-pouilli menstrual mental mere merkel merten mesenchym met meta meta-analysi metab metabol metabolit metacarp metachron metastat metatars method methodolog methyl methylation-sensit methylen meticul metsuyanim metzger mf mg mh mhg michaud michot microarray microcephali microdelet microlit microphthalmia microsatellit microscop mid middl midfaci might miki mil mild mild-tosever milder mill millikan miln minelli minim minimum minor minut miron mismatch mismatch-repair mismatchrepair mismatchrepair-defici miss missens mistaken mitochondri mitogen mitomycin mitot mitra mix mj ml mlh1 mlm mm mmr mmr-deficient mn mo modal mode model moder modifi modifi modific modul mol mole molec molecular moller monbo monga monitor monoallel monoclon monocyt monograph monosomi monoubiquitin monozygot month moran morandi morbid moreau morgan morman morpholog morreaqu morrel mors mortal mosaic moslein mother motion mp mr mri mrna ms msh2 msh3 msh6 msh6-positive msi msi-high msi/ihc msistabl msr1 mt mtor mu much mucin muck mucocutan mucos mucosa muir muir-torr muller mulliken multicent multicentr multidisciplinari multifoc multifunct multigener multimer multinodular multipl multiple-cas multisystem muras murigand murray muschk muscl musculoskelet must mustonen muta28 mutat mutation-associ mutation-neg mutation-posit mutation-rel mutationneg mutationposit muto mutyh mutyh-associ myeloabl myelodysplasia myelodysplast myelogen myelogenous/myeloid myeloid myeloma myelomonocyt myh myh-associ myoepitheli myomectomi myxoid myxoma myxomata myxomatosi mz n na naevoid naggan nail name nanda narla narod narumi nasal nasolaryngoscopi nat nathanson nation natl natur nava nbcc nbs1 nccn nci nci-wg nd near neck need negat neither nelen nelson neonat neoplasia neoplasm neoplast nerv nervous netherland netw network neuhausen neuro neuro-cardio-facial-cutan neuroblastoma neurodegen neuroectoderm neurofibromata neurol neurolog neuroma neuron neurosurg neurothekeoma neurofibroma neurofibromata neurofibromatosi nevanlinna never nevi nevoid nevus new newest newli newman nexus nf nf1 ng ng/ml nh nicholson nickel nickerson nicola nielsen niihori nijmegen nikkila nine nineti nippl nishikawa nj nlindor nm nml node nodul nodular nola3 non non-ashkenazi non-bhd non-carri non-hispan non-hodgkin non-jewish non-medullari non-polyposi noncarri noncutan nondrink none nonepidermolyt nonetheless nonfamili nonhereditari nonhodgkin nonhomolog nonident noninvas nonpapillari nonpenetr nonpolyposi nonrandom nonren nonsens nonsmok nonsteroid nonsyndrom noonan nop10 noralan nordic normal north nose notabl note notochord novel novemb novo nt nuclear nucleolar nucleotid number numer nv nystagmus o obe obligatori observ obtain obvious occasion occipitofront occult occulta occur occurr octob ocular odd odontogen oe oesophag offer offspr often offit ogden oi oja okamura olafsdottir older oldest oliveira oliviera ollier ollikainen olopad olpin olschwang olsen olson om omim omphalocel oncocyt oncocytoma oncocytosi oncogen oncol oncolog oncologist one one-third onlin onset ontario onward oophorectomi oostra oper opin opinion opportun oppos optim option oral order org organ orhan origin orlow orr orthop orthopantogram osato oshimo ossifi ossific osteochondroma osteochondromatosi osteochondromyxoma osteoma osteoporosi osteosarcoma osteotomi ostrer other other-lynch otolaryngol outcom outlin outnumb ovari ovarian over overact overal overexpress overgrowth overlap overnight overrepres overt overutil overview overwhelm owe owen oxford oxyphil ozek p p11.2p12 p11.2p14.2 p12 p12p11.2 p14.2p11.2 p22 p53 p57kip2 pa pace paf pain pair pal palacio palat palb2 pall palld palm palmar palmari palmoplantar palmqvist palpat palpebr pancrea pancreat panel panescu pantaleoni pap papa papillari papilloma papillomat papillomata papillomatosi papul paradox paraganglioma paramet paranas parathyroid parafibromin pardi parenchyma parent parent-of-origin pariet pariti park parmigiani parotid parri part partial particip particular partner pasini pass past pastakia patch patel patern pathogen pathogenesi pathognomon pathol patholog pathologybas pathway patient pattern patterson pautler pavlovich pc pcap pd pde11 pde11a pdgfra pdp pe peacock peak pediatr pediatrician pedigre pedigree-defin pedroni peduncul peltomaki pelvi pelvic penetr peni penil peopl per percent percentag percentil perform perhap perian perifollicular perineum period perior peripher periton peritoneum permiss permit permuth permuth-wey peron perrillat person perspect pertin petersen peto petruzella peutz pezzolesi pf pfeiffer pffs pg ph phalang pharoah phelan phenocopi phenom phenomenon phenotyp phosphodiesteras phosphoinositol3 phosphoinositol3-kinase phosphor physic pierz pigment pigmentosum pilarski pilocyt pilomatricoma pilot pit pitch pithukpakorn pituitari pj pl place plantar plantari plaschk plasma plast plastica platelet platelet-deriv platz plausibl play pleas pleomorph pleural plevriti plug plus pm pms1 pms2 pms2-related pnet pneumothorax pneumothorax-associ po poikilocytosi point poland polici polish pollard polycyst polydactyli polyglutamin polyhydramnio polymorph polyostot polyp polypectomi polyposi ponder ponti pool poor poplit popul population-attribut population-bas populationbas porat porter portier portion posit possibl post post-op post-relaps posterior postgenom postmenopaus postnat potenti potocki pouilli power ppk ppnad pract practic pragmat prat preand precancer preced precis precursor predict predictor predilect predispos predisposit predomin preexist prefer preferenti pregnanc preliminari premalign prematur premenopaus prenat preoper prepar presenc present preserv press presum prev preval prevent previous price primari primarili primit princip principl print prior privaci prkar1a probabl proband problem proc procedur process produc product profound progeria progesteron prognosi prognost program progress prolactin prolactinoma prolymphocyt promin promot prompt prone proof propens prophylact proport propos prose prospect prostat prostate-cancer-suscept prostate-specific prostatectomi protect protein proteus proteus-lik protocol prove proven provid provoc proxim profil prurit pruss ps psa psammomat psas pseudoaneurysm pseudogen psycholog psychosoci pt ptch pten pthr1 ptpn11 ptrend pub puberti public publish puig pukkala pulmon pulmonari pumbo punctat purpos push putat pylka pz q q12 q15 q22.2 q23 q24 q24.13 q25 q26 q28 q33 q43 quadraradi qualiti quantifi question quit r r17 r206 r216 r3 r8 ra rabe racial/ethnic rad51 radial radiat radiation-fre radiation-induc radic radii radiograph radiol radiolog radiomimet radiosensit radiotherapi raedt raeft raf1 rahman rais raloxifen ramenofski rand random rang rapid rare rariti ras/mapk raskind rate rather ratio rauen rawstron rb rc rcc 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riccio rich richard riffaud right right-sid rijcken riley rimmer ring risch rise risk risk-reduc rittierodt rj rl rm rna rnasel roa robinson robinson-whit robson rochest rodl roemel role roobol rose rosen rosenberg rossi rotat rothmund rotondano routin rowan rr rrs rs rubin rudd rule rump runx1/aml1 runxi russia russo rutter ruvalcaba rw rychter sa sacral sadetzki safe saharan sahin said salpingo salpingo-oophorectomi salpingooophorectomi sampl sampson samuelsen sanchez sandrini sankila sanz sarcoma sarcomat saslow satagopan satisfactorili satisfi sato savag sb sc scacheri scan scand scapula scarabin sce sces schaffer schaid schiller schindler schleberg schlegelberg schleutker schmale schmeler schmidt schneider schnyder schrager schreibman schroder schultz schulz schumm schwann schwann-cel schwannoma schwartz sci scienc scientific sclera scleros sclerosi scope score scott screen scriver sdh sdhb sdhc sdhd se seal search sebac second second-degre seconddegre secret section see seek seem 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