JM Chapter 23 Flashcards
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).
Hereditary haemochromatosis (HHC),
Diagnosis
Hereditary haemochromatosis (HHC)
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
Management of
Hereditary haemochromatosis (HHC)
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
failure to thrive + chronic cough + loose bowel actions -
cystic fibrosis
peripheral neurofibromatosis (von Recklinghausen disorder)
NF1-
central type, bilateral acoustic neuromas (schwannomas) (rare)
NF2-
The gene for NF1 is
carried on chromosome 17 and NF2 on chromosome
light-brown skin patches + skin tumours + axillary freckles
NF1
Clinical features of NF19
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
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.
Duchenne muscular dystrophy (DMD)
Clinical features
Duchenne muscular dystrophy (DMD)
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
DxT male child + gait
disorder + bulky calves
DMD
Diagnosis
DMD
Elevated serum
creatinine kinase level
Electromyography
Direct dystrophin gene testing
Muscle biopsy
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
Spinal muscular atrophy (SMA)
Diagnosis of
Spinal muscular atrophy (SMA)
DNA screening at birth and EEG studies.
Treatment of
Spinal muscular atrophy (SMA)
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.
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
Myotonic dystrophy
Investigation of
MYOTONIC DYSTROPHY
Electromyography
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.
Tay-Sachs disease (gangliosidosis),
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.
Phenylketonuria (PKU)”O
Neonatal screening for high blood phenylalanine levels in PKU
Guthrie test)
DXT chorea + abnormal behaviour + dementia + family history
flicking movements of arms, lilting gait, facial grimacing, ataxia, dystonia
Huntington disease
DxT pallor + jaundice + hepatosplenomegaly -
thalassaemia major
DXT neonatal hypotonia + failure to thrive + obesity
PRADER WILLI
syndrome
classic features, especially a bizarre appetite
and eating habits,
Prader-Willi
PRADER WILLI
syndrome
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
Williams syndrome (idiopathic hypercalcaemia or elfin face syndrome)
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
Marfan syndrome’
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
Noonan syndromel7
Abnormal chromosome 15
Hand flapping
Puppet-like ataxia
Frequent laughter/smiling
Microcephaly by age 2 years
Developmental delay
Speech impairment
Seizures
Cannot live independently
Angelman syndrome
Treatment:
minocycline
due to an extra X chromosome,
tall men with long limbs
small firm testes $2 cm (10 mL)
infertility (azoospermia)
Klinefelter syndrome”o
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
Turner syndrome (gonadal dysgenesis)
Tx of zturner syndrome
Hormone Replacement
DxT abnormal facies + growth retardation + microcephaly + history of
alcohol intake during pregnanc
fetal alcohol spectrum disorder
Caused by a mutation in the APC gene
Familial adenomatous polyposis
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.
Gaucher disease,
an autosomal recessive
disorder due to deficiency of glucose-6-phosphatase
(von Gierke disorder),
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).
Glycogen storage disease (liver glycogenoses)
Diagnosis
Glycogen storage disease (liver glycogenoses)
abnormal plasma lactate and lipid levels, liver biopsy and recently by gene
analysis for the G-6-P gene.
Treatment
Glycogen storage disease (liver glycogenoses
prevent hypoglycaemia and lactic acidosis via frequent carbohydrate
feedings, such as uncooked cornstarch and overnight nasogastric glucose infusion.
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)
Acute intermittent porphyria
DxT severe abdominal pain + abnormal illness behaviour + ‘red’ urine
acute intermittent porphyria
Diagnosis
Acute intermittent porphyria
Urine PBGs (high) and serum sodium (very low) during ‘attack’
Erythrocyte PBG deaminase testing to screen relatives
Tx of
Acute intermittent porphyria
Eliminate triggers and avoid ‘unsafe’ drugs
High-carbohydrate diet, glucose oral or IV for attacks
IV haemetin (haemarginate)
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.
Tuberous sclerosis (epiloia)
DxT facial rash -+ intellectual disability + seizures
tuberous sclerosis
Screening for Down syndrome
combined first-trimester screening tests
(maternal serum screening/MSST; cell-free fetal DNA
at 10-12 weeks gestation; nuchal translucency ultrasound at 11-14 weeks)
Screening for Down syndrome
second-trimester MSST (4 analytes):
alpha fetoprotein
oestriol,
free beta hCG,
10-21 weeks maternal serum.
Screening for Down syndrome
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.
diagnostic tests
The most reliable method is
obtaining fetal tissue by these last means but there is a significant risk of miscarriage
(chorionic villus sampling,
amniocentesis).
