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Clinical Applications of Genomics in Rare Disease and Cancer > Paedriatic Genetics 1 > Flashcards

Paedriatic Genetics 1 Flashcards

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1
Q

What is dysmorphology

A

The study of human congenital malformations (birth defects), particularly those affecting the anatomy (morphology) of the individual

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2
Q

What are the classifications of dysmorphic features

A

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

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3
Q

What is the impact of minor anomalies

A

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)

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4
Q

What is a syndrome

A

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

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5
Q

What variants may cause syndromes

A 
Single gene disorders
Chromosomal disorders
Microdeletion syndromes
Polygenic disorders
Environmental causes e.g. CMV, foetal alcohol syndrome
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6
Q

Why are dysmorphic features important to identify

A

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

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7
Q

Why is making a diagnosis important

A

Provides an explanation

Genetic counselling

Screening/management implications

Assess genetic risk

Predictive testing for family

Prenatal testing/PGD

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8
Q

What are some dysmorphic facial features

A

Asymmetry

Midface hypoplasia - bulgy eyes, underbite (seen in achondroplasia and Down Syndrome)

Micrognathia - small jaw

Myopathic faces - muscle weakness = droppy face

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9
Q

What are some dysmorphic ear features

A

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

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10
Q

What are some dysmorphic skull features

A

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

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11
Q

What are some dysmorphic hand features

A

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

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12
Q

What are some dysmorphic nose features

A

Nasal bridge
Alae nasi and nasal tip
Nasal columella and nares

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13
Q

What are some dysmorphic eye features

A

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

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14
Q

What are some dysmorphic mouth features

A

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

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15
Q

What are the dysmorphic features associated with Down syndrome

A

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

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16
Q

How can you postnatally test for Down syndrome

A

Karyotype or qfPCR

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17
Q

What are the dysmorphic features associated with DiGeorge Syndrome

A

Congenital heart defect, nasal speech, slanted ears
Downslant, epicanthal fold, elongated face, tubular nose

Prominent nose with a squared-off nasal tip, micrognathia, microcephaly

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18
Q

What symptoms are associated with DiGeorge syndrome

A

75% congenital heart disease - TOF, VSD, interrupted aortic arch

69% palatal abnormalities

60% hypocalcaemia

36% renal abnormality

70-90% learning difficulties

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19
Q

What are the dysmorphic features associated with Williams syndrome

A

High forehead, folds under eye, bulbous nose tip, larger lower lip, hanging/droopy cheeks
Bright blue eyes, curly hair

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20
Q

What genetic variation causes Williams syndrome

A

7q11.23 deletion

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21
Q

What symptoms are associated with Williams Syndrome

A

Congenital heart disease in 80%
75% supravalvular aortic stenosis
25% supravalvular pulmonary stenosis

Developmental delay

Overfriendly personality

Hypercalcaemia (15%)

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22
Q

What is a gestalt

A

Pattern of symptoms

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23
Q

What are the characteristics of Noonan syndrome

A

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

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24
Q

What is the most common gene causing Noonan syndrome

A

PTPN11

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25
How can you diagnose Noonan's syndrome
ArrayCGH, maybe gene panel If it is still not identified then WES,WGS, trio testing
26
What are the four stages under the endocrine control of growth
Foetal Infancy Childhood Puberty
27
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
28
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
29
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
30
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
31
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)
32
What are the two features that can help differentiate overgrowth syndromes
Learning difficulties Associated clinical features
33
What are some examples of the overgrowth-intellectual disability syndromes
``` Sotos Syndrome Weaver syndrome Bannayan Riley Ruvalcaba Simpson Golabi Behmel DNMT3A Homocystinuria ```
34
What gene and inheritance pattern is involved in Sotos syndrome
Autosomal dominant disease, affecting NSD1
35
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
36
What gene and inheritance pattern is involved in Weaver syndrome
Autosomal dominant, EZH2
37
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
38
What may be a differential diagnosis of Sotos syndrome
Weaver syndrome
39
What may be a differential diagnosis of Weaver syndrome
Sotos syndrome
40
What are some overgrowth syndromes NOT associated with learning difficulties
Marfan syndrome Loeys Dietz syndrome Beckwith-Wiedemann syndrome Constitutional tall stature
41
What is the primary cause of Beckwith Wiedermann syndrome
Disruption of 11p15 imprinting region
42
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
43
What are the features used to differentiate different short stature syndromes
Learning difficulties Proportionate or disproportionate Additional clinical features
44
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
45
What is the cause of silver russell syndrome
Mainly due to 11p15 imprinting disorder (H19DMR) Sometimes abnormalities in chromosome 7
46
What are the features of silver russell syndrome
Normal intelligence Proportionate short stature Hemihypertrophy 'Elfin' face Fifth finger clinodactyly
47
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
48
What are three SHOX-associated diagnoses
Mild - Constitiutional short stature Intermediate - Leri-Welli dyschondrosteosis Severe - langer mesomelic dysplasia
49
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
50
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
51
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
52
What is a differential diagnosis of Turner syndrome
Noonan's syndrome
53
What is Nooan's syndrome
Autosomal dominant = male and female PTPN11 most common cause
54
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
55
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
56
What bones undergo intramembranous ossification
Example = skull bones, clavicles, tips of fingers Mesenchyme forms a membranous sheath Ossification beings in the centre
57
What is endochondral bone formation
Cartilage template with centre ossification This ossification spreads out and develops vasculature
58
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
59
What is the presentation of skeletal dysplasias at birth
Disproportionate short stature Normal or increased head circumference Pattern of disproportion is important
60
What is the presentation of skeletal dysplasias at childhood
Poor growth (height) Increasing disproportion Orthopaedic complications
61
What are the two most important categories of initial investigations
History and examination
62
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
63
What do you look for in the initial examination investigation
Proportionate/disproportionate Head circumference Associated problems or abnormalities Dysmorphic features
64
What is rhizomelia
Short proximal part of limb of limbs
65
What is mesomelia
Short middle part of limb of limbs
66
What is phocomelia
Absent proximal part of limbs
67
What is amelia
Absent proximal and middle part of limbs
68
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
69
What do you do if you suspect achindroplasia
Get DNA sample
70
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
71
What are the characteristics of multiple epiphyseal dysplasia
Irregular smooth epiphysis Mild or severe Symptoms - short, waddling gait, back pain, osteoarthritis
72
What are the two metaphyseal/spondylometaphyseal disorders
MCD type Schmid MCD type McKusick (Cartilage/hair hypoplasia)
73
What is MCD type Schmid
AD Metaphyseal and Spondylometaphyseal Disorder Predominantly hip-bowed legs
74
What is MCD type McKusick / Cartilage/hair hypoplasia
AR Metaphyseal and Spondylometaphyseal Disorder Predominantly affects knee Associated with immunodeficiency and sparse hair
75
What are the anatomic regions of growing bone
Diaphysis - shaft Metaphysis - near edge Growth plate (physis) - connects metaphysis to epiphysis Epiphysis - end
76
What is FGFR3
Fibroblast growth factor receptor 3 a tyrosine kinase It is a negative regulator of growth ``` Gain = short Loss = tall ```
77
What is FGFR3 involved in
Achondroplasia and thanatophoric dysplasia
78
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
79
What is the mild version of achondroplasia called
Hypochondroplasia
80
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
81
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
82
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
83
What gene causes achondroplasia
FGFR3
84
Why is achondroplasia easy to diagnose genotypically
Theres only two possible genes that can use achondroplasia including FGFR3
85
What is thanatophoric dysplasia
AD neonatally lethal disease caused by mutation in FGFR3 Always a de novo mutation
86
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
87
What are the two types of thanatophoric dysplasia
Sporadic, curved femurs (telephone receiver) Straight femurs, cloverleaf skull
88
Where in FGFR3 do mutations occur
Mutations can span this gene Achondroplasia - transmembrane domains Hypochondroplasia - spread Thanatophoric Dysplasia - spread
89
What are the disorders associated with collagen II
Spondyloepiphyseal disorders Stickler syndrome Achondrogenesis
90
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
91
What are spondyloepyphyseal disorders
Autosomal dominant Diagnosed at birth Short limbs and trunk Scoliosis (spinal curvature) Cleft palate +/- eye problems
92
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
93
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
94
What is type 1 Reduced Bone Density Osteogenesis Imperfecta
Blue sclera/ wormian bones/fractures Autosomal dominant Thin bones Dentigenesis imperfecta - poor enamel Deafness
95
What is type 3 Reduced Bone Density Osteogenesis Imperfecta
More severe Multiple fractures Scoliosis
96
What is a randomised controlled trial (RCT)
RCT is a clinical trial where participants are randomly allocated to a test treatment
97
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
98
What are the advantages of RCT
Allow for rigorous evaluation of a single variable Potentially eradicate bias Allow for meta-analysis
99
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

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