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WilkinsonD.Drugs for preventing tuberculosis in HIVinfectedpersons.Cochrane DB Syst Rev 2000;4:CD000171.

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Bope ET,Kdlerman R.Rakel RE.Conn's current therapy.2nded.Philadelphia:Saunders; 2014.

Cathennot E, Lanternierf,Bougnoux ME,etal.Pneumocystis jirovecii pneumonia.Infect DisClin North Am 2010;24:107-138.

Habif TP.Clinical dermatology.5th ed.Philadelphia:Elsevier Inc.Mosby:2009.

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Moiris A.Notley E.Pneumocystis [irovecii pneumonia[Internet].London:BMJ Best Practice;[updated 2021Jan 26:cited 2021 June 25|.Available from:https:77bestpractice.bmi.com/topics/en-us/19.

Pappas PG.Kauffman CA. Andes D.et al.Clinical practice guidelines for the management ol candidiasis:2016 Update by the Infectious Oiseases Society olAmerica. ClinInfect Dis 2016;62|4):e1- c50.

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toxoplasmosistiealth professionals/index.htmIKIx

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Pbrcz Molina JA,MolinaI. Chagas disease,

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Neutropenia in a prospective cohort of patients from the EINIIE study.JClinOncol 2015 Eeb 10;33(5):465-71.

Coyne CJ.Le V. Brennan JJ.Castillo EM,etal. Application of the MASCC and CISNE Risk-Stratification Scores to Identify Low-RiskFebrile NeutropenicPatients in the Emergency Department.Ann Emerg Med

2017:69(61:755-764.

Danziger-lsakovl.Kumar D.Vaccination of solid organ transplant candidalesand recipients:Guidelines from the American society of transplantation infectious diseases community of practice.Clinfransplant

2019:33:e13563.

Fishman JA.Infection in organ transplantation.Am JTransplant 2017:17:856 879.

Klastersky J,Paesmans M. The MultinationalAssociation for Supportive Care in Cancer (MASCC) risk index score:10 years of use for identifying low-risk febrile neutropenic cancer patients.Support Care Cancer

2013:21(5):1487-95.

Mertens J.Laghrib Y,Kenyon C.A Case of Steroid-Responsive.C01/1D-19 Immune ReconstitutionInflammatory SyndromeFollowing the Use of Granulocyte Colony-Stimulating Factor.Open Forum Infect Dis

2020;7(8):ofaa326.

National Transplant Consensus Guidanceon C0V1D-19 Vaccine [Internet].Canadian Society of Transplantation.2020.p.1-4. Available from:https://www.cst-transplant.ca/ Library/Reference Documents/

National Transplant Guidance on COVID vaccine - Dec 18 2020 Final 1.pdf

Taplitz RA.Kennedy EB.Bow EJ. et al.Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy:American Society of Clinical Oncology and Infectious Diseases Society of America Clinical

Practice Guideline Update.JClin One 2018:36:1443-1452 r “t

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Fever of Unknown Origin

Knockaert DC. Vanderschueren S.Blockmans D.Fever of unknown origin in adults:40 years on.J Internal Med 2003;253:263-275.

Mourad 0.Palda V, Dctsky AS.A comprehensive evidence-based approach to fevei of unknown origin.Arch Intern Med 2003:163|5):545-51.

Travel Medicine

Boggild AK,Freedman DO.Bennett JE.Dolin R.Blaser MJ (editors). Mandell. Douglas,and Bennett’sPrinciples and Practice of Infectious Diseases.9thed.Elsevier;2020. Chapter 319.Infections in Returning

Travelers.

Boggild AK,Geduld J.libman M. et al. Travel acquiredinfections in Canada:CanTravNet 2011-2012. Can Commun Dis Rep 2014 Sep 18:40|16):313-325.

Boggild A. Ghcsquiere W. McCarthy A. Fever in the returning international traveler:initial assessment guidelines.Can Commun Ois Rep 2011;37:1-15.

Committee to Advise on Iropical Medicine and Travel [Internet].Ottawa:Government olCanada;2ika Virus Prevention and Treatment Recommendations;lupdated 2020 Mar 25;cited 2020 June101:Available from:

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ID60 Infectious Disease TorontoNotes 2023

hltpsi/.'www.Canada.ca *

•;.b ic health servicesipublications

' diseases -conditions/ zika virus-prevention lreatiie.ut'recom.T-erizti:ns.htn:l.

luzuriaga A.Sullivan J.Infectious mononucleosis. NEJM 2010;362:1993- 2000.

Thwaites 6E. Oay ItPJ.Approachto fever in dieReturning Traveler.NEJM 2017;326(18):1298.

Antimicrobials

e-CPS[Internet],CanadunPharmacists Association. 2008. Available Irom:http:tfe-cps.pharmacists.ca.

Ealagas ME.Vouloumanou EA.Sarrons 6.et at.Fosfomycm.Clin Microbiol Rev 2016:29:321-347.

Letourneau AR.Cephalosporins.Hooper DC (editor).Waltham:UpToOate: 2020.

M0 Consult DrugsOn,

ine[internet!.Arailable from:hltp: home.mdconsuIt.cornJdas/drugs/.

Pocket Guide for Antibiotic Pharmacotherapy[Internet].Universify HealthSystem.2015. Available from:https:.vnvw.urivers.'tyhealthisystem.conv

'-imediaJfiles/clinical-palhsvays/antibiotic-pockel-guide-IS.

pdffla^en.

Schlossberg D (editor).Current therapyof infectious disease.2nd ed.St Louis:Mosby:2001.

Antivirals

Entecavir.Leu-Drugs,[updated 2021Jun1:bted 2021Jun10]InLexicomp Online[Internel],Hudson.Ohio:Wolters Winner ClinicalDrug Information.Inc.Available from:https:/7online.lexi.comi’lco'actionlogin

Ghany MG.Morgan 18:AASLD-IDSA Hepatitis CGuidance Panel.Hepatitis C Guidance 2019 Update:AmericanAssociation for the Study of Liver Diseases-lnfectious Diseases Society of America Recommendations

for Testing.Managing,aidTreabng Hepatitis C Virus Infection.Hepatology 2020;71(2):686-721.

Glecaprevir andPibrentasmr.Lee-Drugs,[updated 2021Jun 4; cited 2021 Jun10] In Lexicomp Online [Internet].Hudson.Ohio:Wolters Wuvrer Clinical Drug Information,Inc.Available from:https:nonime.iexi.com.

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Hammond J.Leister-Tebbe H.Gardner A.etal.OralKirmatrelvlr for High-Risk.Nonhospitalized Adults with Covid-19-N EnglJMed.2022:386(1S):1397-1408.doi:10.1056/NEJMoa2118542

Mandell 6LBennett JE.Dolin R.Mandell.Douglas,andBennett's principles andpractice of infectious disease.9th ed.Elsevier:2020.

Nirmatrelvir andRitonavir.Lee-Drugs,[updated2022 Apr 21:cited 2022 Apr 28] In Lexicomp Online [Internet].Hudson.Ohio:Wolters Wuvrer Clinical Drug Information.Inc.Available from:https:Zlonline.leii.com'

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Ribavirin (systemic|.Lee-Drugs,[updated 2021May 22:cited 2021Jun10]In Lexicomp 0nline(lnternetl.Hudson.Ohio:Wolters Wuwer Clinical Drug Information.Inc.Available from:https:Wonline.lexi.convlco/

action/login

Remdesivir.Lee -Drugs [updated 2021May 7:cited 2021Jun10]InLexicomp Online[Internet],Hudson.Ohio:Wolters Wuwer Orica!Drug Information.Inc. Available from:https://online.lexi.com/lco/action,1ogn

Sofosbuvu and Velpatasvir.Lee Drugs, updated 2021 Jun 9;cited 2021Jun10] In Lexicomp Online [Internet].Hudson,Ono:Walters Wuwer Clinical DrugInformalion,Inc.AvailableIrom:https:/

,'

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count guided interruption of anti retroviral treatment.NEJM 2006:355:2283-2296.

Terraull NA.lok ASf.McMahon BJ.etal.Update onprevention,diagnosis,and treatment o( chronic hepatitis 8:AAS10 2018hepabtis B guidance.Hepatology 2018:67(4):1560-1599.

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updated 2021Mar 17:cited 2021Apr 28]In Lexicomp Online [Internet]. Hudson.Ohio:Wa ters Wuwer Clinical Drug Information.Inc. Available from https://online.lexi.com/lco/actior

login.nazole.lexi Drugs.]updated 2020 Dec 13:cited 2021Apt 28] In Lexicomp Online [Internet].Hudson.Ohio:Wollets ICIuwer Clinical Drug Information.Inc Available Irom:hUps://online.lexi.corolcoi'actiou '

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fluconazole.leu Drugs.[updated 2021Apr 27:cited 2021Apr 28]In Lexicomp Online[Internet]. Hudson.Ohio:Wolters Wuwer Clucal Drug Information.Inc.Available from:https://online.lexi.com/lco'actou login

Itraconazole.Lexi-Drugs.[updated 2021Apr 9:ated 2021 Apr 28]In lexicomp Online|lnternet].Hudson.Ohio:Wolters Wuwer Clinical Drug Information.Inc.Available from:hllps^

/onlinelexi.com'

lcoi'actiorilogin

Isavuconazole.Leid-Orugs.[updated2021June 4:cited 2021 June 8]In lexicomp Online[Internet].Hudson.Ohio:Wolters Wuwer OmicalDrug Information.Inc.Available from:htlps://online.lexi.com1co'

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Voriconazole.Lexi-Drugs.

'

updated 2021Apr 26:cited 2021Apr 28]In lexicompOnline [Internet],Hudson.Ohio:Wolters Wuwer 0 realDrug Information.Inc.Available from:https://online.lexi.com/lco,'action/

i

Posaconazole.Leu-Drugs,[updated 2021Apr 9:cited2021Apr 28]In Lexicomp Online [Internet].Hudson.Ohio:Wolters Wuwer Clinical DrugInformation.Inc.Available from: https://online.lexi.com/lco/action

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Antiparasitics

Chloroquine:Drug Informabai.be UpToOate.PostTW (editor).Waltham:UploDate;2020.

Mandell GL Bennett JE.Dolm R.Mandell.Douglas,andBennett's principles andpractice of infectious disease.7th ed.Church.llLivingstone:2009.

McCarthy JS.MooreIA Bennett JE.Dolin R.andBlaser MJ (editors).Mandell,Douglas,andBennett'sPrinciples and Practce of Infectious Diseases.9th ed.PA:Elsevier:2019.Chapter 42.Drugs for helminths.

Praziquantel:Drug iirforroaboo.hr UpToOate.Post IW (editor).Waltham:UploDate;2020.

Primaquine:Drug information.In:UploDate.Post TW (editor).Waltham:UpToOale; 2020.

Ouinine:Druginformabon.Ire UploDate.Post IW (editor).Waltham:UpToOate;2020.

Showier AJ.Wilson ME.Rain AC.etat Parasitic diseases in travelers:a focus on therapy.Expert Rev AntiInfect Iher 2014;12(4):497 521.

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Medical Genetics

Andrew Mazzanti, chapter editor

Ming Li and Dorrin Zarrin Khat, associate editors

Vijithan Sugumar, EBM editor

Dr. Vanda McNiven and Dr. Graeme Ninnno, staff editors

Acronyms MG2

Introduction to Genetics.

Pedigrees

Genetic Testing and Counselling

Differences in Morphology

Congenital Anomalies

Approach to the Patient with Physical Differences

Genetic Conditions

Other Single Gene Disorders

Metabolic Diseases

Landmark Medical Genetics Trials

References

MG2

MG4

MG6

MG11

MG12

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MGl Medical Genetics Toronto Notes 2023

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MG2 Medical Genetics Toronto Notes 2023

Acronyms

CF cystic Fibrosis

copy number variant

exome sequencing

fluorescence in situ

gestational age

GS genome sequencing

GSD glycogen storage disease

long chain 3- hydroxyacyl-(

dehydrogenase deficiency

MCADD medium chain acyl-CoA

dehydrogenase deficiency

MLPA multiplex ligation-dependent SNP

probe assay

pie syrup

PKU phenylketonuria

single nucleotide polymorphism

very long chain acyl-CoA

dehydrogenase deficiency

CNV

ES LCHAD : : A VLCAD

FISH hybridization MSIID ma urine disease

GA NGS next generation sequencing

Introduction to Genetics

Common Terms

• penetrance: probability that a gene variant is observably expressed in an individual who carriesit

• expressivity: extent of gene expression -refers to the range of variation seen in a phenotype for a

certain genotype

• genetic heterogeneity: when a phenotype/genetic disorder can be caused by different genotypes,

due to genetic variation within the same gene (allelic heterogeneity) or in different genes (locus

heterogeneity)

• phenotypic heterogeneity: pathogenic variants in the same gene result in multiple clinical

manifestations and varying degrees of severity

• mosaicism: presence of two or more genotypes (e.g. chromosome patterns or gene variants) in the

cells of the same person

• nondisjunction: a cell division error in which chromosomesfail to segregate, resulting in daughter

cells with fewer or more chromosomes than expected

• uniparental disomy: the inheritance of two full or partial copies of a chromosome from one par

origin and no corresponding full/partial chromosome from the other parent

• allele: one of two or more versions of a gene that islocated at a given position on a chromosome

ental

Genetic Variation

• a variant is a permanent change in the nucleotide sequence that differs from the most common

nucleotide sequence (reference sequence)

• variants are classified based on their likelihood of disrupting the function of the gene product.

Ihe American College of Medical Genetics and Genomics outlines a commonly used method for

classifying variantsfor single gene disorders:

• benign: not associated with genetic disease

• likely benign: probably not associated with genetic disease, but insufficient evidence to classify as

benign

variant of uncertain significance: insufficient evidence to classify variant as benign or pathogenic

likely pathogenic:90% likely to be pathogenic, and clinically treated as a pathogenic variant

pathogenic:known to be associated with genetic disease

• nomenclature no longer used in clinical genetics:

mutation:previously synonymous with pathogenic variant. Now this term is only used to

describe the actual process of genetic change

• polymorphism: a variant that is relatively common in the population and not typically associated

with a genetic disease,

'

thisterm is used only in the context of population genetics

Types of Genetic Variation

• deletions or duplications of a whole gene(s) caused by aneuploidy, unbalanced chromosome

rearrangements,or copy number variants (e.g. 22ql1.2 deletion, or DiGeorge,syndrome; 17pl 1.2

duplication, or Fotocki-Lupski,svndrome)

• disruption of a gene: inversions, balanced chromosome rearrangements

• variantsthat cause alteration in the protein coding sequence: missense (encodes for a different amino

acid), nonsense (encodes for a premature stop codon) ,frameshift (deletion/insertion of a number of

nucleotides that is not a multiple of 3, thus shifting the reading frame)

• variantsthat affect the transcription of a gene

• variantsthat affect splicing

Single Gene Disorders

• traits or disorders determined by gene(s) at a single locus, which often follow a Mendelian inheritance

pattern:

• autosomal inheritance: disorder is caused by pathogenic variants of a gene located on chromosomes

1-22 (the autosomes)

autosomal dominant: one copy of a gene with a pathogenic variant is sufficient to cause a trait/

disorder

• autosomal recessive: both copies of a gene must have pathogenic variants to cause a trait/disorder;

an individual with one copy of a pathogenic gene variant is a carrier

• sex-linked inheritance: when disease is caused by pathogenic variants in a gene on the X or the Y

chromosome. Because the X chromosome contains many more genes than the Y chromosome, almost

all sex-linked traits are X-linked. X-linked inheritance generally results in a trait/disorder that is

seen more commonly or with greater severity in males than females (e.g. Hemophilia A, Duchenne

muscular dystrophy)

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MG3 Medical Genetics Toronto Notes 2023

Triplet Repeat Expansions

• disorders where the number of trinucleotide repeats in certain genes exceeds the normal number and

results in altered gene expression or production of an abnormal protein

these disorders can demonstrate genetic anticipation, where signs and symptoms are more severe

and appear at an earlier age from one generation to the next due to expansion of the triplet repeat

number

• length of expansion segment is often proportional to severity of clinical phenotype

• e.g. fragile X syndrome, Huntington disease

Imprinting Disorders

• imprinted genes are expressed entirely from either the maternal or paternal allele, depending on the

gene (parent-of-origin gene expression)

• imprinting is determined by allele-specific epigenetic mechanisms (i,e. modifications to DNA other

than a change in the underlying sequence,such as UNA inethylation and/or histone modifications)

• disorders occur when a pathogenic variant disrupts the normally expressed allele of an imprinted

gene, or through uniparental disomy of the normally silenced allele

• e.g. Prader-Willi syndrome. Angelman syndrome, Beckwith-Wiedemann syndrome

Mitochondrial Disorders

• disorders caused by pathogenic variants in mitochondrial DNA or in nuclear genes whose protein

products are important for mitochondrial function

• high phenotypic heterogeneity

• mitochondrial disorders caused by pathogenic variants in nuclear genes demonstrate Mendelian

inheritance (e.g. Alpers syndrome caused by autosomal recessive pathogenic variants in POLG)

• disorders caused by pathogenic variants in mitochondrial DNA are maternally inherited by all

offspring because all mitochondria and associated mitochondrial DNA in the embryo comesfrom the

maternal ovum, with no paternal contribution of mitochondria

• e.g. mitochondrial encephalomyopathy and lactic acidosis with stroke-like episodessyndrome

(MELAS)

Common Indications for Genetic Referrals

• preconception and prenatal:abnormal prenatal screening test, fetal anomaly, recurrent pregnancy

loss, personal or family history of a genetic condition, positive carrierscreening test, consanguinity

• paediatric:major and/or multiple minor congenital anomalies, developmental delay, abnormal

newborn screen, unusual growth pattern, abnormal pubertal development, connective tissue

disorders,congenital hypo- or hypertonia

• adult:family history of adult-onset genetic condition (e.g. Huntington Disease), personal or family

history of cancer concerning for genetic cause, bleeding or clotting disorder, early onset vision or

hearing loss

Pedigrees

• diagrams of a family tree that show the pattern/distribution of phenotypes for a genetic disorder

within that family, often across multiple generations

• pedigrees generally indicate sex assigned at birth, with or without genetic confirmation ofsex

chromosomes; when counselling gender diverse patients, including transgender and non-binary

patients, physiciansshould affirm the patient'

s gender identity while clarifying the role of sex assigned

at birth or chromosomal sex in determining genetic features for the pedigree

fO Male, -o Married/Partners Spontaneous abortion unalflected

& Termination of pregnancy

o Female, unaflected DO Divorced/Sepaialec £

Ectopic pregnancy

o

Gender unknown,

unaffected | |==

^

) Consanguinity

P[o]

Adopted sibling

00 99

Deceased Infertility

Siblings (listed from

left to right, oldest to 6 youngest)

"

Affected individual b

99

No offspring

by choice

(5b

Dizygous twins [10 (fraternal)

Affected individual

>2 conditions r -t

L J

0 Pregnancy

©

Carrier not likely to

manifest disease Monozygous twins

(identical)

00SB SB

Stillbirth (write SB

and gestational age mo if known)

Carrier unaffected at

this time but could

manifest disease later

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Figure1.Common pedigree symbols

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MCM Medical Genetics Toronto Notes 2023

Genetic Testing and Counselling

Meta-analysis ot the Diagnostic and Clinical

Utility ol Genome and homeSequencing and

Chromosomal Microarray in Children

Genomic Med 2018:3:16

Purpose lo comparethe diagnostic andclmeil

utility of WCS and WES to that ol chromosomal

microarray.

Methods:

^

systematic review and neta -analyysof

the literature.

Results: 37studies were included (20068 children).

Diagnostic utility ofWGS (0.41, 953.Cl 0.34-0.48]

and WES (0.36, 95 « Cl 0.33-0.40) were greater than

chromosomal microarray|0.10.953.Cl 0.08-0.12).

Ihe clinical utility olWGS|0.27. 953,Cl 0.17 0.40 )

and WES (0.17.96% Cl 0.12-0.24) were higher than

chromosomal microarray|0.06.9S% Cl 0.05-0.07I

and thisdifference wassignificant lor IGS vs.

chromosomal microarray|P<0.004|I .

Conclusion: Ihe diagnostic and dnical utility of

MGS and WES is greater than that of chromosomal

microarray.

Common Terms

• presymptomatic genetic testing: used to determine whether individuals without current symptoms,

but with a known family history of a genetic disease, carry the familial pathogenic variant associated

with the disease

• newborn screening: performed within the first few days of life lo detect treatable and potentially fatal

disorders before symptoms arise to allow for early therapy

• preconception genetic counselling:pre-pregnancy evaluation to assess the risk of having a child

with an inherited condition

• preimplantation genetic diagnosis:genetic testing of in-vitro fertilized embryosfor specific genetic

conditions before uterine transfer

Table 1. Common Genetic Tests

Karyotype FISH Microarray

Analysis

Sanger

Sequencing

Test NGS

Technique Microscopic analysis

of chromosomes

with a nucleic acid

slain thatshows

large changes in the

number oistructure

ol chromosomes:can

deled large CNVs

Useful in

identification ol

major aneuploidies.

slrudural

chromosomal

rearrangements,

chromosomal

changes related

lo hematological

conditions, oi

olhei genetic

diseases related

to chiomosome

structure

A fluorescent lagged

DNA piobe used lo

identify a gain,loss,

or rearrangement

of chromosomal

material

5MP array:a

collection of DMA

probes attached to a

solid surface lo which

test ONA hybridize in

order to determine

copy number ol DNA

regions

Microarray analysis

can identify

small deletions

or duplicationsol

genetic material

anywhere in the

genome

Commonly indicated

when there is

developmental delay/

autism OR two or

more congenital

anomalies

A method of DNA High -throughput

sequencing which is method used lo

based on Ihe selective sequence multiple

incorporation of

chain - terminating

nucleotides during

replication

genes in parallel:NG 5

is the technology used

for panelsequencing,

WES. andWGS

Can ccHilirm lire

presence or absence

ol specific DNA

sequences and

localicethem. May

be used to detect

aneuploidies

or balanced

rearrangements,

in gene mapping

or identification

oloncogenes, and

in identification of

Uscs/f ndicalions Ihe “gold standard" limiled indications

vary by province

identification of single but may include:

nucleotide variants limiting further

in Ihe gene(s) known invasive diagnostics,

to cause a suspected facilitating early

syndrome

method lor

intervention, when

there is multisystem

involvement, or

when Ihe differential

diagnosis includes *2

conditions that would

require separate

circulating tumour genetic tests

cells

• see Obstetrics. OB7 for information on prenatal screening tests

Differences in Morphology

Congenital Anomalies

Minor and Major Anomalies

• minor anomaly:physical difference that is of no serious medical or cosmetic consequence to the

patient (e.g. ear pit/tag,single palmar crease)

• major anomaly: physical difference that creates significant medical,surgical, or cosmetic problems for

the patient (e.g. ventriculoseptal defect, cleft lip)

Mechanisms for Anomalies

• malformation: resultsfrom an intrinsically abnormal developmental process (e.g. polvdactylv)

• disruption:resultsfrom the extrinsic breakdown of, or interference with, an originally normal

developmental process (e.g. amniotic band disruption sequence)

• deformation: alteration of the final form of a structure by mechanical forces (e.g. Potter deformation

sequence)

• dysplasia:abnormal development that results in abnormal organization of cells into tissues (e.g.

skeletal dysplasia)

Multiple Anomalies

• association: non-random occurrence of multiple independent anomalies that appear together more

often than would be predicted by chance, but are not known to have a single underlying etiology (e.g.

VACTERL association)

• sequence:related anomalies that originate from a single initial major anomaly or precipitating

factor that changes the development of other surrounding or related tissues orstructures (e.g. Potter

sequence or Pierre-Robin sequence)

• syndrome: a pattern of anomalies that occur together and are known or thought to have a single cause

(e.g. CHARGE syndrome)

VACTERL Association

Vertebral dysgenesis

Anal atresia (imperforate anus) ± fistula

Cardiac anomalies

TracheoEsophageal fistula ± esophageal

atresia

Renal anomalies

Limb anomalies

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Approach to the Patient with Physical Differences

General Approach

• are the anomalies major or minor?

• what isthe mechanism underlying the anomaly?

• do the anomalies fit as part of an association,sequence, orsyndrome?

• are the anomaliesseen in other family members?

History

• prenatal/obstctrical history (sec Obstetrics. OB4) with particular attention to potential teratogenic

exposures, developmental history (see Paediatrics. P26), and past medical history

• complete three generation family pedigree: health history, consanguinity, multiple miscarriages/

stillbirths, neonatal deaths, congenital defects, developmental delay/autism, ethnicity

Check the umbilical cord for 2 arteries

and1vein.The presence of a single

umbilical artery may be associated with

other congenital anomalies

Physical Exam

• compare features with other family members

Face: gestalt

Ears: structure,sire,

placement, rotation

Nose: nasal bridge, nostrils

Philtrum: length,shape

Mouth: lips, palate, tongue, teeth

Spine:scoliosis, kyphosis

Skin: hair tufts,sacral

dimples,sinus

Skull: contour and symmetry

Hair: texture, pattern

Eyes: distance apart, brows, lashes,

folds, creases, coloboma,fundus

Chin:size, position

Neck:webbed,redundant nuchal skin

Thorax:shape,size, nipple spacing Limbs: proportions, amputations

Genitalia: ambiguous

Hands and Feet: creases.

structure, nails

Growth parameters ( head circumference, height, weight)

Figure 2. Physical exam in genetic assessment of a child

Investigations

• screening for TORCH infections (toxoplasmosis,syphilis, varicella-zoster, parvovirus Bl9,rubella,

cytomegalovirus, herpes infection)

• serial photographs if patient is older

• x-rays for bony abnormalities

• abdominal U/S and echocardiography to rule out structural abnormalities of organs

• brain imaging, especially ifneurodevelopmental/neurological findings

• cytogenetic studies

» chromosomal microarray analysis (SNP array) if developmental delay/autism or two or more

congenital anomalies

FISH if aneuploidy syndrome (e.g. trisomy 13, 18,or 21) suspected

consider karyotype if a known aneuploidy syndrome is recognized or if there is a family history

of a chromosomal rearrangementsuch as a translocation

• biochemistry: various biochemical tests,specific enzyme assays (e.g. for lysosomal storage diseases)

• single gene testing, gene panel testing, FS, GS

Management

• recurrence risk and prenatal counselling

• referral for specialized medical care or genetic care for symptomatic management

• patient education, connect to social and psychological support services

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Genetic Conditions

Table 2. Common Chromosomal Aneuploidy Syndromes

Trisomy 21 Trisomy 18 Trisomy 13

Disease Down syndrome

1in 600 800 births

Most common abnormality of autosomal chromosomes

Rises vrith advanced maternal age from1in1500 at age 20 to

1in 20 by age 45

Mild microcephaly,flat occiput,third fontanelle.

brachycephaly

Edwards syndrome

1in 6000 live births

F:M-3:1

Patau syndrome

Incidence 1in10000 live births

Cranium/Brain Microcephaly,prominent occiput Microcephaly, sloping forehead,scalp defect,

holoprosencephaly

Eyes Upslanting palpebral fissures, epicanlhal folds, speckled Microphthalmia,hypolclorism,iris coloboma. Microphthalmia,corneal abnormalities

iris(8r ushlicld spots),refractive errors (myopia),acquired retinal anomalies

cataracts,nystagmus,strabismus

low-set.small,overfolded upper helix,frequent acute otitis low-set.malformed

media,hearingloss

Protruding tongue,large cheeks,low flat nasal bridge,small Cleft lip/palate

Small mouth,micrognathia

Intrauterine growth restriction

Clenched fist with overlapping digits,

hypoplastic nails,dinodadyly

Ears low-set.malformed

Facial Features 60-80% cleft lip and palate

nose

Short stature

Excess nuchal skin

Joint hyperflexibility (80%) including dysplastic hips,

vertebral anomalies,atlantoaxial instability

50%. particularly atrioventricular septal defect

Small head size

Polydactyly

Musculoskeletal (MSX)

Cardiac Defect 60% (ventricular seplal defect,patent ductus

arteriosus,atrial septal deled)

Hernia,tracheoesophageal fistula

80% (atrial seplal deled,patent dudus

arteriosus,ventricular seplal defect)

Gastrointestinal (61) Duodenal/esophageal/anal atresia, tracheoesophageal None known

fistula,Hirschsprung's disease, chronic constipation

Cryptorchidism,rarely fertile

Hypotonia at birth

low 10.developmentaldelay,hearing problems

Onset of Alzheimer's disease in 40s

Single transverse palmar crease,dinodadyly. and absent

middle phalanx of the 5th finger

1% lifetimerisk ol leukemia

Polycythemia

Hypothyroidism

long-term management per MP Guidelines (Health

Supervision of Children with Down Syndrome):C6C.

echocardiography,yearly thyroid test,allanto-occipital

x-ray at 2 yr.sleep study,hearing test,and ophthalmology

assessment

Genitourinary (GU)

Central Nervous System (CNS)

Polycystic kidneys,cryptorchidism

Hypertonia

Polycystic kidneys

Hypo- or hypertonia

Seizures, deafness

Small for GA

Rocker -bottom feet

Single umbilical artery

Midline anomalies: scalp,holoprosencephaly.

palate,heart,umbilicus,anus

Other Features

13%1yr survival.10%10 yr survival

Profound intellectual disability insurvivors

20%1yr survival,13%10 yr survival

Profound intellectual disability insurvivors

Prognosis/Management

Table 3. Common Genetic Disorders Involving the Sex Chromosomes

Fragile X Syndrome Klinefelter Syndrome Turner Syndrome

Genotype CGG trinucleotide repeat expansion inFMR1gene onX 47.XXY (most common)

chromosome:"55- “

200 repeats is considered a premutation, 48.XXXY.49JCXXXY

whereas >200repeats is considered a fullmutation

1in 3600 males.1in 6000 females

Most common heritable cause of intellectual disability in boys Increased risk with advanced maternal age

Overgrowth:macroccphaly. prominent jaw.forehead,and Tall. slim,underweight

nasal bridge withlong and thin face,large protuberant ears. No features pre puberty

macroorchidism,hyperexlcnsibllily.and high archedpalate Post-puberty:variable learning/behavioural

Complications:seizures, scoliosis,mitral valve prolapse difficulties,long limbs,gynaccomastia,lack of

Premutation carriers (males more often than females) may facial hair

demonstrate tremor/ataxia syndrome in later life

45.X0 (50% of cases),45JC/46.XX mosaic (15%

of cases)

Incidence 1in 1000 live male births 1in 4000live female births

Risk not increased with advanced maternal age

Short stature,short webbed neck,low posterior

hair line,wide carrying angle

Broad chest,widely spaced nipples

lymphedema of hands and/or feet,cystic

hygroma innewborn with polyhydramnios,lung

hypoplasia

Coarctation of aorta,bicuspid aortic valve

Renal and cardiovascular abnormalities,

increased risk of HTN

less severe spectrum with mosaic

Phenotype

Mild to moderate intellectual disability.20% olaffected

males have normalID

Attention deficit hyperactivity disorder (A0HD) and/or autism

Females with fullmutation may show milder intellectual

impairment

Premutation carrier females at risk of developing premature

ovarian failure

lOand Behaviour Mild intellectual disability oi learning difficulties Typically normal intelligence

Behavioural or psychiatric disorders:anxiety,

shyness,aggressive,and impulsive behaviour

acts

r m Gonad andReproductive

Function

Infertility due tohypergonadotropic

hypogonadism

Streak ovaries with deficient follicles,

infertility,primary amenorrhea,impaired

development Df secondary sexual

characteristics

Karyotype

<- J

Diagnosis Molecular testing of FMR1gene:PCR and/or Southern blot

analysis ol trinucleotide repeat length,melhylation analysis

Karyotype +

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Table 4. Examples of Other Genetic Syndromes

22q11.2 Deletion Syndrome Prader-WilliSyndrome

(DiGeorge syndrome)

Angelman Syndrome Noonan Syndrome CHARGE Syndrome

Lack of gene expression

on paternal chromosome

15q11-13 due to deletion,

maternal uniparental disomy of

chromosome 15,or imprinting

defect

2/3 of children with CHARGE

have been found tohave a

pathogenic variant in CHD7

Genotype Autosomal dominant;microdeletions of

chromosome region 22q11.2

Lack of gene expression

on maternal chromosome

15q11-13 due to deletion,

paternal uniparental disomy

olchromosome15.or an

imprinting defect

Rarely dire to pathogenic

variants in UBE3A

1in10000

Autosomal dominant

with variable expression,

pathogenic variants in

RAS/MAPK pathway genes

(“RASopathies"):autosomal

recessive with pathogenic

variants in L2IR1

Incidence 1in 4000:second most common

genetic diagnosis (next to Down

syndrome)

"CATCH 22”

Cyanotic suggesting congenital heart

disease (CHD)

Anomalies: craniofacial anomalies,

micrognathia,and low set ears

Thymic hypoplasia:immunodeficiency

Cognitive impairment

Hypoparathyroidism,hypocalcemia

22q11microdelelions

High-risk for schuophrenia and other

psychiatric disorders

1in 15000 1in 2000 1in10000

Clinical Features "H30"

Hypotonia and weakness

Hypogonadism,obsessive

Hypcrphagia

Obesity

Short stature,almond-shaped

eyes, small handsand feel with

tapering of fingers

Hypopigmcnlalron.12DM

Short stature,webbed neck,

hypertelorism,low-set cars,

eplcanthal folds,ptosis,

pectus cxcavalum

Right-sided CHD. pulmonary

stenosis

Increased risk of

hematological cancers,

cardiomyopathy, moderate

Intellectual disability,

delayed puberty

Ataxia with severe intellectual

disability,seitures,

tremulousness, midfacc

hypoplasia,large mouth,

fair hair,inappropriately

happy demeanour/laughter.

fascination with water

“CHARGE"

Coloboma

congenital

Heart disease

choanal

Atresia mental Retardation

GU anomalies

Ear anomalies

Table 5. Examples of Familial Cancer Syndromes

Syndrome Gene Associated Cancers Screening and Monitoring

li-Fraumcni Syndrome Breast, osteosarcoma,leukemia,soil Children:

tissue sarcoma,brain, adrenocortical From birth:abdominal/pelvic U/S every 3- 4 mo;annualbrain MR!,annual

carcinoma,and numerous other cancers W8MRI

Adults:

Women age 20- 75:annual breast MRI

Age 18: annual dermatologic examination,abdominal/pelvic U/S.brain MRI,

andWBMfll

Age 25:colonoscopy and upper endoscopy every 2-5 yr

(Moderate recommendation)

MSH2. MLHt, MSHS. PMS2. IPCAM Colorectal,endometrial,ovarian,renal, Age 20- 25 for 2-5 yr younger than earliest age of colorectal cancer diagnosis

pancreatic,liver/biliary dud, stomach, in family): colonoscopy every1-2 yr

Age 30 yr IMSH6) and 35 (PMS2): colonoscopy every1-2 yr

IStrong recommendation)

Age 10:sigmoidoscopy or colonoscopy every1-2 yr.colonoscopy once polyps

develop

IStrong recommendation)

Female:breast,ovarian, pancreatic Age 25-65:annual breast MRI

Male:prostate,breast,pancreatic Age 30:annual breast MRI and mammograms

(Strong recommendation)

Age 2: annualphysical examination,annual ophthalmologic examination,

consider annual catecholamine assessment

Consider baseline audiometry at age of school entry

Ages12,15.and 18: MRI of brain stem,spine,and abdomen,with abdominal

U/S in alternating years

Age 20: MRI every 2yr

(Expert opinion)

Women:

Age 30 (or 5-10 yr before earliest breast cancer in the family):annual

mammography

Age 30:consider random annual endometrial biopsy and/or U/S

Men and Women:

At diagnosis:annual thyroid U/S

Children:evaluation forneurodevelopmental disorders

Age 18:annual comprehensive physical exam

Age 30-35:colonoscopy every 5 yr

(Moderate recommendation)

m3

lynchSyndrome (HNPCC)

brain,breast

FamilialAdenomatousPolyposis (FAP) APE Colorectal, smallintestine/stomach

tumours

Hereditary Breast and Ovarian Cancer BKCAi. BBCA2

Syndrome

VonHippel-lindau Syndrome Kidney *

tumours (e.g.

pheochromocytoma)

PHI

Cowden Syndrome pm Breast,thyroid,endometrial

Heurofibromatosis (NF)

Type1 Children:evaluation for neurodevelopmental disorders

Annual physical examincluding evaluation of growth,blood pressure,skin

examination,bone examination,neurological examination,and vision

screening

(Expert opinion)

Hft Astrocytoma,optic glioma,

neurofibroma,leukemia

r "i

L J

Type 2 HE2 Vestibular schwannoma, meningioma, Annual physical examincluding audiology assessment

ependymoma, astrocytoma Age10:annua!brain MRI.spinal MRI every 2-3 yr

(Expert opinion)

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Table 6. Heritable Connective Tissue Disorders

Loeys-Dietz

Syndrome

Hypermobile

Ehlers- Danlos

Syndrome

Classical Ehlers- Vascular Ehlers- Marian Syndrome

Danlos Syndrome Danlos Syndrome

Incidence of genetic disease vary

markedly by ethnic origin:these values

have historically been derived from

populations of predominantly European

ancestry

Inheritance

Pathophysiology

Autosomal dominant

Pathogenic variants

In KftBI.ICfSBl

SMAD3. I0FB2 genes

affecting the IGE p

pathway

Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant

Underlying molecular Pathogenic variants Pathogenic variants Pathogenic variants in

basis unknown in COISAI ot C01SA2 mttOfgone

genes allecting Type V that affect Type III

collagen

fBHIgene

collagen, which is

most abundant type

ol collagen in aortic

extracellular matrix

Incidence

Clinical Features

Unknown

Vascular findings

(aortic aneurysms

and dissections,

generalized

arterial tortuosity ),

craniofacial features

(dell palate,

hypertelorism),

skeletal features,

easy bruising,

allergic/inflammalory chronic pain

disease

Tin 5000 20000 1in 20000-40000 1 in 100000- 250000 tin 3000-5000

Clinical features vary: Arterial fragility and/ Tall and slender build,

generalized joint

hypermobilily,skin

hypercxtensibilily

and atrophic

scarring, Iragilc

skin, easy bruising,

subcutaneous

spheroids(fatcysts) prominent ears)

on lorearmsand shins

Clinical features

vary:generalized

joint hypermobility,

mild skin

hyperextensibility,

unexplained striae,

recurrent abdominal

hernias, recurrent

joint dislocations in

absence ol trauma.

or rupture,aortic disproportionately

dilatation,intestinal long limbs and digits,

rupture, uterine aortic dilatation,

rupture in pregnancy, lens detachment,

characteristic facies pneumolhoraces

(translucentskin.thin

lips, pinched nose.

Table 7. Intracellular/Extracellular Transport Receptor Disorders

Hereditary

Hemochromatosis

Wilson Disease CF

Gowers'Sign

Child uses hands to “climb up" the legs

to move from a sitting to a standing

position. Observed in individuals with

weakness of the pelvic and proximal

lower limb muscles.

Inheritance

Pathophysiology

Autosomal recessive Autosomal recessive

Pathogenic variants In Hft

gene (rarely FC/K HAMP, IFR2,

and SLC40A1genes), disrupting

regulation of iron

1in 300

Iron overload (elevated transferrin Liver disease (acute andlor

saturation and ferritin), bronze

skin, arthralgia , hormone

disturbance (DM. hypogonadism), Fleischer rings

cirrhosis, caidiomyopalhy

Autosomal recessive

Pathogenic variants In AIP7B Pathogenic variants in CfW gene,

gene, leading to the impairment of which predominantly aflects the

cellular copper transport lungs, but also the Gl tract

Incidence

Clinical Features

Tin 30000 1 in 3200-15000

Severe to mild:

chronic), movement disorders. Malabsorption,failure to

psychiatric disturbance.Kayser- thrive, pancreatic insufficiency

Bronchiectasis, male infertility

More information lound In other

chapters'

More information lound in other

chapters'

Phlebotomy for elevated serum Chela ling agents(c.g.

ferritin and transferrin saturation penicillamine, tnentine)

Management

‘See Respirology.R12 and Paediatrics.P92

Corticosteroidsforthe Treatment of Duchenne

Muscular Dystrophy (DMD|

Cochrane OB Syst Rev 2016:5:00003725

Purpose loassessthe eHeds of corticosteroids

on pioloegation ol walking ability, muscle strength,

lunctonal ability, and quality of tile In DMD and

address whether benefit is maintained over long

term,assess adverse events, and compare efficacy of

different regimens.

Methods: Systematic review mcludmg RCTsor

quas-RCTs of corticosteroids given to patientswith

definitive DMD dagnosisfor at least 3 mo.

Results:12 studies with 662 parti c pants included.

Meta-analysesshowed that corticosteroids improved

muscle strength and function vs. placebo over 6 mo.

Evidence horn single dialsshowed 0.25 mg 'kgi'd

superior to 0.3 mgfkg/d on moststrength and function

measures, with little evidence ol further benefit al

1.5 mgdrgld.Improvements were seen ui lime taken

to nse Iron the floor, limed walk,(our-stair climbing

time, abikty to lift weights, leg function grade, and

forced vital capacity. Moderate quality evidence ol

ad-verse effects:excessive weight gain, behavioural

at-mormalitres.Cushingoid appearance, and excessi ve

hair growth.

Conclusions:Moderate quality evidence from RCTs

indicatesthat corticosteroid therapy in DMD improves

muscle strength and lunctlon in the short term (12

mo),and strength (up lo 2 yr.) Dose of 0.25 mgikg/d

shodd be enough.Adverse effects were common but

not ehiucoD* severe.

Other Single Gene Disorders

SICKLE CELL DISEASE

• autosomal recessive disease caused by mutation of the HBB gene resulting in the production of an

abnormal version of p-globin and subsequently distorted red blood cells

• see Hematology. H 2 I

DUCHENNE MUSCULAR DYSTROPHY

Incidence

• 1 in 4000 males

Etiology

• one type of muscular dystrophy characterized by progressive skeletal and cardiac muscle degeneration

• X-linkcd recessive: 1 /3 de novo pathogenic variants, 2/3 inherited pathogenic variants

• missing structural protein (dystrophin) » muscle fibre fragility *fibre breakdown * necrosis and

degeneration

r n Clinical Features

• proximal muscle weakness by age 3, positive Gowers’sign, waddling gait, toe walking

• pseudohypertrophy of calf muscles (muscle replaced by fat) and wasting of thigh muscles

• decreased reflexes

• non-progressive delayed motor and cognitive development (dysfunctional dystrophin in brain)

• cardiomyopathy

L J

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Diagnosis

• molecular genetic studies of dystrophin gene (DMD) (first line)

• genotype-phenotype correlations:different variants in the gene will cause some dystrophin

production and a milder muscular dystrophy, Becker muscular dystrophy

• family history (pedigree analysis demonstrating X-linked inheritance)

• increased creatine kinase (50-100x normal) and lactate dehydrogenase

muscle biopsy, EMG

Management

• supportive (e.g. physiotherapy, wheelchairs,braces); prevent obesity

• cardiac health monitoring and early intervention

• bone health monitoring and intervention (vitamin D, bisphosphonates)

• steroids(e.g. prednisone or deflazacort)

• surgical (forscoliosis)

• gene therapy trials underway

Complications

• patient usually wheelchair-bound by age 12

• early flexion contractures,scoliosis, osteopenia of immobility, increased risk of fracture

• death due to pneumonia/respiratory failure or CHI-

'