Genetics Flashcards
Overview of achondroplasia
Present from birth, short limbs, mid facial hypoplasia, prominent forehead
Developmental delay
Stenosis of spinal canal
Genetic cause of achondroplasia
Mutations at FGFR3 codon 380 (inhibits linear bone growth - fibroblast growth factor receptor 3)
Autosomal dominant but most cases are sporadic
Overview of Hunter syndrome
Mucopolysaccharidosis II (deficiency of iduronate-2-sulfatase)
Exclusively males, reported in females due to lionisation
Wide clinical manifestations due to marked molecular heterogeneity - coarse facial features, short stature, joint stiffness, ID, dysostosis multiplex, extensive dermal melanocytosis
Genetic cause of Hunter syndrome
X linked, Xq28
IDS gene, 80% point mutations major deletions and rearrangements in the remainder
Overview of Marfan syndrome
1/5000
Tall with long arm span, arachynodactyly, scoliosis
AV valve prolapse/regurg, arrhythmias, aortic dissection
Lens dislocation (60-70%)
Pneumothorax, pectus excavatum/restrictive lung disease
Genetic cause of Marfan syndrome
Autosomal dominant, mutations in gene encoding ECM protein fibrillar-1 (on 15q21)
30% are sporadic, new mutations associated with advanced paternal age
Triad of osteogenesis imperfecta
Fragile bones, blue sclerae, early deafness
Genetic cause of osteogenesis imperfecta
Structural or quantitative defects in type 1 collagen (primary component of the extracellular matrix of bone and skin), leads to osteoporosis
Classic OI is autosomal dominant
Overview of Stickler disease
Midface hypoplasia, P-R sequence
Severe myopia, glaucoma, cataracts, retinal detachment
Hearing loss
Hypermobile joints leading to early arthritis
Genetic cause of Stickler disease
Autosomal dominant - gene mutation causing defect in collagens type II, IX or XI
Which is the only urea cycle defect which is NOT autosomal recessive?
Ornithine transcarbamyase (OTC) deficiency
- X linked disorder, all males are affected, 10% of female carriers are affected
Why will the mother of a child with congenital myotonic dystrophy display a milder form of the condition?
Congenital myotonic dystrophy is a triplet repeat expansion disorder, i.e. expansion of the triplet repeat on transmission from mother to child
Missense mutation
Altered codon produces amino acid substitution
Nonsense mutation
Altered codon becomes a stop codon and produces a truncated protein (mRNA terminates at that point)
Splice site mutation
Insertion or deletion of nucleotides in the specific region at which splicing of an intron would usually take place, therefore one or more introns remain in mature mRNA and may result in aberrant proteins being produced
Child with seizures, developmental regression, post mortem shows bilateral symmetrical necrotising lesions in the brain
= Leigh syndrome (also known as subacute necrotising encephalomyelopathy)
- DD, seizures, ataxia, weakness, dystonia
- lactic acidosis
- bilateral symmetrical necrotising lesions in basal ganglia, thalamus, brainstem and spinal cord
Child with developmental regression, diagnosed with AR lysosomal storage disease
= metachromic leukodystrophy
Caused by arylsulfatase A gene mutation
- can be infantile, juvenile or late onset
Child with loss of language, stereotypical hand movements and MCEP2 mutation
= Rett syndrome
- affects girls, usually normal development initially but then loss of language
- microcephaly and stereotypical hand movements noted
What mutation is associated with AD hereditary pancreatitis?
PRSS1
What are the features of Triple A syndrome/Allgrove syndrome?
Achalasia, alacrima (usually first sign), adrenal insufficiency
AR inheritance, mutation in AAAR gene
Often have seizures and autonomic dysfunction
Symptomatic management
Clinical features of Tay-Sachs disease?
Usually around 6 months of age
Hyperekplexia (enhanced startle response) to sound, macrocephaly, hypertonia, and hyperreflexia with gradual loss of skills and seizures by the age of 2
Early death by the age of 5
>90% can have bilateral macular cherry-red spots
Genetics of Tay-Sachs disease?
AR condition caused by disruption of enzyme beta-hexosaminidase A
GM2 ganglioside build up to toxic levels in neurons leading to progressive neurodegenerative symptoms
Cause of metachromatic leukodystrophy
Results from white matter accumulation of sphingolipid that leads to demyelination and neurodegeneration
Clinical features of metachromatic leukodystrophy?
Infantile form most common
Presents with developmental delay, seizures, ataxia, and mixed upper and lower motor neuron signs due to peripheral neuropathy resulting in reduced/absent deep tendon reflexes
MRI findings in metachromatic leukodystrophy?
Frontal and periventricular confluent white matter T2 hyperintensity
(changes are seen later in disease)
Genetics of Fabry disease
X linked recessive condition due to deficiency in alpha-galactosidase A
Clinical features of Fabry disease?
Disease onset by 10 years
Initial manifestations include neuropathic pain, hyophydrosis, reduced exercise tolerance and fever of unknown cause
Angiokeratomas often develop in the second decade of life
By third decade, ischaemic cardiovascular and renal complications can be seen
What sequence is associated with velocardiofacial syndrome?
15-20% have Pierre-Robin sequence
Overview of velocardiofacial syndrome
22q11.2 micro deletion
Abnormal branchial arch development
Structural and functional palatal abnormalities, conotruncal cardiac defects, typical facies, hyper nasal speech, hypotonia, defective thymic development
Facial features of velocardiofacial syndrome in infancy
Round face with prominent parietal bones and bulbous nasal tip
Facial features of velocardiofacial syndrome in childhood
Long face, narrow palpebral fissures, puffy upper eyelids, squared nasal root, narrow alar base with thin alae nasi
What proportion of genetic material is shared between family members?
First degree relatives = 50%
Second degree relatives = 25%
Third degree relatives = 12.5%
What is the most specific test for identifying Fanconi’s anaemia?
Chromosomal breakage (DEB)
Clinical features of Fanconi’s anaemia?
Lethargy, fatigue, bruising or bleeding
Short stature, upper limb malformations (usually thumb/radius)
Aplastic anaemia
May have other skeletal anomalies (including microcephaly, hypertelorism) or congenital heart disease
Clinical features of Williams syndrome?
Short stature, developmental delay
Supravalvular aortic stenosis
Hypermobile joints
Hypercalcaemia
Elfin facies, long philtrum and wide mouth, flat nasal bridge, periorybital fullness
Crescendo-decrescendo systolic murmur, joint laxity, short stature, hypercalcaemia, wide mouth and elfin facies?
Williams syndrome
Scoliosis, elevated scapula, limited neck movement?
Klippel-Feil syndrome
- congenital fusion of the neck leads to limited neck ROM, 50% have scoliosis
- elevated scapula (has not descended congenitally to correct position) = Sprengel deformity
Classic triad of Klippel-Feil syndrome?
Short neck, low hairline and limited range of movement of the neck
- typical features only seen in <50%
Scoliosis and hypo plastic clavicles?
Cleidocranial dysplasia
- delayed closure of cranial sutures, have dental abnormalities and hypo plastic clavicles
Scoliosis, cardiac murmur, Beighton score is 8
Marfan syndrome
- Beighton score assess hypermobility (maximum score is 9, score of >4 suggests hypermobility)
What is complementary DNA (cDNA)?
= the template for a messenger RNA molecule
(Learnmed suggest mRNA could be a template for cDNA)
cDNA is synthesised from mRNA with reverse transcriptase, it has no introns
Which gene is most commonly associated with Noonan syndrome?
PTPN11 (accounts for 50% of cases)
- there are at least 14 known genes associated with Noonan syndrome
What is Haddad syndrome?
Combination of congenital central hypoventilation syndrome and Hirschsprung disease
Safety advice surrounding children with CCHS?
Children with CCHS have a suboptimal response to hypoxia and hypercarbia and will not have the same urge to resurface when holding their breath underwater, need close supervision when swimming
What is the mechanism associated with risk of spinal cord injury in patients with Down syndrome?
Children with Down syndrome are at risk of atlanto-axial subluxation, should have XR before participating in high risk/contact sports
Overview of trisomy 13 (Patau syndrome)
Scalp defect, holoprosencephaly, cleft lip/palate, heart abnormalities
Often present with multiple malformations in the neonatal period but with NORMAL GROWTH
Median survival 10 days, 80% mortality by 3 months, not necessarily ‘lethal’
Genetics and testing for trisomy 13?
Nondisjunction event (AMA), rarely translocation
Karyotype, microarray or FISH
Clinical features of trisomy 18 (Edwards syndrome)?
Wizened features (small palpebral fissures and microstomia)
Overlapping fingers
Rockerbottom feet
IUGR
Prominent occiput
Multiple malformations
Overview of trisomy 18?
Usually diagnosed prenatally with IUGR/abnormal maternal serum screening (low estriol, PAPP-A and bHCG)
Birth with IUGR, dysmorphic features and malformations
Median survival 14 days, death in first year common
Genetics and testing for trisomy 18?
Nondisjunction event most commonly (AMA)
Karyotype, microarray, FISH
Clinical features of trisomy 12 (Down syndrome)?
Hypotonia
Grimace when crying
Facial/physical features (dysmorphic)
Low IQ/developmental delay
Cardiac and GI features
Genetics and testing for trisomy 21?
Nondisjunction event 95% (AMA)
3-4% due to translocation, 1-2% mosaic (i.e. not seen in all cells)
Often diagnosed antenatally: increased nuchal fold/absent nasal bone on morph scan
Karyotype, microarray (will not show translocation), FISH
Facial features of trisomy 21?
Upslanting palpebral fissures
Epicanthal folds
Small low set ears
Flat nasal bridge
Small, brachycephalic head
Small open mouth, macroglossia
Cardiac features of trisomy 21?
TOF, AVSD, PDA
GIT features of trisomy 21?
Duodenal atresia 12%, TOF, Hirschprung <1%
Hypotonia, dysmorphic facial features, upslanting palpebral fissures, epicentral folds, short neck with excess skin at the back of the neck, TOF/AVSD, low IQ?
Trisomy 21
Trisomy 21 is associated with increased risk of which malignancy?
Leukaemia (particularly AML)
Short stature, coarctation of the aorta, primary ovarian failure?
Turner syndrome (45 XO)
Overview of clinical features of Turner syndrome
Short stature, aortic coarctation, primary ovarian failure
Shield chest, wide nipples, webbed neck
Horseshoe kidney, streaked ovaries (dysgenesis)
Congenital lymphoedema
Complications of Turner syndrome?
Increased risk of autoimmune disease (especially hypothyroidism and coeliac disease)
1/3 enter puberty spontaneously (the remainder need oestrogen treatment)
Genetics and testing for Turner syndrome?
45XO, 1/5000 (most spontaneously abort)
Karyotype, microarray, FISH
Wizened features, overlapping fingers, rockerbottom feet?
Trisomy 18 (Edwards)
Scalp defect, holoprosencephaly, cleft lip/palate, normal growth?
Trisomy 13 (Patau)
Eunochoid body habitus, underdeveloped secondary sex characteristics, learning issues, behavioural phenotypes?
Klinefelter’s
Clinical features of Klinefelter’s syndrome
Eunochoid body habitus (narrow shoulders, minimal body hair, gynaecomastia, wide hips)
Hypogonadism/lack of testosterone (primary gonadal failure)
Genetics and testing for Klinefelter’s syndrome
47XXY (sometimes have more X chromosomes)
Nondisjunction during meiotic division
Karyotype, microarray
Complications of Klinefelter’s syndrome
Low sperm count/infertility
Increased incidence of breast cancer
May need testosterone for pubertal induction
Overview of velocardiofacial syndrome
Result from failure of development of 3rd and 4th branchial arches
Wide phenotypic variation
Also known as di George syndrome
Dysmorphism (micrognathia, low set/square ears, asymmetric crying face)
30% have ID, 75% have learning issues
Clinical features of velocardiofacial syndrome
CATCH22
Cardiac - conotruncal and aortic arch defects
Abnormal facies - low set/square ears, hypertelorism, high nasal bone, micrognathia, short palpebral fissures
Thymic hypoplasia - variable T cell function, SCID in 1%
Cleft palate - full or submucosal
Hypocalcaemia - abnormal parathyroids
22q11.2 microdeletion - but in 5% have 10p13 microdeletion
+ have developmental delay, speech and language issues, cognitive impairment
Genetics and testing for velocardiofacial syndrome
22q11.2 microdeletion, can also be 10p13 microdeletion in rare cases
Microarray primarily, could also use FISH, need to check parents
Complications of velocardiofacial syndrome
Autism 20%
Psychiatric illnesses in 60%
Variable immune function (particularly T cell deficiencies), assess prior to live vaccines
Facial features of Williams syndrome?
Infants: “full” facies - periorbital fullness, short anteverted nose, long philtrum
Children: coarse facial features develop as children get older
Elfin facies, supravalvular aortic stenosis, cocktail personality, hypercalcaemia?
Williams syndrome
Clinical presentation of Williams?
Typically irritable infant
Child with short stature and developmental delay
Specific behaviours: over friendly, social disinhibition (leads to safety issues), attention problems
Mild ID commonly
Genetics and testing for Williams syndrome?
Microdeletion on 7q
Microarray, FISH
Complications of Williams syndrome
Hypothyroidism, hypercalcaemia (abdominal pain)
Increased risk hypertension
Supravalvular aortic stenosis
Joint laxity in infancy, arthritis in later life
Role of methylation testing?
Identifies if genes have been switched on or off, very helpful in imprinting disorders
Role of microarray in imprinting disorder?
Identifies if allele is missing/deleted in the active chromosome
Role of SNP array in imprinting disorder?
Identifies unipaternal disomy (both alleles inherited from the same parent)
Detects some, but not all UPD cases (may need UPD studies)
Neonatal hypotonia, hyperplasia after infancy, obesity, mild ID?
Prader-Willi syndrome
Clinical features of Prader-Willi syndrome?
Hypotonia (ranges from poor feeding up to respiratory issues neonatally)
Hyperphagia after infancy
ID
Obesity
Undescended testes
Hypopigmentation
Small hands and feet, subtle dysmorphism
Genetic features of Prader-Willi and testing?
Imprinting defect at 15q
Loss of paternally active genes (paternal deletion in 2/3 or maternal UPD in 1/3)
Diagnostic test is methylation testing 15q
Microarray abnormal in all deletion cases, and some UPD
Microcephaly, ID with absent speech, hand flapping, bouts of spontaneous laughter?
Angelman syndrome
Clinical features of Angelman syndrome
Microcephaly
Severe ID with absent speech
Hand flapping
Ataxia
Spontaneous laughter
Loves water, poor sleep
Can have seizures
Genetics of Angelman syndrome and testing?
Imprinting defect 15q
Loss of maternally active genes (maternal deletion or paternal UPD)
Diagnostic test methylation testing 15q11.2-q13 (absent in 70%)
UBE3A single gene sequencing (10%)
Maternal and paternal influence of IGF2?
Paternal copy: growth promoting
Maternal copy: growth restricting
Macrosomia, macroglossia, hemihypertrophy, omphalocele?
Overgrowth = Beckwith-Wiedemann syndrome
Key features of Beckwith-Wiedemann syndrome?
Overgrowth: macrosomia, macroglossia, hemihypertrophy, visceromegaly
Anterior abdominal wall defects: omphalocele, umbilical hernia
Ears: anterior lobe creases, posterior helix pits
Hypoglycaemia in neonatal period
Genetic features of Beckwith-Wiedemann syndrome?
Imprinting disorder at 11p15 (varying causes)
- loss of methylation of maternal gene in 50%, paternal UPD in up to 20%, CDKN1C mutations in 5-10%
85% sporadic, 15% inherited
BWS associated with IVF conception (loss of IC2 methylation)
Lose maternal function -> paternal over expression of 11p15 (IGF2)
Diagnostic test = methylation testing 11p (SNP is abnormal in rare cases and some paternal UPD)
Opposite of Russell-Silver syndrome
Complications of Beckwith-Wiedemann syndrome?
Predisposed to embryonal malignancies
Wilms, rhabdomyosarcoma, neuroblastoma, hepatoblastoma -> abdominal USS every 3 months until 8 years
Short stature, macrocephaly, asymmetry, triangular face?
Russell-Silver syndrome
Clinical features of Russell-Silver syndrome
IUGR and short stature
Macrocephaly
Asymmetry
Triangular face (relative sparing of HC)
Clinodactyly
Cafe au lait spots
IQ usually normal, some speech delay
Hypoglycaemia risk in infancy
Genetics of Russell-Silver syndrome and testing?
11p methylation defect in 50-60%, maternal UPD7 in <10%, remainder unknown
Methylation defect turns off IGF2 gene
Loss of paternal 11p (opposite of BWS)
First test is 11p methylation testing, if normal then UPD7 studies (from parents), or sometimes can detect UPD7 on SNP
Summary of Beckwith-Wiedemann syndrome
Loss of maternal 11p15 gene
IGF-2 gene overactive (paternally expressed fetal growth factor)
Overgrowth disorder
Macrosomia, hypoglycaemia
Hemihypertrophy, macroglossia, visceromegaly
Beckworth = Big babies
Summary of Russell-Silver syndrome
Loss of paternal 11p15 gene
IGF-2 gene turned off
Short stature
IUGR
Asymmetry, triangular face, preserved HC
Silver = Small
Hirsutism, ulnar ray defects, severe GORD, synophrys, arched eyebrows, long eyelashes
Cornelia de Lange syndrome
Key features of Cornelia de Lange syndrome?
IUGR
Hirsutism
Ulnar ray defects
Severe GORD (feeding issues +++)
Often severe ID with autistic traits
Face - short nose, long philtrum, synophrys (unibrow), arched eyebrows, long eyelashes
Genetics of Cornelia de Lange syndrome and testing?
Single gene disorder: mutation in NIPBL most common (2/3)
Other genes include RAD21, SMC3, SMC1A (XL), HDAC8 (XL)
Clinical exome or panel including NIPBL, SMC1A, SMC3, HDAC8, RAD21
Short stature, webbed neck, pulmonary stenosis, posteriorly rotated ears?
Noonan syndrome
Features of Noonan syndrome
Short stature, webbed neck, pulmonary stenosis, developmental delay
Downslanting palpebral fissures, hypertelorism, low set rotated ears, chest wall deformity, cryptorchidism
Genetics and testing for Noonan syndrome
Autosomal dominant
Single gene disorder: RASMAPK pathway, multiple genes, PTPN11 most commonly
Noonan gene panel or clinical exome
Complications of Noonan syndrome
Small risk of bleeding disorders (need coags)
Small risk leukaemia (no screening recommended)
Overgrowth, high anterior/temporal hairline, tall stature, macrocephaly, long face/pointed chin, mild ID?
Sotos syndrome
Key features of Sotos syndrome
Overgrowth, advanced bone age
High anterior/temporal hairline
Long face, pointed chin, high bossed forehead
Tall stature, large head
Mild ID
Genetics and testing for Sotos syndrome?
NSD1 mutations (>95% de novo)
10% deletions, 90% point mutations
Test with microarray (deletions in 10%) or clinical exome with overgrowth panel applied
Tall stature, long arm span, joint laxity, lens dislocation, aortic root dilatation?
Marfan syndrome
Key features of Marfan syndrome?
‘Tall and stretchy’
Tall with long arm span
Joint laxity
Ectopia lentis (upwards lens dislocation)
Aortic root dilatation
Chest wall deformity
Normal IQ
Genetics and testing for Marfan syndrome?
Autosomal dominant, 1/4000
Single gene disorder: FBN1 mutations
Test: single gene FBN1 sequencing or aortopathy panel
Complications and treatment for Marfan syndrome
Screen first degree relatives
ARBs/beta blockers to reduce dissection risk
Pneumothorax risk
Tall stature, intellectual disability, ectopia lentis (downwards)?
Homocystinuria
Key features of homocystinuria
‘Tall and stiff’
Tall stature with long limbs
ID
Ectopia lentis (downwards) +/- severe myopia
Genetics and testing for homocystinuria?
AR metabolic condition, CBS gene
Diagnostic test: plasma total homocysteine (most detected on NBST)
Treatment for homocystinuria?
Can’t process certain AAs: accumulate homocysteine therefore need protein restricted, methionine restricted diet with folate/B12 supplementation
Complications of homocystinuria?
Thromboembolism
Seizures
Intrahepatic biliary dysgenesis, butterfly vertebrae, pulmonary stenosis, posterior embryotoxon?
Alagille syndrome
Key features of Alagille syndrome?
Intrahepatic biliary dysgenesis
Butterfly vertebrae
Pulmonary stenosis
Posterior embryotoxon
Triangular face, deep set eyes, prominent jaw, forehead prominence
Present as neonates with cholestatic jaundice with bile duct paucity
Genetics and testing for Alagille syndrome
Single gene disorder: JAG1 deletion (10%) or point mutation, 30-50% are de novo (NOTCH2 1-2%)
Microarray (10%), exome with JAG1 and NOTCH2 analysis
Complications of Alagille syndrome
Mortality 10% - liver and cardiac issues
?Renal issues
Fractures in utero/minimal trauma, blue sclerae, hearing loss?
Osteogenesis imperfecta
Key features of osteogenesis imperfecta?
Brittle bone disease
Fractures with minimal/no trauma
Prenatally can be noted to have short long bones
Hearing loss, blue sclerae, osteoporosis, wormian bones
Dental anomalies
Broad phenotypic severity
Genetics and testing for osteogenesis imperfecta?
Single gene disorders of gene encoding collagen proteins: COL1A1 (most common) or COL1A2, mostly AD
If de novo, gonadal mosaicism risk is 3-5%
Testing: exome with OI gene panel analysis or OI gene panel
Short stature, disproportionate short limbs, macrocephaly, trident hand?
Achondroplasia
Key features of achondroplasia
Short stature
Disproportionate short limbs
Hypotonia and gross motor delay but normal IQ
Normal growth until 3rd trimester
Macrocephaly, flat nasal bridge, trident hand, normal trunk with rhizomelic limb shortening
Genetics and testing for achondroplasia?
AD inheritance
Single gene disorder: FGFR3 mutation (causes inappropriate activation of MAPK pathway)
Diagnostic test is skeletal survey
Genetic testing: single gene sequencing FGFR3 mutation
Complications of achondroplasia
Stenotic spinal canal (hydrocephalus, foramen magnum compression, lumbar canal stenosis)
OSA
Middle ear disease
Management of achondroplasia
Monitor for complications
C natriuretic peptide (encoded by NPPC) and its receptor (NPR2) are potent stimulators of endochondrial ossification
Vosoritide is a recombinant form of CNP that blocks the activation of the MAPK pathway
Large ears, large testes, long face, developmental delay, behavioural issues?
Fragile X syndrome
Key features of fragile X syndrome?
ID, dev delay, autistic traits
Large ears, large testes, long face, joint laxity
Behaviour (ADHD, autistic traits, impulsive, shy, anxious)
Most common form of inherited ID (1-2% of children with ID have fragile X)
Genetics and testing for Fragile X?
Triplet repeat disorder, X linked
Females with full mutations can have full picture/milder phenotype
Fragile X testing: sizing of triplet repeat, PCR/Southern blot
Complications of Fragile X?
MVP
Aortic root dilatation
Autism diagnosis in 25%
Seizures in 20%
Short palpebral fissures, flat philtrum, thin upper lip, developmental delay, IUGR, microcephaly?
Fetal alcohol syndrome
- not genetic but is a syndrome
- variation in phenotypes
- main implications are cognitive/behavioural
- complications include seizures
Syndromes to consider in short stature?
Turners - nondysmorphic, webbed neck, shield chest
Noonan - dysmorphic, PS, CMP
Russell-Silver - macrocephaly, facial, asymmetry, CAL
Fanconi anaemia - microcephaly, BMF, thumb/radius anomalies
Williams - elfin face, SVAS, cocktail personality
Achondroplasia/skeletal dysplasias
Short stature - proportionate?
Noonan
Turner
Williams
22q11 deletion, other CNVs
Fanconi anaemia
Short stature - disproportionate?
Skeletal dysplasia (e.g. achondroplasia)
Russell-Silver syndrome
Genetics of Fanconi anaemia
AR condition but mutations in DNA repair genes
Test: chromosome breakage studies, exome with Fanconi genes analysed
Clinical features of Fanconi anaemia
Short stature and microcephaly
Developmental delay
Abnormal thumb/radius
Renal anomalies, GI atresias
Hyper/hypopigmentation, freckles, CAL patches
Pancytopenia/bone marrow failure
Short stature, developmental delay, abnormal thumb/radius, pancytopenia?
Fanconi anaemia
Syndromes associated with tall stature?
Marfan - joint laxity, superior lens dislocation, normal IQ
Homocystinuria - joint contractures, inferior lens dislocation, low IQ, risk of stroke
Klinefelters - nondysmorphic, eunuchoid habitus, mild learning difficulties, pubertal delay, infertility
Sotos - macrocephaly, not Marfanoid habitus, dysmorphic, advanced bone age
BWS - coarse facial features, abdominal wall defects, hypoglycaemia, asymmetry
Syndromes associated with obesity?
Prader-Willi - hypotonia (feeding issues in neonatal period), hyperplasia and obesity, undescended testes, developmental delay
Bardet-Biedel - polydactyly, renal anomalies
Syndromes associated with hypotonia in infancy?
PWS - undescended testes, micrognathia
Myotonic dystrophy - present with hypotonia, examine mother, percussion myotonia
SMA - alert and interactive with profound hypotonia and weakness
Peroxisomal disorders (Zellweger) - tall forehead, abnormal brain MRI, screen for these with VLCFAs
CDG - congenital disorders of glycosylation, screen for these with transferrin isoforms
Key features of SMA
Muscle atrophy leading to weakness, normal intellect
Floppy baby, frog leg posture, expressive facies, tongue fasciculations
Muscles of respiration and swallowing involved over time
Genetics of SMA?
AR, mutation in SMN1 gene
Doesn’t produce enough SMN protein therefore motor neurons die
SMN2 gene (next door) can produce some SMN protein, seen in milder forms
Test: SMN gene testing for common deletion, parents should be tested for carrier status
Types of SMA?
Type 1: infantile onset, never sit, respiratory failure, life span <2 years
Type 2: 6-18 months onset, never walk, scoliosis, lifespan early adulthood
Type 3: 18 month to 12 years, walk in childhood, lose ability to walk as adult
Type 4: adult onset, mild weakness in adulthood, swallow/breathing normal
SMA treatment
Nusinersen - disease modifying therapy
Targets SMN2 gene to upregulate the effects
Delays disease progression, improved acquisition of motor milestones
Severe hypotonia, tall forehead, abnormal brain MRI, abnormal VLCFAs?
Zellweger syndrome
Syndromes associated with pubertal delay?
Turner (45XO) - streak ovaries, short nondysmorphic female, webbed neck, shield chest with wide nipples, normal IQ
Klinefelter (47XXY) - hypogonadism, tall nondysmorphic male, eunochoid habitus, small testes, low IQ, impulsive behaviour
Any syndrome with short stature often causes pubertal delay (but other causes usually present earlier with other issues)
Coarse facies, organomegaly, thick nose/ears?
Mucopolysaccharidosis
Syndromes associated with aortic stenosis?
Williams (supravalvular)
Storage disorders (MPS)
Syndromes associated with pulmonary stenosis
Noonan (valvular)
?Williams
Alagille (supravalvular pulmonary artery stenosis)
Turner
Down syndrome
Syndrome associated with conotruncal anomalies?
22q11.2 deletion (truncus arteriosus)
Syndromes associated with atrial/ventricular septal defects?
T21
22q11
FAS
Cornelia de Lange, Kabuki, Noonan
Syndromes associated with coarctation?
Turner
Kabuki (short stature, cleft, CHD, dysmorphism, interrupted eyebrows, single gene disorder)
Syndromes associated with aortic dilatation?
Marfan (also MVP, MR, AR)
Ehlers Danlos - connective tissue
Loeys Dietz (Marfan like syndrome with bifid uvula, tall stature, scaphocephaly, aortic dilatation)
Syndromes associated with radial ray defects?
Fanconi anaemia
TAR - thrombocytopenia, absent radius (normal thumb)
VACTERL
Blackfan Diamond (thumb abnormal)
Goldenhar (OAVS)
Syndromes associated with deafness - external ear normal?
Waardenburg - iris heterochromia, white forelock
Jervell-Lange-Nielson - long QT
Usher - retinitis pigmentosa
Pendred - hypothyroidism
Alport - collagen disorder affecting kidneys
NF2 - later onset deafness, CAL patches, cataracts
T21
Syndromes associated with deafness - external ear abnormal?
Goldenhar - microtia (small ear), epibulbar dermoid, vertebral abnormalities
Treacher-Collins - bilateral microtia, hypoplastic zygoma
Features of Waardenburg syndrome
Pigmentation disorder
Sensorineural hearing loss
White forelock
Heterochromia irides
Genetics of Waardenburg syndrome
AD, usually single gene disorder caused by mutations in PAX3, MITF, SOX10 and others
Testing: single gene sequencing/panel
Features of Goldenhar syndrome
Also known as oculi-auriculo-vertebral syndrome
Maldevelopment of the 1st and 2nd branchial arch
Hemifacial microsomia
Conductive deafness
Vertebral defects
Sporadic (cause unknown), clinical diagnosis
Features of Treacher Collins syndrome
Single gene disorder caused by mutations in TCOF1
Mandibulofacial dysostosis
Sloping eyes, lower eyelid coloboma (keyhole defect)
Microtia
Malar hypoplasia (small midface)
Clinical diagnosis, but can do single gene testing for TCOF1
Conductive hearing loss, normal IQ
Non-syndromic causes of deafness?
GJB2 gene - most common, AR, 1 in 30 carrier frequency
CMV - PCR, look for microcephaly/retinal issues
LQT - JLN, deafness, long QT
consider testing parents hearing
Syndromes associated with cleft lip/palate
22q11.2 (cleft palate only, not lip)
Stickler syndrome
Pierre Robin sequence
T13
Kabuki syndrome
Syndromes associated with coloboma
Coloboma = keyhole defect of iris, eyelid or retina
Cat eye syndrome - caused by inverted duplication of part of chromosome 22
CHARGE
Treacher Collins
Syndromes associated with ocular lens dislocation
Marfan - up
Homocystinuria - down
Syndromes associated with cataracts
T21
Smith Lemli Opitz - disorder of cholesterol metabolism, diagnosed on exome
Syndromes associated with RBC abnormalities
Fanconi (pancytopenia around 5yo)
Diamond Blackfan anaemia (BMF, triphalyngeal thumbs)
Syndromes associated with WBC abnormalities
22q11 - thymic aplasia -> SCID in some
CHARGE (leukopenia)
Syndromes associated with platelet abnormalities
TAR (thrombocytopenia, absent radius with normal thumb)
Wiskott Aldrich (immune deficiency, eczema, thrombocytopenia)
Syndromes associated with leukaemias
T21 - AML, ALL, transient myeloproliferative disease
Ataxia telangiectasia - leukaemia and lymphoma
Fanconi, Noonan - weak association with leukaemia
Syndromes associated with bowel malignancy
Familial adenomatous polyposos - colorectal polyps
Peutz-Jegher - small bowel hamartomatous polyps, lip/buccal pigmentation (STK11 single gene mutations)
Syndrome associated with wilms/hepatoblastoma/rhabdomyosarcoma?
Beckwith-Wiedemann syndrome
Malignancy associated with neurofibromatosis?
NF1 - optic glioma (unilateral)
NF2 - vestibular schwannomas (bilateral)
Syndromes associated with cafe au lait spots?
NF1 - short with big head, neurofibromas, Lisch nodules, axillary/inguinal freckling, learning issues, optic gliomas
Fanconi anaemia - short with small head, only a few CALs
McCune-Albright - polyostotic fibrous dysplasia, coast of Maine CAL, precocious puberty
Features of Pierre Robin sequence
Micrognathia, cleft palate, airway obstruction
= SEQUENCE not a syndrome
Overview of Stickler syndrome
Commonest syndrome associated with Pierre Robin sequence
Orofacial features: cleft palate/submucous cleft/bifid uvula
Ocular: myopia, vitreous changes, retinal detachment
Auditory: high frequency hearing loss
MSK: femoral head failure, scoliosis, osteoarthritis
Features of VACTERL?
Vertebral
Anal
Cardiac
Tracheo-
Esophageal
Renal
Limb
Features of CHARGE?
Coloboma
Heart defects
Atresia of choanae
Retardation (growth and mental)
Genital anomalies
Ear anomalies
Also: TOF, renal, skeletal
Cause of CHARGE?
Mutations in CHD7 gene, perform single gene sequencing (often diagnosed on exome)
Abnormal architecture of the vitreous gel?
Stickler syndrome
- often also have cleft palate or PR sequence, joint hyper mobility is common, can have Marfanoid habitus
Congenital ichthyosiform erthroderma and cataracts?
Conradi disease
- ichthyosiform erthroderma resolves with time
- limb defects and cataracts also associated
Brachycephaly, frontal bossing micrognathia, facial skin atrophy, cataracts?
Hallerman-Streiff syndrome
- beaked shaped nose
- ocular and dental abnormalities are common
- associated with skin trophy of the face and telangiectasia
- genetic cause unknown
A defect in the gene coding for dysferlin is associated with which disease?
Limb-girdle muscular dystrophy
Mutation causing Marfan’s syndrome?
Mutation in FBN1 - codes for fibrillin
Consequences of FLNB mutations?
FLNB - codes for filming B
Larsen syndrome
Spondylocarpotarsal syndrome
Boomerang dysplasia
Examples of disorders associated with anticipation?
Myotonic dystrophy
Huntington’s disease
Triplet repeat disorders most commonly affect?
The nervous system
Triplet repeats and anticipation?
Triplet repeat disorders tend to have a more severe phenotype with each generation (increasing severity referred to as anticipation)
- larger repeats with each generation, and larger means more severe and more unstable
Fragile X syndrome is what kind of disorder?
Triple repeat disorder
How is severity of a triplet repeat disorder determined?
Number of repeats
Best test for detecting triple repeat disorder?
PCR or Southern blot
Different coloured eyes, white hair?
Waardenburg syndrome
- sensorineural hearing loss
- pigmentation abnormalities affecting hair/eyes
Which is the most common cardiac condition associated with neurofibromatosis?
Pulmonary stenosis
Overview of Smith-Lemli-Opitz syndrome?
AR disorder
Caused by abnormal cholesterol metabolism
Cardiac and craniofacial abnormalities, photosensitivity, syndactyly, polydactyly, abnormal dermatoglyphics, microcephaly, FTT, developmental delay, hypotonia
Definition of telomeres?
Specialised structures which “cap” the ends of chromosomes
A region of repetitive nucleotide sequences which protect the end of the chromosome from deterioration or fusion with neighbouring chromosomes
Carrier risk of SMA?
1 in 40
Older child with fatigue, weakness, muscle cramps, low K/Mg on bloods, low urinary calcium, symptoms improve with magnesium supplementation, microarray shows an NCCT (SLA12A3) gene mutation?
Gitelman’s syndrome (causes decreased sodium and chloride transport in the DCT)
Electrolyte abnormalities in Bartter’s syndrome?
Hypokalaemia
Hypomagnesaemia
High urinary calcium
(present in infancy)
High urinary calcium with mutation of CLCN5 or OCRL1?
Dent’s disease
Proteinuria, renal tubular acidosis, congenital cataracts and developmental delay?
Lowe’s syndrome (= oculocerebrorenal syndrome)
Short stature, microcephaly, micrognathia, under-developed/absent patella and small ears?
Meier-Gorlin syndrome
Malar hypoplasia, micrognathia, cleft lip and cleft palate and downward slanting eyes?
Miller syndrome
Why is Pierre Robin sequence referred to as a sequence?
Described as a sequence, because mandibular hypoplasia initiates a sequence of events antenatally that causes the other signs and symptoms
Ear malformations (decreased folds, narrow ear canals, pre and post auricular ear tags), micrognathia, malfunction of the TMJ?
Auriculo-condylar syndrome
- can also have facial asymmetry, prominent cheeks, microstomia and cleft palate
If a child with Pierre-Robin sequence is found to have ocular abnormalities, what should be suspected?
Stickler or Marshall syndrome
- ocular abnormalities are not a feature of Pierre-Robin sequence
Possible syndromes associated with retinitis pigmentosa?
Usher syndrome (most common): congenital/early onset hearing problems, then develop RP
Bardet-Biedel syndrome (next most common): associated with polydactyly, obesity, renal anomalies and intellectual disability
Lissencephaly, growth restriction and dysmorphic features?
Miller-Dieker syndrome
LIS1 point mutations or deletions (17p13.3)
15q11-13 deletion?
If paternal deletion = Prader-Willi
If maternal deletion = Angelman
13q4 deletion?
Retinoblastoma syndrome (following deletion of RB1 gene)
16p13.3 deletion?
Rubenstein-Taybi syndrome
17p11.2 deletion?
Smith-Magenis syndrome
7q11.23 deletion?
Williams syndrome (deletion of elastin gene)
22q11.2 deletion?
diGeorge syndrome/velocardiofacial syndrome (CATCH22)
Features of Stickler syndrome?
AD, gene mutation causing defect in collagen
Midface hypoplasia, PR sequence
Severe myopia, glaucoma, cataracts, retinal detachment
Hearing loss, hypermobile joints
Inheritence of haemophilia A and B?
X linked
Types of Duane syndrome with regards to extraocular movements?
Type 1: difficulty abducting the eye (one D)
Type 2: difficulty adducting the eye (two Ds)
Type 3: difficulty with both abduction and adduction
80% of cases are type 1
Causes and associations of Duane syndrome?
Caused by congenital strabismus, and abnormal development of CN VI, and anomalous innervation of the lateral rectus muscle
Left eye affected in 60% of cases
Associated with Klippel-Feil anomaly and hemifacial microsomia, bony abnormalities and deafness
Most cases are sporadic but can have AD inheritance
Diagnostic criteria for NF1?
> 6 cafe au lait macules
2 neurofibromas or one plexiform neurofibroma
Freckling in axillary or inguinal regions
Optic glioma
Two or more Lisch nodules
Osseous lesions
First degree relative who is affected
Overview of Goltz syndrome?
Also known as focal dermal hypoplasia
X linked disorder, affects girls (boys die)
Skin and skeletal abnormalities
Ocular abnormalities (coloboma, cataracts, microphthalmia, anophthalmia)
Child with chronic sinusitis and bronchiectasis has genetic mutation affecting inner dynein arms?
Primary ciliary dyskinesia
Various genetic mutations can affect outer or inner dynein arms
What is the most common abnormality leading to Prader-Willi syndrome?
Deletion of paternal allele 65-75%
Maternal UPD 20-30%
Imprinting defect 5%
Gene mutation 0.1%
Balanced translocation 0.1%
Antibodies to test for neonatal lupus erythematosus?
Anti-Ro antibodies (category of anti-ENA antibodies)
Transplacental passage of maternal antibodies result in neonatal lupus, can manifest as congenital heart block
Risk increases with subsequent pregnancies
What disorder is caused by a 22q11 microduplication?
Cat eye
NOT diGeorge - 22q11 microDELETION
