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

Paedriatic Genetics 1 Flashcards

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
Q

How can you diagnose Noonan’s syndrome

A

ArrayCGH, maybe gene panel

If it is still not identified then WES,WGS, trio testing

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26
Q

What are the four stages under the endocrine control of growth

A

Foetal
Infancy
Childhood
Puberty

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27
Q

What are the features of the foetal growth stage

A

Fastest growing period

Dependant on
Maternal health, nutrition and placental function

IGF-I, IGF-II and insulin

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28
Q

What are the features of the infancy growing stage

A

Initially very rapid but then slows down considerably

Growth velocity is primarily determined by:
Nutritional status
Growth hormone (GH)
Thyroxine

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29
Q

What are the features of the childhood growing stage

A

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

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30
Q

What are the features of the pubertal growing stage

A

During puberty there is a surge in GH and IGF-I triggered by increasing levels of testosterone and oestrogen

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31
Q

What boundaries define overgrowth and growth retardation

A

Growth above 98th percentile (2 SD above mean)

Growth retardation between 2nd percentile (2 SD below the mean)

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32
Q

What are the two features that can help differentiate overgrowth syndromes

A

Learning difficulties

Associated clinical features

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33
Q

What are some examples of the overgrowth-intellectual disability syndromes

A 
Sotos Syndrome
Weaver syndrome
Bannayan Riley Ruvalcaba 
Simpson Golabi Behmel
DNMT3A
Homocystinuria
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34
Q

What gene and inheritance pattern is involved in Sotos syndrome

A

Autosomal dominant disease, affecting NSD1

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35
Q

What are the features of Sotos syndrome

A

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

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36
Q

What gene and inheritance pattern is involved in Weaver syndrome

A

Autosomal dominant, EZH2

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37
Q

What are the features of Weaver syndrome

A

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

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38
Q

What may be a differential diagnosis of Sotos syndrome

A

Weaver syndrome

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39
Q

What may be a differential diagnosis of Weaver syndrome

A

Sotos syndrome

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40
Q

What are some overgrowth syndromes NOT associated with learning difficulties

A

Marfan syndrome

Loeys Dietz syndrome

Beckwith-Wiedemann syndrome

Constitutional tall stature

41
Q

What is the primary cause of Beckwith Wiedermann syndrome

A

Disruption of 11p15 imprinting region

42
Q

What are the features of Beckwith-Wiedermann syndrome

A

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
Q

What are the features used to differentiate different short stature syndromes

A

Learning difficulties

Proportionate or disproportionate

Additional clinical features

44
Q

Describe how to differentiate short stature syndromes by proportion

A

Proportional and prenatal onset > SRS (11p15)

Proportional but NOT prenatal = Turner’s, SHOX, GH deficiency, Noonan’s

Disproportionate = skeletal dysplasia

45
Q

What is the cause of silver russell syndrome

A

Mainly due to 11p15 imprinting disorder (H19DMR)

Sometimes abnormalities in chromosome 7

46
Q

What are the features of silver russell syndrome

A

Normal intelligence

Proportionate short stature

Hemihypertrophy

‘Elfin’ face

Fifth finger clinodactyly

47
Q

What is the cause of SHOX

A

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
Q

What are three SHOX-associated diagnoses

A

Mild - Constitiutional short stature

Intermediate - Leri-Welli dyschondrosteosis

Severe - langer mesomelic dysplasia

49
Q

What are the features of Leri-Weill dyschondrosteosis

A

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
Q

What are the features of Turner syndrome

A

Monosomy X = female

Characteristic appearance and habitus - neck webbing , low hairline, shortneck, wider distance between nipples

Short stature

Prenatal hydrops

51
Q

What symptoms are associated with Turner syndrome

A

Cardiovascular abnormalities:
Coarctation of the aorta
Bicuspid aortic valve

Genito-urinary
Renal abnormalities, horseshoe kidney
Ovarian failure

Endocrine
Thyroid problems

52
Q

What is a differential diagnosis of Turner syndrome

A

Noonan’s syndrome

53
Q

What is Nooan’s syndrome

A

Autosomal dominant = male and female

PTPN11 most common cause

54
Q

What are the features of Noonan’s syndrome

A

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
Q

What are three major bone classifications

A

Sclerotome - vertebrae and ribs

Pharyngeal arches - craniofacial bone

Mesenchyme
Skull/flat bones by intramembranous ossification
Limb bones by endochondral bone formation

56
Q

What bones undergo intramembranous ossification

A

Example = skull bones, clavicles, tips of fingers

Mesenchyme forms a membranous sheath
Ossification beings in the centre

57
Q

What is endochondral bone formation

A

Cartilage template with centre ossification

This ossification spreads out and develops vasculature

58
Q

What is the antenatal presentation of skeletal dysplasias

A

Unusual skull shapes, short ‘long’ bones, missing bones, fractures

Lethal - critical bone = chest/ribs, observe hydrops

Non lethal

59
Q

What is the presentation of skeletal dysplasias at birth

A

Disproportionate short stature

Normal or increased head circumference

Pattern of disproportion is important

60
Q

What is the presentation of skeletal dysplasias at childhood

A

Poor growth (height)

Increasing disproportion

Orthopaedic complications

61
Q

What are the two most important categories of initial investigations

A

History and examination

62
Q

What do you look for in the initial history investigation

A

Family history of skeletal abnormalities

Height of parents

Paternal age - achondroplasia, dwarfism

Antenatal findings

Fractures

63
Q

What do you look for in the initial examination investigation

A

Proportionate/disproportionate

Head circumference

Associated problems or abnormalities

Dysmorphic features

64
Q

What is rhizomelia

A

Short proximal part of limb of limbs

65
Q

What is mesomelia

A

Short middle part of limb of limbs

66
Q

What is phocomelia

A

Absent proximal part of limbs

67
Q

What is amelia

A

Absent proximal and middle part of limbs

68
Q

What are the initial skeletal survey locations

A

Skull AP and lateral

Spine AP and lateral

Chest

Pelvis

One arm/ one hand

One leg/ one foot

69
Q

What do you do if you suspect achindroplasia

A

Get DNA sample

70
Q

What are the classifications of skeletal dysplasia

A

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
Q

What are the characteristics of multiple epiphyseal dysplasia

A

Irregular smooth epiphysis

Mild or severe

Symptoms - short, waddling gait, back pain, osteoarthritis

72
Q

What are the two metaphyseal/spondylometaphyseal disorders

A

MCD type Schmid

MCD type McKusick (Cartilage/hair hypoplasia)

73
Q

What is MCD type Schmid

A

AD Metaphyseal and Spondylometaphyseal Disorder

Predominantly hip-bowed legs

74
Q

What is MCD type McKusick / Cartilage/hair hypoplasia

A

AR Metaphyseal and Spondylometaphyseal Disorder

Predominantly affects knee

Associated with immunodeficiency and sparse hair

75
Q

What are the anatomic regions of growing bone

A

Diaphysis - shaft

Metaphysis - near edge

Growth plate (physis) - connects metaphysis to epiphysis

Epiphysis - end

76
Q

What is FGFR3

A

Fibroblast growth factor receptor 3 a tyrosine kinase

It is a negative regulator of growth

Gain = short
Loss = tall
77
Q

What is FGFR3 involved in

A

Achondroplasia and thanatophoric dysplasia

78
Q

What is achondroplasia

A

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
Q

What is the mild version of achondroplasia called

A

Hypochondroplasia

80
Q

What is the complication with a woman with achondroplasia giving birth

A

If the baby is normal size, it may be too big and thus premature birth is induced

81
Q

What are the symptoms involved with achondroplasia

A

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
Q

What is the inheritance pattern for achondroplasia

A

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
Q

What gene causes achondroplasia

A

FGFR3

84
Q

Why is achondroplasia easy to diagnose genotypically

A

Theres only two possible genes that can use achondroplasia including FGFR3

85
Q

What is thanatophoric dysplasia

A

AD neonatally lethal disease caused by mutation in FGFR3

Always a de novo mutation

86
Q

Why is thanatophoric dysplasia always de novo even though it is an AD disease

A

There are no individuals born with thanatophoric dysplasia thus all occurances have to be new

87
Q

What are the two types of thanatophoric dysplasia

A

Sporadic, curved femurs (telephone receiver)

Straight femurs, cloverleaf skull

88
Q

Where in FGFR3 do mutations occur

A

Mutations can span this gene

Achondroplasia - transmembrane domains

Hypochondroplasia - spread

Thanatophoric Dysplasia - spread

89
Q

What are the disorders associated with collagen II

A

Spondyloepiphyseal disorders

Stickler syndrome

Achondrogenesis

90
Q

What are the disorders associated with collagen I

A

Reduced Bone Density Osteogenesis Imperfecta

Type 1 - mild
Type 2A/B - sporadic/lethal
Type 3 - severe, not always lethal
Type 4 - intermediate

91
Q

What are spondyloepyphyseal disorders

A

Autosomal dominant

Diagnosed at birth

Short limbs and trunk

Scoliosis (spinal curvature)

Cleft palate +/- eye problems

92
Q

What is stickler syndrome

A

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
Q

What is achondrogenesis Type II

A

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
Q

What is type 1 Reduced Bone Density Osteogenesis Imperfecta

A

Blue sclera/ wormian bones/fractures

Autosomal dominant

Thin bones

Dentigenesis imperfecta - poor enamel

Deafness

95
Q

What is type 3 Reduced Bone Density Osteogenesis Imperfecta

A

More severe
Multiple fractures
Scoliosis

96
Q

What is a randomised controlled trial (RCT)

A

RCT is a clinical trial where participants are randomly allocated to a test treatment

97
Q

What are the biases controlled by randomised controlled trials

A

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
Q

What are the advantages of RCT

A

Allow for rigorous evaluation of a single variable

Potentially eradicate bias

Allow for meta-analysis

99
Q

What are the disadvantages of RCT

A

Expensive and time consuming

Ethically problematic at times - a trial is sometimes stopped early if dramatic effects are seen

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