Chromosomal syndromes Flashcards
Commonest causes of chromosomal syndromes
Chromosomal abnormalities are either:
- Numerical
- Structural
Vocab
Malformation → primary structural defect occurring during the development of a tissue/organ
Deformation → abnormal intrauterine mechanical force that distorts a normally formed structure (e.g. oligohydramnios)
Disruption → destruction of a foetal part that may have initially formed normally
Dysplasia → abnormal cellular organisation or function
Single system defect → single congenital malformations
Sequence → pattern of multiple abnormalities occurring after one initiating defect (i.e. posterior urethral valves)
Association → group of malformations that occur together but in different combinations case to case
Syndrome → multiple abnormalities occurring repeatedly in a consistent pattern, common underlying causal mechanism
Patau’s syndrome
Trisomy 13; 1 in 14,000 births
- 80% die in first month of life, 90% by 1 year of age
Investigations:
* USS analysis in 2nd trimester
* Chromosomal analysis from amniocentesis/cffDNA (NIPT)
Features:
1. Microcephaly (and brain defects)
2. Microphthalmia (small eyes)
3. Other eye defects
4. Cleft lip/palate
5. Polydactyl
6. Omphalocele / Gastroschisis
7. Cardiac and kidney defects (VSD, PDA, dextrocardia)
Management
* Palliative care as most babies will die within the first few days
* Counselling and support
Edward’s syndrome
Trisomy 18; 1 in 14,000 births
* Many will die in infancy, but prolonged survival is possible
Features:
1. LBW
2. Small mouth/chin
3. Low-set ears
4. ‘Rocker-bottom’ feet
5. Overlapping fingers
6. Intellectual disability
7. Cardiac, renal and GI abnormalities ·
8. Omphalocele / Gastroschisis
Investigations:
* USS analysis in 2nd trimester
* Chromosomal analysis from amniocentesis/cffDNA (NIPT)
Management
* MDT approach
* NG tube
* Nursing care
* Counselling and parent support
Complications and Prognosis
* Cardiac abnormalities, feeding difficulties, aspiration pneumonia
* 12% survive longer than a year
Noonan’s syndrome
Autosomal dominant with a normal karyotype (affects both males and females)
* Penetrance varies greatly (from lethal prenatally to minimal morbidity)
* Mutated RAS/Mitogen Activated Protein Kinase
* Autosomal dominant condition on Chromosome 12
Features:
1. Webbed neck
2. Trident hairline
3. Pectus excavatum
4. Short stature
5. Pulmonary stenosis
6. Characteristics facies
7. Occasional mild learning difficulties
Investigations
* Molecular genetic test: Ras/ MAPK
* ECG: wide QRS, giant Q waves, LAD
Imaging:
* Echo- congenital heart defects
* Abdo USS- splenomegaly
* Renal USS- renal hypoplasia
Management
* Correction of heart defects
* Recombinant GH
* Refer to urology for cryptorchidism
Prader Willi
Aetiology
Imprinting disorder → expression of a gene is influenced by the sex of parent who has transmitted it
* Lack of paternal PWS region on chromosome 15 → PWS
* Lack of maternal PWS region on chromosome 15 → Angelman syndrome
Either through:
De novo deletion in the child (loss of paternal/maternal chromosome 15q11-13 )
- Loss paternal -> PWS
- Loss maternal -. Angelman’s
Uniparental disomy (two copies from one parent, none from the other)
- No paternal, 2 maternal copies -> PWS
- No maternal, 2 paternal copies -> Angelman’s syndrome
Presentation ‘fat, floppy, flacid’
- Characteristic facies
- Hypotonia
- Almond-shaped eyes
- Hypogonadism
- Epicanthal folds · Flat nasal bridge + upturned nose
- Neonatal feeding difficulties
- Failure to thrive in infancy
- Hyperphagia and obesity in later childhood
- Hypogonadism
- Developmental delay
- Learning difficulties
Management
- Weight management: refer to obesity clinics
- Cryptorchidism: surgery
- Hormone treatments: GH supplements
- Psychological: CBT, SSRIs
Complications
- Obesity
- T2DM
- Metabolic syndrome
- Psychosis
Turner’s
1 in 2,500 (>95% result in early miscarriage)
45 chromosomes, with only 1 X chromosome
- Lymphoedema of hands/feet in neonate
- Short stature, spoon-shaped nails
- Wide carrying angle
- Thick or webbed neck
- Infertility
- Bicuspid aortic valve > Aortic coarctation
- ESM over aortic valve
- Delayed puberty
- Hypothyroidism
- Omphalocele / Gastroschisis
Other: Cystic hygroma (may resolve early ->skin on the back of the neck), Pyloric stenosis Horseshoe kidney (COMMON))
Investigations
* Antenatal USS
* Foetal oedema of the neck, hands or feet
* Cystic hygroma, horseshoe kidney, left-sided cardiac abnormalities
* Postnatal
Management:
- Surgical: cardiac anomaly, grommets
* Growth hormone therapy (plot height on syndrome specific growth charts)
* Oestrogen replacement (at time of puberty for development of secondary sexual characteristics)
Kleinfelter’s
- 1-2 per 1,000 males live-bor
- Normal appearance and normal I
- Genetic defect of sex chromosomes in males leading to a karyotype of 47XXY (80-90%) or more rarely, mosaic of 46 XY/47XXY
Presentation
1. Infertility- MOST COMMON
2. Hypogonadism with small testes
3. Appearance of normal pubertal development
4. Gynaecomastia (adolescents)
5. Tall stature
6. Intelligence normal range
7. May have some educational and psychological problems
Management
Conservative: SALT, educational + behavioural therapy, OT, PT and psychological therapy
Medical: fertility treatment, testosterone replacement or ICSI
Surgery: breast reduction surgery
Fragile X
1 in 4,000 births; although X-linked, some males can be unaffected and assume the role of ‘genetic carriers’ and transmit the condition through daughters to their grandsons (potentially due to variable penetrance due to genetic anticipation)
X-linked recessive disorder
* The normal copy of the FMR1 gene contains < 50 copies of the ‘CGG’ trinucleotide repeat sequence
* Genes with the pre-mutation contain 55-199 copies
* Genes with the full mutation contain > 200 copies
* Second most common genetic cause of severe learning difficulties after Down syndrome
Moderate-severe learning difficulties (IQ: 20-80, mean: 50)
Fragile X =
1. XL balls (macroorchidism)
2. XL head (macrocephaly –> mild-moderate intellectual disability with ADHD and ASH associations)
3. XL ears
4. XLong face and fingers
5. XLinked dominant
6. XLong CGG (trinucleuotide repeat disorder, genetic anticipation disorder)
- Macrocephaly
- Macro-orchidism (postpubertal)
- Characteristic facies: Long face. Large everted, low set ears
- High arched palate
- Prominent mandible
- Broad forehead
- Hypotonia
- Mitral valve prolapse
- Joint laxity
- Scoliosis
- Autism
- Hyperactivity- ADHD
· Exhibit genetic ‘anticipation’ = mutation is unstable and can expand between subsequent generations resulting in more severe forms of the disease
· Management:
- Genetic counselling to all fragile-X families
- Molecular analysis- ‘CGG’ trinucleotide repeat expansion in FMR1 gene
Summary
Williams
Patterns of Inheritance
Autosomal recessive conditions are ‘metabolic’ - exceptions: inherited ataxias
Autosomal dominant conditions are ‘structural’ - exceptions: Gilbert’s, hyperlipidaemia type II
Infections/ Drugs
