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Genetics And Syndromes Notes

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This is an extract of our Genetics And Syndromes document, which we sell as part of our Paediatrics Notes collection written by the top tier of University Of Nottingham students.

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Genetics And Syndromes Chromosomal Abnormalities - Down Syndrome (Trisomy 21)

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Incidence in live born infants (without antenatal screening) is about 1 in 650

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Craniofacial AppearanceHypotonia (head lag)Round faceShort neckFlat nasal bridgeSingle palmar creasesUpslantedShort

palpebral

fissuresEicanthic foldsBrushfield spots in irisSmall

mouthandSmall earsFlat occiput and third

fontanelle

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Other anomalies

Later Medical Problems 85% survive to 1 year, 50% survive to 50 years

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Delayed motor milestones

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Moderate to severe learning difficulty

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Small stature

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Hearing impairment from secretory otitis media

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Visual impairment - cataracts, squints, myopia

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Increased risk of:InfectionLeukaemia and tumorsHypothyroidCoeliacAtlantoaxial instability

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Epilepsy

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Alzheimer's

Diagnosis

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hands

5th

finger

(brachydactyly)

protruding tongue

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broad

Blood sample is sent for FISH (fluorescent in situ hybridisation)

Incurved

(clinodactyly)Sandal gap between

toesCongenital

heart

defect (40%) esp. AVSD, ASD, VSD, FallotDuodenal atresiaHirschsprung disease

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Cytogenetics

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Meiotic NonDisjunction (94%)Error at meiosis one gamete have two 21s, and one has noneFertilisation of the gamete with 2 chromosomes gives rise to a trisomyIncidence is related to maternal age (although the extra 21 can be of paternal origin)o

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20 - 1 in 1530

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30 - 1 in 900

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40 - 1 in 110

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44 - 1 in 37

Risk of recurrence is 1 in 200 under the age of 35

Translocation (5%)When the extra chromosome 21 is joint onto another chromosome (typically 14) - Robertsonian translocationParental chromosomal analysis is recommended since one of the parents may carry the translocation in a balanced form (25%)

oRecurrence is 10% if mother is carrier (only 2.5% if Dad)If neither parent is a carrier risk of recurrence is <1%21:21 translocation means ALL babies will have Down syndrome

Mosaicism (1%)Some cells are normal, some have trisomyUsually arises following formation of a normal zygote by nondisjunction at mitosisPhenotype may be milder

Turner Syndrome (45 X)

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95% results in early miscarriage

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1 in 2500 live female births

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Clinical Features

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Lymphoedema of hands and feet in neonate

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Spoon shaped nails

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Short stature*

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Neck webbing or a thick nec

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Wide carrying angle (cubitus valgus)

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Widely spaced nipples

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*

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Congenital heart defects (coarction)

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Delayed puberty

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Ovarian dysgenesis - infertility (IVF is possible)

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Hypothyroid

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Renal anomalies

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Pigmented moles

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Recurrent otitis media

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Normal intellectual function in most

Treatment

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Growth hormone therapy

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Oestrogen replacement for development of secondary sexual characteristics

Cytogenetics

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In 50% there are 45 chromosomes with only one X due to non disjunction

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Other cases have a deletion of the short arm of one X, an isochromosome that has two long arms but no short arm, or a variety of other structural defects of one of the X chromosomes

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The presence of a Y chromosome sequence may increase the risk of gonadoblastoma

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Risk of recurrence is very LOW and NOT dependent on maternal age

Fragile X

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X linked recessive

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Males are affected

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Females are typically healthy unless showing mild signs (manifesting carrier)

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Son of a female carrier has a 1 in 2 risk of being affected

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Daughters of affected males will all be carriers

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Sons of affected males will not be affected

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Trinucleotide repeat expansion mutation inherited in an X linked recessive fashion = Fragie X

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1 in 4000

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Diagnosis now achieved by molecular analysis of the CGG nucleotide repeat expansion in the FMR1 gene

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Although X linked recessive - female carriers have learning difficulties (mild to moderate)

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1/5 of males who inherit the disorder are phenotypically normal due to

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2 forms of the mutation

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Premutation 55199 repeats - NO disability but may become larger in transmission through females

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Full mutation >200 copies causing clinical features in virtually all males and half of females carriers always arise from expansion of pre mutation and NEVER arise directly from normal genes*

Hence ALL mothers of affected males are carriers

Clinical Findings

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Moderate - severe learning difficulty / developmental delay

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Macrocephaly

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Macroorchidism

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Characteristic facies long face, large everted ears, prominent mandible and broad forehead

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Other features mitral valve prolapse, joint laxity, scoliosis, autism, hyperactivity

Dysmorphology

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Study of the abnormal form - assessment of birth defects and unusual physical features that have their origin during embryogenesis

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Pathogenic Mechanisms

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Malformation primary structural defect occuring during developmento

Spina bifida, cleft lip or palate

Deformation abnormal intrauterine mechanical forceJoint contractures or pulmonary hypoplasia due to fetal compression as a result of oligohydramnios

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Disruption detruction of fetal part which initially formed normallyo

Dysplasia abnormal cellular organisation or function of specific tissue types*

Amniotic membrane rupture leads to amniotic bands - limb defects

Skeletal dysplasia, dysplastic kidney

Clinical Classification of Birth Defects

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Single system .eg. Spina Bifida

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Sequence - pattern of multiple abnormalities after one initiating eventPotter syndrome - due to renal agenesis

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Association .eg. VACTERL associations

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Syndrome - genetic, teratogens, unknown cause.

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Examples of syndromes recognisable by facial appearance include Noonan, Williams, Prader Willi

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Noonan Syndrome

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Similarities to the phenotype seen in Turner syndrome

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Autosomal dominant (normal karyotype)

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