Li-Fraumeni Syndrome

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Cowden Disease
Multiple hamartoma syndrome, or Cowden disease, is a rare genetic syndrome with multiple clinical features. The most consistent and characteristic findings are mucocutaneous lesions, including multiple facial trichilemmomas, papillomatosis of the lips and oral mucosa, and acral keratoses. Benign proliferations in other organ systems, including thyroid goiter and adenomata, gastrointestinal polyps, uterine leiomyomata, and lipomata, are common in patients with Cowden disease. Nonmalignant abnormalities of the breast are similarly noted in these patients and include fibroadenomas, fibrocystic lesions, areolar and nipple malformations, and ductal epithelial hyperplasia.

A marked increase in breast cancer incidence compared with that in the general population was observed in an early series of cases of Cowden disease. Breast neoplasms occurred in 10 of the 21 female patients; lesions were bilateral in 4 women. Additional cases of Cowden syndrome now have been published, bringing the total number of reported patients to 83, of whom 51 are female. The total number of women with breast cancer and Cowden syndrome totals 15 (29%). Because many of the women in these families are still alive and are at risk of developing breast cancer, the number of Cowden syndrome women with breast cancer is likely to increase, raising current estimates for the lifetime risk of developing breast cancer for women with this syndrome.

The gene for Cowden disease was mapped to band 10q22-23 in 1996. In 1997, PTEN/MMAC1/TEP1 (phosphatase and tensin homologue/mutated in multiple advanced cancers 1/transforming growth factor b–regulated and epithelial cell–enriched phosphatase 1) was identified as the responsible gene.

The wild-type PTEN protein has been shown to be a “dual-specificity” phosphatase. These proteins remove phosphate groups from other proteins, an important regulatory function that often reversibly inactivates proteins. Tyrosine phosphatases have been postulated to act as tumor suppressors by offsetting the oncogenic, growth-promoting action of tyrosine kinases-proteins that put phosphate groups onto proteins, often activating them. PTEN also has homology to tensin, a cytoskeletal protein that binds actin in focal adhesions. The biological significance of this finding has yet to be determined, but further study of this gene product should provide additional insight into the factors that result in malignant transformation.

Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome, first described in the 1920s, is characterized by the occurrence of hamartomatous polyps in the small bowel and pigmented macules of the buccal mucosa, lips, fingers, and toes. It is an autosomal dominant disorder that has been reported to occur in approximately 1 in 20,000 live births. More recently, it has been associated with an excess incidence of tumors involving the breast, gastrointestinal tract, ovary, testis, and uterine cervix. Two studies have attempted to define the degree of cancer risk associated with the syndrome.

Giardiello et al. described a cohort of 31 patients followed from 1973 to 1985. Forty-eight percent of the patients developed cancer in that interval: Four developed gastrointestinal cancer and ten developed nongastrointestinal cancer, representing a relative risk 18 times that of the general population.

Subsequently, another group of investigators reported an elevated risk of breast and gynecologic cancers in women with Peutz-Jeghers syndrome. In this cohort of 34 patients, the affected women had a relative risk of cancer of approximately 20, whereas male patients had a lower cancer risk, approximately sixfold that of the general population.

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