This document discusses two case studies of patients presenting with polyposis and other features. The first case is a 45-year-old man who previously had colon polyps and jejunal adenocarcinoma. Genetic testing was negative for familial adenomatous polyposis (FAP). The second case details a family with a history of colon cancer and a brain tumor. Genetic testing found the patient has a constitutional mismatch repair deficiency (CMMRD), also known as Turcot syndrome, caused by biallelic mutations in the PMS2 gene. CMMRD is characterized by colon polyps and brain tumors occurring at a young age. The document provides background on Turcot syndrome and compares the features

1. CASE DISCUSSIONS
IN POLYPOSIS.
D O U G L A S R I E G E R T J O H N S O N
M AY O C L I N I C F L O R I D A

3. CASE1
A 45 year-old man presented for medical genetics
evaluation. Between the ages of 20 and 30
years, the patient had nasal polyps and several
large stalked colon polyps removed. At 43
years-old, he was diagnosed with jejunal
adenocarcinoma (T1N0). Upper endoscopy
following surgery showed several stomach and
small bowel polyps. A genetic test for familial
adenomatosis polyposis (APC gene) was
negative. There was no family history of
cancer.
What is the diagnosis?

5. NASAL POLYPOSIS
Originally published in Dutch as: Peutz J. Very remarkable
case of familial polyposis of mucous membrane of
intestinal tract and nasopharynx accompanied by
peculiar pigmentations of skin and mucous membrane.
Nederl Maandschr Geneesk. 1921; 10:134-146.

6. RRIR
Smooth muscle arborizing through PJS polyp

7. CASE2
4 years old. Alive and well.
28 years old
Alive and well
48 years old
Thyroid disease
50 years old
Alive and well
25 yo dx with transverse
CRC,
25 tubular adenomas in left
colon (right colon not seen
due to obstruction).
A few stomach polyps.
At 22 yo dx left temporal
lobe glioblastoma.
“Freckles in Eye”.

9. CASE2
4 years old. Alive and well.
28 years old
Alive and well
48 years old
Thyroid disease
50 years old
Alive and well
25 yo dx with transverse
CRC,
25 tubular adenomas in left
colon (right colon not seen
due to obstruction)
A few stomach polyps.
At 22 yo dx left temporal
lobe glioblastoma.
“Freckles in Eye”.
DX: ? FAP NEW
MUTATION TURCOT

10. TERM “TURCOT SYNDROME”
AS CURRENTLY USED
FAP + brain tumor (usually meduloblastoma) = Turcot
syndrome
LS + brain tumor (usually glioblastoma) = Turcot
syndrome

11. TURCOT SYNDROME
Described in 1959 by Jacques Turcot in Diseases of the Colon and
Rectum
 Hôtel Dieu de Quebec hospital (1640) and the Laval University
 2 teenage siblings with numerous colorectal polyps. The brother (15
years old) with meduloblastoma of the spinal cord and
adenocarcinomas of the sigmoid colon and rectum. The sister (13
years old) with cerebral glioblastoma and pituitary adenoma.
 Mckusick and Osler communicated that parents were third cousins.
Crail Syndrome case report (1949)
 Adenomatous polyposis, mebullastoma of the brain stem, and
papillary thyroid cancer.
New England Journal Medicine article describing molecular phenotype.
Turcot original report 1959. 13839882.

12. CASE2
4 years old. Alive and well.
28 years old
Alive and well
48 years old
Thyroid disease
50 years old
Alive and well
25 yo dx with transverse
CRC,
25 tubular adenomas in left
colon (right colon not seen
due to obstruction)
A few stomach polyps.
At 22 yo dx left temporal
lobe glioblastoma.
“Freckles in Eye”.
Test Diagnosis Result
APC
MUTYH
MLH1/MSH2
Mismatch repair gene IHC
DNA Microsatellite Instability
DX: ? FAP NEW
MUTATION TURCOT

13. CASE2
4 years old. Alive and well.
28 years old
Alive and well
48 years old
Thyroid disease
50 years old
Alive and well
25 yo dx with transverse
CRC,
25 tubular adenomas in left
colon (right colon not seen
due to obstruction)
A few stomach polyps.
At 22 yo dx left temporal
lobe glioblastoma.
“Freckles in Eye”.
Test Diagnosis Result
APC FAP
MUTYH MAP
MLH1/MSH2 Lynch syndrome 2 genes
Mismatch repair gene IHC Lynch syndrome 5 genes
DNA Microsatellite Instability Lynch syndrome 5 genes
DX: ? FAP NEW
MUTATION TURCOT

14. CASE2
4 years old. Alive and well.
28 years old
Alive and well
48 years old
Thyroid disease
50 years old
Alive and well
25 yo dx with transverse
CRC,
25 tubular adenomas in left
colon (right colon not seen
due to obstruction)
A few stomach polyps.
At 22 yo dx left temporal
lobe glioblastoma.
“Freckles in Eye”.
Test Diagnosis Result
APC FAP Normal
MUTYH MAP Normal
MLH1/MSH2 Lynch syndrome 2
genes
Normal
Mismatch repair gene IHC Lynch syndrome 5 Abnormal
DX: ? FAP NEW
MUTATION TURCOT

15. Normal Staining of PMS2 in tumor.
Both copies of PMS2 present.
Lynch syndrome. No staining in
tumor. (Both copies of PMS2
inactivated, one inherited, one
acquired in tumor) Staining in tumor
lymphocytes and normal tissue.
Patient Results: Constitutional mismatch repair deficiency.
No staining in tumor and normal tissue.
(Both copies of PMS2 inactivated in tumor and normal by inherited mutations.)

16. CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY
First described in 1999 in two simultaneously published
reports (Ricciardone et al. 1999; Wang et al. 1999)
Synonyms.
 Childhood cancer syndrome (CCS)
 Lynch III syndrome
 „„CoLoN‟‟, Colon tumours or/and Leukaemia/Lymphoma
Constitutional mismatch repair-deficiency syndrome:
have we so far seen only the tip of an iceberg?

17. MICRO SATELLITE INSTABILITY UNRELIABLE IN
CMMRD
DNA measurements of microsatellite instability based
on comparing normal and tumor tissue MS. In LS,
the tumor MS change, so a difference can be seen.
(I think) in CMMRD normal and tumor both change
so no difference can be seen.
Only one out of the 14 brain tumours exhibited an
MSI-high genotype.
Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional
mismatch repair deficiency consortium. 24440087.

18. CMMR OVERLAPS WITH NF1: CASE 2 WITH 50 CALM.
All CMMRD patients with available clinical data (n = 18) had café-
au-lait spots (>6 spots) and three patients had
hypopigmentation. Three individuals had axillary freckles, and
one had a plexiform neurofibroma; meeting the criteria for NF-1,
but lacked germline NF-1 mutations.
Genetic and clinical determinants of constitutional mismatch repair deficiency
syndrome: Report from the constitutional mismatch repair deficiency consortium.
. 24440087.

19. TUMOR SPECTRUM OF CMMRD IN 92 PATIENTS
Cancer Number Median age (range)
of diagnosis
Hematological 30 6 (0.4-17)
Brain tumor 44 8 (2-35)
Colorectal cancer 37 16 (8-35)
Small bowel 9 26 (11-42)
2010 CMMRD Review of 92 patients.

20. DIFFERENCES IN TUMOR SPECTRUM BASED ON
GENOTYPE IN CMMRD
PMS2/MSH6> MLH1/MSH2
n 65 24
Median age of dx 9 years 4 years
Hematological
(#1 Non Hodgkins Lymphoma
Tcell)
29%
46%
Brain
35% 8%
Lynch syndrome cancer
(colon, endometrial)
68% 29%

21. CMMRD MUTATION SPECTRUM
PMS2 dominates, followed by MSH6 and MLH1.
“MSH2 mutations which are most commonly found in
Lynch syndrome are less common to absent in
CMMRD, while PMS2 and MSH6 are more commonly
observed in the syndrome. A possible explanation for
this phenomenon is low penetrance of heterozygous
mutations in MSH6 and PMS2 found in CMMRD and the
deleterious functional consequence of homozygous
mutations. Highly penetrant mutations in MSH2, may
be embryonically lethal when homozygous leading to
the lower prevalence observed in CMMRD.”

22. LABORATORY FINDINGS OF CMMRD: IGG CLASS
SWITCH
Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. 18824584.

23. Surveillance protocol for patient with for Biallelic MMR mutations.
Cancer Surveillance strategy
Children
Colon Colonoscopy annuallya
Upper GI tract and small
bowel
EGD annuallya,
video capsule endoscopy annuallya
Brainb Ultrasound at birth then MRI brain every 6 months
Leukemiab, Lymphomab Complete blood count, erythrocyte sedimentation rate,
lactate dehydrogenase every 4 months
Adults
Colon Colonoscopy annuallya
Upper GI tract and small
bowel
EGD annuallya,
video capsule endoscopy annuallya
Brainb Ultrasound at birth then MRI brain every 6 months
Leukemiab, Lymphomab Complete blood count, erythrocyte sedimentation rate,
lactate dehydrogenase every 4 months
Uterus Ultrasound annually
Upper urinary tract Ultrasound and urine cytology annually
EGD-esophagogastroduodenoscopy. a To start at 3 years of age or at diagnosis; b Brain,
leukemia/lymphoma screening should commence at birth if diagnosed prenatally.
Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional
mismatch repair deficiency consortium. 24440087.

24. EU CMMRD PARIS - JUNE 2013
“In 1968, criteria were proposed by WHO
that should be met prior to the
implementation of screening
programmes. These criteria were used to
assess surveillance in CMMR-D. The
evaluation showed that surveillance for
CRC is the only part of the programme
that largely complies with the WHO
criteria.”
Guidelines for surveillance of individuals with constitutional mismatch
repair-deficiency proposed by the European Consortium "Care for CMMR-
D" (C4CMMR-D). J Med Genet. Vasen HF and others behalf of the EU-
Consortium Care for CMMR-D (C4CMMR-D).

26. CASE 2 GENETIC TEST RESULTS
4 years old. Alive and well.
28 years old
Alive and well
48 years old
Thyroid disease
50 years old
Alive and well
PMS2 gene
mutation
(Pro246Cysfsx3)
PMS2 gene
mutation
(Ile611Asnfsx3)
25 yo dx
with
transverse
CRC.
PMS2 gene
wildtype
(normal)
CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY =
1 LS MUTATION FROM FATHER, AND 1 FROM MOTHER,
(BIALLELIC)

27. CASE 2 GENETIC TEST RESULTS
4 years old. Alive and well.
28 years old
Alive and well
48 years old
Thyroid disease
50 years old
Alive and well
PMS2 gene
mutation
(Pro246Cysfsx3)
PMS2 gene
mutation
(Ile611Asnfsx3)
PMS2 gene
wildtype
(normal)
25 yo dx
with
transverse
CRC.
or

28. ECCLESIASTES 1:9
The thing that hath been, it is that which
shall be; and that which is done is that
which shall be done: and there is no new
thing under the sun.

29. Described in 1959 by Jacques Turcot in Diseases of the Colon and
Rectum
Hôtel Dieu de Quebec hospital (1640) and the Laval University
2 teenage siblings with numerous colorectal polyps. The brother
(15 years old) with meduloblastoma of the spinal cord and
adenocarcinomas of the sigmoid colon and rectum. The sister (13
years old) with cerebral glioblastoma and pituitary adenoma.
Mckusick and Osler communicated that parents were third
cousins.
“Every case of familial polyposis should be followed
and explored, not only looking for new occurrences
of polyps in the colon and rectum, when they are not
removed by also for the appearance of other tissue
tumors elsewhere in the body.”

31. FEATURES OF TURCOT BY ITOH AND OTHERS
(1) In Turcot's syndrome the manifestations of brain tumour and colonic
polyposis are significantly associated and are not merely coincidental,
although the association of brain tumour is only incidental in the few cases of
familial polyposis coli.
(2) Moreover, an autosomal recessive mode of transmission is most likely in this
syndrome.
(3) The number of colonic polyps in Turcot's syndrome was frequently less than
100, in contrast with the study of Bussey (1975) who noted that the average
number of polyps in familial polyposis coli was about 1000 and rarely less
than 200. The analysis of macroscopic findings of colonic polyps showed that
they were fewer in number and larger in size in Turcot's syndrome compared
with familial polyposis coli.
(4) Therefore, we present the hypothesis that Turcot's syndrome is
genetically distinct from familial polyposis coli.
Turcot syndrome and its characteristic colonic
manifestations.
Itoh H, Ohsato K. Dis Colon Rectum. 1985 Jun;28(6):399-

32. There were several cafr-au-lait spots on the
skin of the chest, back, abdomen, and extremities,
but there were no nodules on the body surface.
H Itoh and others, Gut
1979. Kyushu University
Faculty of Medicine,
Fukuoka, Japan.
“There were several
cafe-au-lait spots on
the
skin of the chest,
back, abdomen, and
extremities, but
there were no
nodules on the body
surface.”

33. Proband. 13 yo from
Brazil. Youngest in a
family of 7 children. No
gastric or extracolonic
features of FAP.

36. Compared with familial polyposis coli, colonic polyps in Turcot‟s syndrome are fewer in
number and larger in size.