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HEREDITARY MIXED POLYPOSIS SYNDROME
ASSOCIATED WITH A BMPR1A GERMLINE
MUTATION: A CASE-REPORT
A. Martayan, L. Sanchez Mete, A. Antenucci, M. Diodoro, N. Resta, V. Stigliano
XII Congresso Nazionale A.I.F.E.G.
Centro Congressi Villa Cagnola Gazzada Schianno (VA)
16-17 Ottobre 2014
Albero genealogico della famiglia Sxxx
Kcolon+poliposi?
45aa
3
2
Alcuni deceduti per senectus o
altre cause
1935
Dec. a 10 anni
Cause imprecisate
LL
PoliposiCCR 35 (sx)
1961
1967
1969
LS
AS
1996
1999
Case description
• In 2011 two brothers of 11 and 14 years of age referred to the
Hereditary Colorectal Cancer Clinics of our Institution with a diagnosis
suspicion of Familial Adenomatous Polyposis (FAP)
– The 14 years old girl had 10 adenomatous polyps in the right colon and the 11
years old boy had about 20, diffuse, adenomatous and one hyperplastic
polyps.
– Their father died from colon cancer associated with diffuse polyposis at the age
of 35
APC testing was first performed and no clearly pathogenic mutations
could be detected. Two distinct rare variants could be detected:
– In the girl: c.7504G>A (p.Gly2502Ser) - “likely benign”
– In the boy: c.3949G>C (p.Glu1317Gln) – “controversy on clinical significance”
• At follow-up colononoscopies the girl had 2 polyps <1cm, in the right
colon, histologically classified as inflammatory pseudopolyps and the
boy had 10 polyps <1,5 cm, in the right colon, histologically classified as
hamartomatous, adenomatous and hyperplastic polyps.
• A diagnosis suspicion of
– Serrated Polyposis (SPS) or
– Juvenile Polyposis (JPS) or
– Hereditary Mixed Polyposis syndrome (HMPS)……… was raised
• SMAD4 and BMPR1A genes were tested
• In both patients a bona fide pathogenic mutation
in BMPR1A gene (c.517_519delinsATGA) was
detected
• The same mutation was also detected in the
tumour tissue of the father
Albero genealogico della famiglia Sxxx
BMPR1A c.517_519delinsATGA
mutation status
Kcolon+poliposi?
45aa
3
2
Alcuni deceduti per senectus o
altre cause
1935
+
Dec. a 10 anni
poliposi?
-
Poliposi 30
CCR 35
1967
1961
1969
LS
AS
+
1996
1999
+
HGMD®
Discussion and Conclusions
The diagnosis of a specific hereditary gastro-intestinal polyposis
syndrome is complicated due to:
– A considerable genetic heterogeneity
– The common variable intra- and inter-familial expressivity of
the same underlying genotype
BMPR1A gene pathogenic variants are associated with both JPS
and HMPS (type 2)
Multiple polyps showing hyperplastic, adenomatous and
inflammatory morphology could be detected in either of the two
patients
A diagnosis of Hereditary Mixed Polyposis Syndrome type 2
(HMPS2 as to OMIM# 610069) was made
AXIN2, PPP2R1B, WIFI, SFRP1 (Wnt pathway) and SMAD4 and BMPR1A (TGF-B)
In 17% (6/38) of the patients the causative
mutation of thepolyposis was identified
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