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Riegert-Johnson DL, Boardman LA, Hefferon T, et al., editors. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2009-.

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Cancer Syndromes [Internet].

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Identifying Patients with Familial Cancer Syndromes

, MD, PhD.

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Created: ; Last Update: February 27, 2010.


The identification of families with familial cancer syndromes would be relatively easy if all the genes for these syndromes were known and all newly diagnosed cancer patients could be screened using genetic testing. However, even if all of the genes were known, there would be several ethical, technical, financial, and other barriers to the introduction of mass genetic screening. Nevertheless, we have seen slow movement in this direction, with the suggested screening of all newly diagnosed patients with colorectal cancer for Lynch syndrome as an example (1). Still, for many years to come, the identification of familial cancer syndromes in the majority of families will rely on the alertness of clinicians and on the families’ awareness of the importance of their personal and family cancer history (2). Key elements in the diagnostic process are formulating a genetic differential diagnosis based on the cancer history and other traits. Some of the diagnostic clues may be easily observed by the clinician, whereas others need to be actively searched for. This chapter reviews the tell-tale signs of hereditary cancer and also presents an online tool, the Familial Cancer Database (www.facd.info), which may assist the clinician in the diagnostic process.

Diagnostic clues

The most common characteristics of familial cancer syndromes used to diagnosis them are discussed below. Often it is a combination of features that “sounds the alarm.”

Family history of cancer: It’s in the details!

Drawing and interpreting the patient’s medical pedigree is a crucial step. Most familial cancer syndromes have an autosomal dominant inheritance, and a family history of a particular type of cancer in successive generations is suggestive of such a syndrome, especially if the ages at diagnosis are relatively young. The suggestion of a familial cancer syndrome is stronger for familial clustering of rare cancer types like sarcomas than for clustering of common types like breast cancer.

The occurrence of different types of cancer within the same family may strongly suggest hereditary cancer if these combinations are known to be associated with a syndrome (3), e.g., breast and ovarian cancer and BRCA1 or 2 mutations; colorectal and endometrial cancer in Lynch syndrome; breast cancer and sarcoma in Li-Fraumeni syndrome; and diffuse type gastric cancer and lobular breast cancer in hereditary diffuse gastric cancer. Diagnosis of a cancer that predominantly affects one gender in a patient of the opposite gender — with breast cancer in males as the best known example — is another clue. Cancer diagnosis later in life never fully excludes a familial cancer syndrome as the range of ages at diagnosis are notoriously wide for most of these syndromes.

A positive cancer family history in itself is usually not enough to diagnose a cancer syndrome with certainty, especially when common type cancers are involved. Chance alone may cause the clustering of cancer (especially in large families), and an appreciation of the size of the family, the number of unaffected relatives, and their place in the pedigree is important. Shared environmental risk factors may contribute heavily to the familial occurrence of cancer, e.g., a familial habit of heavy smoking to the clustering of lung cancer, and they should be ascertained.

A negative family history of cancer does not exclude a familial cancer syndrome for several reasons. Virtually none of the germline mutations involved in hereditary cancer have a 100% penetrance. Families may be small or non-informative for other reasons including lack of knowledge of the family history, the death of parents and other relatives at a relatively young age from non-cancer causes, or the small number of females relatives of a proband with breast or ovarian cancer. Also, cancer patients may have a new, de novo, mutation and therefore be the first in their family with a syndrome. This phenomenon has been reported for many genetic disorders, most commonly for familial adenomatous polyposis and multiple endocrine neoplasia type 2B. De novo mutations are uncommon in patients with Lynch syndrome and BRCA1/2 hereditary breast-ovarian cancer. Apparent single cases in a family can also be caused by a different mode of inheritance, such as autosomal recessive, e.g., in MUTYH-associated polyposis, X-linked, e.g., in X-linked lymphoproliferative syndrome, or genomic imprinting, e.g., in SDHD gene-associated familial paraganglioma. In these single cases in a family, a relatively young age at diagnosis should still raise suspicion of a familial cancer syndrome.

A family history of cancer is not necessarily accurate (4-6) and should therefore be verified if possible before making a diagnosis. Clinical as well as pathological data are important. Pathology reports can supply important details on the classification of tumors, e.g., renal oncocytoma rather than clear cell renal cancer, which would be highly relevant to the genetic differential diagnosis (7). In addition, pathology reports may contain other clues, for example, basal-like phenotype and triple-negativity of breast cancer associated with BRCA1 mutations (8) or the tumor-infiltrating lymphocytes in colorectal cancer associated with Lynch syndrome and MUTYH-associated polyposis (9).

Multiple primary malignant tumors

A history of multiple primary malignancies may indicate a familial cancer syndrome, especially if these tumors occur in combinations associated with cancer syndromes and have been diagnosed at a relatively young early age. The occurrence of multiple primary common type cancers may of course simply be due to chance, especially when diagnosed at ages typical for sporadic cancer. Shared environmental risk factors can also explain some of the occurrences, e.g., primary lung and laryngeal cancer in heavy smokers. Secondary cancers may be therapy related, e.g., tumors following treatment for Hodgkin’s disease. Some may be therapy related but still be a strong indicator for a genetic predisposition. The massive occurrence of skin cancer after radiotherapy for basal cell cancer in patients with basal cell nevus syndrome, and the development of sarcomas in the field of radiation treatment for hereditary retinoblastoma are typical examples.

Multiple precursor lesions and other benign tumors

It’s not just malignant tumors that can signal a familial cancer syndrome. Benign tumors can do the same. The presence of more than 10 adenomatous colorectal polyps should prompt consideration of testing for familial adenomatous polyposis and, depending on the pedigree, for the autosomal recessive MUTYH-associated adenomatous polyposis. Multiple hamartomatous polyps, depending on the subtype, juvenile or Peutz-Jeghers type, suggest particular hamartomatous polyposis syndromes. Some types of benign skin tumors are well recognized in their association with familial cancer syndromes (10). Examples are atypical, dysplastic, nevi of the skin suggestive of hereditary melanoma and less common benign skin tumors like neurofibromas, trichilemmomas and acrochordons, suggest neurofibromatosis, Cowden syndrome and Birt-Hogg-Dubé syndrome, respectively. Ophthalmological signs may significantly contribute to the diagnosis, for example Lisch nodules of the iris which suggest neurofibromatosis type 1 or hemangioblastomas of retina which suggest von Hippel-Lindau disease.

The occurrence of common type benign tumors has generally less impact on the genetic differential diagnosis. However, common tumors can still be useful in making the diagnosis. Lipomas are a component of the multiple endocrine neoplasia type 1 and Cowden syndrome phenotype. Uterine leiomyomas, another common benign tumor, may indicate Cowden syndrome but more importantly can suggest the hereditary leiomyomatosis and renal cell cancer syndrome.

Rare neoplasms

Some rare cancer types have a much higher than average risk of being a manifestation of a familial cancer syndrome and clinicians should be aware of these types. Some well known examples are shown in Table 1.

Table 1


Table 1. Rare tumor types and their associated cancer syndrome(s). WAGR = Wilms’ tumor, aniridia, genital-urinary anomalies and retardation.

Congenital anomalies and other non-oncological features

In general, the presence of congenital anomalies in a patient with cancer should prompt thinking of the possibility of one of the rare cancer syndromes. Dedicated handbooks or software tools can help the clinician in classifying and interpreting these anomalies (11-13). Pediatric cancer and congenital overgrowth syndromes are a well known combination, e.g. Wilms’ tumor in Beckwith-Wiedemann syndrome. Many more examples exist and we name just a few. Macrocephaly can be a sign of Cowden syndrome, a disorder associated with breast cancer, thyroid cancer and other tumor types. Some clinicians promote measuring the head circumference in young breast cancer patients for this reason alone. Typical facies and rib anomalies in a patient with multiple basal cell skin carcinomas suggest basal cell nevus syndrome. Short stature can be associated with, for example, chromosomal breakage syndromes, including Fanconi anemia. Spots of congenital hypertrophy of the retinal pigment epithelium (CHRPE) are a classical sign of familial adenomatous polyposis.

The skin can give many clues (10). Café-au-lait spots can be seen in a range of genetic conditions, including neurofibromatosis, Fanconi anemia, and patients with two inherited (bialelic) mutated copies of a DNA mismatch repair gene. Spotty pigmentation of skin and oral mucosa can be observed in Peutz-Jeghers syndrome and Carney complex. Palmo-plantar pitting is a feature of basal cell nevus syndrome and Cowden syndrome.

Not only should one know what to look for, but also what to ask for. For example, one should consider asking for a personal or family history of pneumothorax in patients with renal cancer, as this combination is indicative of Birt-Hogg-Dubé syndrome (14).

Adding it all up

The sum of all observed features in a cancer patient and his or her family leads to the next step. Depending on the results, this can range from reassuring the patient that the cancer is unlikely to be genetic, to DNA testing or other lab analysis, or to a final diagnosis on the basis of a set of clinical and pedigree criteria alone. Discussing these next steps and final diagnoses is beyond the scope of this chapter. It is important to realize that many (if not most) families with clustering of common type cancers like breast or colorectal cancer will in the end not be diagnosed with a familial cancer syndrome but can still be at significantly increased cancer risk and may be eligible for enrollment into a cancer surveillance program.

The Familial Cancer Database (www.facd.info)


The Familial Cancer Database (FaCD) has primarily been developed as a tool to support the genetic differential diagnosis of cancer (15, 16). In 2008, a new online version of FaCD was published and updates have subsequently been provided on a regular basis. Use of FaCD is free for health professionals after registration. FaCD is not an expert system, but rather a tool for experts and is therefore no substitute for consulting an specialist in genetic diseases.

The software tries to match tumor and non-tumor features observed in patients and their families with any of the nearly 500 disorders presently contained in its database and provides a synopsis for each of these disorders. This synopsis focuses on phenotype and cancer risk estimates. The following classes of disorders have been included:

  • Hereditary disorders certainly or possibly associated with increased cancer risk
  • Reported familial clustering of particular types of cancer
  • Known patterns of multiple primary tumors
  • Common disorders and external risk factors associated with increased cancer risk (e.g. diabetes, alcohol). These disorders have been added to the database because they can occur in familial clusters and can be associated with their own particular cancer risks

FaCD is intended to be a comprehensive resource and includes all reported syndrome tumor associations, even if not confirmed by molecular evidence. When searching the database, the user is able to include or exclude uncertain associations from the search results. We also wanted the system to allow the user to input not only very specific search terms, e.g. ‘malignant fibrous histiocytoma’, but also broad search terms like ‘renal tumor’ (whatever type) or ‘gastrointestinal tumor’ because the user might want to check the database at a time when a reported family history still lacks details. FaCD does not contain all possible search terms but only the tumor and non-tumor features that have actually been reported in association with the syndromes included in the database.

Searching FaCD for matching disorders

A typical search would go as follows:

First, the user selects symptoms from the dropdown lists in the Symptoms-by-System menu (not shown) or through the Find symptoms box (Figure 1).

Figure 1


Figure 1. Search results of the Familial Cancer Database (www.facd.info) using the term “colo”.

Next, the user adds symptoms of his or her choice to the Selected Symptoms box (Figure 2). Bearing in mind the typical tell-tale signs of familial cancer syndromes, most users will select the most suspect features from all those that have been observed in the family under investigation. However, FaCD offers the option of including a long list of observed features and allows the user to include or exclude a selection of them in different searches by checking or unchecking the Ignore boxes in the search profile.

Figure 2


Figure 2. The Selected Symptoms box used to refine queries of the Familial Cancer Database (www.facd.info)

Next, the user has FaCD run the search profile through the database specifying:

  • how many of the symptoms should be present in a disorder to match the search criterion (e.g. “all” or “2 or more”)
  • if only disorders that are associated with the selected symptoms should be searched for (narrow search) or also those that are possibly/probably associated (wide search).

Running the search profile will return a list of matching disorders (Figure 3).

Figure 3


Figure 3. Search results from the Familial Cancer Database (www.facd.info).

The user then selects disorders of interest from this list and views them in detail, with an option to print any of these detailed syndrome descriptions. The user can also return to the search profile box, make changes to the search parameters and re-run the profile.


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Copyright © 2009-, Douglas L Riegert-Johnson.
Bookshelf ID: NBK45295PMID: 21249759


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