in second-third decade

Metabolic Diseases

• individually rare but collectively occur in 1 in 1500 births

•inherited disorders of metabolism:most are autosomal recessive

• infants and older children may present with failure to thrive or developmental delay

• organelle disorders can present with dysmorphism

• universal newborn screening in Ontario,Canada includessome treatable metabolic disorders

Table 8. Metabolic Disorders

Protein Metabolism Disorders Carbohydrate Disorders Fatty Acid Disorders Organelle Disorders

Examples of Conditions PKU* Galactosemia*

GSDs:von Gierke,Pompe,Cori.

Andersen.McArdle

MCADD"

VLCAD*

LCHAD*

Congenital disorders of glycosylation

Lysosomal storage diseases:

mucopolysaccharidosis (Hunter.Hurler*),

ttemann-Pick.Tay-Sachs.Gaucher. Fabry,

Krabbe

Peroxisomal defects:Zellweger syndrome.

X-linked adrenoleukodystrophy

Tyrosineraia*

Homocystinurra*

HSUD*

Alkaptonnria

Propionic acidemia*

Urea cycle defects (Ornithine

transcarbamylase deficiency)

Clinical Manifestations Coma,irritab.hty,lethargy,poor feeding Hypoglycemia, hepatomegaly, liver

failure,cardiomyopathy

Growth retardation,failure to thrive

Lethargy,poor feeding

Seirures.coma

Symptoms triggered by lasting

Liver dysfunction

Sudden infant death

Progressive neurological problems

Developmentalregression

Chronic encephalopathy

Developmental delay

Bone crises (Gaucher)

Deafness,blindness

Elevated urine oligosaccharides

(oligosacdraridoses)

and glycosaminogtycans

(mucopolysaccharidoses),abnormal

transferrin isoelectric focusing (congenital

disorders of glycosylation).abnormal

very long chain fatty acids (peroxisomal

defects)

Dysmorphic facial features

Macrocephaly (Lysosomal storage

diseases)

Hepatosplenomegaly (Niemann-Pick type

A BC.not Tay-Sachs)

Cherry-red spot onmacula (Niemann-Pick

type AJB.Tay-Sachs.Gaucher)

Corneal clouding (Hurler)

Infantile cataract (Fabry)

Peripheral neuropathy (Fabry.Krabbe)

Spasticity

Seizues

Intellectual disability

Vomiting and acidosis after feeding

initiation

Sweet-smellingurine (MSUD)

Hyperammonemia withnormal anion gap Elevated liver enzymes (galactosemia)

(urea cycledefects),hyperammonemia Hypoglycemia,

withhigh anion gap (organic acidemia) lactic acidosis.

hyperlipidemia (GSD)

laboratory Findings Hypoketotic hypoglycemia

Elevated free fatty acids

Elevated creatine phosphokmase

Physical Exam Infantile cataracts (galactosemia)

Hepatomegaly

Muscle weaknessfcramping

HypotoniaTrypertonia

M ctocephaly.musty odour,eczema,

hypopigmentabon (PKU)

Dark urine,pigmented sderae.

arthralgias (alkaptonuria)

Lens subluxabon.Marfanoid appearance

(homocystinuria)

Hepatomegaly

Hypotonia

* Metabolic disorders ird*

_dedir Newborn Screen-g Ontario

ri

Initial Investigations for a Child with Acute Problems Thought to be Due to an Inborn

Error of Metabolism

• important to send lab studies at initial presentation in order to facilitate immediate diagnosis and

treatment

• check newborn screening results

• electrolytes, arterial blood gases (calculate anion gap, rule out acidosis)

• CBC with differential and smear

• blood glucose (hypoglycemia seen with organic acidemia, fatty acid oxidation defects, and GSDs)

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• lactate,ammonium (hyperammonemia with urea cycle defects or organic acidemias),plasma Cat

*

and Mg’’

,plasma amino acid screen

• routine U/A: ketonuria must be investigated in a neonate,urinary organic acids

• carnitine levels with acylcarnitinc profile

• others:urate,urine nitroprusside,(1ST glycine,free fatty acids (3-(5-hydroxybutyrate ratio >4 in fatty

acid oxidation defect)

Treatment

• varies according to inborn error of metabolism but includes dietary restrictions,toxic metabolite

sequestrants,enzyme replacement,etc.

• in the presentation of acute decompensation potentially caused by an inborn error ofmetabolism,

discontinue feeding to prevent further buildup of toxic metabolites

Table 9. Presentation and Management of Select Metabolic Disorders

PKU Galactosemia MSUD GSD Type 1(Von Tay-Sachs

Gierke Oisease) Disease

1in 10000:autosomal 1in 60000:autosomal 1in 185000,

recessive disease recessive disease

(mutations inPW

gene)

1in100000:

autosomal recessive autosomal recessive autosomal recessive

disease (pathogenic disease.1in 20000 in disease.1in 3600 in

variants in BCKDHA. Ashkenazi Jewish Ashkenazi Jewish

BCKDH8,and DBT

genes),1in 25000 in

Ashkenazi Jewish.1in

400 InMcnnoniles

Inheritance and 1in 320000:

Incidence

Pathophysiology Deficiency ol

phenylalanine

hydroxylase prevents of galactose1-phosphate

uridyltransferase

leading to an inability

to process lactose/

Most commonly

due to deficiency

Mutations in C6K Mutations inHIXi

elimination of protein (cause of GSOta) and gene,which encodes

complex needed for SLC3JA4 (cause of alpha subunit of

amino acidsleucine, GSDtb) genes prevent hexosaminidase A:

isoleucine,andvaline effective conversion leads to intracellular

accumulation of GM2

Deduction or

conversion of

phenylalanine to

tyrosine leading

lo buildup of

phenylalanine and its galactose

toxic metabolites

breakdown,leading of glucose-6-

to toxic build-up phosphate to glucose, ganglloside.lysosome

Glucose- 6 phosphate dysfunction,and

Is converted to neurodegeneration

glycogen and fat

which subsequently

accumulate in cells,

especially in the liver

and kidneys

Mothers who

have PKU may

have infants with

multiple congenital

abnormalities

Clinical Features Baby is normal at Signs of liver and

birth,then develops renal failure,

a musty odour. jaundice,failurelo

eczema,hypertonia, thrive,and cataracts

tremors,and mental withingestionof

lactose/galactose

Feeding intolerance, fypicallyprescnts

failure lo thrive. between 3-6

vomiting,lethargy, mo ol age with

and maple syrup hepatomegaly,

odour inurine and hypoglycemia,poor

fasting tolerance,

growth failure,and

"doll-like'facies

(full cheeks with thin Psychomolor

regression,

hypotonia.increased

startle response,

macular cherry red

spot,seizures,and

hyperlipidemia. hearing impairment

delayed puberty,

renal disease,

hypoglycemic

seizures,hepatic

adenomas,

osteoporosis

Various

presentations:

infantile form (onset

at 3-6 mo),juvenile

form (onset at 2-6 yr),

and adult or chronic

form (onset at >10 yr)

retardation cerumen

May progress

to irreversible

mental retardation,

hyperactivity,severe extremities)

failure to thrive,

seizures,coma,

cerebral edema,and

Hypopigmentation

due tolow tyrosine Complications:

levels (lair hair,blue Increased risk of

irises) sepsis,especially

l. coli

If the diagnosis is

not made at birth,

liver and brain

damage may become

irreversible

Complications:

Lactic acidosis.

death if inadequately hyperuricemia,

treated

Diagnosis and

Management

PKU screening at birth Screened for in many

Life-long dietary

restriction of

phenylalanine

starting within the

first 10 d ol life: f. coli sepsis belore

especially important screening result

during pregnancy reported

to maintainnormal Elimination of

MSUD is screened Hypoglycemia

in most newborn when interval

screening programs, between feeds are

Increased (»3- 4 h).

Clinical suspicion

6-Kexosaminidase

enzyme activity

(scrum)

ladle acidemia. Ashkenazi Jewish

hypertriglyceridemia, carriers often

and hepatomegaly identified by

Treatwith nutrition preconception

screening

Treatment is

supportive

newborn screening

programs but

generally present

with liver failure and

Serum amino

acid evaluation

(leucine,isoleucine,

alloisoleucine,and

valine) andurine

organic acid analysis therapy Ismail

Protein-restricted. frequent feedings,

high- carbohydrate avoid fructose/

diet tolimit branched sucrose/galadosc).

continuous overnight

A trial of thiamine feedings,raw

therapy in addition cornstarch (for slow,

may be recommended sustained glucose

for some infants

phenylalanine levels galactose from the

lo prevent maternal diet (e.g.dairy,breast

PKU effects on fetus milk)

large neutral amino Most infants arc led a amino acid intake

acid (tyrosine) soy-based diet

replacement.BH4

enzyme treatment,

phenylalanine lyase

treatment are other

options

release),vitamin

supplementation, +

frequent blood

glucosemonitoring

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MG11 Medical Genetics Toronto Notes 2023

Landmark Medical Genetics Trials

Trial Name Reference Clinical Trial Details

PHENYLKETONURIA

Glycomacropeptide for Nutritional

Management of Phenylketonuria: A 345

Random!red.Controlled,Crossover

AmiClin Hulr 2016:104(2):334 Title:Glycomacropeptide for Nutritional Management of Phenylketonuria:A Randomircd.Controlled.Crossover Trial

Purpose: To evaluateIhe eflicacy and safety of a low phenylalanine|Phe) diet in combination with either glycomacropeptide

medical foods (GMP MFs) or Iradilional amino acid medical loods|AA MFs) in individuals with phenylketonuria (PKU).

Methods: Thirty early treated individuals aged 15- 49 yr with PKU participated in a 2 stage,randomircd ciossovcr trial

involving consumption ol a low Pile diet with AA - MFs or GMP MFs for periods of 3 wk each.

Results: Dietary management of PKU with GMP MFs compared lo AA Mfs resulted inhighci intake amongparticipants.

GMP Mfs were rated as more acceptable in terms ol taste and had less side effects.

Conclusions: GMP Mfs are sale lor dietary management of PKU.GMP Mfsmay improve dietary adherence for patients with

Trial

PKU.

Title: Pegvaliase lor Ihe Treatment of Phenylketonuria:Resullsof a longTermPhase 3 Clinical trial Program (PRISM)

Purpose:Evaluate the eflicacy and safely of pegvaliase trcatmenl in adults with phenylketonuria (PKU).

Methods: Pegvaliase- naive participants with blood Phe >600 pmol/ were randomircd to receive 20 mg/d or 40 mg/d of

pegvaliase.

Results: Pegvaliase treatment was given to 261participants.Within 24 mo.68 4% of participants achieved blood Phe < 600

pmol/L. Reductions in bloodPhe were associated with neuropsychiatric outcomes,which weremaintained with long- term

treatment.Ihe vast majority of adverse events (99%) weremild or moderate in seventy.

Conclusions:Results from this trial suggest pegvaliase is safe and elftcacious in treating adults with PKU.

PRISM MolGenet Melab 2018:

124(1):27.38

CYSTIC FIBROSIS

NCT03691779 Am J Respir Crit Care Med.

2021:203(12):1522

Title:Study of Elcxacaftor/Teracaftor/lvacaftor in Children 6 through 11Years ol Age with Cystic fibrosis and at least One

F508del Allele

Purpose:Elexacaflor/teracaftor/ivacaltor as a combination therapy was effective in treatingpatients aged greater than 12

years with CF and an accompanying F508del.This 24-week study served to evaluate the efficacy of treatment in patients

less than <12 yr.

Methods:RCT consisting of 66 children aged between 6 and11 with CF who were assessed for the primary outcome of

interest being safety and tolerability of the proposed treatment of oral Eleiacaflor100 mg once daily.Tezacaftor 50 mg

once daily,andIvacaftor 75 mg q12h for children weighing <30 kg and oralEleiacaflor 200 mg once daily.Tezacaftor 100

mg once daily,and Ivacaftor 150 mg g12 h for children weighing <30kg.Additionally,efficacy of the treatment was also

assessed (FEVi, and Cystic Fibrosis Questionnaire-Revised respiratory domain score).

Results:Commonly reported side effects included cough,headache,and fever.Treatment also resultedinimprovements

in predicted FEVi (10% improvement),and Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points

improvement).

Conclusion:Results show that treatment of CF with accompanying F508del usingElexacaftor/Tezacaftor/lvacaftor resulted

in significant improvements in patients aged under 12.

NON-SMALL CELLLUNG CANCER

N Engl J Med.2018:378|2):113.

Epub 2017 Hov18.

Title:Osimertinib in Untreated EGFR- Mutated Advanced Non-Small-Cell Lung Cancer (NSCLC)

Purpose:To compare Osimertinib (a third-generation EGFR inhibitor) againstenisling standard EGER inhibitors in patients

with previously untreated EGFR mutation-positive NSCLC

Methods: Double-blind, RCT consisting of 556 previously untreated EGFR mutation positive NSCLC patients. Patients were

randomized toreceive osimertinib ora standard EGFR -TKI.Outcome of interest includedclinician-assessed progression- free

survival.

Results:MedianprogressionTree survival was greater in osimertinib when compared to standard EGFRTKIs in EGFR

mutation positive NSCLC patients (18.9 mo vs.10.2 mo).

Conclusion: Results of this study show that osimertinib had superior efficacy when compared tostandard EGFRTKIs.

FLAURA

ALKAPTONURIA

S0NIA - 2 lancet Diabetes Endociinol. 2020 Title: Using Once Daily Nitisinonc for Treatment of Alkaptonuria

Purpose: No homogentisic acid (HGA) lowering medications have been for treatment of Alkaptonuria.

Methods: RCT consisting of 138 palients aged 25 or older with confirmed alkaptonuria were randomized to receive either

oral nitisinonc 10 mg daily or no treatment.Ihe outcome of interest was daily urinary HGA excretion (U- HGA24) after 12 mo.

Results: 55 patients in Ihenitisinonc group and 53 inIhe control group completedIhe study,u-H6A24 al12 mo was

significantly decreased by 99

-7%Inthe nitislnone groupcompared with the control group.

Conclusion: Nitisinonc was well tolerated within Ihe treatment group and shows evidenceol bcingan effective treatment

lor alkaptonuria.

Sop:8|9|:762-772.

ACHONDROPLASIA

NC101603095. NCI02055157,

HCI02724223

N Engl jMed. 2019 7ul

4:381(1):25-35.

Title: C Type Natriuretic Peptide Analogue Iherapy in Children with Achondroplasia

Purpose:lo assess Ihe efficacy and safety ol vosoritidc at treatingachondroplasia in children

Methods: RCT consisting of 35 children aged 5 lo14 with achondroplasia. Dosages were stratified based on weight; dose of

2.5 pg per kilogram olbody weight|8 patients in cohort 1). 7.5 pg per kilogram (8 pabents in cohort 2).15.0 pg per kilogram

|10 patients in cohort 3). or 30.0 pg per kilogram|9 patients in cohort 4|.Patients wereobserved for 24 mo.the outcomes of

interest were prevalence of adverse events and growth velocity.

Results:Each patient experienced minor adverse effects such as pyrexia,hypothermia,erythema,cough,swelling and

headaches. 4/35 patients experienced severe adverse effects including giade 3 obstructive sleep apnea,grade1tonsillar

hypertrophy,grade 3 thyroglossal cyst,and grade 3 syrinx.At 6 mo.there were increases in annualized growth velocity in

all cohorts except for that which received 2.5 pg.

Conclusion:Although associated with mild side effects,with larger scale trials,vosonlide may be used as a treatment for

achondroplasia in children.

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References

Amato RS.Nelson's essentials of pediatrics, 4th ed.Philadelphia:WB Saunders.2002.Human genetics and dysmorphology.129-146.

Anbar RD, NationalOrganization for Rare Disorders.Cystic Fibrosis [Internet],NationalOrganization for Rare Disorders;2017.Available from:https://rarediseases.org/rare-diseases/cysticfibrosis/.

Barnes,H. Morris,E. Austin,J.Trans-inclusive genetic counseling services:Recommendations frommembers of the transgender and non-binary community.J GenetCouns.2019;29:

423-434.

Baumann N,Turpin J.Tay-Sachs disease [Internet],Orphanet;2006.Available from:https://www.orpha.net/consor/cgi-bin/OC Exp.php?Lng=GB&Expert=845.

BC Cancer Agency.Von Hippel lindauSyndrome [Internet]. BC Cancer Agency;2017.Available from:http://www.bccancer.bc.ca/coping-and-support-site/0ocuments/Hereditary%20

Cancer%20Program/HCP GuidelinesManuals vonHippelLindauSyndrome.pdf.

Biggnr W. Ouchenne muscular dystrophy.Pediatr Rev 2006;27:83-88.

BlakeKD, Prasad C. CHARGE syndrome. Orphanet J Rare DIs. 2006,1:34.

Campos MA,Wanner A. Zhang G.et al.Trends in the diagnosis ol symptomatic patients with al-antitrypsin deficiency between1968 and 2003, Chest. 2005;128{3):1179-1186.

Chudley AE,Conry J,Cook Jl,et al.Fetal alcohol spectrum disorder:Canadian guidelines for diagnosis.CMA J 2005:172(5 Suppl):S1-21.

Committee on Practice Bulletins—Gynecology,Committee. "Practice Bulletin No 182:Hereditary Breast and Ovarian Cancer Syndrome.” Obstet Gynecol 2017;130.3:e110.

Cury M.Zeidan F,lobato AC.Aortic disease in the young:genetic aneurysm syndromes,connective tissue disorders,and familial aortic aneurysms and dissections.Int J Vase Med

2013;267215:1-7.

Daly MB,Pilarski R,Berry M,et al.NCCN guidelines insights:genetic/familial high-risk assessment:breast and ovarian,version 2.J Natl Compr Cane Ne 2017;15(1):9-20.

De Paepe A,Devereux RB,Dietz HC,et al.Revised diagnostic criteria for Marfan syndrome.Am J Med Genet1996;62(4):417-426.

De Paepe A,Malfait F.The Ehlers—Danlos syndrome,a disorder with many faces.Clinical Genet 2012;82(1):1-1.

Elieff MP,Lopez-Beltran A,Montironi R,et al.Familial cancer syndromes.Humana Press.2008. Molecular genetic pathology.449-466.

Evans DG,Salvador H,Chang VY,et al. Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 2 and related disorders. Clin Cancer Res 2017;23(12):e54-e61.

Genetics Education CanadaKnowledge Organization.Non-invasive prenatal testing [Internet],Genetics Education Canada Knowledge Organization;2015 [updated 2017],Available from:

http://geneticseducation.ca/educational-resources/gec-ko-on-the-run/non-invasive-prenatal-testing/.

Genome-wide Sequencing Ontario.Patient Eligibility [Internet],GSO;2022.Available from:https://gsontario.ca/for-providers/patient-eligibility/

Giardiello FM,Allen Jl,Axilbund JE. et al.Guidelines on genetic evaluation and management of lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal

Cancer. Gastrointest Endosc 2014;80(2):197-220.

Grati FR. Malvestiti F,Ferreir JC. et al. Fetoplacental mosaicism:potential implications for false-positive and false-negative noninvasive prenatal screening results. Genet Med

2014;16(8):620-624.

Hersh JH.Health supervision for children v/ith neurofibromatosis.Pediatrics 2008;121(3):633-642.

Grosse SD,Gurrin LC,Bertalli NA,et al.Clinicalpenetrance inhereditary hemochromatosis:estimates of the cumulative incidenceof severe liver disease among HFE C282Y homozygotes.

Genet Med. 2018;20(4):383-389.

Hamosh A,FitzSimmons SC,Macek Jr M,et al.Comparison of the clinical manifestations of cystic fibrosis in black and white patients.J Pediatr1998;132(2):255-259.

Huster D.Wilson disease.Best Pract Res Cl Ga.2010;24(5):531-539.

Johnston,J.,van der Smagt,J.,Rosenfeld,J.et al..Autosomal recessive Noonan syndrome associated with biallelic LZTR1variants.Genetics In Medicine 2018;20(10),1175-1185.

Kaback MM,National Organization for Rare Disorders.Tay Sachs Disease [Internet],National Organization for Rare Disorders; 2017 .Available from:https://rarediseases.org/rarediseases/tay-sachs-disease/.

Kratz CP. Achatz Ml,Brugiereslet al. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome.Clin Cancer Res. 2017;(23) (11) e38-e45.

Kruszka P,Regier D.InbornErrors of Metabolism:From Preconception to Adulthood.Am FamPhysician 2019;99(1):25-32.

MacCarrick G,Black JH.Bowdin S. et al.loeys-Dietz syndrome:a primer for diagnosis andmanagement.Genet Med 2014;16(8):576-587.

Malfait F,Francomano C.ByersP. et al.The 2017 International Classification of the Ehlers-Danlos Syndromes. Am J MedGenet Part C (Seminars in MedicalGenetics) 2017;175C:8-26.

Moeschler JB,Shevell M. Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays.Pediatrics 2014;134(3):e903-918.

Monaghan,K„lyon,E..8 Spector, E).ACMG Standards and Guidelines for fragile X testing:a revision to the disease-specific supplements to the Standards and Guidelines for Clinical

Genetics Laboratories of the American College of Medical Genetics andGenomics. Genetics In Medicine 2013;15(7),575-586.

National Institute of NeurologicalDisorders and Stroke. Tay-Sachs Disease InformationPage [Internet],National Institute of Neurological Disorders andStroke;2019.Available from;

https://www.ninds.nih.gov/Disorders/AII-Disorders/Tay-Sachs-Disease-lnformation-Page.

Nicholson JF.Nelson’s essentialsof pediatrics,4th ed.Philadelphia:WB Saunders.2002.Inborn errors of metabolism,p.153-178.

NIH:U.S.National library of Medicine.Ehlers-Danlos syndrome [Internet].2020.Available from:https://ghr.nlm.nih.g0v/c0nditi0n/ehlers-danl0s-syndr0me#diagn0sis.

Pietrangelo A.Hereditary hemochromatosis—a new look at an old disease. NEJM 2004;350(23):2383-2397.

Polli JB,Groff DdP,Petry P,et al.Trisomy13 (Patau Syndrome) and Congenital Heart Defects.Am J Med Genet 2014:Part A 164A:272—275.

Richards S,Aziz N.Bale S,et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of theAmerican College of Medical Genetics and

Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.

Sobel E,lange K. Descent graphs in pedigree analysis: applications to haplotyping,location scores,and marker-sharing statistics. Am J Hum Genet 1996;58(6):1323.

Pletcher 6, Toriello H.Noblin S,et al.Indications for genetic referral:a guide for healthcare providers. Genet Med. 2007;9.385-389.

Therrell BL. Adams J. Newborn screening in North America. J Inherit Metab Dis 2007;30(4):447-465.

US National Library of Medicine.Sickle cell disease [Internet],US National library of Medicine; 2012(updated 2020]. Available from: https://ghr.nlm.nih.gov/condition/sickle-cell-disease.

US National library of Medicine.Glycogen storage disease type1[Internet],US National Library of Medicine;2015 Jul[updated 2020]. Available from:https://ghr.nlm.nih.gov/condition/

glycogen-storage-disease-type-i.

Vasen HF,Tomlinson I,Castells A.Clinical management of hereditary colorectal cancer syndromes.Nat Rev GastroHepat.2015;12(2):88.

Vissers LE,van Ravenswaaij CM,Admiraal R,et al.Mutations in a new member of the chromodomain gene family cause CHARGE syndrome.Nat Genet 2004;36:955-957.

Zucker EJ.Syndromes withaortic involvement:pictorial review.Cardiovasc Diagn Ther 2018;8(Suppl1):S71-S81.

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Medical Imaging

Jeffrey Lam Shin Cheung and Grace Gradient, chapter editors

Ming Li and Dorrin Zarrin Rhat, associate editors

Vijithan Sugumar, HBM editor

Dr. Andrew Brown, Dr. Benjamin Fine, Dr. Kieran Murphy, Dr. Ciara O’Brien, and

Dr. Anastasia Oikonomou,staff editors

Acronyms

Imaging Modalities

X-Ray Imaging

Ultrasound

Magnetic Resonance Imaging

Positron Emission Tomography Scans

Contrast Agents

Chest Imaging.

Chest X-Ray

Chest Computed Tomography

Lung Abnormalities

Pulmonary Vascular Abnormalities

Pleural Abnormalities

Mediastinal Abnormalities

Tubes,Lines, and Catheters

Abdominal Imaging

Abdominal X-Ray

Abdominal Computed Tomography

Approach to Abdominal Computed Tomography

Contrast Studies

Specific Visceral Organ Imaging

“itis"Imaging

Angiography of Gastrointestinal Tract

Genitourinary System and Adrenal

Urological Imaging

Gynaecological Imaging

Adrenal Mass

Neuroradiology

Approach to Head Computed Tomography

Selected Pathology

Musculoskeletal System.

Modalities

Approach to Bone X-Rays

Trauma

Arthritis

Bone and Soft Tissue Tumours

Infection

Metabolic Bone Disease

Nuclear Medicine

Brain

Thyroid

Respiratory

Cardiac

Abdomen and Genitourinary System

Interventional Radiology

Vascular Procedures

Nonvascular Interventions

Breast Imaging

Modalities

Breast Interventional Procedures

Breast Findings

Landmark Radiology Trials

References

MI2

MI2

MI4

MI11

MI16

MI19

MI22

MI25

MI27

MI29

MI31

MI32 r-i

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Acronyms

ISFDG 18-fluofodeoxyglucose

ADC apparent diffusion coefficient

anteroposterior

ARDS acute respiratory distress

syndrome

arteriovenous

BOOP bronchiolitis obliterans

organizingpneumonia

CHF congestive heart failure

CNS central nervous system

CSF cerebrospinal fluid

computed tomography

CIA computed tomographic

angiogram

CVD collagen vascular disease

CVP central venous pressure

DDH developmental dysplasia of the ICS

DWI diffusion-weighted image

ECO ethyl cysteinate dimer

cGFR estimated glomerular filtration IV

ERCP endoscopic retrograde

cholangio-pancreatography

FLAIR fluid-attenuated inversion

recovery

FNA fine needle aspiration

GPA granulomatosis with polyangiitis MRCP

HCC hepatocellular carcinoma

HIDA hepatobiliary iminodiacetic acid MS

HMPAO hcxamethylpropylcneamine

oxime

HSG hysterosalpingogram

inflammatory bowel disease

intercostal space

ileocecal valve

interstitial pulmonary fibrosis PICC

intravenous pyelogram

KUB kidneys,ureters,bladder

left atrium

left lower lobe

LLO left lower quadrant

LUL left upper lobe

left upper quadrant

left ventricle

macroaggregatcd albumin

mertiatide

middle cerebral artery

metaiodobenzylguanidine

magnetic resonance

right atrium

RAIU radioactive iodine uptake

RLL right lower lobe

RLO right lower quadrant

RML right middle lobe

right upper lobe

RUQ right upper quadrant

right ventricle

magnetic resonance angiogram SPECT single photon emission

magnetic resonance

cholangiopancreatography

multiple sclerosis

multiple gated acquisition

posteroantcrior

percutaneous biliary drainage TPN

pulmonary embolism

positron emission tomography TVUS

pulmonary function test

peripherally-inserted central U/S

catheter

percutaneous transluminal

angioplasty

percutaneous transhepatic

cholangiography

RA

LUO

AP

rate MAA

MAG3

AV MCA RUL

MIBG

MR RV

MRA

computed tomography

superior vena cava

transient ischemic attack

SVC

CT TIA

MUGA INK tcncctcplase

tissue plasminogen activator

total parenteral nutrition

transrectal ultrasound

transvaginal ultrasound

ureteropelvic junction

ultrasound

voiding cystourethrogram

ventilation/perfusion

PA tPA

PBD

IBD PE TRUS

PET

nip ICV PFT UPJ

DEXA dual-energy x-ray

absorptiometry

DMSA dimercaptosuccinic acid

OSA

DTPA

IPF

IVP VCUG

PTA V/Q

digital subtraction angiography LA

dicthylenc triamine pentaacctic LLL PTC

acid

Imaging Modalities

X-Ray Imaging Typical Effective Doses from Diagnostic

Medical Exposures (in Adults)*

Diagnostic

Procedure type

Equivalent Approximate

Number Equivalent

of Chest Period of

X-Rays Natural

Background

Radiation"

|

“3mSv.'yr)

• x-rays:form of short wavelength electromagnetic energy

• as x-ray photons traverse matter, they can be absorbed (a process known as “attenuation”) and/or

scattered

• the density of a structure determines its ability to attenuate or “sveaken” the x-ray beam

air < fat < water < bone < metal

• structures that have high attenuation (e.g. bone) appear svhite on the resulting images

Plain Films

• x-rays pass through the patient and interact with a detection device (film) to produce a 2-dimensional

projection image

• structures closer to the film appearsharper and less magnified

• contraindications: pregnancy (relative)

• advantages:inexpensive, non-invasive, readily available, portable, reproducible,fast,easily read

• disadvantages:radiation exposure (minimal), generally poor at distinguishing soft tissues

Fluoroscopy

• continuous x-rays used for guiding angiographic and interventional procedures, in contrast

examinations of the (il tract, and in the OK for certain surgical procedures (e.g. orthopaedic,

urological)

• on the fluoroscopic image,structures that are radiolucent on plain film appear bright, and structures

that are radiopaque on plain film appear dark

• in comparison to continuous fluoroscopy, pulsed fluoroscopy reduces fluoroscopy time and radiation

dose

• advantages: real-time visualization of structures

• disadvantages: increased radiation dose compared to plain films

X-Ray

Skull

Cental spine ID

Ibonclcipini 50

lumbai spine /5

CM(single PA(

IMi) I

Shouldei

Mammography 20

Abdomen

5 12 d

3 wk

4 mo

6 no

2 d

1d

7wk

35 3 nn

Hip 35 3 mu

Pelvis 30 10 wk

Xnee 0.25 <1d

!r«<

IV uiogiam

Oja ' energy x -ray 0.512

absorptiometry

(witliout/wflh CT)

tipper 01 series 300

Small bowel series 200

Rarii.m enema

2 y

20-mo

too 2 hr

CT

Heed 100 8 no

Heck 150 If Spine :::

: ost 3S0

Chest (pulmonary ISO

embolism)

Coronary angiography 800

Abdomen

Pelvis

Radionuclide

6rair ( TO) 705

Bone|SdkmTc) 315

Thyroid ponlc) 240

Thyroid (

,!|t 95

Cardiac rest-stress

5 yr

5.3 yr

t:: 2.7 yr Computed Tomography

• x-ray beam opposite a detector moves in a continuous 360° arc as patient is advanced through the

scanner

anatomical structures are then reconstructed

• attenuation is quantified in Hounsfield units:

windowing and leveling: adjusting the “window width” (range of Hounsfield units displayed) and

“ window level” (midpoint value of the window width ) to maximally visualize certain anatomical

structures (e.g. CT chest can be viewed using “lung”, “soft tissue", and “bone" settings)

• contraindications:pregnancy ( relative), adverse reactions to contrast agents (e.g. previous anaphylaxis

allergy, renal failure)

• advantages:delineatessoft tissues, excellent at delineating bones and identifying lung/liver masses,

may be used to guide biopsies, helical multidetector CT hasfast data acquisition and allows 3D

reconstruction, CTA is non-invasive compared to conventional angiography for visualization of

vasculature

• disadvantages: high radiation exposure, soft tissue characterization is inferior to MRI,some studies

require contrast (e.g. IV, oral, rectal), patient anxiety when going through scanner.Increased cost and

decreased availability compared to plain film, requires expert interpretation of images

300 2 ,r

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1.6 yr

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: 3 yr

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MI3 Medical Imaging Toronto Notes 2023

Ultrasound

• high-frequency sound waves are transmitted from a transducer and passed through tissues;

reflections of the sound waves are picked up by the transducer and transformed into images

• reflection (or “echo”) occurs when the sound waves reflect off tissue interfaces of different acoustic

impedance

• structures are described based on their echogenicity;hyperechoic (echogenic)structures appear bright

(U/S reflected) whereas hypoechoic structures appear dark (U/S waves are relatively less reflected

with more waves passing through the structure).A simple cyst is anechoic (pure black) as there are no

interfaces to produce any echoes

• a gel is used on the skin surface to reduce the difference of impedance between the skin and

transducer

• use of higher frequencies on U/S results in greater resolution but poorer penetrance, thus decreased

visualization of deeper structures

• artifacts; acoustic shadowing refers to the echo-free area located behind an interface that strongly

reflects (e.g. air) or absorbs (e.g. bone) sound waves; enhancement refers to the increase in reflection

amplitude (i.e. increased brightness) from objects that lie below a weakly attenuating structure (e.g.

cyst)

• duplex scan:grey-scale imaging that utilizes the Doppler effect (sound reflecting off a moving target)

to visualize the velocity of Wood moving past the transducer

• colour Doppler: assigns a colour based on the direction of blood flow (i.e. red

= toward transducer,

blue = away)

• advantages:relatively low cost, excellentspatial and soft tissue contrast resolution, non-invasive,

no radiation, portable, real-time imaging, may be used for guided biopsies, many different imaging

planes (axial,sagittal), differentiates cystic vs.solid

• disadvantages:highly operator-dependent,air in bowel may prevent imaging of midline structuresin

the abdomen, may be limited by patient habitus, poor for bone evaluation, limited field-of-view

Attenuation

Bone (= bright)> grey matter >white

matter (“fatty" myelin) >CSF>air (

~

dark)

Magnetic Resonance Imaging

U

• imaging technique that uses electromagnetic properties of tissue (mainly water) to produce images in

virtually any plane. It does not use ionizing radiation

• patient is placed in a magnetic field generated by electric current; protons, typically from water

molecules, align themselves along the direction of magnetization due to their intrinsic polarity. A

pulsed radiofrequency beam issubsequently turned on and deflects all the protons off their aligned

axes. When the radiofrequency beam is turned off, the protons return to their pre-excitation axis,

giving off the energy they absorbed. This energy is measured with a detector and interpreted by

software to generate MR images

• MR image reflectssignal intensity picked up by receiver.Signal intensity is dependent on:

1.hydrogen density: tissues with low hydrogen density (e.g. cortical bone, lung) generate little to no

MR signal compared to tissues with high hydrogen density (e.g.water)

2.magnetic relaxation times (T1 and T2): reflect quantitative alterations in MR signalstrength due to

intrinsic properties of the tissue and itssurrounding chemical and physical environment

Remember that water is "white" on T2

as "World War II"

Methods to Reduce the Risk of

Contrast-Induced Nephropathy

• Optimal:0.9% NaCI at1mL/kg/h for

12 h pre-procedure and12 h postcontrast administration

• For same-day procedure:0.9%Nad

or NaHCOaat 3 ml/kg/h for1-3 h preprocedure and for 6 h post-contrast

administration Table 1. Differences Between Diffusion, T1- and T2-Weighted MR Imaging

Imaging Techniques Signal Intensity Main Application Advantages

Dilfusion-Weightcd Imaging Signal intensity dependenton the Neuroradiology

free molecular motion of water

Decreased diffusion is

Irypcrinlensc (bright), whereas

increased diffusion is hypointense

(dark)

Sensitive for detection of

acute ischemic stroke and

differentiating an acute stroke

from other neurologic pathologies

Acule infarction and abscess

collections appear hypeiinlenso

due to restricted diffusion

Often considered an anatomic

scan since it providesa reference

for functional imaging

Often considered a pathologic

scan since it will highlight

edematous areas associated with

certain pathologies

11-Wcightcd Fluid is hypointense (dark) and fat Body soft tissues

is hyperintense (bright)

T2-Weighted Fluid is hyperintense (bright) and Body soft tissues

fat is hypointense (dark)

Positron Emission Tomography Scans

<§>

L J

• nuclear tracers arc employed (o produce images of functional processes in the body

• current generation models integrate PET'

and CT technologies into a single imaging device (PET-CT)

that collects both anatomic and functional information during a single acquisition

• positron-producing radioisotopes,such as 18F, are chemically incorporated into a mctabolically active

molecule (e.g. glucose).These are then injected into the patient, where they travel to and accumulate

in the tissues of interest. As the radioactive substance decays, y rays are produced, and are detected by

the PET scanner

Contraindications to IV Contrast

MADD Failure

Multiple myeloma

Adverse reaction previously

+

Dr.'

Dehydration

Failure (renal,severe heart)

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Mi l Medical Imaging Toronto Notes 2023

• contraindications: pregnancy

• advantages:shows metabolism and physiology of tissues (not only anatomic);in oncology, allows for

diagnosis, staging, and restaging; has predictive and prognostic value; can evaluate cardiac viability

• disadvantages: cost, ionizing radiation, availability

Contrast Agents

Table 2. Contrast Agents

FDG PEIImaging in Patients with Pathologically

Verified Dementia

JNucIMed 2000;4f (11):1920-8

Purpose: loconfirin two beliefssurrounding

bilateral temporo parietal Irypometabolism an

FDG PtI in Aliheimer'sdrsease|AD|:|t) !I isthe

metabolic abnormality associated with DO and|2) that

sensitivity,specificity,and diagnostic accuracy of this

metabolic pattern allowsfor ADto be differentiated

from other degenerative causes of dementia.

Methods: FOG PET scansfrom 22 individuals with

path olog it confirmation of AD d iagnosis we re

visually graded by aneipeiiecced nutlear medicine

physician to identify dassK bilateral lemporo parietal

hypometa holism.

Results: Sensitivity,specificity, and diagnostic

accuiacy ol bilateral temporo parietal

hyporaetabolism for ID neie 93V63%. and 82%.

respectively.

Conclusions:Bilateral temporo-parietal

hpometabolism is the classic metabolic abnormality

associated with AD.FOG PET may identify this

metabolic pattern and can be used clinically to

differentiate dementia syndromes.

Imaging Modality Types Advantages Disadvantages Contraindications

Radiopaque substance that

helps lo delineate Intraluminal

anatomy:may demonstrate

patency,lumen integrity, or large

filling defects

Delineates intraluminal anatomy:

may demonstrate patency,lumen

integrity, or large filling defects;

under fluoroscopy, may also

give information on function of

an organ

Previous adveise reaction

to contrast: barium enema

is contraindicated in tonic

megacolon, acute colitis, and

suspected perforation

Previous adverse reaction to

contrast,renal failure.DM.

pregnancy, multiple myeloma,

severe heart failure,and

dehydration

cGFR '60 may require

preventative measures and

followup

Previous adverse reaction

to contrast or end-stage

renal disease (relative

contraindication)

X-Ray Barium (c.g. oral or

rectal)

CT lodinated agents

(routes * oral.rectal.

IV)

Gadolinium Chelates Shortens 11relaxation time,

thereby increasing signal

intensity in 11-weighted

sequences: highlights highly

vascular structures(e.g.

tumours)

tiny gas bubbles crcalemany

Interlaces and appear very

echogenic. The microbubbles

allow for echo-enhancement of

vascularstructures or cavities

(l.e.echocardiography)

MR! Risk ol nephrogenic

systemic fibrosis in

patients with endstage renal disease

UfS Microbubbles(IV ) Contraindicated in individuals

with right-to left cardiac

shunts or people with known

hypersensitivity reactions

Chest Imaging

Chest X-Ray

Standard Views

• PA: anterior chest against film plate to minimize magnification of the cardiac silhouette

• lateral: better visualization of retrocardiac space and thoracic spine; more sensitive at detecting small

pleural effusions

• improves localization of lesions when combined with PA view

• AP: alternative to PA view for admitted or acutely ill patients who are unable to tolerate standing

or transport; erect or supine; generally a lower quality film than PA because of magnified cardiac

silhouette

• lateral decubitus: can help to assess for pleural effusion and pneumothorax;however, POCUS can also

be utilized for both of these purposes

• lordotic: angled beam allowing better visualization of apices normally obscured by the clavicles and

anterior ribs on PA and AP views

Posterior-anterior Position Lateral Position

Figure 1. CXR views

Anterior-posterior Position LateralDecubitus Position Lordotic Position j

+

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MIS Medical Imaging Toronto Notes 2023

Approach to CXR

Basics

• ID: patient name, medical record number (MRN),sex, age

• date of exam

• markers: right and/or left

• technique: view (e.g. HA, AH, lateral), supine or erect

• indicationsfor the study

• comparison:date of previousstudy for comparison (if available)

• quality of film:inspiration (10 posterior and 7 anterior ribsshould be visible),penetration (thoracic

spine should be visible), rotation (spinous processesshould be equidistant from medial ends of

clavicles),magnification (AH films magnify the heart), angulation (clavicles should be S shaped)

Analysis

• tubes and lines: check position and be alert for pneumothorax or pneumomediastinum

• soft tissues: neck, axillae, pectoral muscles, breasts/nipples, chest wall

nipple markers can help identify nipples (may mimic lung nodules)

amount of soft tissue (check for any asymmetry), presence of masses, presence of air

(subcutaneous emphysema)

• abdomen (see Abdominal Imaging, Mill )

free air under the diaphragm, air-fluid levels, distention in small and large bowel

• herniation of abdominal contents (i.e. diaphragmatic hernia)

• hones: cervical spine, thoracic spine,scapulae, ribs, sternum, clavicles, proximal humerus

lytic and sclerotic lesions,fractures

• mediastinum: trachea, heart, great vessels

cardiomegaly (cardiothoracic ratio >0.5 on HA), trachealshift, tortuous aorta, widened

mediastinum

• hila: pulmonary vessels, mainstem and segmental bronchi,lymph nodes

• lungs:parenchyma, interstitium, pleura,diaphragm

• abnormal iung opacity, pleural effusions or thickening

right hemidiaphragm usually higher than left due to liver

• right vs. left hemidiaphragm can be discerned on lateral CXR due to heart resting directly on left

hemidiaphragm

• please refer to Toronto Notes website for supplementary material on how to approach a C.

'

XR

Anatomy

Localizing Lesions for Parenchymal Lung Disease

• silhouette sign: when two objects of the same radiodensity abut, they appear indistinguishable on

imaging (i.e. the silhouette expected at an anatomical border due to difference in density disappears)

can be used to identify lung pathology (consolidation, atelectasis, mass) and localize disease to

specific lung segments

this sign can be applied to imaging studies throughout the body

• spine sign: on lateral films, vertebral bodiesshould appear progressively radiolucent (dark) as one

moves down the thoracic vertebral column;if they appear more radiopaque, it is an indication of

pathology (e.g. consolidation in overlying lower lobe)

• air bronchogram:branching pattern of air-filled bronchi made visible on a background of

opacification (i.e.solid or fluid-filled alveoli)

(§)

Chest X-Ray Interpretation

Basics ABCDEF

AP. PA or other view

Body position/rotation

Confirm name

Oate

Exposure/quality

Films for comparison

Analysis ABCDEF

Airways and hilar Adenopathy

Bones and Breast shadows

Cardiac silhouette and Costophrenic

angle

Diaphragm and Digestive tract

Edges of pleura

Fields (lung fields)

Table 3. Localization Using the Silhouette Sign

Interface Lost Location of Lung Pathology

SVC/right superior mediastinum

Right heart border

Right hemidiaphragm

Aortic knob left superior mediastinum

Left heart border

left hemidiaphragm

RUL

RML

RLL

LUL

Lingula

ILL

n

L J

+