JM Chapter 23

Question 1

disorder of iron overload, is the most commot
serious single gene genetic disorder in our population

is a common condition in which the total body iron concentration is increased to 20-60 g
(normal 4 g).

Answer 1

Hereditary haemochromatosis (HHC),

Question 3

Diagnosis
Hereditary haemochromatosis (HHC)

Answer 3

Increased serum transferrin saturation: >50% (F); >60% (M)
Increased serum ferritin level: >200 mcg/L (F); >300 mcg/L (M)

CT, MRI or FerriScan- increased iron deposition in liver

Liver biopsy (if liver function test enzymes are abnormal or ferritin >1000 mcg/L or
hepatomegaly) FerriScan now preferred

Question 4

Management of
Hereditary haemochromatosis (HHC)

Answer 4

Weekly venesection 500 mI (250 mg iron) until serum iron stores are normal (may take at
least 2 years), then every 3-4 months to keep serum ferritin level <100 mcg/L (usually
40-80 mcg/L), serum transferrin saturation <50% and iron levels normal

Desferrioxamine can be used but not as effective as venesection

Question 5

failure to thrive + chronic cough + loose bowel actions -

Answer 5

cystic fibrosis

Question 6

peripheral neurofibromatosis (von Recklinghausen disorder)

Answer 6

NF1-

Question 7

central type, bilateral acoustic neuromas (schwannomas) (rare)

Answer 7

NF2-

Question 8

The gene for NF1 is

Answer 8

carried on chromosome 17 and NF2 on chromosome

Question 9

light-brown skin patches + skin tumours + axillary freckles

Answer 9

NF1

Question 10

Clinical features of NF19

Answer 10

Six or more café-au-lait spots (increasing with age)

Freckling in the axillary or inguinal regions

Flesh-coloured cutaneous tumours (appear at puberty)

Hypertension

Eye features (iris
hamartomas)

Learning difficulty

Musculoskeletal problems (e.g. scoliosis, fibrous dysplasia, pseudoarthrosis)

Optic nerve gliomas

Question 11

is a progressive proximal muscle weakness disorder with replacement of muscle by
connective tissue.

is an X-linked recessive condition. It is caused by a mutation in the gene coding for
dystrophin, a protein found inside the muscle cell membrane.

Answer 11

Duchenne muscular dystrophy (DMD)

Question 12

Clinical features
Duchenne muscular dystrophy (DMD)

Answer 12

Usually diagnosed from 2-5 years

Weakness in hip and shoulder girdles

Walking problems: delayed onset or starting in boys aged 3-7

Waddling gait, falls, difficulty standing and climbing steps

Pseudohypertrophy of muscles, especially calves

Most in wheelchair by age 10-12

+ Intellectual retardation/learning difficulties

Most die of respiratory problems by age 25

Gower sign: patient uses ‘trick’ method by using hands to climb up his or her legs when rising
to an erect position from the floor

Question 13

DxT male child + gait
disorder + bulky calves

Answer 13

DMD

Question 14

Diagnosis
DMD

Answer 14

Elevated serum
creatinine kinase level

Electromyography

Direct dystrophin gene testing

Muscle biopsy

Question 15

Claimed to be the leading genetic cause of infant death

progressive muscle wasting

due to mutation in SMN1 gene on chromosome 5

Muscle weakness, poor tone and floppiness

Feeding difficullties and fephle crv in hahies

Answer 15

Spinal muscular atrophy (SMA)

Question 16

Diagnosis of
Spinal muscular atrophy (SMA)

Answer 16

DNA screening at birth and EEG studies.

Question 17

Treatment of
Spinal muscular atrophy (SMA)

Answer 17

no cure at present and
treatment is mainly supportive. Zolgensma gene therapy is given as a single IV injection into
children <2 years before symptoms appear. Intrathecal injections of nusinersen are available.

Question 18

Typically presents 20-30 years as myotonia (tonic muscle spasm), occasionally in childhood

Muscle weakness, esp. hands, legs, face, neck
Slow relaxation of hand grip

‘Hatchet face’- long haggard look with atrophy of facial muscles

Frontal baldness in men

Cataracts

Mental impairment

Cardiac disturbances, e.g.cardiomyopathy
Endocrine abnormalities, e.g. diabetes

Answer 18

Myotonic dystrophy

Question 19

Investigation of
MYOTONIC DYSTROPHY

Answer 19

Electromyography

Question 20

total deficiency of hexosaminidase resulting in an accumulation of gangliosides in
the brain.

infantile form - fatal by age 3 or 4 with early progressive loss of motor skills, dementia,
blindness, macrocephaly and cherry-red retinal spots.

juvenile-onset -
dementia and ataxia, with death at age 10-15.

adult form has - clumsines s in childhood and motor weakness in adolescence.

Answer 20

Tay-Sachs disease (gangliosidosis),

Question 21

deficiency of phenylalanine hydroxylase activity, leading to an elevation of plasma
phenylalanine, which if untreated can cause intellectual disability (often very severe) and other
neurological symptoms, such as seizures.

Answer 21

Phenylketonuria (PKU)”O

Question 22

Neonatal screening for high blood phenylalanine levels in PKU

Answer 22

Guthrie test)

Question 23

DXT chorea + abnormal behaviour + dementia + family history

flicking movements of arms, lilting gait, facial grimacing, ataxia, dystonia

Answer 23

Huntington disease

Question 24

DxT pallor + jaundice + hepatosplenomegaly -

Answer 24

thalassaemia major

Question 25

DXT neonatal hypotonia + failure to thrive + obesity

Answer 25

PRADER WILLI
syndrome

Question 26

classic features, especially a bizarre appetite
and eating habits,

Answer 26

Prader-Willi
PRADER WILLI
syndrome

Question 27

due to a microdeletion
on chromosome 7, a deletion in the elastin gene.

Children have a distinctive elfin facial appearance, mild pre- and postnatal growth retardation,
mild microcephaly and mild-to-moderate developmental delay. In the first 2 years of life, feeding
problems, vomiting, irritability, hyperacusis, constipation and failure to thrive may lead to
presentation, but children are rarely diagnosed at this stage

Answer 27

Williams syndrome (idiopathic hypercalcaemia or elfin face syndrome)

Question 28

systemic connective tissue disorder characterised by abnormalities of the skeletal,
cardiovascular and ocular systems.

DxT tall stature + dislocated lens and myopia + aortic root dilatation

Mutations in the fibrillin gene on chromosome 15

Disproportionally tall and thin

Long digits arachnodactyly

Kyphoscoliosis
Joint laxity (e.g. genu recurvatum)

Myopia and ectopic ocular lens

Answer 28

Marfan syndrome’

Question 29

mutation of chromosome 11. It has been described as a male Turner
syndrome but affects both sexes.

mutation of chromosome 11.

down-slanting palpebral fissures, widespread eyes, low-set ears t ptosis

Short stature

Pulmonary valve stenosis

Webbed neck

Answer 29

Noonan syndromel7

Question 30

Abnormal chromosome 15

Hand flapping

Puppet-like ataxia

Frequent laughter/smiling

Microcephaly by age 2 years

Developmental delay

Speech impairment

Seizures

Cannot live independently

Answer 30

Angelman syndrome

Treatment:
minocycline

Question 31

due to an extra X chromosome,

tall men with long limbs
small firm testes $2 cm (10 mL)
infertility (azoospermia)

Answer 31

Klinefelter syndrome”o

Question 32

due to only one X chromosome,

Short stature average adult height 143 cm

Primary amenorrhoea in XO patient; infertility

Webbing of neck

Typical facies: micrognathia, low hairline

Lymphoedema of extremities

Cardiac defects (e.g.coarctation of aorta)

Mental deficiency is rare.

45 chromosomes of XO karyotype

Answer 32

Turner syndrome (gonadal dysgenesis)

Question 33

Tx of zturner syndrome

Answer 33

Hormone Replacement

Question 34

DxT abnormal facies + growth retardation + microcephaly + history of
alcohol intake during pregnanc

Answer 34

fetal alcohol spectrum disorder

Question 35

Caused by a mutation in the APC gene

Answer 35

Familial adenomatous polyposis

Question 36

due to a deficiency of the lysosomal enzyme glucocerebrosidase, leads
to anaemia and thrombocytopenia as a result primarily of hypersplenism.

chronic bone
pain and crises’ of bone pain, Consider it in children with fatigue, bone pain, delayed growth,
epistaxis, easy bruising and hepatosplenomegaly.

Answer 36

Gaucher disease,

Question 37

an autosomal recessive
disorder due to deficiency of glucose-6-phosphatase

Answer 37

(von Gierke disorder),

Question 38

growth retardation, hepatomegaly, renomegaly, hypoglycaemia (can be
severe), lactic acidosis and hyperlipidaemia.

Children have characteristic morphological features
⁃short, doll-like facies with fat cheeks, thin extremities and large abdomen (hepatomegaly).

Answer 38

Glycogen storage disease (liver glycogenoses)

Question 39

Diagnosis
Glycogen storage disease (liver glycogenoses)

Answer 39

abnormal plasma lactate and lipid levels, liver biopsy and recently by gene
analysis for the G-6-P gene.

Question 40

Treatment
Glycogen storage disease (liver glycogenoses

Answer 40

prevent hypoglycaemia and lactic acidosis via frequent carbohydrate
feedings, such as uncooked cornstarch and overnight nasogastric glucose infusion.

Question 41

due to a deficiency of
porphobilinogen (PBG) deaminase

Recurrent unexplained abdominal pain crises

Usually young women (teens or 20s)

Recurrent psychiatric illnesses, abnormal behaviour

Acute peripheral or nervous system dysfunction (e.g. peripheral neuropathy, hypotonia)

PBG in urine during attack

Hyponatraemia

Attacks precipitated by various drugs (e.g. anti-epileptics, alcohol, sulfonamides, barbiturates)

Answer 41

Acute intermittent porphyria

Question 42

DxT severe abdominal pain + abnormal illness behaviour + ‘red’ urine

Answer 42

acute intermittent porphyria

Question 43

Diagnosis
Acute intermittent porphyria

Answer 43

Urine PBGs (high) and serum sodium (very low) during ‘attack’

Erythrocyte PBG deaminase testing to screen relatives

Question 44

Tx of
Acute intermittent porphyria

Answer 44

Eliminate triggers and avoid ‘unsafe’ drugs
High-carbohydrate diet, glucose oral or IV for attacks
IV haemetin (haemarginate)

Question 45

autosomal dominant disorder due to mutations in one of two genes located on
chromosomes 9 and 16. A feature is tube-like growths that affect multiple systems including the
brain.

Answer 45

Tuberous sclerosis (epiloia)

Question 46

DxT facial rash -+ intellectual disability + seizures

Answer 46

tuberous sclerosis

Question 47

Screening for Down syndrome
combined first-trimester screening tests

Answer 47

(maternal serum screening/MSST; cell-free fetal DNA
at 10-12 weeks gestation; nuchal translucency ultrasound at 11-14 weeks)

Question 48

Screening for Down syndrome
second-trimester MSST (4 analytes):

Answer 48

alpha fetoprotein
oestriol,
free beta hCG,

Question 49

10-21 weeks maternal serum.
Screening for Down syndrome

Answer 49

non-invasive prenatal test (NIPT)
aneuploidy test usually covers three
trisomies:
21 Down syndrome,
18 Edward syndrome, 13 Patau syndrome.

offered as a choice to women.

Question 50

diagnostic tests
The most reliable method is
obtaining fetal tissue by these last means but there is a significant risk of miscarriage

Answer 50

(chorionic villus sampling,
amniocentesis).