Paediatrics JC122: The Malformed Child: Hereditary Syndromes And Anomalies Flashcards
Contributions of genetic + environmental factors to human diseases
A spectrum: usually very few pure genetic + pure environmental syndromes
Single gene conditions:
- Chromosomal, Mitochondrial disorders
- Rare
- Simple genetics: one genetic factor play a major role in causation of disorder
- Unifactorial
- High recurrence rate (e.g. AD: 50%, AR: 25%)
Multifactorial conditions:
- Gene + Environment
- Common
- Complex genetics
- Multifactorial
- Low recurrence rate (hard to calculate accurately, ∵ multifactorial: require all factors added together in next pregnancy to reproduce same disease)
Rare:
- **1 in 2000 for a single disease
- **80% are genetic in origin
- 8000 types of disease
- 50% have paediatric onset
- add all rare disease together —> 1 in 17 will have a rare disease
Work of clinical geneticists
In clinic:
1. Patient assessment
2. Taking family history
3. Dysmorphic examination
Back-stage work:
1. Literature review
2. Searching rare disease database
3. Overseas consultation
4. Organise clinical / research genetic testing
Research and development:
1. Develop new testing platform for undiagnosed genetic diseases
Reaching genetic diagnosis + genetic counselling
Evaluation for Failure to thrive / Short stature
DDx:
1. Achondroplasia
2. Turner syndrome
3. Short syndrome
4. Myhre syndrome
5. Metatrophic dysplasia
6. Russell-Silver syndrome
Abnormal stature:
- Proportionate —> Chromosome, Endocrine, Nutritional, Others
- Disproportionate —> Skeletal dysplasia (Rhizomelic (proximal) bone shortening)
—> interpedicular distance should get wider
Achondroplasia
Gain-of-function mutation in FGFR-3 (Fibroblast growth factor receptor 3)
Classes of mutation:
1. Hypochondroplasia
2. Achondroplasia
3. Thanatophoric (i.e. lethal) dysplasia type 1
4. Thanatophoric dysplasia type 2
Long term complications:
- ***Spinal canal stenosis
Prevention:
1. **Firm back support from birth
2. **Reclined seating (delayed upright sitting) + Reclined handling
3. ***Prone play in older infants
4. Trunk strengthening exercise
5. Shock absorbing footwear
6. Good sitting posture
7. Providing a foot rest
8. Maintaining weight on the 25th percentile for achondroplasia
Treatment:
- ***C-type Natriuretic peptide analogue (Vosoritide) —> inhibitory effect on downstream signaling of FGFR-3
Turner syndrome (TS) (Refer to Neonatal Teaching: Approach To The Newborn With Multiple Congenital Abnormalities (MCAs))
**45X:
- Phenotypic females lost an entire / a portion of X chromosome
—> include **tip of short arm
Epidemiology:
- affects approximately 1/2500 live female births
- only 1% of embryo survive to term
—> responsible for 7-10% of all spontaneous abortions
2 common features (>90%):
1. **Short stature
2. **Premature ovarian failure
Other features:
1. **Micrognathia
2. **↑ Carrying angle (cubitus valgus)
3. ***Concave hypoplastic nails
Variability of phenotypes in TS:
- Early surveys emphasised physical traits (typical clinical features: webbed neck, low-set / malrotated ears, ptosis, skeletal abnormalities)
- BUT only 50% truly dysmorphic
Medical conditions in TS:
1. **Short stature —> GH injection
2. **Gonadal insufficiency —> Monitor pubertal development +/- Estrogen replacement
3. Cardiovascular —> Refer cardiology (need continuous monitoring ∵ conditions can occur later in life)
- **Bicuspid aortic valve
- **Coarctation of aorta
- Aorta dilation + dissection
- Hypertension
4. Renal anomalies —> Renal USG
5. Autoimmune hypothyroidism —> Screen TFT
6. IBD
7. Hearing loss —> Refer ENT
8. DM
9. Osteoporosis
Genotype vs Phenotype:
- Various type of karotypic abnormalities (~50% classical 45X)
—> others karyotypes can also lead to TS (e.g. 46 Xi)
Autism Spectrum Disorders
DDx:
1. Fragile X syndrome
2. Isodicentric chromosome 15
3. Distal chromosome 16p11.2 deletions
4. PTEN mutation
5. Phelan-McDermid syndrome (SHANK3/22q13 del)
Fragile X syndrome
Molecular mechanism:
1. ***Trinucleotide repeat (CGG) in FMR1 gene
- Normal: 6-50
- 60-200: pre-mutation, can have clinical problems during adulthood
- >200: ↑methylation —> Full mutation —> affect function of promoter of gene
- repeat at promoter region —> Transcription affected
- repeat at middle region —> Protein affected
Clinical features:
1. Long face
2. Large ears
3. Large testes (macro-orchidism)
SpC Paed:
Premutation carriers:
- May have children with Fragile X syndrome due to expansion
- Ladies may have POI
- Old age: Fragile X-associated tremor/ataxia syndrome (FXTAS)
Felix Lai:
- **X-linked disorder
- **MOST common inherited cause of intellectual disability
- Previously known as Fragile X mental retardation syndrome / X-linked mental retardation and **macro-orchidism
- **Loss-of-function mutation in the Fragile X mental retardation 1 (FMR1) gene located at chromosome Xq27.3
Full mutation:
- Unstable expansion of ***trinucleotide (CGG) repeat at the 5’ untranslated region in 99% of cases
—> Elongation of CGG repeats allows hypermethylation of FMR1 (silencing of the FMR1 gene)
—> DNA methylation turns off gene activity thus preventing gene transcription
—> Impaired transcription and reduced production of FMRP
—> Decreased or absent levels of Fragile X mental retardation protein (FMRP)
—> Causing the classical FXS phenotype
Premutation:
- FMR1 gene remains transcriptionally active, FMRP is produced and the classic FXS phenotype does not occurs but is associated with spectrum of clinical finding
Phelan-McDermid syndrome (SHANK3/22q13 del)
SHANK:
- a gene inside neuron
- functioning in synapse
- related in causation in ASD
Related to:
1. Angelman syndrome
2. Rett syndrome
3. PTEN mutation
4. Tuberous sclerosis
Investigations used to detect **tiny deletion mutation:
**Chromosomal microarray (higher resolution than Karyotype):
- probe production —> printing onto glass slides —> hybridisation of control DNA (red) + patient DNA (green)
—> if normal: red + green —> yellow colour
—> if deletion (more control DNA): more red dots
—> if duplication (more patient DNA): more green dots
Indications of Chromosomal microarray:
1. Unexplained developmental delay
2. ASD
3. Multiple congenital anomalies
Rare cardiac diseases
DDx:
1. **Marfan syndrome
2. Williams syndrome
3. **Noonan syndrome
4. 22q11.2 deletion
5. LDS syndrome
6. ***Long QT syndrome
Marfan syndrome
Mutation in **FBN1 gene (Fibrillin 1 gene) in chromosome 15 (detected by **DNA sequencing)
—> Loss of docking protein FBN1
—> ***↑ TGFβ signalling
Inheritance: ***Autosomal Dominant
DDx:
- Ehlers-Danlos syndrome
- Loeys-Dietz syndrome (LDS)
- Klinefelter syndrome
Revised **Ghent criteria of systemic features —> Diagnosis of Marfan syndrome
(Ghent criteria (2010) (Vinson Cheng)
Four major features:
1. **Dilated aortic diameter
2. **Ectopia lentis
3. **Systemic score >7
4. ***FBN1 mutation
- Family history plus 1 / 2 / 3
- No family history: 1+2 / 1+3 / 1+4)
Clinical features
1. **Arachnodactyly: Wrist + Thumb sign
2. **Pectus carinatum
3. **Ectopia lentis
4. Arm-span-to-height ratio **>=1.05
5. Pes planus (flat foot)
6. **Dolicocephaly (longer head than normal)
7. **High arched palate (SpC Paedi Cardi website)
8. ***Pneumothorax
Investigations (SpC Paedi Cardi website):
1. CXR (scoliosis, cardiomegaly, dilated aorta)
2. Echo (aortic root diameter, aortic valve)
3. MRI spine (dural ectasia)
4. Slit lamp (ectopia lentis)
5. FBN1 gene testing
Treatment:
1. **β-blocker: to reduce aortic wall stress
2. **Losartan: TGFβ inhibitor —> more helpful than β-blocker (control in aortic dilation in Marfan)
Hereditary cancer syndromes (Paediatric cancers)
Some have Germline mutation —> make condition difficult to treat
- every cells have that mutation —> predispose to multiple cancers
DDx:
1. **Noonan syndrome
2. **NF2 syndrome
3. Gorlin syndrome
4. ***Beckwith-Wiedemann syndrome (BWS)
5. X-linked Alport + diffuse leiomyomatosis
Beckwith-Wiedemann syndrome (BWS)
- ***Imprinting gene disorder
- Imprinting gene (60 in body):
—> important in development / growth
—> important whether come from father / mother
—> usually monoallelic expression (only 1 copy expressed, depends on origin e.g. father / mother)
Overgrowth syndrome:
- Abnormal regulation of imprinted region ***11p15
—> IGF2, KCNQ1 expressed in paternal allele —> promote growth
—> H19, CDKN1C expressed in maternal allele —> suppress growth
- if balance offset (e.g. ↑ methylation of H19 / ↓ methylation of KCNQ1 (i.e extra expression) —> Beckwith-Wiedemann syndrome (BWS)
(- Opposite: Russell-Silver syndrome (self notes))
- Risk of embryonal cancer (e.g. **Hepatoblastoma, **Wilms’ tumour (Nephroblastoma))
BWS subgroup:
1. Paternal UPD
2. ***Hypomethylation on DMR2
3. Hypermethylation on DMR1
Management:
1. Monitor for **hypoglycaemia in neonatal period (∵ cells more demanding)
2. Cancer surveillance for **embryonal tumour (Hepatoblastoma, Nephroblastoma)
3. **Abdominal USG every 3-6 months until 8 yo
4. **AFP concentration measurement in first 4 years of life for hepatoblastoma early detection
Exon sequencing
Whole-exome sequencing (WES) now applied in paediatric rare diseases
- only detect protein-coding regions of human genome
- 85% of all diseases causing mutation happen in exons
- easier than whole genome sequencing (∵ exon only 1% of whole genome)
- cost-effective
Mechanisms of genetic disease (SpC Paed)
- Epigenetic changes
- changes not in gene sequence but expression of genes
—> DNA methylation
—> Histone modification
—> RNA silencing
—> Chromatin packaging of 3D architecture of genes - Anticipation
- in Trinucleotide repeat disorder
—> Fragile X syndrome
—> Huntington’s disease
—> Friedreich ataxia
—> Spinocerebellar ataxia
- Accumulation of trinucleotide repeat —> earlier onset of disease - Genetic imprinting
- Beckwith–Wiedemann syndrome
- Russell-Silver syndrome
- Angelman syndrome
- Prader-Willi syndrome - Mosaicism
- Presence of 2 populations of cells with different genotypes in one individual who has developed from a single fertilised egg
- Risk of recurrence just same as general population (since mutation not in gamete but in somatic cells) - Expressivity (嚴重程度)
- Individuals with genetic mutations will have different levels of severity of phenotype - Penetrance (i.e. 有無表現出黎)
- Proportion of individuals with genetic mutations will have expressed phenotype
