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Ethical, Legal, and Organizational Medicine

Ethical, Legal, and Organizational Medicine

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Medical Genetics



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Spencer van Mil, chapter editor

Sheliza Halani and Taraneh Tofighi, associate editors

Arnav Agarwal and Sukhmani Sodhi, EBM editors

Dr. Hanna Faghfoury and Dr. Joyce So, staff editors



Acronyms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2



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Introduction to Genetics. . . . . . . . . . . . . . . . . . . . . 2

Background

Pedigrees

Genetic Testing and Counselling



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Dysmorphisms. . . . . . . . . . . . . . . . . . . . . . .

Congenital Anomalies

Approach to the Dysmorphic Child



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Syndromes and Diseases . . . . . . . . . . . . . . . . . . . . 5

Large Genomic Changes

Single Gene Disorders

Metabolic Diseases

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9



Medical Genetics MG1



Toronto Notes 2018



MG2 Medical Genetics



Toronto Notes 2018



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Acronyms



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Acronyms

ONTD open neural tube defect

PKUphenylketonuria

SCID

severe combined immunodeficiency

USultrasound



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cystic fibrosis

copy number variation

fluorescence in situ hybridization

first trimester screening

integrated prenatal screening



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CF

CNV

FISH

FTS

IPS



Introduction to Genetics



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Background



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Terms

• Penetrance: extent that a gene is observably expressed in an individual that carries it

• Expressivity: extent of gene expression

• Genetic heterogeneity: genetic disorder can arise from different allele/locus mutations

• Phenotypic heterogeneity: mutations in the same gene resulting in multiple diverse clinical

manifestations and degree of severity

• Imprinting: epigenetic process that involves methylation or acetylation of DNA, affecting gene

expression

• Uniparental disomy: two full or partial copies of a chromosome from one parent and no chromosome

from the other parent



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Mendelian Inheritance

• disorders caused by mutation of one or both copies (alleles) of a gene, inherited in one of two patterns

■■ autosomal: when disorder is caused by genes on one of 22 pairs of autosomes (chromosomes 1-22)

■■ X-linked: when disease is caused by a gene on the X chromosome



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Triplet Repeat Expansions

• disorder in which trinucleotide repeats in certain genes exceed the normal number and result in altered

gene expression or production of an abnormal protein (e.g. Fragile X syndrome, Huntington's disease)



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Imprinting Disorders

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

gene (parent-of-origin gene expression)

• occur when a mutation disrupts the normally expressed allele of imprinted gene (e.g. Prader-Willi

syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome) or through uniparental disomy of

the normally silenced allele



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Mitochondrial Disorders

• disorders caused by mutations of the DNA present in mitochondria or nuclear genes whose protein

products are important for mitochondrial function

• inheritance pattern of mitochondrial DNA mutations: mother passes on the defect to all her children;

father cannot pass on defect since embryo only receives mitochondria from the mother (in the egg)



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Copy Number Variation

• difference in the amount of genetic material

■■ decrease: deletion of a chromosomal region, leaving only one copy of the genetic material in that

region (e g. 22q11.2 deletion syndrome due to deletion on chromosome 22)

■■ increase duplication of a chromosomal region, resulting in more than two copies of the genetic

material in that region (e.g. Potocki-Lupski syndrome due to duplication of chromosome 17p11.2)

• CNVs can be part of normal range of genetic variation



MG3 Medical Genetics



Toronto Notes 2018



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Introduction to Genetics



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Pedigrees



Married/Partners



Female, unaffected



Divorced/Separated



Spontaneous Abortion



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Male, unafffected



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• diagrams that show the pattern/distribution of phenotypes for a genetic disorder within a family, often

across multiple generations



Termination of Pregnancy



Consanguinity



Deceased



Infertility



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Affected Individual



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Carrier unaffected at

this time but could

manifest disease later



Adopted Sibling

Siblings (listed from

left to right (oldest to

youngest)



No Offspring

by choice



Affected Individual

≥2 conditions

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Dizygous Twins

(fraternal)



Pregnancy



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Carrier not likely to

manifest disease



Ectopic Pregnancy

ECT



Gender Unknown,

unaffected



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Monozyous Twins

(identical)



Stillbirth (write SB

and gestational age

if known)



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Figure 1. Common pedigree symbols



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Genetic Testing and Counselling



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Whole-Genome Sequencing Expands

Diagnostic Utility and Improves Clinical

Management in Paediatric Medicine

Genomic Med 2016;1:15012

While the standard of care for neurodevelopmental

and congenital malformations is chromosome

microarray analysis for copy number variations,

whole exome sequencing a lows the identification

of sequence-level mutations across all known

coding genes. Whole genome sequencing has

been previo sly associated with a diagnostic yield

of ~25% for neurological disorders or congenital

anomalies. A recent study published in Genomic

Medicine has demonstrated that whole genome

sequencing exceeds other technologies in detecting

genetic variants with a 34% diagnostic yield, a

four-fold increase in molecular diagnosis relative to

chromosome microarray analysis and a two-fold

increase relative to all genetic testing protocols.

These results suggest that whole genome

sequencing may be used as a first-tier molecular

test in individuals with development delays and

congenital abnormalities, with a higher diagnostic

yield than conventional genetic testing and

decreased time to genetic diagnosis.



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• microarray analysis

■■ array comparative genomic hybridization (CGH): a collection of DNA probes attached to a solid

surface to which test DNA hybridizes in order to determine copy number of DNA regions

■■ microarray analysis can identify small deletions or duplications of genetic material anywhere in the

genome

■■ commonly indicated when there is developmental delay OR two or more congenital anomalies

• FISH (fluorescence in situ hybridization): a DNA probe used to identify a gain or loss of chromosomal

material

• karyotype: microscopic analysis of chromosomes with a special stain that shows large changes in the

number or structure of chromosomes; can detect large CNVs

• Sanger sequencing: the ‘gold-standard’ method for identification of single nucletotide variants in short

DNA sequences (e.g. the exons of the gene(s) known to cause suspected syndrome)

• next-generation sequencing: high throughput method to sequence exomes or whole-genomes; useful

when genetic syndrome is suspected, but diagnosis is unclear: increasingly used for multi-gene test

panels

• prenatal screening

■■ offer optional prenatal screening before diagnostic testing

■■ first trimester screening (FTS)

◆◆ biochemistry (b-hCG, PAPP-A)

◆◆ US est mate of gestational age and measurement of nuchal translucency

◆◆ screen for trisomy 21 and 18

◆◆ done between 11 and 14 wk, sensitivity=80-85%

■■ integrated prenatal screening (IPS)

◆◆ ONTD, trisomy 21 and 18

◆◆ use results from FTS and combine with additional biomarkers completed between 15-21 weeks

(inhibin A, unconjugated estradiol, AFP, 2nd trimester b-hCG)

◆◆ improved sensitivity, reduced false positive rate compared to FTS

■■ fetal anatomy scan

◆◆ US at 18-20 wk

• newborn screening

■■ detect potentially fatal, treatable disorders before symptoms begin to allow for early therapy

■■ performed on all newborns in Canada

■■ heel puncture to collect blood

■■ screens for CF, congenital hypothyroidism, congenital adrenal hyperplasia, SCID,

hemoglobinopathies, metabolic diseases, etc.



MG4 Medical Genetics



Toronto Notes 2018



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Dysmorphisms



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Dysmorphisms



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Congenital Anomalies



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Minor and Major Anomalies

minor anomaly: an unusual anatomic feature that is of no serious medical or cosmetic consequence to

the patient

• major anomaly: anomaly that creates significant medical, surgical, or cosmetic problems for the patient



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Mechanism for Anomalies

• malformation: results from an intrinsically abnormal developmental process (e.g. polydactyly)

• disruption: results from 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. bone

dysplasia)



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Multiple Anomalies

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

than would be predicted by chance but are not known to have a single etiology (e.g. VACTERL)

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

changes the development of other surrounding or related tissues or structures (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. Down syndrome)



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Approach to the Dysmorphic Child



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• congenital abnormalities are the most common cause of infant death in developed countries



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General Approach to the Dysmorphic Child

• Are the anomalies major or minor?

• What is the mechanism underlying the anomaly?

• Do the anomalies fit as part of an association, sequence, or syndrome?



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History

• prenatal/obstetrical history (see Obstetrics, OB4) with particular attention to potential teratogenic

exposures, developmental history (see Pediatrics, P22), and past medical history

• complete 3 generation family pedigree: health history, consanguinity, stillbirths, neonatal deaths,

specific illnesses, intellectual disability, multiple miscarriages, ethnicity

Physical Exam



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Ears: structure, size,

placement, rotation



Skull: contour and symmetry

Hair: texture, pattern

Eyes: distance apart, brows, lashes,

folds, creases, coloboma, fundus



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Nose: nasal bridge, nostrils

Philtrum: length, shape

Mouth: lips, palate, tongue, teeth



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Face: gestalt



Spine: scoliosis, kyphosis



Chin: size, position



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Skin: hair tufts, sacral

dimples, sinus



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Neck: webbed, redundant nuchal skin

Thorax: shape, size, nipple spacing



Limbs: proportions, amputations



Genitalia: ambiguous



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Hands and Feet: creases,

structure, nails



Growth parameters (head circumference, height, weight)



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Figure 2. Physical exam of the dysmorphic child



VACTERL Association

VVertebral dysgenesis

AAnal atresia (imperforate anus)

± fistula

CCardiac anomalies

T-ETracheoEsophageal fistula

± esophageal atresia

RRenal anomalies

LLimb anomalies



MG5 Medical Genetics



Toronto Notes 2018



Syndromes and Diseases



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Investigations

• screening for TORCH infections

• serial photographs if child is older

• x-rays for bony abnormalities

• cytogenetic studies

■■ karyotype if recognized aneuploidy syndrome

■■ chromosomal microarray analysis (array comparative genomic hybridization) if developmental

delay OR two or more congenital anomalies

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

• biochemistry: various biochemical profiles, specific enzyme assays

• single gene testing, multi-gene panel testing



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Check the umbilical cord for 2 arteries and 1 vein.

The presence of a single umbilical artery may be

associated with other congenital anomalies



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Management

• prenatal counselling and assessing risk of recurrence

• referral for specialized pediatric or genetic care for symptomatic management

• specific treatments are available for certain metabolic disorders and genetic syndromes

■■ metabolic disorders: enzyme replacement therapy, substrate reduction therapy, etc. (e.g. low-protein

diet in PKU patients)

■■ genetic syndromes: e.g. mTOR inhibitors in tuberous sclerosis



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Large Genomic Changes

Table 1. Trisomy Chromosomal Syndromes



Trisomy 13



Disease



Patau syndrome



Incidence



1:600-800 births

Most common abnormality of autosomal chromosomes

Rises with advanced maternal age from 1:1,500 at age 20

to 1:20 by age 45



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Trisomy 18

Edwards’ syndrome



1:10,000 live births



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1:6,000 live births

F:M = 3:1



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Microcephaly, prominent occiput



Microcephaly, sloping forehead, occipital

scalp defect, holoprosencephaly



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Mild microcephaly, flat occiput, 3rd fontanelle,

brachycephaly



Microphthalmia, corneal abnormalities



Ears



Low-set, small, overfolded upper helix frequent AOM,

hearing loss



Low-set, malformed



Low-set, malformed



Facial Features



Protruding tongue, large cheeks, low flat nasal bridge,

small nose



Cleft lip/palate

Small mouth, micrognathia



60-80% cleft lip and palate



Skeletal/MSK



Short stature

Excess nuchal skin

Joint hyperflexibility (80%) including dysplastic hips,

vertebral anomalies, atlantoaxial instability



Short stature

Clenched fist with overlapping digits, hypoplastic

nails, clinodactyly, polydactyly



Severe growth retardation

Polydactyly, clenched hand



Cardiac Defect



50%, pa ticularly atrioventricular septal defect



60% (VSD, PDA, ASD)



80% (VSD PDA, ASD)



GI



Duodenal/esophageal/anal atresia, TEF, Hirschsprung’s

disease, chronic constipation



Hernia, TEF



GU



Cryptorchidism, rarely fertile



Polycystic kidneys, cryptorchidism



CNS



Hypotonia at birth

Low IQ, developmental delay, hearing problems

Onset of Alzheimer’s disease in 40s



Hypertonia



Hypo- or hypertonia

Seizures, deafness

Severe developmental delay



Other Features



Transverse palmar crease, clinodactyly, and absent middle

phalanx of the 5th finger

1% lifetime risk of leukemia

Polycythemia

Hypothyroidism



SGA

Rocker-bottom feet



Single umbilical artery

Midline anomalies: scalp, pituitary, palate,

heart, umbilicus, anus

Rocker-bottom feet



Prognosis/

Management



Prognosis: long term management per AAP Guidelines

(Health Supervision of Children with Down syndrome),

recommend chromosomal analysis, CBC, Echo, yearly

thyroid test, atlanto-occipital x-ray at 2 yr, sleep study,

hearing test, and ophthalmology assessment



13% 1-year survival, 10% ten-year survival

Profound intellectual disability in survivors



20% 1-year survival, 13% ten-year survival

Profound intellectual disability in survivors



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Polycystic kidneys



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Microphthalmia, hypotelorism, iris coloboma,

retinal anomalies



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Upslanting palpebral fissures, inner epicanthal folds,

speckled iris (Brushfield spots), refractive errors (myopia),

acquired cataracts, nystagmus, strabismus



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Eyes



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Cranium/Brain



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Trisomy 21

Down syndrome



MG6 Medical Genetics



Toronto Notes 2018



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Syndromes and Diseases



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Table 2. Common Genetic Disorders Involving the Sex Chromosomes

Klinefelter Syndrome



Turner Syndrome

45,X (most common)



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Fragile X Syndrome



47,XXY (most common)

48,XXXY, 49,XXXXY



Incidence



1:3,600 males, 1:6,000 females

Most common heritable cause of intellectual

disability in boys



1:1,000 live male births

Increased risk with advanced maternal age



1:4,000 live female births

Risk not increased with advanced maternal age



Phenotype



Overgrowth: prominent jaw, forehead, and nasal

bridge with long and thin face, large protuberant

ears, macroorchidism, hyperextensibility, and high

arched palate

Complications: seizures, scoliosis, mitral valve

prolapse



Tall, slim, underweight

No features prepuberty

Postpuberty: male may suffer from developmental

delay, long limbs, gynecomastia, lack of facial

hair



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 in

newborn with polyhydramnios, lung hypoplasia

Coarctation of aorta, bicuspid aortic valve

Renal and cardiovascular abnormalities, increased

risk of HTN

Less severe spectrum with mosaic



IQ and Behaviour



Mild to moderate intellectual disability, 20% of

affected males have normal IQ

ADHD and/or autism

Female carriers may show intellectual impairment

Male carriers may demonstrate tremor/ataxia

syndrome in later life



Mild intellectual disability

Behavioural or psychiatric disorders – anxiety,

shyness, aggressive behaviour, antisocial acts



Mild intellectual disability to normal intelligence



Gonad and

Reproductive

Function



Premutation carrier females at risk of developing

premature ovarian failure



Infertility due to hypogonadism/hypospermia



Streak ovaries with deficient follicles, infertility,

primary amenorrhea, impaired development of

secondary sexual characteristics



Diagnosis/

Prognosis/

Management



Molecular testing of FMR1 gene: overamplification

of the trinucleotide repeat, length of segment

is proportional to severity of clinical phenotype

(genetic anticipation)



Increased risk of germ cell tumours and breast

cancer

Management: testosterone in adolescence



Normal life expectancy if no complications

Increased risk of X-linked diseases

Management: Echo, ECG to screen for cardiac

malformation

GH therapy for short stature

Estrogen replacement at time of puberty for

development of secondary sexual characteristics



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X-linked

Genetic anticipation

CGG trinucleotide repeat on X chromosome

measurable by molecular analysis



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Genotype



Noonan Syndrome



CHARGE Syndrome



Lack of expression of genes

on paternal chromosome

15q11-13 due to deletion,

maternal uniparental disomy

of chromosome 15, or

imprinting defect



Lack of expression of genes

on maternal chromosome

15q11-13 due to deletion

or inactivation or paternal

uniparental disomy



Autosomal dominant with

variable expression

PTPN11 mutation most

common cause but multiple

genes known



2/3 of children with

CHARGE have been found

to have a CHD7 mutation on

chromosome 8



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Incidence



1:4000; Second most

common genetic diagnosis

(next to Down syndrome)



1:15,000



1:10,000



1:2,000 male and female

live births



“CATCH 22”

Cyanotic CHD

Anomalies: craniofacial

anomalies, micrognathia

and low set ears

Thymic hypoplasia:

immunodeficiency

Cognitive impairment

Hypoparathyroidism,

hypocalcemia

22q11 microdeletions

High risk for schizophrenia

and other psych disorders



“H3O”: Hypotonia and

weakness, Hypogonadism,

obsessive Hyperphagia,

Obesity

Short stature, almond-shaped

eyes, small hands and feet

with tapering of fingers

Developmental delay

(variable)

Hypopigmentation, type 2 DM



Ataxia with severe intellectual

disability, seizures,

tremulousness, hypotonia

Midface hypoplasia, fair hair,

uncontrollable laughter



Short stature, webbed

neck, triangular facies

hypertelorism, low set ears,

epicanthal fo ds, ptosis,

pectus excavatum

Right sided CHD, pulmonary

stenosis

Increased risk of

hematological cancers,

moderate intellectual

disability, delayed puberty



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Clinical Features



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Microdeletions of

chromosome region

22q11.2



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Genotype



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Angelman Syndrome



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Prader-Willi Syndrome



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22q11.2 Deletion

Syndrome



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Table 3. Other Genetic Syndromes



“CHARGE”

CColoboma

Hcongenital Heart disease

Achoanal Atresia

Rmental Retardation

G GU anomalies

EEar anomalies



MG7 Medical Genetics



Toronto Notes 2018



Syndromes and Diseases



Gene



Associated Cancers



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Li-Fraumeni Syndrome



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Syndrome



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Table 4. Familial Cancer Syndromes

Breast, osteosarcoma, leukemia, soft tissue carcinoma, and

numerous other cancers



FAP



APC



Colorectal, small intestine/stomach tumours



Hereditary Breast and Ovarian

Cancer Syndrome



BRCA1, BRCA2



Female: breast, ovarian, pancreatic

Male: prostate, breast, pancreatic



Von Hippel-Lindau Syndrome



VHL



Kidney + tumours (e.g. pheochromocytoma)



PTEN



Breast, thyroid, endometrial



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Cowden Syndrome



Colorectal, endometrial, ovarian, renal, pancreatic, liver/biliary

duct, stomach, brain, breast



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MSH2, MLH1, MSH6,

PMS2, EPCAM



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Lynch Syndrome (HNPCC)



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Astrocytoma, optic glioma, neurofibroma, leukemia

Vestibular schwannoma, meningioma, ependymoma,

astrocytoma



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NF1

NF2



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Type 1

Type 2





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Single Gene Disorders



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CYSTIC FIBROSIS

• see Respirology, R12 and Pediatrics, P82

SICKLE CELL DISEASE

• see Hematology, H20



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DUCHENNE MUSCULAR DYSTROPHY

Epidemiology

• 1:4,000 males



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Etiology

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

• X-linked recessive: 1/3 spontaneous mutations, 2/3 inherited mutations

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

regeneration



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Clinical Presentation

• proximal muscle weakness by age 3, positive Gower’s 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



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Diagnosis

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

• family history (pedigree analysis)

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

• elevated transaminases

• muscle biopsy, EMG



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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 (for scoliosis)

• gene therapy trials underway



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Complications

• patient usually wheelchair-bound by 12 yr of age

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

• death due to pneumonia/respiratory failure or CHF in 2nd-3rd decade



Gower’s Sign

Child uses hands to “climb up” the legs to

move from a sitting to a standing position



MG8 Medical Genetics



Toronto Notes 2018



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Syndromes and Diseases



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Metabolic Diseases



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• inherited disorders of metabolism; often autosomal recessive

• infants and older children may present with FTT or developmental delay

•organelle disorders can present with dysmorphism

universal newborn screening in Ontario includes metabolic disorders

Table 5. Metabolic Disorders

Carbohydrate

Disorders



Fatty Acid Disorders



Organelle Disorders



PKU

Tyrosinemia

Homocystinuria

MSUD

Alkaptonuria

Urea cycle defects



Galactosemia

GSDs: von Gierke’s,

Pompe’s, Cori’s,

Andersen, McArdle



MCAD deficiency

Carnitine deficiency



Mucopolysaccharidosis

Congenital disorders of

glycosylation

Lysosomal storage diseases:

Hurler’s, Niemann-Pick, TaySachs, Gaucher, Fabry, Krabbe



Clinical

Manifestations



Irritability, lethargy, poor

feeding

Seizures

Intellectual disability

Vomiting and acidosis

after feeding initiation

Sweet-smelling urine

(MSUD)



Vomiting and acidosis

after feeding initiation

Growth retardation, FTT



Lethargy, poor feeding

Seizures, coma

Symptoms triggered by

fasting

Liver dysfunction

Sudden infant death



Seizures/early-onset severe

epilepsy

Chronic encephalopathy

Developmental delay

Bone crises (Gaucher)

Deafness, blindness



Laboratory

Findings



Hypoglycemic

hyperammonemia,

high anion gap (organic

acidemia)

Normoglycemic

hyperammonemia,

normal an on gap (urea

cycle defects)



Hypoglycemia,

hyperlipidemia (GSD)



Hypoketotic

hypoglycemia

Elevated free fatty acids



Elevated urine oligosaccharides

(oligosaccharidoses)

and glycosaminoglycans

(mucopolysaccharidoses)

Enzyme deficieny



Infantile cataracts

(galactosemia)

Hepatomegaly

Muscle weakness/

cramping



Hepatomegaly

Hypotonia



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Dysmorphic facial features

Macrocephaly (Tay-Sachs,

Hurler’s)

Hepatosplenomegaly (NiemannPick type A/B/C, not Tay-Sachs)

Cherry-red spot on macula

(Niemann-Pick type A/B, TaySachs, Gaucher’s)

Corneal clouding (Hurler’s)

Infantile cataract (Fabry)

Peripheral neuropathy (Fabry,

Krabbe)

Spasticity



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Hypotonia/hypertonia

Microcephaly, musty

odour, eczema,

hypopigmentation (PKU)

Dark urine, pigmented

sclerae, arthralgias

(alkaptonuria)

Lens subluxation,

marfanoid appearance

(homocystinuria)



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Examples of

Conditions



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Organic and Amino

Acid Disorders



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Initial Investigations

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

treatment

• check newborn screening results

• electrolytes, ABGs (calculate anion gap, rule out acidosis)

• CBC with differential and smear

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

• lactate, ammonium (hyperammonemia with urea cycle defects), plasma Ca2+ and Mg2+

• routine urinalysis: ketonuria must be investigated

• carnitine levels with acylcarnitine profile

• others: urate, urine nitroprusside, plasma amino acid screen, urine organic acids, CSF glycine, free fatty

acids (3-β-hydroxybutyrate ratio >4 in fatty acid oxidation defect)

• storage diseases: urine mucopolysaccharide and oligosaccharide screen



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Treatment

• varies according to inborn error of metabolism

• dietary restrictions, supplementation, enzyme replacement therapy, gene therapy, liver transplant, stem

cell transplant



MG9 Medical Genetics



Toronto Notes 2018



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References



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PHENYLKETONURIA



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Epidemiology

• 1:10,000; autosomal recessive disease



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Etiology

• deficiency of phenylalanine hydroxylase prevents conversion of phenylalanine to tyrosine leading to

build up of toxic metabolites

• mothers who have PKU may have infants with congenital abnormalities



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Management

• PKU screening at birth

• dietary restrict on of phenylalanine starting within the first 10 d of life

• duration of dietary restriction controversial – lifelong or until end of puberty; should be resumed

during pregnancy to maintain normal phenylalanine levels

• large neutral amino acid (tyrosine) replacement, BH4 enzyme treatment, phenylalanine lyase treatment

are other options

GALACTOSEMIA

Epidemiology

• 1:60,000; autosomal recessive disease

Etiology

• most commonly due to deficiency of galactose-1-phosphate uridyltransferase leading to an inability to

process lactose/galactose



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Clinical Presentation

• signs of liver and renal failure, jaundice, FTT, and cataracts with ingestion of lactose/galactose



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Management

• elimination of galactose from the diet (e.g. dairy, breast milk)

• most infants are fed a soy-based diet



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Complications

• increased risk of sepsis, especially E. coli

• if the diagnosis is not made at birth, liver and brain damage may become irreversible



References



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o



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

Blake KD, Prasad C. CHARGE syndrome, o phanet. J Rare Diseases 2006;1.

Biggar W. Duchenne muscular dystrophy. Pediatr Rev 2006;27:83-88.

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

Elieff, M. P., Lopez-Beltran, A., Montironi, R., & Cheng, L. (2008). Familial cancer syndromes. In Molecular genetic pathology (pp. 449-466). Humana Press.

Grati, F. R., Malvestiti, F Ferreira, J. C., Bajaj, K., Gaetani, E., Agrati, C., ... & Maggi, F. (2014). Fetoplacen al mosaicism: potential implications for false-positive and

false-negative noninvasive prenatal screening results. Genetics in Medicine, 16(8), 620-624.

Moeschler JB, Sheve l M. Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 2014

Sep;134(3):e903 18. doi:10.1542/peds.2014-1839.

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

Sobel, E , & Lange, K. (1996). Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. American journal of human

genetics, 58(6), 1323.

Therrell, B. L., & Adams, J. (2007). Newborn screening in North America. Journal of inherited metabolic disease, 30(4), 447-465.

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.



Metabolic disease must be ruled out in any

newborn who becomes acut ly ill after a period

of normal behaviour and development or with a

Reffamily history of early infant death even if the

newborn screen is negative



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Clinical Presentation

• baby is normal at birth, then develops a musty odour, eczema, hypertonia, tremors, and mental

retardation

• hypopigmentation due to low tyrosine (fair hair, blue eyes)



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Notes



Toronto Notes 2018



Syndromes and Diseases



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MG10 Medical Genetics



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Medical Imaging



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Mark Barszczyk, Tian Yang (Darren) Liu, Zafir Syed, and Jinhui Yan, chapter editors

Sheliza Halani and Taraneh Tofighi, associate editors

Arnav Agarwal and Sukhmani Sodhi, EBM editors

Dr. Nasir Jaffer and Dr. Eugene Yu, staff editors



Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2



References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32



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Imaging Modalities. . . . . . . . . . . . . . . . . . . . . . . . . 2

X-Ray Imaging

Ultrasound

Magnetic Resonance Imaging

Positron Emission Tomography Scans

Contrast Enhancement



Breast Imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Modalities

Breast Interventional Procedures

Breast Findings



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Chest Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Chest X-Ray

Computed Tomography Chest

Lung Abnormalities

Pulmonary Vascular Abnormalities

Pleural Abnormalities

Mediastinal Abnormalities

Tubes, Lines, and Catheters



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Abdominal Imaging. . . . . . . . . . . . . . . . . . . . . . . . 10

Abdominal X-Ray

Approach to Abdominal X-Ray

Abdominal Computed Tomography

Approach to Abdominal Computed Tomography

Contrast Studies

Specific Visceral Organ Imaging

“itis” Imaging

Angiography of Gastrointestinal Tract



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Genitourinary System and Adrenal. . . . . . . . . . 16

Urological Imaging

Gynecological Imaging

Adrenal Mass



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Neuroradiology . . . . . . . . . . . . . . . . . . . . . . . . . 18

Modalities

Approach to CT Head

Selected Pathology



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Musculoskeletal System . . . . . . . . . . . . . . . . . . . 21

Modalities

Approach to Bone X-Rays

Trauma

Arthritis

Bone Tumour

Infection

Metabolic Bone Disease



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Nuclear Medicine. . . . . . . . . . . . . . . . . . . . . . . . . . 25

Brain

Thyroid

Respiratory

Cardiac

Abdomen and Genitourinary System

Bone

Interventional Radiology. . . . . . . . . . . . . . . . . . . . 28

Vascular Procedures

Nonvascular Interventions



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Medical Imaging MI1



Toronto Notes 2018



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