Lynch syndrome: still not a familiar picture
© Hes; licensee BioMed Central Ltd. 2008
Received: 18 December 2007
Accepted: 20 February 2008
Published: 20 February 2008
Germ line mutations in mismatch repair genes underlie Lynch syndrome and predispose carriers for colorectal carcinoma and malignancies in many other organ systems.
A large Lynch syndrome family with 15 affected family members and involvement in 7 organs is reported. It illustrates a lack of awareness and knowledge about this hereditary tumor syndrome among doctors as well as patients. None of the described family members underwent presymptomatic screening on the basis of the family history.
Hereditary features, like young age at diagnosis, multiple tumors in multiple organs and a positive family history, should lead to timely referral of suspected cases for genetic counseling and diagnostics. For Lynch syndrome, these features can be found in the Amsterdam and Bethesda criteria. Subsequently, early identification of mutation carriers might have diminished, at least in part, the high and early morbidity and mortality observed in this family.
Amsterdam criteria II and revised Bethesda guidelines.
Amsterdam criteria II
There should be at least three relatives with colorectal cancer (CRC) or with a Lynch syndrome associated cancer: cancer of the endometrium, small bowel, ureter or renal pelvis.
- one relative should be a first-degree relative of the other two;
- at least two successive generations should be affected,
- at least one tumor should be diagnosed before the age of 50 years,
- FAP should be excluded in the CRC case if any,
- tumours should be verified by histopathological examination.
Revised Bethesda guidelines
1. CRC diagnosed in a patient aged <50 years.
2. Presence of synchronous, metachronous colorectal, or other Lynch syndrome-related tumours*, regardless of age.
3. CRC with MSI-high phenotype diagnosed in a patient aged < 60 years.
4. Patient with CRC and a first-degree relative with a Lynch syndrome-related tumor, with one of the cancers diagnosed aged <50 years.
5. Patient with CRC with two or more first-degree or second-degree relatives with a Lynch syndrome-related tumor, regardless of age.
In retrospect, some doctors had indeed signaled noteworthy features in this family. First, in 1979, a gynecologist who was treating patient II-6 consulted a colleague about the very early onset of endometrial carcinoma. His colleague reassured him at that time that the age at presentation, 41 years old, was not in fact very rare. Second, in 2005, a gastroenterologist spoke of possible HNPCC in patient III-2, who was diagnosed with carcinoma of the papilla of Vater after she had developed three separate colon carcinomas, but no further action was taken. Third, in 2006, an oncologist treating patient IV-1 suggested MSI testing on tumor material after his mother (III-1) had expressed her concern about the family history, but did not proceed.
This family is a fine example of the plethora of tumors that may occur in Lynch syndrome and demonstrates why the term Lynch syndrome is preferred nowadays over HNPCC (hereditary non-polyposis colorectal cancer), which only refers to CRC. The organ involvement in this family included seven organ systems: colon, uterus, skin, stomach, urinary tract, pancreas and hepatobiliary system. The manifestation of keratoacanthoma in this family enabled a sub-classification to Muir Torre syndrome (MTS). MTS is a variant of Lynch syndrome and germline mutations in the three main Lynch syndrome genes (MLH1, MSH2 and MSH6) have been identified in MTS families [7, 8]. Keratoacanthoma should be regarded as one of the tumors that lie in the constellation of Lynch syndrome but their manifestation could depend on modifier genes and/or environmental factors.
This case report shows a considerable delay in diagnosing Lynch syndrome which negatively influenced the management of many family members. None of the family members underwent presymptomatic screening on the basis of the family history, while clinical surveillance has been shown to decrease mortality in Lynch syndrome families . Remarkably, in none of the medical reports we obtained was a family history reported extending further than first-degree relatives.
This family clearly illustrates a lack of awareness about a hereditary tumor syndrome among doctors as well as patients. In general, it is prudent to be aware of classic hereditary features, like young age at diagnosis, multiple tumors in multiple organs and a positive family history, and to refer suspected cases for genetic counseling. More specifically, these features can be found in the Amsterdam and Bethesda criteria (Table 1). Subsequently, the identification of at-risk persons will optimize the timing and efficiency that surveillance and treatment are carried out.
hereditary non-polyposis colorectal cancer
multiplex ligation-dependent probe amplification
Muir Torre syndrome
Written permission was obtained from the index-patient for publication of this case report. The author should like to thank Dr. C.M.J. Tops for carrying out the molecular genetic studies and Prof. H. Morreau for immunohistochemical analysis.
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