Paedriatic Genetics 1 Flashcards
What is dysmorphology
The study of human congenital malformations (birth defects), particularly those affecting the anatomy (morphology) of the individual
What are the classifications of dysmorphic features
Physical features are not usually found in a child of the same age or ethnic background
Major anomaly = with clinical significance
Minor anomaly = without or little clinical significance
What is the impact of minor anomalies
1 = 15% of all new borns, 3% also have a major anomaly
2 = less usual, 10% have a major anomaly
> 3 = 1% of all new borns, 90% have a major anomaly
(I.e the more minor anomalies the more likely there is a major anomaly with clinical significance)
What is a syndrome
A particular set of developmental anomalies occurring together in a well-recognisable and predictable pattern (Greek –’ running together’) presumably due to a single underlying aetiology
What variants may cause syndromes
Single gene disorders Chromosomal disorders Microdeletion syndromes Polygenic disorders Environmental causes e.g. CMV, foetal alcohol syndrome
Why are dysmorphic features important to identify
Most children/ adults are not referred because they are ‘dysmorphic’ but because they have a developmental abnormality
Recognising patterns help you to - pick the right test, consider differential diagnosis, interpret results of genetic investigation
Why is making a diagnosis important
Provides an explanation
Genetic counselling
Screening/management implications
Assess genetic risk
Predictive testing for family
Prenatal testing/PGD
What are some dysmorphic facial features
Asymmetry
Midface hypoplasia - bulgy eyes, underbite (seen in achondroplasia and Down Syndrome)
Micrognathia - small jaw
Myopathic faces - muscle weakness = droppy face
What are some dysmorphic ear features
Low-set - line between eye corners = top ear
Posteriorly rotated (ears rotated backwards) Noonan's syndrome
Auricular pits/tags
Kidney or heart problems
Microtia - underdeveloped ear
External ear variants
Ear lobe variants
What are some dysmorphic skull features
Macro/microcephaly - head size
Frontal bossing - protruding forehead
Plagiocephaly - odd head shape
Shape determined when sutures close
Early close = different shape
Metopic ridge - suture in middle of forehead
Scalp defects
Can point towards Adams-Oliver
Frontal hairline variants
Low posterior hairline
Turner syndrome
What are some dysmorphic hand features
Postaxial or preaxial polydactyly
Syndactyly - fused fingers/toes
Clinodactyly - curving of finger
Brachydactyly - shortening of fingers/toes
Ectrodactyly - split/cleft hand, missing central digit
Fetal finger pads
Single palmar crease
Down’s
Sandal gap - space between big toe and others
Down’s
What are some dysmorphic nose features
Nasal bridge
Alae nasi and nasal tip
Nasal columella and nares
What are some dysmorphic eye features
Hyper/hypotelorism - distance between eyes
Up/downslant
Line between inner/outer corner of eye
Up = Down’s
Down = Noonan
Epicanthus - fold of skin in the inner corner
Down’s
Ptosis (hanging eyelid)
Myopathic face
Corneal clouding
Coloboma - defect of iris closure
Anopthalmia/micropthalmia
Eyelash variants
Epibulbar dermoid
What are some dysmorphic mouth features
Microstomia - small mouth
Upper lip clefts
Lip pits
Thick and thin upper lips
Lip and oral mucosa pigmentation
Macroglossia
Gum hyperplasia
Bifid uvula (split uvula) Connective tissue disorder
Long philtrum
What are the dysmorphic features associated with Down syndrome
Low set ears, small nose, upslant eyes, open mouth
Also
Midface hypoplasia, upslant, folded helix, sparse hair
Heart defect, intellectual disability, single palmar crease
Hypertonia (weak muscles), leukaemia, early onset dementia
How can you postnatally test for Down syndrome
Karyotype or qfPCR
What are the dysmorphic features associated with DiGeorge Syndrome
Congenital heart defect, nasal speech, slanted ears
Downslant, epicanthal fold, elongated face, tubular nose
Prominent nose with a squared-off nasal tip, micrognathia, microcephaly
What symptoms are associated with DiGeorge syndrome
75% congenital heart disease - TOF, VSD, interrupted aortic arch
69% palatal abnormalities
60% hypocalcaemia
36% renal abnormality
70-90% learning difficulties
What are the dysmorphic features associated with Williams syndrome
High forehead, folds under eye, bulbous nose tip, larger lower lip, hanging/droopy cheeks
Bright blue eyes, curly hair
What genetic variation causes Williams syndrome
7q11.23 deletion
What symptoms are associated with Williams Syndrome
Congenital heart disease in 80%
75% supravalvular aortic stenosis
25% supravalvular pulmonary stenosis
Developmental delay
Overfriendly personality
Hypercalcaemia (15%)
What is a gestalt
Pattern of symptoms
What are the characteristics of Noonan syndrome
Short stature, hearing impairment, low set ears, wide neck/neck skin webbing, curly hair, inverted triangle shaped head
Pulmonary stenosis (obstruction of flow from right ventricle to pulmonary artery),
Cardiomyopathy, lymphoedema, coagulation defects
Learning difficulties
What is the most common gene causing Noonan syndrome
PTPN11
How can you diagnose Noonan’s syndrome
ArrayCGH, maybe gene panel
If it is still not identified then WES,WGS, trio testing
What are the four stages under the endocrine control of growth
Foetal
Infancy
Childhood
Puberty
What are the features of the foetal growth stage
Fastest growing period
Dependant on
Maternal health, nutrition and placental function
IGF-I, IGF-II and insulin
What are the features of the infancy growing stage
Initially very rapid but then slows down considerably
Growth velocity is primarily determined by:
Nutritional status
Growth hormone (GH)
Thyroxine
What are the features of the childhood growing stage
Childhood growth phase emerges at about 6 months and continues until puberty
Growth velocity during this phase is relatively constant
Nutrition is now less important
Dependent upon hormones:
GH
IGF-I
Thyroxine
What are the features of the pubertal growing stage
During puberty there is a surge in GH and IGF-I triggered by increasing levels of testosterone and oestrogen
What boundaries define overgrowth and growth retardation
Growth above 98th percentile (2 SD above mean)
Growth retardation between 2nd percentile (2 SD below the mean)
What are the two features that can help differentiate overgrowth syndromes
Learning difficulties
Associated clinical features
What are some examples of the overgrowth-intellectual disability syndromes
Sotos Syndrome Weaver syndrome Bannayan Riley Ruvalcaba Simpson Golabi Behmel DNMT3A Homocystinuria
What gene and inheritance pattern is involved in Sotos syndrome
Autosomal dominant disease, affecting NSD1
What are the features of Sotos syndrome
Tall stature and / or macrocephaly
Variable learning disability and autism spectrum disorder
Characteristic facial appearance - frontal bossing, downslant, high hairline, frontal-temporal hair sparsity, different face shape (upside down triangle = dolichocephalic?), malar flashing (rosy cheeks)
Hypermobility and scoliosis
Associated with congenital heart disease, seizures and genito-urinary abnormalities
What gene and inheritance pattern is involved in Weaver syndrome
Autosomal dominant, EZH2
What are the features of Weaver syndrome
Similar presentation to Sotos syndrome with increased growth and variable intellectual disability
Consider Sotos syndrome and Weaver syndrome in each other’s differential diagnosis
Overlapping facial phenotype but different!
But camptodactyly, hoarse cry, umbilical hernia distinguish Weavers V Sotos
Features - round face, almond shapes eyes, pointed chin (stuck on chin, with horizontal crease), wide-set hypertelorism
What may be a differential diagnosis of Sotos syndrome
Weaver syndrome
What may be a differential diagnosis of Weaver syndrome
Sotos syndrome
What are some overgrowth syndromes NOT associated with learning difficulties
Marfan syndrome
Loeys Dietz syndrome
Beckwith-Wiedemann syndrome
Constitutional tall stature
What is the primary cause of Beckwith Wiedermann syndrome
Disruption of 11p15 imprinting region
What are the features of Beckwith-Wiedermann syndrome
Overgrowth, abdominal wall defects, omphalocele, visceromegaly (enlarged internal organs)
Macroglossia (large tongue), ear lobe creases/pits
Hemihypertrophy (one side of body larger)
Predisposition to developing embryonal tumours
Usually normal learning
What are the features used to differentiate different short stature syndromes
Learning difficulties
Proportionate or disproportionate
Additional clinical features
Describe how to differentiate short stature syndromes by proportion
Proportional and prenatal onset > SRS (11p15)
Proportional but NOT prenatal = Turner’s, SHOX, GH deficiency, Noonan’s
Disproportionate = skeletal dysplasia
What is the cause of silver russell syndrome
Mainly due to 11p15 imprinting disorder (H19DMR)
Sometimes abnormalities in chromosome 7
What are the features of silver russell syndrome
Normal intelligence
Proportionate short stature
Hemihypertrophy
‘Elfin’ face
Fifth finger clinodactyly
What is the cause of SHOX
SHOX gene on pseudoautosomal region of (PAR) of the X chromosome at Xp22.3 and the Y at Yp11.2
Its not autosomal but males and females both have two copies
Deletion = short stature - reason why short stature occurs in Turner’s syndrome
What are three SHOX-associated diagnoses
Mild - Constitiutional short stature
Intermediate - Leri-Welli dyschondrosteosis
Severe - langer mesomelic dysplasia
What are the features of Leri-Weill dyschondrosteosis
Caused by loss of ONE copy of the SHOX gene
Short stature
Usually have mesomelia - the distal arm is shorter
Madelung deformity, predominantly girls - angulation to the forearm
Likely to be influenced by differential closure of the growth plate as effected by the female hormones
What are the features of Turner syndrome
Monosomy X = female
Characteristic appearance and habitus - neck webbing , low hairline, shortneck, wider distance between nipples
Short stature
Prenatal hydrops
What symptoms are associated with Turner syndrome
Cardiovascular abnormalities:
Coarctation of the aorta
Bicuspid aortic valve
Genito-urinary
Renal abnormalities, horseshoe kidney
Ovarian failure
Endocrine
Thyroid problems
What is a differential diagnosis of Turner syndrome
Noonan’s syndrome
What is Nooan’s syndrome
Autosomal dominant = male and female
PTPN11 most common cause
What are the features of Noonan’s syndrome
Short stature
Mild learning disability
Characteristic facial appearance - bright blue eyes, slanted eyes, ptosis - drooping eyelid, coarse facial features, low-set posteriorly rotated ear
Right sided heart abnormalities e.g. pulmonary stenosis
Cardiomyopathies
What are three major bone classifications
Sclerotome - vertebrae and ribs
Pharyngeal arches - craniofacial bone
Mesenchyme
Skull/flat bones by intramembranous ossification
Limb bones by endochondral bone formation
What bones undergo intramembranous ossification
Example = skull bones, clavicles, tips of fingers
Mesenchyme forms a membranous sheath
Ossification beings in the centre
What is endochondral bone formation
Cartilage template with centre ossification
This ossification spreads out and develops vasculature
What is the antenatal presentation of skeletal dysplasias
Unusual skull shapes, short ‘long’ bones, missing bones, fractures
Lethal - critical bone = chest/ribs, observe hydrops
Non lethal
What is the presentation of skeletal dysplasias at birth
Disproportionate short stature
Normal or increased head circumference
Pattern of disproportion is important
What is the presentation of skeletal dysplasias at childhood
Poor growth (height)
Increasing disproportion
Orthopaedic complications
What are the two most important categories of initial investigations
History and examination
What do you look for in the initial history investigation
Family history of skeletal abnormalities
Height of parents
Paternal age - achondroplasia, dwarfism
Antenatal findings
Fractures
What do you look for in the initial examination investigation
Proportionate/disproportionate
Head circumference
Associated problems or abnormalities
Dysmorphic features
What is rhizomelia
Short proximal part of limb of limbs
What is mesomelia
Short middle part of limb of limbs
What is phocomelia
Absent proximal part of limbs
What is amelia
Absent proximal and middle part of limbs
What are the initial skeletal survey locations
Skull AP and lateral
Spine AP and lateral
Chest
Pelvis
One arm/ one hand
One leg/ one foot
What do you do if you suspect achindroplasia
Get DNA sample
What are the classifications of skeletal dysplasia
Predominantly epiphyseal - important for joints
Spondyloepiphyseal
Metaphyseal and spondylometaphyseal
Short limbs with normal trunk OR with short trunk
Lethal forms of dwarfism
Storage disorders
Metabolic bone disease
Sclerosing bone disorders
What are the characteristics of multiple epiphyseal dysplasia
Irregular smooth epiphysis
Mild or severe
Symptoms - short, waddling gait, back pain, osteoarthritis
What are the two metaphyseal/spondylometaphyseal disorders
MCD type Schmid
MCD type McKusick (Cartilage/hair hypoplasia)
What is MCD type Schmid
AD Metaphyseal and Spondylometaphyseal Disorder
Predominantly hip-bowed legs
What is MCD type McKusick / Cartilage/hair hypoplasia
AR Metaphyseal and Spondylometaphyseal Disorder
Predominantly affects knee
Associated with immunodeficiency and sparse hair
What are the anatomic regions of growing bone
Diaphysis - shaft
Metaphysis - near edge
Growth plate (physis) - connects metaphysis to epiphysis
Epiphysis - end
What is FGFR3
Fibroblast growth factor receptor 3 a tyrosine kinase
It is a negative regulator of growth
Gain = short Loss = tall
What is FGFR3 involved in
Achondroplasia and thanatophoric dysplasia
What is achondroplasia
Disorder of bone growth that prevents the changing of cartilage (particularly in the long bones of the arms and legs) to bone
It is characterized by dwarfism, limited range of motion at the elbows, large head size (macrocephaly), small fingers, and normal intelligence
What is the mild version of achondroplasia called
Hypochondroplasia
What is the complication with a woman with achondroplasia giving birth
If the baby is normal size, it may be too big and thus premature birth is induced
What are the symptoms involved with achondroplasia
Depressed nasal bridge
Breathing issues, could die in sleep - sleep studies
Hearing loss due to connection
Narrow foramen magnum - hole where spine comes up
Hydrocephaly - fluid of brain
Spinal stenosis - puts pressure on the nerve
What is the inheritance pattern for achondroplasia
Most cases of achondroplasia are not inherited. When achondroplasia is inherited, it is inherited in an autosomal dominant manner. Over 80 percent of individuals who have achondroplasia have parents with normal stature and are born with achondroplasia as a result of a new (de novo) gene alteration (mutation)
Genome.gov and Pauli 2012
What gene causes achondroplasia
FGFR3
Why is achondroplasia easy to diagnose genotypically
Theres only two possible genes that can use achondroplasia including FGFR3
What is thanatophoric dysplasia
AD neonatally lethal disease caused by mutation in FGFR3
Always a de novo mutation
Why is thanatophoric dysplasia always de novo even though it is an AD disease
There are no individuals born with thanatophoric dysplasia thus all occurances have to be new
What are the two types of thanatophoric dysplasia
Sporadic, curved femurs (telephone receiver)
Straight femurs, cloverleaf skull
Where in FGFR3 do mutations occur
Mutations can span this gene
Achondroplasia - transmembrane domains
Hypochondroplasia - spread
Thanatophoric Dysplasia - spread
What are the disorders associated with collagen II
Spondyloepiphyseal disorders
Stickler syndrome
Achondrogenesis
What are the disorders associated with collagen I
Reduced Bone Density Osteogenesis Imperfecta
Type 1 - mild
Type 2A/B - sporadic/lethal
Type 3 - severe, not always lethal
Type 4 - intermediate
What are spondyloepyphyseal disorders
Autosomal dominant
Diagnosed at birth
Short limbs and trunk
Scoliosis (spinal curvature)
Cleft palate +/- eye problems
What is stickler syndrome
Milder
Autosomal dominant
Predominantly epiphyseal problems
Associated with
Premature osteoarthritis
Myopia with increased risk of retinal detachment
Hearing loss
Pierre-robin sequence - cleft palate with small jaw, big tongue, and have breathing problem
What is achondrogenesis Type II
Lethal
Short limbs and chest
Loss of function of collagen II
Missense is worse than truncated as it is a dominant negative mechanism which affects the normal protein on the other allele
What is type 1 Reduced Bone Density Osteogenesis Imperfecta
Blue sclera/ wormian bones/fractures
Autosomal dominant
Thin bones
Dentigenesis imperfecta - poor enamel
Deafness
What is type 3 Reduced Bone Density Osteogenesis Imperfecta
More severe
Multiple fractures
Scoliosis
What is a randomised controlled trial (RCT)
RCT is a clinical trial where participants are randomly allocated to a test treatment
What are the biases controlled by randomised controlled trials
Bias is defined as any tendency which prevents unprejudiced consideration of a question
Selection bias - systematic differences in comparison groups due to incomplete randomisation
Performance bias - systematic differences in the care provided apart from the intervention evaluated
Exclusion bias - systematic differences in withdrawals from the trials
Detection bias - systematic differences in outcome assessment
What are the advantages of RCT
Allow for rigorous evaluation of a single variable
Potentially eradicate bias
Allow for meta-analysis
What are the disadvantages of RCT
Expensive and time consuming
Ethically problematic at times - a trial is sometimes stopped early if dramatic effects are seen
