Journal Pre-proof

Lynch syndrome or hereditary non polyposis colorectal cancer (HNPCC) in a

moroccan family: Case report

F.Z. Outtaleb, A. Alami, N. Serbati, N. Benchakroun, Z. Bouchbika, H. Jouhadi, N.

Tawfiq, S. Sahraoui, A. Benider, H. Dehbi

PII: S2049-0801(21)00011-X
DOI: https://doi.org/10.1016/j.amsu.2021.01.017
Reference: AMSU 2069

To appear in: Annals of Medicine and Surgery

Received Date: 23 December 2020

Revised Date: 5 January 2021
Accepted Date: 8 January 2021

Please cite this article as: Outtaleb FZ, Alami A, Serbati N, Benchakroun N, Bouchbika Z, Jouhadi H,
Tawfiq N, Sahraoui S, Benider A, Dehbi H, Lynch syndrome or hereditary non polyposis colorectal
cancer (HNPCC) in a moroccan family: Case report, Annals of Medicine and Surgery (2021), doi: https://
doi.org/10.1016/j.amsu.2021.01.017.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.

© 2021 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.

SCARE 2020 Checklist

Page
Topic Item Checklist Item Description
Number

Title - The words ‘case report’ should appear in the title. The ok
title should also describe the area of focus (e.g.
1
presentation, patient population, diagnosis, surgical
intervention or outcome).

Key Words - Include three to six keywords that identify what is ok

covered in the case report (e.g. patient population,
2

of
diagnosis or surgical intervention).
- Include ‘case report’ as one of the keywords.

ro
Abstract Introduction and Importance ok
-
-p
Describe what is important, unique or educational about
3a
re
the case, and what does this add to the surgical
literature.
lP

Case Presentation ok
na

3b - Presenting complaints, clinical and demographic details,

and the patient’s main concerns.
ur

Clinical Findings and Investigations ok

Jo

3c - Clinical findings, investigations performed, main

differentials, and subsequent diagnosis.

Interventions and Outcome ok

3d - Describe the rationale for choosing the intervention.
- Describe what was the end result.

Relevance and Impact ok

3e - Describe the main take-away lessons or potential
implications for clinical practice (minimum of three).

Introduction Background ok
- Describe briefly the area of focus and the relevant
background contextual knowledge.
4 Rationale
- Describe why the case is different to what is already
known and why it is important to report?
- Is the case rare or interesting for the specific healthcare
 setting, population or country, or is it applicable globally?
Guidelines and Literature
- Give reference to relevant surgical literature and current
standards of care, including any specific guidelines.

Patient Demographic Details ok

Information - Include de-identified demographic details of the patient
(e.g. age, sex, ethnicity, occupation).
5a
- Where possible, include other useful pertinent
information (e.g. body mass index, hand dominance,
income, level of education, marital status).

of
Presentation ok

ro
- Describe the patient’s presenting complaint.

5b
- -p
Include a collateral account of the history if relevant.
- Describe the patient’s mode of presentation (e.g. self-
re
presentation, ambulance or referred by family physician
lP

or other hospital clinicians).

Past Medical and Surgical History ok

na

5c - Include any previous interventions and relevant

ur

outcomes.

Drug History and Allergies ok

Jo

- Specify any acute, repeat, and discontinued

5d
medications.
- Include any allergies and/or adverse reactions.

Family History ok
- Health information regarding first-degree relatives,
specifying any inheritable conditions.
Social History
- Indicate smoking, alcohol, and recreational drug use.
5e
- Level of social independence, driving status, and type of
accommodation.
Review of Systems
- If appropriate, report on any other information gathered
outside of the focused history.

Clinical 6
Findings - Describe the general and significant clinical findings
 based on initial inspection and physical examination.

Timeline - Summarise the sequence of events leading up to the ok

patient’s presentation.
- Delays from presentation to diagnosis and/or
7
intervention should be reported.
- Use tables or figures to illustrate the timeline of events if
needed.

Diagnostic Diagnostic Assessment ok

Assessment - Bedside (e.g. urinalysis, electrocardiography,
and

of
echocardiography).
Interpretation
8a - Laboratory (e.g. biochemistry, haematology,

ro
immunology, microbiology, histopathology).
- -p
Imaging (e.g. ultrasound, X-ray, CT/MRI/PET).
- Invasive (e.g. endoscopy, biopsy).
re
Diagnostic Challenges ok
lP

8b - Where applicable, describe what was challenging about

the diagnoses (e.g. access, financial, cultural).
na

Diagnostic Reasoning ok
ur

8c - Describe the differential diagnoses, why they were

considered, and why they were excluded.
Jo

Prognostic Characteristics ok
8d
- Include where applicable (e.g. tumour staging).

Intervention Pre-Operative Patient Optimisation ok

- Lifestyle (e.g. weight loss).
- Medical (e.g. medication review, treating any relevant
9a
pre-existing medical concerns).
- Procedural (e.g. nil by mouth, enema).
- Other (e.g. psychological support).

Surgical Interventions ok
- Describe the type(s) of intervention(s) used (e.g.
pharmacological, surgical, physiotherapy, psychological,
9b
preventative).
- Describe any concurrent treatments (e.g. antibiotics,
analgesia, antiemetics, venous thromboembolism
 prophylaxis).
- Medical devices should have manufacturer and model
specifically mentioned.

Specific Details regarding Interventions ok

- Describe the rationale behind the treatment offered, how
it was performed and time to intervention.
- For surgery, include details on the intervention (e.g.
anaesthesia, patient position, preparation used, use of
9c other relevant equipment, sutures, devices, surgical
stage).

of
- The degree of novelty for a surgical technique/device

ro
should be mentioned (e.g. ‘first in human’).
- -p
For pharmacological therapies, include information on
the formulation, dosage, strength, route, and duration.
re
Operator Details and Setting of Intervention ok
lP

- Where applicable, include operator experience and

position on the learning curve, prior relevant training,
na

and specialisation (e.g. ‘junior trainee with 3 years of

9d
surgical specialty training’).
ur

- Specify the setting in which the intervention was

Jo

performed (e.g. district general hospital, major trauma

centre).

Deviation from Initial Management Plan ok

- State if there were any changes in the planned
9e
intervention(s), and describe these alongside the
rationale (e.g. delays to intervention).

Follow-Up Specify Details regarding the Follow-Up ok

and - When (e.g. how long after discharge, frequency,
Outcomes maximum follow-up length at time of submission).
- Where (e.g. home via video consultation, primary care,
10a secondary care).
- How (e.g. telephone consultation, clinical examination,
blood tests, imaging).
- Any specific long-term surveillance requirements (e.g.
imaging surveillance of endovascular aneurysm repair or
 clinical exam/ultrasound of regional lymph nodes for skin
cancer).
- Any specific post-operative instructions (e.g. post-
operative medications, targeted physiotherapy,
psychological therapy).

Intervention Adherence and Compliance ok

- Where relevant, detail how well the patient adhered to
and tolerated the advice provided (e.g. avoiding heavy
10b
lifting for abdominal surgery, or tolerance of
chemotherapy and pharmacological agents).

of
- Explain how adherence and tolerance were measured.

ro
Outcomes ok
- -p
Expected versus attained clinical outcome as assessed
by the clinician. Reference literature used to inform
re
10c
expected outcomes.
lP

- When appropriate, include patient-reported measures

(e.g. questionnaires including quality-of-life scales).
na

Complications and Adverse Events ok

ur

- Precautionary measures taken to prevent complications

(e.g. antibiotic or venous thromboembolism prophylaxis).
Jo

- All complications and adverse or unanticipated events

should be described in detail and ideally categorised in
accordance with the Clavien-Dindo Classification (e.g.
blood loss, length of operative time, wound
complications, re-exploration or revision surgery).
10d - If relevant, was the complication reported to the relevant
national agency or pharmaceutical company.
- Specify the duration of time between completion of the
intervention and discharge, and whether this was within
the expected timeframe (if not, why not).
- Where applicable, the 30-day post-operative and long-
term morbidity/mortality may need to be specified.
- State if there were no complications or adverse
outcomes.

Discussion 11a Strengths ok

 - Describe the relevant strengths of the case.
- Detail any multidisciplinary or cross-speciality relevance.

Weaknesses and Limitations ok

- Describe the relevant weaknesses or limitations of the
case.
11b
- For novel techniques or devices, outline any
contraindications and alternatives, potential risks and
possible complications if applied to a larger population.

Relevant Literature ok

of
- Include a discussion of the relevant literature and, if
11c appropriate, similar published cases.

ro
- Describe the implications for clinical practice guidelines
-p
and any relevant hypotheses generated.
re
- Provide a rationale for the conclusions drawn from the ok
11d
case.
lP

Take-Away Lessons ok
na

- Outline the key clinical lessons from this case report.

- Discuss any differences in approach to diagnosis or
11e
ur

patient management which the authors might adopt in

future similar cases, based on their experience of the
Jo

case.

Patient - Where appropriate, the patient should be given the ok

Perspective opportunity to share their perspective on the
12
intervention(s) they received (e.g. sharing quotes from a
consented and anonymised interview).

Informed ok
- The authors must provide evidence of consent, where
Consent
applicable, and if requested by the journal.
- State the method of consent at the end of the article

13 (e.g. verbal or written).

- If not provided by the patient, explain why (e.g. death of
patient and consent provided by next of kin). If the
patient or family members were untraceable then
document the tracing efforts undertaken.
Additional - Please state any author contributions, ok
Information acknowledgments, conflicts of interest, sources of
funding, and where required, institutional review board
14
or ethical committee approval.
- Disclose whether the case has been presented at a
conference or regional meeting.

Clinical - Where relevant and available, include clinical images to ok

Images and help demonstrate the case pre-, peri-, and post-
Videos intervention (e.g. radiological, histopathological, patient
photographs, intraoperative images).

of
- Where relevant and available, include a link (e.g. Google

ro
15
Drive, YouTube) to the narrated operative video can be
-p
included to highlight specific techniques or operative
findings.
re
- Ensure all media files are appropriately captioned and
lP

indicate points of interest to allow for easy interpretation.

Referencing - Include reference to the SCARE 2020 publication by ok

na

the Checklist stating: ‘This case report has been reported in line with
16
the SCARE Criteria [include citation]’ at the end of the
ur

introductory section.
Jo

Annals of Medicine and Surgery

The following information is required for submission. Please note that failure to respond to these
questions/statements will mean your submission will be returned. If you have nothing to declare in any of these
categories then this should be stated.

Please state any conflicts of interest

All authors must disclose any financial and personal relationships with other people or organisations that could
inappropriately influence (bias) their work. Examples of potential conflicts of interest include employment,
consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or
other funding.

The authors declare having no conflicts of interest.

Please state any sources of funding for your research

All sources of funding should be declared as an acknowledgement at the end of the text. Authors should declare
the role of study sponsors, if any, in the collection, analysis and interpretation of data; in the writing of the
manuscript; and in the decision to submit the manuscript for publication. If the study sponsors had no such
involvement, the authors should so state.
 There is no sources of funding.

Ethical Approval

Research studies involving patients require ethical approval. Please state whether approval has been given,
name the relevant ethics committee and the state the reference number for their judgement.

of
ro
-p
re
lP

Consent
Studies on patients or volunteers require ethics committee approval and fully informed written consent which
na

should be documented in the paper.

Authors must obtain written and signed consent to publish a case report from the patient (or, where
ur

applicable, the patient's guardian or next of kin) prior to submission. We ask Authors to confirm as part of the
submission process that such consent has been obtained, and the manuscript must include a statement to this
effect in a consent section at the end of the manuscript, as follows: "Written informed consent was obtained from
Jo

the patient for publication of this case report and accompanying images. A copy of the written consent is
available for review by the Editor-in-Chief of this journal on request”.

Patients have a right to privacy. Patients’ and volunteers' names, initials, or hospital numbers should not
be used. Images of patients or volunteers should not be used unless the information is essential for scientific
purposes and explicit permission has been given as part of the consent. If such consent is made subject to any
conditions, the Editor in Chief must be made aware of all such conditions.

Even where consent has been given, identifying details should be omitted if they are not essential. If identifying
characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance
that alterations do not distort scientific meaning and editors should so note.

Written informed consent was obtained from the patient for the publication for the
publication this case report. A copy of the written consent is available for review by the
Editor-in-Chief of this journal on request.

Author contribution
Please specify the contribution of each author to the paper, e.g. study concept or design, data
collection, data analysis or interpretation, writing the paper, others, who have contributed in other ways
should be listed as contributors.

Fatima Zahra Outtaleb : Corresponding author, writing the paper,

The guarantor
The guarantor is that individual who accepts full responsibility for the work and/or the conduct of the
study, had access to the data, and controlled the decision to publish.

A. Alami : writing the paper

N. Serbati : correction of the paper
N. Benchakroun : correction of the paper
Z. Bouchbika : correction of the paper
H. Jouhadi : correction of the paper
N. Tawfiq : correction of the paper
S. Sahraoui : correction of the paper

of
A. Benider : correction of the paper
H. Dehbi : correction of the paper

ro
-p
re
lP
na
ur
Jo

Registration of Research Studies

In accordance with the Declaration of Helsinki 2013, all research involving human participants has to
be registered in a publicly accessible database. Please enter the name of the registry and the unique
identifying number (UIN) of your study.

You can register any type of research at http://www.researchregistry.com to obtain your UIN if you
have not already registered. This is mandatory for human studies only. Trials and certain observational
research can also be registered elsewhere such as: ClinicalTrials.gov or ISRCTN or numerous other
registries.

1. Name of the registry: http://www.researchregistry.com

2. Unique Identifying number or registration ID: researchregistry6394

3. Hyperlink to your specific registration (must be publicly accessible and will

be checked): https://www.researchregistry.com/browse-the-registry#home/
Guarantor

The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct
of the study, had access to the data, and controlled the decision to publish

of
Fatima Zahra Outtaleb

ro
-p
re
lP
na
ur
Jo
 Other histories – Describe the patient’s pharmacological
history including allergies, psychosocial history (Drug,
5d
smoking, and if relevant, accommodation, walking aids),
family history including relevant genetic information.

Clinical Describe the relevant physical examination and other ok

Findings 6 significant clinical findings. Include clinical photographs

where relevant and where consent has been given.

Timeline Inclusion of data which allows readers to establish the ok

sequence and order of events in the patient's history and
7

of
presentation (using a table or figure if this helps). Delay
from presentation to intervention should be reported.

ro
Diagnosti Diagnostic methods – describe all investigations taken to ok
c 8a
-p
arrive at methods: physical exam, laboratory testing,
re
Assessme radiological imaging, histopathology.
nt Diagnostic challenges – describe what was challenging
lP

8b about the diagnoses, where applicable, for example

na

access, financial, cultural.

Diagnostic reasoning – Describe the differential

ur

8c
diagnoses and why they were considered.
Jo

Prognostic characteristics when applicable (e.g. tumour

8d staging or for certain genetic conditions). Include relevant
radiological or histopathological images in this section.

Therapeut Pre-intervention considerations – if there were patient-specific ok

ic optimisation measures taken prior to surgery or other
Interventi intervention these should be included e.g. treating
9a
on hypothermia/hypovolaemia/hypotension in a burns patient,
Intensive care unit treatment for sepsis, dealing with
anticoagulation/other medications, etc.

Interventions – describe the type(s) of intervention(s) deployed

9b (pharmacologic, surgical, physiotherapy, psychological,
preventive). Describe the reasoning behind this treatment
 offered. Describe any concurrent treatments (antibiotics, ok
analgesia, anti-emetics, nil by mouth, Venous thrombo-
embolism prophylaxis, etc). Medical devices should have
manufacturer and model specifically mentioned.

Intervention details – describe what was done and how. For

surgery include details on; anaesthesia, patient position, use of
tourniquet and other relevant equipment, prep used, sutures,
devices, surgical stage (1 or 2 stage, etc). For pharmacological
9c therapies include information on the formulation, dosage,
strength, route, duration, etc. Include intra-operative

of
photographs and/or video or relevant histopathology in this

ro
section. Degree of novelty for a surgical technique/device
-p
should be mentioned e.g. "first in human".

Who performed the procedure - operator experience (position

re
on the learning curve for the technique if established,
9d
lP

specialisation and prior relevant training). For example, “junior

resident with 3 years of specialised training”
na

Changes – if there were any changes in the interventions,

9e
ur

describe these details with the rationale.

Follow-up Follow-up – describe 1) When the patients was followed up. 2) ok

Jo

and Where. 3) How (imaging, tests, scans, clinical examination,

Outcomes phone call), and 4) whether there were any specific post-
10a operative instructions. Future surveillance requirements - e.g.
imaging surveillance of endovascular aneurysm repair or
clinical exam/ultrasound of regional lymph nodes for skin
cancer.

Outcomes - Clinician assessed and (when appropriate) patient-

reported outcomes (e.g. questionnaire details). Relevant
10b
photographs/radiological images should be provided e.g. 12
month follow-up.

Intervention adherence/compliance - where relevant how well

10c
patient adhered to and tolerated their treatment. For example,
 post-operative advice (heavy lifting for abdominal surgery) or
tolerance of chemotherapy and pharmacological agents

Complications and adverse events – all complications and

adverse or unanticipated events should be described in detail
and ideally categorised in accordance with the Clavien-Dindo
Classification. How they were prevented, diagnosed and
10d managed. Blood loss, operative time, wound complications, re-
exploration/revision surgery, 30-day post-op and long-term
morbidity/mortality may need to be specified. If there were no
complications or adverse outcomes this should also be

of
included.

ro
Discussio 11a Strengths – describes the strengths of this case ok

n -p
Weaknesses and limitations in your approach to this case. For
re
new techniques or implants - contraindications and
alternatives, potential risks and possible complications if
lP

11b
applied to a larger population. If relevant, has the case been
reported to the relevant national agency or pharmaceutical
na

company (e.g. an adverse reaction to a device)

ur

Discussion of the relevant literature, implications for clinical

11c
practice guidelines and any relevant hypothesis generation.
Jo

11d The rationale for your conclusions.

11e The primary “take-away” lessons from this case report.

Patient ok

Perspectiv 12 When appropriate the patient should share their perspective on

e the treatments they received.

Informed Did the patient give informed consent for publication? Please ok
Consent provide if requested by the journal/editor. If not given by the
patient, explain why e.g. death of patient and consent provided
13
by next of kin or if patient/family untraceable then document
efforts to trace them and who within the hospital is acting as a
guarantor of the case report.
Additional ok

Informatio 14 Conflicts of Interest, sources of funding, institutional review

n board or ethical committee approval where required.

AUTHOR AGREEMENT

of
ro
TO,
The Managing Editor,
Annals of Medicine and surgery
-p
re
Respected Sir,
lP

Reference
na

Title Lynch syndrome or hereditary non polyposis colorectal cancer (HNPCC) in a

moroccan family: Case Report:
ur

Type Case Report

Subject Health Science Section: Medical Genetic and Oncology
Jo

In reference to the above, I as a corresponding author, submit the manuscript for

publication in International Annals of Medicine and surgery. This manuscript has not been
published or considered for publication by any other journal or elsewhere. Kindly consider the
manuscript for publication in your journal.

Written informed consent was obtained from the patient for publication of this case report and
accompanying images. A copy of the written consent is available for review by the Editor-in-
Chief of this journal on request
The guarantor is that individual who accepts full responsibility for the work and/or the
conduct of the study, had access to the data, and controlled the decision to publish.

of
ro
-p
re
lP
na
ur
Jo
 Lynch syndrome or hereditary non polyposis colorectal
cancer (HNPCC) in a moroccan family: Case Report

F.Z. Outtaleb1, A. Alami2, N. Serbati1, N. Benchakroun2, Z. Bouchbika2,

H. Jouhadi2, N. Tawfiq2, S. Sahraoui2, A. Benider2, H. Dehbi1, 3.
(1) Laboratory of Medical Genetics. Ibn Rochd University hospital of Casablanca
(2) Mohamed VI Oncology Center. Ibn Rochd University hospital of Casablanca
(3) Cellular and Molecular Pathology Laboratory. Casablanca Faculty of Medicine and
Pharmacy. Hassan II University

of
ro
-p
re
Corresponding author: Fatima Zahra OUTTALEB
lP

Telephone : +212620057991

E-mail : outtaleb.fz@gmail.com
na
ur
Jo
 ABSTRACT:
Introduction and importance:

Colorectal cancer is a major global health problem. In 5% of cases, a genetic predisposition to

cancer’s syndrome is the etiology, such as Lynch syndrome. The population prevalence of Lynch
syndrome has been estimated at 1/440. The objectives of this study are to show the interest of
the oncogenetic consultation in the management of patients with suspicion of Lynch syndrome.
Case presentation:
It is a 70-year-old patient with a family history of different neoplasms. The patient has also been
followed for an adenocarcinoma of the colon. An oncogenetic consultation was indicated, which
led to the diagnosis of Lynch syndrome, according to the Amsterdam II criteria. A study of the
MisMatch Repair genes was requested,to allow a pre-symptomatic diagnosis of apparented
subjects at risk, and thus to also allow monitoring and early diagnosis of neoplasms or

of
prophylactic measures.

ro
Discussion:
Lynch syndrome is one of the most common cancer susceptibility syndromes. A constitutional
-p
deleterious mutation in one of the DNA MisMatch Repair genes, is responsible for nearly 70% of
cases of this syndrome. The oncogenetic consultation and the identification of the genetics cause,
re
makes it possible to set up specific monitoring and to offer a pre-symptomatic test to all major
relatives of the index case.
lP

Conclusion:
na

This medical observation shows the benefit of the oncogenetic consultation, if a genetic
predisposition to cancer’s syndrome is suspected. The diagnostic of this predisposition and
monitoring of the propositus and his exposed, like in Lynch syndrome will help in the early
ur

management of cancers, specially colorectal cancer and endometrial adenocarcinoma.

Jo

Keywords:
Lynch syndrome, oncogenetic consultation, MisMatch Repair genes.
 MANUSCRIPT:

Introduction :
Colorectal cancer (CRC) is a major global health problem, it is the third cancer in the world after
lung cancer and breast cancer [1]. In Morocco, CRC is also the third most frequent tumor, the
most common cancers in men being successively lung, prostate and colorectal cancer. While in

of
women, the most frequent cancers are successively breast cancer, followed by cervical cancer
and colorectal cancer, with a mortality of 12% in men and 7.1% in women [3 ], cancer being the

ro
second cause of death in our country after cardiovascular disease [2].

In 5 % of cases of CRC, a genetic predisposition to cancer’s syndrome is responsible of the

-p
disease, such as Lynch syndrome, the most common hereditary CRC, responsible of 3% of cases
of CRC, and other tumors, specially endometrial cancer [4]. The population prevalence of Lynch
re
syndrome has been estimated at 1/440 [5]. Lynch syndrome results from an inherited germline
mutation responsible of an accelerated process of carcinogenesis, due to mismatch repair gene
lP

mutations[6].

The objectives of this case report are to show the Interest of the oncogenetic consultation and
na

the benefit of a family investigation, in the management of patients with suspicion of hereditary
form of CRC.
ur

Patient and methods :

Jo

This is a case report about a patient followed at the Ibn Rochd university hospital in Casablanca,
for a colonic adenocarcinoma, suggesting Lynch syndrome, based on the Amsterdam II criteria
(table 1) [7], and tumoral spectre of Lynch syndrome (table 2) [8]. This work has been reported
in line with the SCARE 2020 criteria [9].
Case Presentation :
It is a 70-year-old patient with a personal history of diabetes mellitus, dyslipidemia, ischemic
heart disease and cholecystectomy. He has also a family history of different neoplasms (figure I),
as a brother died at the age of 50 from colorectal cancer (CRC) diagnosed at the age 45, 3
maternal cousins, first degree, died between the age of 50 and 60 years of gynecological cancer,
and a maternal uncle, who died from a CRC.
The patient has also been followed since the age of 65 for a differentiated adenocarcinoma of the
left colon, revealed by an occlusive syndrome, and treated by left colectomy and curage
ganglionnaire and chemotherapy, and complicated one year ago by pulmonary metastasis,
treated by stereotaxic radiotherapy. The colonoscopy surveillance has revealed two non-
cancerous polyps of the colon.
In view of the suspicion of an inherited form of colorectal cancer, an oncogenetic consultation
was indicated, which led to the diagnosis of Lynch syndrome, according to the Amsterdam II
criteria. Subsequently, a study of the MMR genes was requested, in order to identify the germinal
mutation responsible of the syndrome, and allow a pre-symptomatic diagnosis of apparented
subjects at risk by detecting this mutation, and thus to allow monitoring and early diagnosis of
neoplasms of Lynch spectrum, specially CRC and endometrial carcinoma.

Discussion :
1. Genetics of Lynch syndrome and the MisMatch Repair system :
Lynch syndrome is one of the most common genetic predisposition to cancer’s syndrome,
Individuals with Lynch syndrome have 50% to 70% lifetime risk of colorectal cancer, 40% to
60% risk of endometrial cancer, and increased risk of several other malignancies. This syndrome
is characterized by an autosomal dominant inheritance, with high penetrance (about 85%) [6].

of
In Lynch syndrome, a constitutional deleterious mutation in one of the DNA MisMatch Repair

ro
genes (MMR), is responsible for nearly 70% of cases of this syndrome. The causes of the other
cases are not known. The genes of the MMR system (MSH2, MLH1, MSH6 and PMS2) code for
-p
proteins that are involved in repairing DNA mismatches. Those proteins act in the form of
heterodimers [10].
re
About 90% of alterations in the MMR system are constitutional mutations of the MSH2 (40%) or
MLH1 (50%) genes. Germline mutations in MSH6 and in PMS2 are also described in about 10%
lP

of cases [11].
Two subgroups of Lynch syndrome have recently been identified, linked to constitutional
na

biallelic mutations in an MMR gene [12] :

The CMMRD syndrome (constitutional mismatch repair deficiency) :
ur

This entity was recently described. It is caused by biallelic mutations in one of the MMR genes
(MLH1, MSH2, MSH6 or PMS2).
Jo

The tumors are mainly located in the brain (high grade gliomas) and colorectal. An aspect of
type 1 neurofibromatosis is also present with cutaneous manifestations, malignant hemopathies
(acute leukemia, lymphomas) and rhabdomyosarcomas [13].
MSH3 gene:
It is caused by homozygous constitutional mutations of the MSH3 gene. Studies on larger series
of patients are currently underway to understand this entity [14].
2. Clinical presentation of Lynch syndrome and Amsterdam Criteria II :
Clinically, Lynch syndrome is defined by the Amsterdam Criteria II (table1) [7]. Using these
revised criteria, the sensitivity increases to 80%, but the specificity becomes less than 50% [15].
Thus some patients can validate these clinical criteria, without microsatellite instability or an
abnormality of expression of MMR proteins. And without a mutation of an MMR genes has been
demonstrated. "Syndrome X predisposition to colorectal cancer" [15] is the termz used to
describ this constatio.
3. Bethesda criteria and orientation tests in tumor biopsy (somatic analysis) :
There are criteria, called Bethesda criteria (table 3) [7], which are used to determine whether
tumors should be analyzed by orientation tests [17 ; 18]. Those pre-screening or orientation
tests are performed only on tumoral biopsys from subjects with cancer of the tumor spectrum.
Two principale techniques are used :
The immunohistochemistry :
This technique is used to study the tissue expression of proteins of the MMR system in tumor
biopsy. The principle of this test is to look for a loss of expression of one or more of the proteins
of the MMR system, within tumor cells compared to an internal control, usually normal colonic
mucosa [19].
The RER or MSI phenotype by PCR:
The MSI (Micro Satellite Instability) phenotype, formerly called the RER (Positive Replication
ERror) phenotype, corresponds to instability of microsatellites. These microsatellites are DNA

of
sequences made up of patterns of one to five nucleotides repeated 10 to 20 times on average.
Replication errors result in a change in the length of the microsatellites, and successive errors

ro
usually result in a shortening of the size of the microsatellites [19].
About 15% of all CRC cases have MSI status without constitutional alteration of the MMR system.
-p
In this case, it is a somatic alteration. The mechanism involved in the development of these
cancers is methylation of the promoter of the MLH1 gene linked to senescence [20]. Those
re
sporadic cancers are charterized using two tests :
lP

-The study of methylation of the MLH1 gene promoter : by a mechanism of senescence (aging)
of the colonic mucosa in sporadic cancers.
na

-The study of BRAF gene mutation : which is absent in CRC of the MSI phenotype of Lynch
syndrome [19, 21].
ur

The search for tumor instability (MSI test) and the immunohistochemistry of MMR proteins are
Jo

two orientation tests, making it possible to provide arguments for or against a continuation of
the analysis of the genetic heritage :
- Immunohistochemistry and MSI test negative : the probability of Lynch syndrome is less than
5% ;
- Immunohistochemistry and/or positive MSI test: the probability of Lynch syndrome is
considerably increased. In this context, an anomaly is identified in almost 30% of cases if the
family does not meet the Amsterdam criteria, and up to 90% if these criteria are met [16].
When the pre-screening tests are positive, the constitutional analysis of the MMR genes, ordered
during an oncogenetic consultation is indicated.

4. Oncogenetics consultation and constitutional genetics analysis :

The oncogenetic consultation is selected from the outset for all patients meeting the Amsterdam
II criteria, as well as subjects with cancer of the Lynch spectrum, for whom the pre-screening
tests are positive. If loss of expression of the MLH1 protein is demonstrated, the patient should
be less than 60 years old.
Currently, it is recommended that the MSH2 and MLH1 genes be analyzed first for point
mutations. If no mutation is identified, the analysis continues with the study of the MSH6 gene,
since it represents the third MMR gene involved in this syndrome.
In the absence of identified mutations, the search for a complex anomaly (large deletion or
insertion) of the MMR genes is undertaken. A large deletion is understood to mean the loss of
one or more exons or even an entire gene. Large deletions are not detectable during sequencing.
Indeed, the wild allele being present, all the exons are amplified by Polymerase Chain Reaction
and sequenced, which masks the anomaly of the other allele.

Two outcomes are possible after the genetics analysis:

- No clearly deleterious mutation has been identified :
A genetics predisposition cannot be certainly eliminated, due to the technological limits, and the

of
possible involvement of other genes unknown to date. Surveillance is then offered to all close
relatives without knowing which subjects are really at risk. This monitoring is adapted

ro
according to the history of each family.
- A clearly deleterious mutation is identified : -p
This makes it possible to set up specific monitoring and to offer a pre-symptomatic test to all
re
major relatives of the index case [16]. If the pre-symptomatic test detect the mutation reponsible
of Lynch syndrome in one of the relatives, regular colonoscopic surveillance and preventive
lP

hysterctomy after realisation of the sibling project are proposed.

In the case reported in this article, the the constitutional analysis of the MMR genes has not been
na

performed, due to the difficulty to access to the MMR gene analysis. The diagnosis of Lynch
syndrome was based on the Amsterdam II criteria. In this case, the surveillance is offered to the
propositus and all his relatives, specially to detect early CRC and endometrial cancers, by regular
ur

colonoscopic surveillance and gynecological surveillance, with a colonoscopy every 1 to 2 years

for CRC screening and endometrial swab with endovaginal ultrasound every 1 to 2 years for
Jo

endometrial cancer screening.

Conclusion :
In Morocco, cancer is a major public health problem. The management of this pathology is
generally done late, because the diagnosis is still frequently made at an advanced stage is often
made at an advanced stage. Therfore, the diagnostic of genetic predisposition to cancer’s
syndrome, and monitoring of the propositus and his exposed relatives, like in Lynch syndrome
will help in the early management of cancers, specially CRC and endometrial adenocarcinoma.

The authors declare having no conflicts of interest.

Patient consent :
Written informed consent was obtained from the patient for the publication for the publication
this case report . A copy of the written consent is available for review by the Editor-in-Chief of
this journal on request.

Provenance and peer review

Not commissioned, externally peer-reviewed

References :
1. International Agency for Research on Cancer. Cancer Incidence and Mortality Worldwide in
2015.
2. Ministère de la Santé, 2008. Santé en chiffres, 2010, ed.DPRF (www.sante.gov.ma).

of
3. IARC, 2010.- http://www.iarc.fr/indexfr.php.
4. Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch

ro
syndrome : history, molecular genetics, screening, differential diagnosis, and medicolegal
ramifications. Clinical Genetics. 2009;76(1):1–18.
-p
5. Chen S, Wang W, Lee S, Nafa K, Lee J, Romans K, Watson P, Gruber SB, Euhus D, Kinzler KW,
Jass J, Gallinger S, Lindor NM, Casey G, Ellis N, Giardiello FM, Offit K, Parmigiani G. Colon
re
Cancer Family Registry. Prediction of germline mutations and cancer risk in the Lynch
syndrome. JAMA. 2006;296:1479–87. PubMed PMID: 17003396.
lP

6. Muller A et al. Exclusion of breast cancer as an integral tumor of hereditary non polyposis
colorectal cancer. Cancer Res., 2002;62 1014-9.
7. Chirurgie prophylactique des cancers avec prédisposition génétique. Syndrome
na

HNPCC/Lynch. INCA, Collection Recommandations et Référentiels, 2009, 1-47.

8. E. Frémont, D. Tougeron. Syndrome de Lynch. 2016 Elsevier Masson SAS. EMC - Gastro-
entérologie . Volume 11, n4 , octobre 2016
ur

9. Agha RA, Franchi T, Sohrabi C, Mathew G, for the SCARE Group. The SCARE 2020 Guideline:
Updating Consensus Surgical CAse REport (SCARE) Guidelines, International Journal of
Jo

Surgery 2020;84:226-230.
10. Silva FCC da, Valentin MD, Ferreira F de O, Carraro DM, Rossi BM. Mismatch repair genes in
Lynch syndrome: a review. Sao Paulo Medical Journal. 2009 Jan;127(1):46–51.
11. Caspari R., Lambert CH. Impact de la génétique moléculaire sur le dépistage du cancer
colorectal héréditaire non polypoïde. Acta Endoscopica 2007, 37, 2, 165-73.
12. Grandval, S. Olschwang. Consultation d’oncogénétique digestive. EMC - Gastro-entérologie.
Volume 13, n◦2. Avril 2018. 9-008-B-12.
13. Wimmer K, Rosenbaum T, Messiaen L. Connections between constitutional mismatch repair
deficiency syndrome and neurofibromatosis type 1. Clin Genet 2016.
14. Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, et al. Exome sequencing identifies
biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous
polyposis. Am J Hum Genet 2016;99:337–51.
15. Schischmanoff P-O., Lagorce C., Wind P., Benamouzig R. Le syndrome HNPCC : Diagnostic et
prise en charge. Gastroenterol Clin Biol 2005 ; 29, 1028-34.
16. Caron O., Consolino E., Byrde V., Bressac-de-Paillerets B. et Malka D. Oncogénétique
colorectale : acquis récents. Rev. Hepato-Gastro, 2009, 5, 329-39.
17. Hamelin R et al. Conséquences cliniques et moléculaires de l’instabilité des microsatellites
dans les cancers humains. Bull Cancer 2008, 95 (1) : 121-32.
18. Buisine M-P « Les analyses génétiques – Dépistage du syndrome de Lynch dans la région
Nord-Pas de calais ».
19. .Paraf F. Comment et quand rechercher une instabilité des microsatellites dans les cancers
colorectaux en 2008 ? Ann Pathol 2007, 27,433-8.
20. Pariente A. Le dépistage des polypes dans le syndrome HNPCC. Site http://www.hnpcc-
lynch.com/ArticlesEnd9.htm.
21. Olschwang S., et al. Contributions récentes pour l’identification et le dépistage du syndrome
de Lynch. Gastroenterol Clin Biol 2007, 31, 136-4.

of
ro
-p
re
lP
na
ur
Jo

Figure I: Genealogical tree of the family showing cases of colorectal

cancers (in green), narrow spectrum cancers of Lynch syndrome: 3
cases of endometrium cancers (in pink), a case of large spectrum
cancers : a cerebral tumor (in blue) in a 8 years-old child, and a case
died at the age of 55 years-old of peritoneal carcinoma of
undetermined origin (in orange).
The genealogical tree shows also the affection of 2 successive
generations.
 Table 1: Amsterdam II criteria [7]:

Amsterdam II criteria [7]:

of
• Colorectal or narrow spectrum cancers of HNPCC syndrome (endometrium, urothelium,

ro
small intestine) diagnosed in at least 3 relatives,

-p
• An affected individual related in the first degree to the other 2,

• Affection of at least 2 successive generations,

re
• Diagnosis at an age of less than 50 years in at least one of the affected subjects,
lP

• Exclusion of the diagnosis of familial adenomatous polyposis (FAP)

na
ur
Jo

Table 2 : Tumoral spectrum of Lynch syndrome |8]:

Types of Lynch Syndrome Cancers:

Narrow spectrum: - Colorectal adenocarcinoma

- Endometrial adenocarcinoma
- Adenocarcinoma of the small
intestine
- Carcinoma of the upper urinary tract

Narrow spectrum: - Adenocarcinoma of the stomach

- Ovarian adenocarcinoma
- Bile duct adenocarcinoma
- Glioblastoma
- Sebaceous carcinoma
 Table 3: Bethesda criteria revised in 2004 [7], used to determine
whether tumors should be analyzed by pre-screening techniques:

Bethesda criteria revised in 2004 [7] :

of
ro
• Colorectal cancer diagnosed at an age of less than 50 years

• Colorectal cancer diagnosed in an individual with a personal history of colorectal cancer or

-p
HNPCC spectrum, synchronous or metachronous, regardless of age at diagnosis
re
• Colorectal cancer with suggestive pathological features (low degree of differentiation,
"medullary" type architecture, dense lymphocytic infiltration of the tumor stroma) diagnosed
lP

at an age of less than 60 years

• Colorectal cancer diagnosed in an individual with at least one first-degree relative with
na

HNPCC spectrum cancer diagnosed at an age of less than 50 years

• Colorectal cancer diagnosed in an individual with at least 2 first or second degree relatives
ur

with HNPCC spectrum cancer regardless of age at diagnosis.

Jo
 Highlights for review :
Lynch syndrome or hereditary non polyposis colorectal cancer
(HNPCC) in a moroccan family: A case report:

- This case report is about a genetic predisposition to cancer’s syndrome; Lynch

syndrome.
- It shows the interest of a oncogenetic consultation if we suspect a hereditary
predisposition to cancers.
- And the necessity of the surveillance of the propositus and his exposed relatives, to make
possible an early management of cancers.

of
ro
-p
re
lP
na
ur
Jo
SCARE 2020 Checklist

Page
Topic Item Checklist Item Description
Number

Title - The words ‘case report’ should appear in the title. The ok
title should also describe the area of focus (e.g.
1
presentation, patient population, diagnosis, surgical
intervention or outcome).

Key Words - Include three to six keywords that identify what is ok

of
covered in the case report (e.g. patient population,
2

ro
diagnosis or surgical intervention).
- Include ‘case report’ as one of the keywords.
-p
Abstract Introduction and Importance ok
re
- Describe what is important, unique or educational about
3a
lP

the case, and what does this add to the surgical

literature.
na

Case Presentation ok
3b - Presenting complaints, clinical and demographic details,
ur

and the patient’s main concerns.

Jo

Clinical Findings and Investigations ok

3c - Clinical findings, investigations performed, main
differentials, and subsequent diagnosis.

Interventions and Outcome ok

3d - Describe the rationale for choosing the intervention.
- Describe what was the end result.

Relevance and Impact ok

3e - Describe the main take-away lessons or potential
implications for clinical practice (minimum of three).
Introduction Background ok
- Describe briefly the area of focus and the relevant
background contextual knowledge.
Rationale
- Describe why the case is different to what is already
4 known and why it is important to report?
- Is the case rare or interesting for the specific healthcare
setting, population or country, or is it applicable globally?

of
Guidelines and Literature
- Give reference to relevant surgical literature and current

ro
standards of care, including any specific guidelines.

Patient Demographic Details -p ok

Information - Include de-identified demographic details of the patient
re
(e.g. age, sex, ethnicity, occupation).
lP

5a
- Where possible, include other useful pertinent
information (e.g. body mass index, hand dominance,
na

income, level of education, marital status).

ur

Presentation ok
- Describe the patient’s presenting complaint.
Jo

- Include a collateral account of the history if relevant.

5b
- Describe the patient’s mode of presentation (e.g. self-
presentation, ambulance or referred by family physician
or other hospital clinicians).

Past Medical and Surgical History ok

5c - Include any previous interventions and relevant
outcomes.

Drug History and Allergies ok

- Specify any acute, repeat, and discontinued
5d
medications.
- Include any allergies and/or adverse reactions.
 Family History ok
- Health information regarding first-degree relatives,
specifying any inheritable conditions.
Social History
- Indicate smoking, alcohol, and recreational drug use.
5e
- Level of social independence, driving status, and type of
accommodation.
Review of Systems

of
- If appropriate, report on any other information gathered
outside of the focused history.

ro
Clinical - Describe the general and significant clinical findings
Findings 6 -p
based on initial inspection and physical examination.
re
Timeline - Summarise the sequence of events leading up to the ok
patient’s presentation.
lP

- Delays from presentation to diagnosis and/or

7
intervention should be reported.
na

- Use tables or figures to illustrate the timeline of events if

ur

needed.

Diagnostic Diagnostic Assessment ok

Jo

Assessment - Bedside (e.g. urinalysis, electrocardiography,

and
echocardiography).
Interpretation
8a - Laboratory (e.g. biochemistry, haematology,
immunology, microbiology, histopathology).
- Imaging (e.g. ultrasound, X-ray, CT/MRI/PET).
- Invasive (e.g. endoscopy, biopsy).

Diagnostic Challenges ok
8b - Where applicable, describe what was challenging about
the diagnoses (e.g. access, financial, cultural).

8c Diagnostic Reasoning ok
 - Describe the differential diagnoses, why they were
considered, and why they were excluded.

Prognostic Characteristics ok
8d
- Include where applicable (e.g. tumour staging).

Intervention Pre-Operative Patient Optimisation ok

- Lifestyle (e.g. weight loss).
- Medical (e.g. medication review, treating any relevant
9a
pre-existing medical concerns).

of
- Procedural (e.g. nil by mouth, enema).

ro
- Other (e.g. psychological support).

Surgical Interventions -p ok
- Describe the type(s) of intervention(s) used (e.g.
re
pharmacological, surgical, physiotherapy, psychological,
lP

preventative).
9b - Describe any concurrent treatments (e.g. antibiotics,
na

analgesia, antiemetics, venous thromboembolism

prophylaxis).
ur

- Medical devices should have manufacturer and model

specifically mentioned.
Jo

Specific Details regarding Interventions ok

- Describe the rationale behind the treatment offered, how
it was performed and time to intervention.
- For surgery, include details on the intervention (e.g.
anaesthesia, patient position, preparation used, use of
9c other relevant equipment, sutures, devices, surgical
stage).
- The degree of novelty for a surgical technique/device
should be mentioned (e.g. ‘first in human’).
- For pharmacological therapies, include information on
the formulation, dosage, strength, route, and duration.
 Operator Details and Setting of Intervention ok
- Where applicable, include operator experience and
position on the learning curve, prior relevant training,
and specialisation (e.g. ‘junior trainee with 3 years of
9d
surgical specialty training’).
- Specify the setting in which the intervention was
performed (e.g. district general hospital, major trauma
centre).

of
Deviation from Initial Management Plan ok
- State if there were any changes in the planned

ro
9e
intervention(s), and describe these alongside the
-p
rationale (e.g. delays to intervention).
re
Follow-Up Specify Details regarding the Follow-Up ok
and - When (e.g. how long after discharge, frequency,
lP

Outcomes maximum follow-up length at time of submission).

- Where (e.g. home via video consultation, primary care,
na

secondary care).
ur

- How (e.g. telephone consultation, clinical examination,

blood tests, imaging).
Jo

10a
- Any specific long-term surveillance requirements (e.g.
imaging surveillance of endovascular aneurysm repair or
clinical exam/ultrasound of regional lymph nodes for skin
cancer).
- Any specific post-operative instructions (e.g. post-
operative medications, targeted physiotherapy,
psychological therapy).

Intervention Adherence and Compliance ok

- Where relevant, detail how well the patient adhered to
10b
and tolerated the advice provided (e.g. avoiding heavy
lifting for abdominal surgery, or tolerance of
 chemotherapy and pharmacological agents).
- Explain how adherence and tolerance were measured.

Outcomes ok
- Expected versus attained clinical outcome as assessed
by the clinician. Reference literature used to inform
10c
expected outcomes.
- When appropriate, include patient-reported measures
(e.g. questionnaires including quality-of-life scales).

of
Complications and Adverse Events ok

ro
- Precautionary measures taken to prevent complications
(e.g. antibiotic or venous thromboembolism prophylaxis).
-
-p
All complications and adverse or unanticipated events
re
should be described in detail and ideally categorised in
accordance with the Clavien-Dindo Classification (e.g.
lP

blood loss, length of operative time, wound

complications, re-exploration or revision surgery).
na

10d - If relevant, was the complication reported to the relevant

ur

national agency or pharmaceutical company.

- Specify the duration of time between completion of the
Jo

intervention and discharge, and whether this was within

the expected timeframe (if not, why not).
- Where applicable, the 30-day post-operative and long-
term morbidity/mortality may need to be specified.
- State if there were no complications or adverse
outcomes.

Discussion Strengths ok
11a - Describe the relevant strengths of the case.
- Detail any multidisciplinary or cross-speciality relevance.

Weaknesses and Limitations ok

11b
- Describe the relevant weaknesses or limitations of the
 case.
- For novel techniques or devices, outline any
contraindications and alternatives, potential risks and
possible complications if applied to a larger population.

Relevant Literature ok
- Include a discussion of the relevant literature and, if
11c appropriate, similar published cases.
- Describe the implications for clinical practice guidelines

of
and any relevant hypotheses generated.

ro
- Provide a rationale for the conclusions drawn from the ok
11d
case.

Take-Away Lessons
-p ok
re
- Outline the key clinical lessons from this case report.
lP

- Discuss any differences in approach to diagnosis or

11e
patient management which the authors might adopt in
na

future similar cases, based on their experience of the

case.
ur

Patient - Where appropriate, the patient should be given the ok

Jo

Perspective opportunity to share their perspective on the

12
intervention(s) they received (e.g. sharing quotes from a
consented and anonymised interview).

Informed ok
- The authors must provide evidence of consent, where
Consent
applicable, and if requested by the journal.
- State the method of consent at the end of the article

13 (e.g. verbal or written).

- If not provided by the patient, explain why (e.g. death of
patient and consent provided by next of kin). If the
patient or family members were untraceable then
document the tracing efforts undertaken.
Additional - Please state any author contributions, ok
Information acknowledgments, conflicts of interest, sources of
funding, and where required, institutional review board
14
or ethical committee approval.
- Disclose whether the case has been presented at a
conference or regional meeting.

Clinical - Where relevant and available, include clinical images to ok

Images and help demonstrate the case pre-, peri-, and post-

of
Videos intervention (e.g. radiological, histopathological, patient
photographs, intraoperative images).

ro
- Where relevant and available, include a link (e.g. Google
15 -p
Drive, YouTube) to the narrated operative video can be
included to highlight specific techniques or operative
re
findings.
lP

- Ensure all media files are appropriately captioned and

indicate points of interest to allow for easy interpretation.
na

Referencing - Include reference to the SCARE 2020 publication by ok

ur

the Checklist stating: ‘This case report has been reported in line with
16
the SCARE Criteria [include citation]’ at the end of the
Jo

introductory section.