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
CASE1
A 45 year-old man presented for medical genetics
evaluation. Between the ages of 20 and 30
years, the patient had na...
NASAL POLYPOSIS
Originally published in Dutch as: Peutz J. Very remarkable
case of familial polyposis of mucous membrane o...
RRIR
Smooth muscle arborizing through PJS polyp
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...
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...
TERM “TURCOT SYNDROME”
AS CURRENTLY USED
FAP + brain tumor (usually meduloblastoma) = Turcot
syndrome
LS + brain tumor (us...
TURCOT SYNDROME
Described in 1959 by Jacques Turcot in Diseases of the Colon and
Rectum
 Hôtel Dieu de Quebec hospital (1...
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...
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...
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...
Normal Staining of PMS2 in tumor.
Both copies of PMS2 present.
Lynch syndrome. No staining in
tumor. (Both copies of PMS2
...
CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY
First described in 1999 in two simultaneously published
reports (Ricciardone et ...
MICRO SATELLITE INSTABILITY UNRELIABLE IN
CMMRD
DNA measurements of microsatellite instability based
on comparing normal a...
CMMR OVERLAPS WITH NF1: CASE 2 WITH 50 CALM.
All CMMRD patients with available clinical data (n = 18) had café-
au-lait sp...
TUMOR SPECTRUM OF CMMRD IN 92 PATIENTS
Cancer Number Median age (range)
of diagnosis
Hematological 30 6 (0.4-17)
Brain tum...
DIFFERENCES IN TUMOR SPECTRUM BASED ON
GENOTYPE IN CMMRD
PMS2/MSH6> MLH1/MSH2
n 65 24
Median age of dx 9 years 4 years
Hem...
CMMRD MUTATION SPECTRUM
PMS2 dominates, followed by MSH6 and MLH1.
“MSH2 mutations which are most commonly found in
Lynch ...
LABORATORY FINDINGS OF CMMRD: IGG CLASS
SWITCH
Human PMS2 deficiency is associated with impaired immunoglobulin class swit...
Surveillance protocol for patient with for Biallelic MMR mutations.
Cancer Surveillance strategy
Children
Colon Colonoscop...
EU CMMRD PARIS - JUNE 2013
“In 1968, criteria were proposed by WHO
that should be met prior to the
implementation of scree...
CASE 2 GENETIC TEST RESULTS
4 years old. Alive and well.
28 years old
Alive and well
48 years old
Thyroid disease
50 years...
CASE 2 GENETIC TEST RESULTS
4 years old. Alive and well.
28 years old
Alive and well
48 years old
Thyroid disease
50 years...
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: ...
Described in 1959 by Jacques Turcot in Diseases of the Colon and
Rectum
Hôtel Dieu de Quebec hospital (1640) and the Laval...
FEATURES OF TURCOT BY ITOH AND OTHERS
(1) In Turcot's syndrome the manifestations of brain tumour and colonic
polyposis ar...
There were several cafr-au-lait spots on the
skin of the chest, back, abdomen, and extremities,
but there were no nodules ...
Proband. 13 yo from
Brazil. Youngest in a
family of 7 children. No
gastric or extracolonic
features of FAP.
Compared with familial polyposis coli, colonic polyps in Turcot‟s syndrome are fewer in
number and larger in size.
Case discussions in polyposis
Case discussions in polyposis
Case discussions in polyposis
Case discussions in polyposis
Case discussions in polyposis
Case discussions in polyposis
Case discussions in polyposis
of 36

Case discussions in polyposis

Published on: Mar 4, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Case discussions in polyposis

  • 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
  • 2. 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?
  • 3. 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.
  • 4. RRIR Smooth muscle arborizing through PJS polyp
  • 5. 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”.
  • 6. 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
  • 7. TERM “TURCOT SYNDROME” AS CURRENTLY USED FAP + brain tumor (usually meduloblastoma) = Turcot syndrome LS + brain tumor (usually glioblastoma) = Turcot syndrome
  • 8. 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.
  • 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”. Test Diagnosis Result APC MUTYH MLH1/MSH2 Mismatch repair gene IHC DNA Microsatellite Instability DX: ? FAP NEW MUTATION TURCOT
  • 10. 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
  • 11. 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
  • 12. 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.)
  • 13. 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?
  • 14. 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.
  • 15. 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.
  • 16. 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.
  • 17. 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%
  • 18. 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.”
  • 19. LABORATORY FINDINGS OF CMMRD: IGG CLASS SWITCH Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. 18824584.
  • 20. 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.
  • 21. 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).
  • 22. 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)
  • 23. 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
  • 24. 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.
  • 25. 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.”
  • 26. 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-
  • 27. 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.”
  • 28. Proband. 13 yo from Brazil. Youngest in a family of 7 children. No gastric or extracolonic features of FAP.
  • 29. Compared with familial polyposis coli, colonic polyps in Turcot‟s syndrome are fewer in number and larger in size.

Related Documents