Definition

MUTYH-associated polyposis (MAP, OMIM #608456) is a genetic disease caused by a biallelic mutation in the MUTYH gene that predisposes to colorectal carcinoma. Carcinomas and commonly occurring adenomatous colon polyps (between 10 and a few hundred) generally do not appear until adulthood. In addition, there is also an increased risk of developing duodenal polyps and a duodenal carcinoma. Extraintestinal manifestations are possible as well.

Key Data

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Synonyms Familial adenomatous polyposis 2 (FAP2)
Colorectal adenomatous polyposis, autosomal recessive
Multiple colorectal adenomas, autosomal recessive
Gene MUTYH
Gene product MUTYH
Function Adenine-DNA glycosylase, a DNA repair enzyme (base excision repair)
A defect leads to an accumulation of G:C>T:A transversions, resulting in a stop codon in the mRNA following replication and thus to a protein malfunction.
Heredity Autosomal recessive
Prevalence 1-2% of the population in Northern Europe is heterozygous for a MUTYH mutation.
The prevalence of biallelic MUTYH mutations is around 1:20,000-1:40,000.
Genotype-phenotype correlation Patients with a homozygous c.536A>G mutation have a greater risk of a severe disease progression and early onset (around 8 years earlier) of the disease than patients with a homozygous mc.1187G>A mutation.
Penetrance High for colorectal carcinoma, but incomplete (lifetime risk 43-100%)
Unknown for colorectal polyps, but probably incomplete (around one third of patients with colorectal carcinoma do not present with any polyps)
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Diagnosis

Suspected Diagnosis

MUTYH-associated polyposis is suspected in cases presenting with the following:

Clinical:

  • Colon adenomas and/or hyperplastic/serrated sessile polyps in the following quantities:

    • 1-10 (at < 40 years of age)
    • 10 (at 40-60 years of age)
    • 20 (at > 60 years of age)
  • 20 to several hundred colon adenomas and/or hyperplastic/serrated sessile polyps

  • Polyposis coli (e.g. > 100 colon polyps) without a heterozygous APC germline mutation

  • Colorectal carcinoma at < 40 years of age

  • A concomitant family history of colon carcinoma (± polyps), compatible with autosomal-recessive inheritance

Histological / Molecular Genetic:

  • A somatic KRAS mutation in colorectal carcinoma

  • Microsatellite instability in colorectal carcinoma

Genetic Diagnostics

The diagnosis of “MUTYH-associated polyposis” is confirmed by the detection of a biallelic germline mutation in the MUTYH gene through sequence analysis and, if necessary, subsequent deletion/duplication analysis. It may be helpful to use panel examinations consisting of multiple genes.

Differential Diagnoses

Clinical Presentation

Colon Polyps

The number of colon polyps that occur is usually between ten and a few hundred in patients with a MUTYH mutation. On average, the polyps appear at the age of 50, rarely before the age of 30, and may be classic or serrated adenomas or else hyperplastic/serrated sessile or mixed (hyperplastic and adenomatous) polyps.

Colon Carcinoma

If no early-detection measures are performed, the lifetime risk of developing colorectal carcinoma is between 43% and 100%. The majority of carcinomas do not occur until adulthood, meaning that the risk of developing colon carcinomas is extremely low during childhood and adolescence.

Duodenal Polyps and Duodenal Carcinoma

Duodenal polyps can be found in 17-25% of patients with a MUTYH mutation. The lifetime risk of duodenal carcinoma is around 4%.

Gastric Fundus Polyps and Gastric Carcinoma

Lesions were discovered during screening gastroscopies in 11% of MAP patients.

Extraintestinal Manifestations

The incidence of extraintestinal malignancies is about twice as high for people with a MUTYH mutation compared to the general population. The following extraintestinal manifestations have been described to date:

  • Ovarian, bladder, mammary, and endometrial carcinomas

  • Skin: benign and malignant tumors of the sebaceous glands, squamous epithelial carcinoma, basal cell carcinoma, benign skin tumors

  • Thyroid: thyroid carcinoma, multinodular goiter, singular thyroid nodules

  • Cysts in the jaw

Therapeutic Considerations

A polypectomy should be performed whenever colon polyps are suspected. If the number and density of polyps is high, a subtotal colectomy or a proctocolectomy is worth considering. As when treating FAP and AFAP, a colectomy is likewise recommended as soon as adenomas occur, although this measure can be delayed depending on the size, histology, and number of adenomatous polyps. If colorectal cancer is diagnosed, a colectomy is inevitable.

Surveillance Recommendations

Surveillance Recommendations

For Children and Adolescents

No surveillance measures are recommended for children and adolescents.

For Adults

  • A colonoscopy every 2 years starting at the age of 18

  • An esophagogastroduodenoscopy as of 25-30 years of age

Since MAP is an autosomal recessively inherited disease, a preliminary diagnosis of the partner of an identified MUTYH mutation carrier may be considered prior to conception in order to assess the risk of any future children developing a MAP.

Additional Information