Elsevier

The Lancet Oncology

Volume 9, Issue 5, May 2008, Pages 462-472
The Lancet Oncology

Review
Lessons from the skin—cutaneous features of familial cancer

https://doi.org/10.1016/S1470-2045(08)70126-8Get rights and content

Summary

As the molecular basis of disease continues to be elucidated, familial cancer syndromes, which consist of a range of neoplastic and non-neoplastic features, are emerging. The usual pathway of referral to a genetics clinic or familial cancer centre is via an oncologist, when high-risk features that suggest a possible hereditary basis for the presenting cancer are recognised. Traditionally, these high-risk features include more than two family members with similar cancers over two or more generations, a young age of onset, and more than one synchronous or metachronous tumour. These features are effective in ascertaining a substantial proportion of families with hereditary breast and ovarian cancer due to a BRCA mutation, or the more common bowel-cancer predisposition syndromes, such as hereditary non-polyposis colon cancer and familial adenomatous polyposis. However, there are a range of familial cancer syndromes that are not easily detected and that can remain undiagnosed when history and examination are not extended to include non-malignant features. The identification of cutaneous signs associated with rare familial-cancer syndromes provides individuals and their families with the opportunity to undertake early surveillance for malignant and non-malignant complications that might in time be shown to improve outcomes.

Introduction

This Review outlines several important familial cancer syndromes in which cutaneous features form part of the clinical diagnostic criteria. Many of the familial cancer syndromes are recognised by so-called high-risk features, including a cluster of relatives within the patient's family who have the same or similar cancers, the development of cancer at a young age, the presentation of more than one tumour, either synchronous or metachronous, or more than one tumour within a specific group of tumours that are features of a syndrome. However, several familial cancer syndromes have additional non-malignant cutaneous features, which serve as the vital clue for a clinical diagnosis (figure 1).1, 2, 3 Many of these conditions occur as the result of a de-novo mutation and present without a family history. The role of the genetic counsellor and clinical geneticist in this setting can be useful to elucidate the significance of clinical signs. Cutaneous features can be present in many familial cancer syndromes, but this Review is restricted to conditions where a diagnosis is often delayed until the proband presents to a medical oncologist in adulthood. Focus is made on naevoid basal-cell carcinoma syndrome; syndromes predisposing to colorectal cancer; syndromes predisposing to renal cancer; and the endocrine-neoplasia syndromes. The cutaneous, neoplastic, and non-neoplastic features of neurofibromatosis type I and type II have been extensively reviewed elsewhere,4 and have not been described in any further detail in this Review.

Of note, some skin signs are very specific and can be easily recognised. However, many of the skin signs associated with cancer syndromes are non-specific skin coloured papules, and referral for histological examination can be an essential step towards a unifying family diagnosis.

Section snippets

Naevoid basal-cell carcinoma syndrome (Online Mendelian Inheritance in Man [OMIM] number 109400)

Naevoid basal-cell carcinoma syndrome is a clinically variable condition due to an autosomal dominantly inherited mutation in PTCH on 9q22.5 The estimated prevalence is one in 57 000 people, with a high new mutation rate.5, 6 PTCH functions as both a developmental regulator and a tumour-suppressor gene.7, 8 Consequently, naevoid basal-cell carcinoma syndrome (NBCCS; also known as Gorlin syndrome) is characterised by features involving many organs, including the skin. The diagnosis of NBCCS is

Hereditary non-polyposis colorectal cancer (OMIM 120435)

Hereditary non-polyposis colorectal cancer (HNPCC) is a familial cancer syndrome, with onset in young people, which results from mutations in one of the mismatch repair genes.13 Cellular loss of expression of MLH1, MSH2, MSH6, or PMS2 results in the accumulation of undetected and unrepaired DNA mismatches, and consequently, increased tumour formation. Individuals with a heterozygous germline mutation in one of these genes—and who therefore only have one functional copy—are at an increased risk

Birt-Hogg-Dube syndrome (OMIM 135150)

Birt-Hogg-Dube (BHD) syndrome is a variable autosomal dominant renal cancer predisposition condition due to a heterozygous mutation in FLCN which encodes folliculin. The prevalence of BHD syndrome is yet to be established. BHD is characterised by a triad of cutaneous signs including fibrofolliculomas, trichodiscomas, and acrochordons. In addition to an increased risk of renal neoplasm, BHD is associated with a wide spectrum of non-neoplastic features, including spontaneous pneumothorax and lung

Multiple endocrine neoplasia type 1 (OMIM 131100)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome due to heterozygous MEN1 mutations on 11q13, which results in a genetic predisposition to tumours of the pituitary gland, pancreas, and parathyroid glands, and to peptic ulcer disease. About 10% of MEN1 is caused by de-novo mutations.53, 54

Facial angiofibromas occur in 88% of patients, with more than half of individuals having more than five signs.55 These angiofibromas can cross the vermilion border of the lips. The

Conclusion

Recognition of characteristic cutaneous signs and extracutaneous features (table), in addition to the history of neoplasia, will improve the diagnosis of rare familial cancer syndromes. Many of these syndromes are associated with a high mutation rate and no family history of cancer to alert the clinician to the possibility of a germline mutation, which has a 50% chance of being passed on to subsequent offspring. For the individual, this can afford a surveillance strategy, with the possibility

Search Strategy and Selection Criteria

Data for this Review were identified by searches of Pubmed, Medline, and Online Mendelian Inheritance in Man with the search terms “familial cancer”, “cutaneous and hereditary”, “hereditary non-polyposis colorectal cancer”, “Lynch syndrome”, “Muir-Torre syndrome”, “familial polyposis”, “hamartoma syndromes”, “Peutz-Jerghers syndrome”, “Birt-Hogg-Dube syndrome”, “hereditary leiomyomatosis renal-cell carcinoma”, “familial renal cancer”, “tuberous sclerosis”, chromosome and kidney”, “Gorlin

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