Genetics Child Health Flashcards
Autosomal recessive conditions are often thought to be ‘metabolic’ as opposed to autosomal dominant conditions being ‘structural’
True
The following conditions are autosomal dominant
Huntington’s disease
Myotonic dystrophy
Osteogenesis imperfecta
Von Willebrand’s disease - except T3
The following conditions are autosomal recessive
Cystic fibrosis
Gilbert’s syndrome
Haemochromatosis
Sickle cell anaemia
In X-linked recessive inheritance only males are affected
true
In X-linked recessive inheritance only males are affected - exception
Turner’s syndrome, who are affected due to only having one X chromosome
X-linked recessive
Each male child of a heterozygous female carrier has a ?% chance of being affected whilst each female child of a heterozygous female carrier has a ?% chance of being a carrier.
Each male child of a heterozygous female carrier has a 50% chance of being affected whilst each female child of a heterozygous female carrier has a 50% chance of being a carrier.
X-linked recessive - possibility of an affected father having children with a heterozygous female carrier is generally speaking extremely rare
true
However, in certain Afro-Caribbean communities G6PD deficiency is relatively common and homozygous females with clinical manifestations of the enzyme defect are seen.
The following conditions are inherited in a X-linked recessive fashion
Duchenne muscular dystrophy
G6PD deficiency
Haemophilia A,B
The following conditions are inherited in a X-linked dominant fashion
Alport’s syndrome
Rett syndrome
Vitamin D resistant rickets
Inheritance pattern of - Achondroplasia
autosomal dominant disorder
In most cases (approximately 70%) it occurs as a sporadic mutation
It is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR-3) gene. This results in abnormal cartilage
Achondroplasia sx
short limbs (rhizomelia) with shortened fingers (brachydactyly)
large head with frontal bossing and narrow foramen magnum
midface hypoplasia with a flattened nasal bridge
‘trident’ hands
lumbar lordosis
Achondroplasia main risk factor
advancing parental age at the time of conception. Once present it is typically inherited in an autosomal dominant fashion.
Achondroplasia mx
There is no specific therapy.
some individuals benefit from limb lengthening procedures
Down’s syndrome features - face
upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongue, small low-set ears, round/flat face
flat occiput
Down’s syndrome features - hands and feet
single palmar crease, pronounced ‘sandal gap’ between big and first toe
Down’s syndrome features hyper/hypotonia
hypotonia
Down’s syndrome features which cardiac complications?
congenital heart defects (40-50%)
multiple cardiac problems may be present endocardial cushion defect ventricular septal defect (c. 30%) secundum atrial septal defect (c. 10%) tetralogy of Fallot (c. 5%) isolated patent ductus arteriosus
Down’s syndrome features which atresia
duodenal
Later complicactions of Down’s syndrome - describe fertility issues
males are almost always infertile due to impaired spermatogenesis. Females are usually subfertile, and have an increased incidence of problems with pregnancy and labour
Later complicactions of Down’s syndrome which infections?
repeated respiratory infections (+hearing impairment from glue ear)
Later complicactions of Down’s syndrome which dementia?
Alzheimer’s disease
Later complicactions of Down’s syndrome hyper/hypothyroidism
hypothyroidism
Later complicactions of Down’s syndrome causes atlantoaxial instability
true
Later complicactions of Down’s syndrome - which leukaemia?
acute lymphoblastic leukaemia
Duchenne muscular dystrophy is associated with which cardiac complication
dilated cardiomyopathy
Duchenne muscular dystrophy causes calf hypertrophy
false
calf pseudohypertrophy
Duchenne muscular dystrophy 30% of patients have intellectual impairment
true
Fragile X syndrome is a
trinucleotide repeat disorder.
Fragile X syndrome Features in males
- face
large low set ears, long thin face, high arched palate
Fragile X syndrome Features in males
micro/macro orchidism
macroorchidism
Fragile X syndrome Features in males
hyper/hypotonia
hypotonia
Fragile X syndrome - cardiac issues
mitral valve prolapse
Features in females (who have one fragile chromosome and one normal X chromosome) range from normal to mild
true
Fragile X syndrome diagnosis cannot be made antenatally
false
can be made antenatally by chorionic villus sampling or amniocentesis
Fragile X syndrome diagnosis based analysis of
number of CGG repeats using restriction endonuclease digestion and Southern blot analysis
Gene & Associated cancers
- p53
Common to many cancers, Li-Fraumeni syndrome
Gene & Associated cancers
- APC
Colorectal cancer
Gene & Associated cancers
- BRCA
Breast and ovarian cancer
Gene & Associated cancers
- NF1
Neurofibromatosis
Gene & Associated cancers
- Rb
Retinoblastoma
Gene & Associated cancers
- WT1
Wilm’s tumour
Gene & Associated cancers
- Multiple tumor suppressor 1 (MTS-1, p16)
Melanoma
Turner’s syndrome
is caused by?
resence of only one sex chromosome (X) or a deletion of the short arm of one of the X chromosomes. Turner’s syndrome is denoted as 45,XO or 45,X.
Turner’s syndrome - cardiac complication?
bicuspid aortic valve (15%), coarctation of the aorta (5-10%)
Turner’s syndrome - gonadotrophin levels will be elevated/low
elevated
Turner’s syndrome causes lymphoedema in neonates (especially feet)
true
Whilst most DNA is found in the cell nucleus, a small amount of double-stranded DNA is present in the mitochondria. It encodes
protein components of the respiratory chain and some special types of RNA
Mitochondrial inheritance inheritance is only via
the maternal line as the sperm contributes no cytoplasm to the zygote
Mitochondrial inheritance
none of the children of an affected male will inherit the disease
all of the children of an affected female will inherit the disease
true
heteroplasmy is
poor genotype:phenotype correlation - within a tissue or cell there can be different mitochondrial populations
Mitochondrial diseases histology?
muscle biopsy classically shows ‘red, ragged fibres’ due to increased number of mitochondria
Mitochondrial diseases examples?
Leber's optic atrophy MELAS syndrome MERRF syndrome Kearns-Sayre syndrome sensorineural hearing loss
MELAS syndrome features?
mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes
MERRF syndrome features?
myoclonus epilepsy with ragged-red fibres
Kearns-Sayre syndrome features?
onset in patients < 20 years old, external ophthalmoplegia, retinitis pigmentosa. Ptosis may be seen
Trinucleotide repeat disorders are
genetic conditions caused by an abnormal number of repeats (expansions) of a repetitive sequence of three nucleotides
Trinucleotide repeat disorders are usually
neurological disorders
Trinucleotide repeat disorders examples?
Fragile X (CGG) Huntington's (CAG) myotonic dystrophy (CTG) Friedreich's ataxia* (GAA) spinocerebellar ataxia spinobulbar muscular atrophy dentatorubral pallidoluysian atrophy
Trinucleotide repeat disorders may lead to an earlier age of onset in successive generations due to?
expansions are unstable and may enlarge
phenomenon known as anticipation
Key features of Patau syndrome (trisomy 13)
Microcephalic, small eyes
Cleft lip/palate
Polydactyly
Scalp lesions
Key features of Edward’s syndrome (trisomy 18)
Micrognathia
Low-set ears
Rocker bottom feet
Overlapping of fingers
Key features of Fragile X
Learning difficulties Macrocephaly Long face Large ears Macro-orchidism
Key features of Noonan syndrome
Webbed neck
Pectus excavatum
Short stature
Pulmonary stenosis
Key features of Pierre-Robin syndrome
Micrognathia
Posterior displacement of the tongue (may result in upper airway obstruction)
Cleft palate
Key features of Prader-Willi syndrome
Hypotonia
Hypogonadism
Obesity
Key features of William’s syndrome
Short stature Learning difficulties Friendly, extrovert personality Transient neonatal hypercalcaemia Supravalvular aortic stenosis
Key features of Cri du chat syndrome (chromosome 5p deletion syndrome)
Characteristic cry (hence the name) due to larynx and neurological problems
Feeding difficulties and poor weight gain
Learning difficulties
Microcephaly and micrognathism
Hypertelorism
Prader-Willi syndrome is an example of genetic imprinting where the phenotype depends on whether the deletion occurs on a gene inherited from the mother or father:
Prader-Willi syndrome if gene deleted from father
Angelman syndrome if gene deleted from mother
Prader-Willi syndrome is associated with the absence of the active Prader-Willi gene on the long arm of chromosome 15. This may be due to:
microdeletion of paternal 15q11-13 (70% of cases)
maternal uniparental disomy of chromosome 15
Prader-Willi syndrome causes anorexia
false
childhood obesity
McCune-Albright syndrome is not inherited
True
it is due to a random, somatic mutation in the GNAS gene.
McCune-Albright syndrome - Features
precocious puberty
cafe-au-lait spots
polyostotic fibrous dysplasia
short stature
What is Often thought of as the ‘male Turner’s’?
Noonan syndrome
Noonan syndrome is thought to be caused by
a defect in a gene on chromosome 12
Noonan syndrome characteristic clinical signs
cardiac: pulmonary valve stenosis ptosis triangular-shaped face low-set ears coagulation problems: factor XI deficiency
William’s syndrome is
inherited neurodevelopmental disorder caused by a microdeletion on chromosome 7
William’s syndrome sx
elfin-like facies characteristic like affect - very friendly and social learning difficulties short stature transient neonatal hypercalcaemia supravalvular aortic stenosis
William’s syndrome diagnosis
FISH studies
Phenylketonuria (PKU) is
is an autosomal recessive condition caused by a disorder of phenylalanine metabolism. This is usually due to defect in phenylalanine hydroxylase, an enzyme which converts phenylalanine to tyrosine
High levels of phenylalanine lead to problems such as
learning difficulties and seizures
Phenylketonuria sx
usually presents by 6 months e.g. with developmental delay
child classically has fair hair and blue eyes
learning difficulties
seizures, typically infantile spasms
eczema
‘musty’ odour to urine and sweat*
Phenylketonuria diagnosis
Guthrie test: the ‘heel-prick’ test done at 5-9 days of life - also looks for other biochemical disorders such as hypothyroidism
hyperphenylalaninaemia
phenylpyruvic acid in urine
Phenylketonuria mx
dietary restrictions are however important during pregnancy as genetically normal fetuses may be affected by high maternal phenylalanine levels
hypochromic and microcytic, but the Hb level would be typically normal suggests which alpha thalassemia?
1 or 2 alpha globulin alleles are affected
hypochromic microcytic anaemia with splenomegaly suggests which alpha thalassemia?
Hb H disease
3 alpha globulin alleles are affected
death in utero (hydrops fetalis, Bart’s hydrops) suggests which alpha thalassemia?
4 alpha globulin alleles are affected (i.e. homozygote)
High LH
Low Testosterone
- Which disorder of sex hormones?
Primary hypogonadism (Klinefelter’s syndrome)
Low LH
Low Testosterone
- Which disorder of sex hormones?
Hypogonadotrophic hypogonadism (Kallman’s syndrome)
High LH
Normal/high Testosterone
- Which disorder of sex hormones?
Androgen insensitivity syndrome
Low LH
High Testosterone
- Which disorder of sex hormones?
Testosterone-secreting tumour
Klinefelter’s syndrome is associated with karyotype
47, XXY
Klinefelter’s syndrome features?
often taller than average lack of secondary sexual characteristics small, firm testes infertile gynaecomastia - increased incidence of breast cancer
Kallman’s syndrome is a recognised cause of delayed puberty secondary to hypogonadotrophic hypogonadism. It is usually inherited as
X-linked recessive trait
Kallman’s syndrome is thought to be caused by
failure of GnRH-secreting neurons to migrate to the hypothalamus.
Androgen insensitivity syndrome is an
X-linked recessive condition due to end-organ resistance to testosterone causing genotypically male children (46XY) to have a female phenotype
Androgen insensitivity syndrome
features
‘primary amenorrhoea’
undescended testes causing groin swellings
breast development may occur as a result of conversion of testosterone to oestradiol
Androgen insensitivity syndrome diagnosis
buccal smear or chromosomal analysis to reveal 46XY genotype
Androgen insensitivity syndrome management
counselling - raise child as female bilateral orchidectomy (increased risk of testicular cancer due to undescended testes) oestrogen therapy
Homocystinuria is
a rare autosomal recessive disease caused by a deficiency of cystathionine beta synthase. This results in severe elevations in plasma and urine homocysteine concentrations.
Homocystinuria Features
often patients have fine, fair hair
musculoskeletal
Marfanoid body habitus: arachnodactyly etc
osteoporosis
kyphosis
neurological: may have learning difficulties, seizures
ocular
downwards (inferonasal) dislocation of lens
severe myopia
increased risk of arterial and venous thromboembolism
also malar flush, livedo reticularis
Homocystinuria ix
increased homocysteine levels in serum and urine
cyanide-nitroprusside test: also positive in cystinuria
Homocystinuria mx
Treatment is vitamin B6 (pyridoxine) supplements.
