Skin phenotyping improves genotyping in familial cancer syndromes: an illustrative case series

Ing Winship1,2, Finlay Macrae3, Daniel Buchanan4,5

1Department of Medicine, The University of Melbourne, Melbourne, Australia. 2Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Melbourne, Australia. 3Colorectal Medicine and Genetics, Royal Melbourne Hospital, Melbourne, Australia. 4Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Melbourne, Australia. 5University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Australia


Objectives: Many familial cancer and polyposis predisposition syndromes have ectodermal indicators of potential risks of internal cancers; these external phenotypic features generally precede the onset of cancer.  The ectoderm includes the skin, hair, nails and teeth; easily recognisable physical signs may alert individuals to a hitherto unrecognised increased risk of cancer, facilitating preventive strategies for familial cancer.


Methods: An illustrative case series, where the ectodermal indicators of familial cancer syndromes have altered patient care, was reviewed against the literature.  These include Peutz Jeghers Syndrome (STK11)(n=17), polyposis/ oligodontia (AXIN 2) (n=3), Hereditary Haemorrhagic Telangiectasia and Juvenile Polyposis (SMAD4) (n=5), Birt Hogg Dube Syndrome (FLCN) (n=21), Hereditary Leiomyomatosis Renal Cell Cancer (FH) (n=17), Gorlin Syndrome (PTCH1/SUFU) (n=9). and Lynch Syndrome (MSH2/ MLH1).


Examination of facial papules, pigmentation or telangiectasias may be informative. Syndromic features may overlap, with similar features occurring in several cancer predisposition syndromes. The recognition of skin lesions is thus used to triage genotyping, where definitive risk management strategies are then based upon evidence. The yield of pathogenic mutations from the panel of genes directed by ectodermal phenotype is higher than other cancer predisposition panels.



Genotype phenotype correlation based on good clinical assessment provides clinical utility in familial cancer predisposition syndromes.  The co-existence of skin lesions and the presence of a mutation, with or without a family history, will help to shape the clinical management of individuals and develop the critical mass to change practice.  Furthermore, those found not at risk within families can be released from surveillance.