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hereditary mixed polyposis syndrome - Humpath.com - Human pathology

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hereditary mixed polyposis syndrome

MIM.601228

Friday 26 September 2003

HMPS, CRAC1,

The hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile polyps ( MIM.174900 ), colonic adenomas, and colorectal carcinomas. Many polyps are mixed in pattern.

The term ‘mixed’ relates both to the variety of polyps observed in this condition and the presence of polyps with features reminiscent of more than one of the classic types of colorectal polyp.

Synopsis

Hereditary syndrome characterized by the appearance of various types of polyps, many of which are mixed in pattern.

- atypical juvenile polyps (MIM.174900)
- colonic adenomas
- colorectal adenocarcinomas
- increased propensity to develop inflammatory polyps and metaplastic polyps.

The term ‘mixed’ relates both to the variety of polyps observed in this condition and the presence of polyps with features reminiscent of more than one of the classic types of colorectal polyp.

Grossly, the polyps resemble adenomas but show a variety of histological patterns. They frequently have an edematous and expanded lamina propria like juvenile polyps.

Polyps may also be multilobated or villiform, resembling the atypical juvenile polyps of JPS.

Glands may show a strikingly serrated architecture. The serrated epithelium may be non-dysplastic (as in a hyperplastic polyp) or adenomatous (as in a serrated adenoma).

The appearance of serration is achieved by marked crypt branching, but the branches are typically separated by a relatively abundant lamina propria whether they appear dysplastic or not.

In "traditional serrated adenomas", by contrast, the branching process is often incomplete so that the serrated contour is produced by rows of intra-epithelial micro-acini.

Additionally, the epithelium of "traditional serrated adenoma" is more overtly dysplastic, the crypts are back-to-back with little intervening lamina propria, and the architecture is frequently tubulovillous or villous.

Conventional adenomas may also occur and may be the dominant polyp type in some families or individual family members. There is an increased risk of colorectal cancer in this condition.

Polyp numbers generally range from 1 to 15 and rarely exceed 50. No extra-colonic features have been described.

The histological composition of polyps varies considerably from subject to subject, even within the same family.

Genetics

|WKP|

Neuroendocrine protein 7B2 is a protein that in humans is encoded by the SCG5 gene.

The protein expressed by this gene is widely distributed in neuroendocrine tissues. It functions as a chaperone protein for the proprotein convertase PC2 by blocking the aggregation of this protein and is required for the production of an active PC2 enzyme .
It is an intrinsically disordered protein that may also function as a chaperone for other proteins in addition to proPC2.

Pathology

- Hereditary mixed polyposis syndrome (HMPS)

  • HMPS is caused by a duplication spanning the 3’ end of the SCG5 gene and a region upstream of the GREM1 locus.
  • Hereditary mixed polyposis syndrome (HMPS) is characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals.
  • Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. (22561515)

- Locus 15q13-q14 (HMPS2/CRAC1 locus) (12696020)

  • To date, examples of HMPS have been restricted to one large and extended Ashkenazi Jewish family and smaller Ashkenazi Jewish families.
  • The HMPS locus (CRAC1) was originally mapped to chromosome 6q, but one of the subjects considered originally to be unaffected subsequently developed multiple colorectal adenomas.
  • With the benefit of more informative markers and stringent definitions of affected status, the disease locus was mapped to 15q13-q21 and in a second family to 15q14-q22. The locus was then narrowed down to 15q13-q14 when information from the two families was combined.

Differential diagnosis

HMPS may be confused with both juvenile polyposis syndrome (JPS) and "hyperplastic polyposis syndrome" (HPS). The phenotypes of JPS and HMPS may overlap and at times be indistinguishable.

An ‘HMPS’ family from Singapore was found to have a germline mutation in the BMPR1A gene (linked with JPS).

It is possible that the underlying genetic defect in HMPS will be shown to implicate a gene that is functionally related with BMPR1A.

HMPS is distinguished from "hyperplastic polyposis syndrome" (HPS)
by the relative lack of typical hyperplastic polyps and variant hyperplastic polyps known as "sessile serrated adenomas".

The polyps in HMPS present as protuberant lesions that resemble adenomas grossly regardless of the underlying histology.

The majority of polyps in "hyperplastic polyposis syndrome" (HPS) resemble hyperplastic polyps grossly, being sessile and pale.

HMPS appears to be inherited as an autosomal dominant trait, and kindreds showing linkage to 15q13-14 are all of Ashkenazi Jewish origin. Most cases of HPS are sporadic, and no Jewish link has been reported.

HMPS and HPS are unrelated conditions and the clinico-pathological distinction is usually straightforward.

Diagnostic Criteria

- Individuals and families may have mixtures of types of polyps and polyps containing mixed patterns

  • Adenomas are most frequent type
    • Both tubular and villous
  • Many polyps have features of juvenile polyps
    • Prominent edematous stroma
    • Cystic dilation of glands
    • Frequently resemble the polyps of Juvenile Polyposis syndrome
  • Epithelium frequently serrated
    • May be mixed with other patterns
    • Classic hyperplastic polyps may be seen
      • Not clear if increased over normal
  • Mixtures of above patterns are common
    - Polyps confined to colon and rectum
  • Most cases have 1-15 polyps at presentation
    • Rarely over 50

- Mean age at presentation 41 years
- Increased incidence of colorectal adenocarcinoma

  • Mean age 48, range 32-74
    - No familial extra-colorectal disorders reported
  • Autosomal dominant inheritance
    • Genetic lesion not entirely resolved
      • BMPR1A has been proposed (Cheah, O’Riordan)
      • CRAC1 15q13-q21 has been proposed (Jaegher)
    • Few kindreds reported
      • Most belong to one large Ashkenazi Jewish kindred

Open references

- Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1.
Jaeger E, Leedham S, Lewis A, Segditsas S, Becker M, Cuadrado PR, Davis H, Kaur K, Heinimann K, Howarth K, East J, Taylor J, Thomas H, Tomlinson I.
Nat Genet. 2012 May 6;44(6):699-703. doi : 10.1038/ng.2263
PMID: 22561515 Free