A 20-year-old man was found to have iron deficiency anaemia when he went to donate blood. The Blood Transfusion Service contacted his general practitioner, who referred the patient to the outpatient clinic for further investigation.
Generally, the patient was very well. He had a good appetite, his weight was steady and he ate a normal diet. He had a normal bowel habit and had never passed any blood, mucus or diarrhoea in his stools. The patient denied knowledge of any overt blood loss from any other source.
His general practitioner had organised an open access endoscopy which was normal; duodenal biopsies were unremarkable. He had a limited knowledge of his family history as his mother had died in childbirth and as a result he was an only child. His father had died of what he thought was secondary liver and lung cancer but he was unsure.
On general physical examination he was fit and athletic. The skin and mucosal membranes were unremarkable. Pulse was 70 beats per minute and regular with a blood pressure of 132/78 mmHg. Heart sounds were normal and the chest was clear. His abdomen was soft and non-tender with no palpable masses or organs. Rectal examination was normal. On viewing the rectal mucosa through a rigid sigmoidoscope the colonic mucosa was covered in innumerable polyps.
What specific genetic abnormality is responsible for this appearance?
(Please select 1 option)
1-Germline mutation of the STK11 gene on chromosome 19
2-Homozygous mutation of the MYH gene
3-Loss of the APC gene on chromosome 5
4-Mutations in mismatch repair genes (e.g. MSH2)
5-Mutation of the p53 tumour suppressor gene
answer 3.
ReplyDeleteThe patient will need a full colonoscopy and biopsy but the information presented is highly suggestive of familial adenomatous polyposis (FAP), caused by the loss of the APC gene on the short arm of chromosome 5.
Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder caused by a germline mutation of the STK11 (serine threonine kinase 11) gene, usually located on the long arm of chromosome 19. Peutz-Jeghers syndrome is associated with intestinal hamartomatous polyps, but is usually (90%) associated with peri-oral pigmentation.
Hereditary nonpolyposis colon cancer (HNPCC) and MYC polyposis do not cause multiple polyps as suggested in this case. In HNPCC, affected individuals inherit a mutation in one of several genes involved in DNA mismatch repair, including MSH2, MLH1, and PMS2. Homozygous mutations in the MYH gene have been associated with a phenotype of multiple colorectal adenomas with or without cancer. This accounts for a proportion of FAP patients without a pathogenic APC mutation.
Mutations in the p53 tumour suppressor gene are found in many different cancers. While mutations in p53 are seen in cases of colon cancer, the question asks for the specific mutation associated with polyposis coli.
The main differential in this question is between FAP and PJS but the lack of perioral pigmentation favours FAP as the diagnosis.