Genetic Anticipation

Chromosomal Abnormalities Genetic Anticipation Earlier / more severe in subsequent generations E.g. Fragile X, Huntingtons, Myotonic Dystrophy & Spino-cerebellar atrophy type I Modes of inheritance AD & AR have no gender bias Rare AR conditions often indicate consanguinity XLR Genes passes from mothers to Sons – NEVER from father to sons Carrier status passes from mother to daughter OR affected father to daughter XLD Mother to any child = 50% NEVER father to son ALWAYS father to daughter Mitochondrial Passes from mother to ALL children Mosaicism ALWAYS happens after fertilisation THEREFORE is never passed from parent Meaning low recurrence risk Genetic Screening Sensitivity = proportion of people with a disease, with a + disease - disease positive test + Test True + False + = true +ve / disease total Test False True Specificity = proportion of people without the disease with a negative test = true –ve / normal total Positive predictive value = % of +ve tests who have disease (true +ve / Positive total) Negative predictive value = % of –ve test who do not have disease (True –ve / negative total) Pre-test probability = true + AND false – (i.e. people with disease) / total tested Indications for Chromosomal analysis Pre-natal Advanced maternal age Previous child with chromosome disorder Parent with balanced translocation Fetal malformation on scan suggestive of chromosomal disorder Post natal Recurrent unexplained abortions Fresh stillbirth with physical abnormalities Neonate with features suggestive of chromosomal abnormality Neonate with 2+ dysmorphic features Chromosomal culture Sources of DNA include – lymphocytes from peripheral blood, bone marrow, skin (useful for up to 2 days after death), desquamated cells from amniotic fluid (amniocentesis), Chorionic villus sampling (10-12/40) Staining – Giemsa (G) stain give karyotype appearance with banding. Karyotyping - Rearrange with largest chromosomes 1st. P = long arm, Q = short arm divided by telomere. Should take 24-48 hours but with full staining can take up to 14 day. FISH allows more detailed examination including for translocations Types of Abnormality Trisomy - 21 = Downs, 13 = Patau, 18 = Edwards Monosomy – usually incompatible with life. Only common one is 45 XO = Turners Deletions – e.g. short arm deletion of 5p = Cri-du-chat Translocations – breakage & re-joining. May be balanced or unbalanced. E.g. Robertsonian Triplet repeat expansions – repeated copies of some base triplets – more repeats = more severely affected e.g. Fragile X Mosaicism – 2 distinct cell lines e.g. mosaic T21= 2% of Downs Single gene defects – may be AR, AD or XL Polygenic – no clear Mendelian inheritance e.g. cleft lip, pyloric stenosis, and congenital hip dislocation Prevention of birth defects Pre-conception counselling in high risk groups e.g. DM, epileptics on valproate etc. Prenatal surveillance & diagnosis Folic acid in planned pregnancy to reduce neural tube defects Rubella immunisation Avoidance of known teratogens Community education of harmful practices e.g. smoking & drinking Neonatal screening for early treatment before harm occurs Genetic counselling if prior affected family members Downs Syndrome Trisomy 21 (can be mosaic or full) 1/600 pregnancies (= historical incidence) 1/1000 live births due to terminations 94% non-disjunction (mostly maternal), 3.5% translocations (usually 14:21), 2.5% mosaicism Linked with advancing maternal age (1% >40yrs). Incidence decreasing due to screening & termination Screening Amnio is diagnostic but 1% miscarriage rate. Maternal alpha-fetoprotein & hCG level can be used to calculate risk. Can be combined with nuchal thickness measurements on US. à Triple Test = NOT DIAGNOSTIC but gives risk Diagnosis If not diagnosed antenatally then based on clinical concerns around time of birth à karyotype Features: Face – flattened face, large occiput, up sloping palpebral fissures, protruding tongue, epicanthic folds, strabismus, nystagmus, small ears, brushfield spots in eyes Limbs - single palmar crease (45%), clinodactyly, mild short stature, sandal gap, Hypermobile with assoc joint pain. Can get inflammatory arthritis (RA) Organs - 40-50% have congenital heart disease (AVSD or VSD) duodenal atresia in 8% (30% of children with duodenal atresia will have downs) Neuro – Hypotonia, poor feeding, mod - severe developmental delay (IQ 25-75) better outlook if mosaic. Milestones during 1st year can be normal, but then slow significantly between 1-2yrs. Language very variable. 10% are autistic à less friendly / sociable Associations - 1/3 are hypothyroid - should have checked every year AND other autoimmune (e.g. RA, DM, coeliac) with risk increasing with increasing age , increased incidence leukaemia, increased risk of obstructive sleep apnoea, increased glue ear and refractive errors of vision. Often overweight – but don’t have to be if good diet etc Outlook Good quality of life – happy children, friendly, loving with love of music As adults limited equivalent service to paediatrician for families to oversee condition Recommend on-going thyroid, vision (optician) and hearing (audiology) testing and consider coeliac screening if changes in wt / diet etc 15-20% die before 5yrs (cardiac) Tend to contract Alzheimer’s before 40-50 years – but similar prevalence to normal ppn Life expectancy now up-to 60+ years Patau Syndrome Trisomy 13, 1/6000 Assoc with advance maternal age (mean maternal age = 31) 75% non-disjunction, 20% translocation, 5% mosaicism Features: Face – microcephaly, large onion nose, small dysplastic ears, micropthalmia, defects of fusion of eyes, nose lip & forebrain (à holoprosencephaly, cleft lip/palate) Limbs – polydactyl, single palmar crease, talipes Neuro – hypertonic Organs - single umbilical artery, exomphalos, polycystic kidneys, cryptochidism, hypospadias Outlook - 50% die within 3 days, rest within a few weeks Edwards Syndrome Trisomy 18, 1/6000 3x more likely in women Weak link with increased maternal age (mean age 32) 85-95% non-disjunction, 5% mosaicism Features: General - IUGR (<2kg), FTT Face – triangular face (small jaw), prominent occiput, low set dysplastic ears, Limbs - small hands, overlapping fingers, hooked flexion deformity of 2nd fingers, small nails, short dorsiflexed toes, & rocker bottom feet Organs - 90% have congenital heart disease, oesophageal atresia & tracheooesophageal fistula, spina bifida Neuro - mental retardation, Outlook - 50% die in 1st week, almost all die by 1 yr. Cri-du-chat syndrome 5p- (petit = short arm) = deletion, 1/50,000 Features: High pitched cat-like cry (due to laryngeal abnormality). In older children heard as “feeble voice” External anomalies are limited - microcephaly, round face, hypertelorism, bilateral epicanthic folds, high arched palate, wide, flat nasal bridge, abnormal palmar crease, hypotonia, short stature, Rarely have severe internal anomalies therefore long term survival is normal but severely impaired intellect Klinefelter Syndrome 47 XXY, 1/1000 male 80-90% = XXY - Extra X equally likely from either parent 10-20% are mosaicism or further X’s (e.g. XXXY, XXXXY) à more marked hypogonadism & mental retardation Many not diagnosed until adult life (Barr body seen with extra X) Features: PHYSICALLY NORMAL = no anomalies etc. TEND TO BE - taller with longer legs, 30% mild-mod gynaecomastia, infertile with soft small testes (but sex function normal), Increased risk of varicose veins IQ 10-20 points lower than peers Treatment - testosterone replacement in adolescence will prevent osteoporosis & increase psychosexual development Turners Syndrome 45 XO, 1/2500 females Occurs in 1-2% of all conceptions & common findings in aborted/miscarried foetuses Only 3-5% of Turners survive to term Features: Classical triad of • short stature • ovarian dysgenesis (pubertal failure and infertility) • dysmorphic traits. In Utero - hydrops & local nuchal swelling in utero (delayed lymph formation) Lymph malformations à neck webbing, puffy hands & feet, hyperconvex nails, Middle ear infections are common Heart - 15% coarctation of aorta, can also have bicuspid aortic valve Other features - short stature, low posterior hair line, increased carrying angles, shield chest, Madelung wrist deformity (see right) Risk of renal malformations inc horse-shoe kidney As adults - 1o amenorrhoea & infertility Gonads develop normally until 20/40, then regress (ovarian dysgenesis) leaving small “streak” gonads. Neuro – normal schooling, may have difficulty with maths Assoc with - hypothyroidism (1/4) – usually autoimmune as hashimoto’s Treatment - treat with GH & oestrogen replacement therapy Noonan ( prev known as male turners) AD – 1 in 1000 to 2500 , Affects males & females equally Features 66% - Congenital heart defect. Usually Pulmonary valve stenosis (50%), ASD (10%), or less commonly murmurs, VSDs and cardiomyopathy Lymphatic – webbed neck & oedema as per 45XO Short stature (considered a type of dwarfism) Face – Triangular face with broad forehead & narrow jaw, high anterior hairline, wide spaced eyes (95%) with epicanthic folds, prominent ears (low set with backwards rotation and thickened helix in 90%), deep philtrum (>90%), high arched palate, low posterior hairline, Body - Wide carrying angle, Pectus excavatum or carinatum, scoliosis, joint contractures or hypermobility, winging of scapulae GI – FTT, poor appetite, vomiting & swallowing difficulties GU – undescended testis Neuro – clumsy with poor co-ordination. 1/3 have developmental delay. Can have Arnoldchiarii malformation. Hearing & vision problems Blood - Impaired clotting, low plts, easy bruising, vWD, partial clotting factor deficiencies Fragile X Syndrome 1/3500 males, 1/6000 females, commonest inherited cause of mental retardation FMR1 gene mutation Genetic anticipation – increased copies of bad section in progressive generations 29-31 = NORMAL 40-60 = Intermediate 55-200 = Carrier 200+ = Affected Features: Face - long face, large ears, prominent jaw, high arched palate In children Delayed motor & speech development Hyperactivity & Behavioural Problems, can be autistic, occasional self-mutilation Toe walking, Double jointed / hyper-extensible joints, Hypotonia Occasionally seizures After Puberty - large testes, tall Can have heart problems – mitral valve prolapse Juvenile Huntingtons Disease Triad of AD inheritance, dementia & chorea 5-10% of cases are juvenile onset Accumulation of abnormal proteins Caudate nucleus à choreiform movements & rigidity Cerebral cortex atrophy à personality changes, seizures & dementia Genetic Anticipation - Each generation the condition starts earlier due to increasing no of repeats <27 = normal 27-35 = “carrier” – unlikely to onset in this lifetime 36-39 = during lifetime 40+ = adult onset > 60 = juvenile onset (typically 3-9yrs) – decreased academic behaviour, seizures, rigidity & dyspraxia. Death within approx 8 yrs of onset Cornelia de Lange Syndrome Usually sporadic mutations, Occasionally AD – Chr 5, Chr 10, X Chr Clinical diagnosis based on signs & symptoms – then to prove with genetics General - Low birth wt. & ongoing small stature with delayed growth. Head - Microcephaly with thick eyebrow meeting in middle, long eyelashes, short upturned nose & down-turned lids, long philtrum, wide spaced teeth, low set ears. Cleft palate Limbs - Limb differences, small hand & feet +/- missing bones. Incurved 5th fingers & partial joining of 2nd & 3rd toes Developmental - delay, hearing impairment, myopia, nystagmus, ptosis, feeding problems (à PEG). Aggressive behaviour, autistic like behaviour with set routines Organs – seizures, heart defects, reflux Rubenstein Taybi syndrome Aka broad thumb-hallux syndrome AD (1 in 125,000) (CREBBP gene on 16p13) Broad thumbs & 1st toes (100%) – also syndactyly, polydactyly and ulnar deviation of the thumb Short stature with moderate / small head – growth retardation Moderate to severe learning difficulties – IQ usually < 50, speech difficulties, hypotonia, feeding problems, echolalia Distinctive facial features – ALL have hypoplastic maxilla with narrow palate (à tracheostomy), 90% beaked nose, low set ears, strabismus, large AF, microcephaly, crowded mouth Eyes – strabismus, glaucoma, retinal abnormalities, ptosis, refractive errors, micropthalmia Skeletal – vertebral & sternal abnormalities, patellar dislocation with patellofemoral instability, 4th cuniform bones & joint hypermobility Skin – hirsuitism, keloids, piebaldism, naevi Cardiac – VSD & PDA most common. Also ASD, Co-arc, Pulmonary artery stenosis etc. Arrhythmias with use of succinylcholine Others – cryptoorchidism, reflux, constipation, laryngeal wall collapsible (airway probs), insomnia, OCD, epilepsy, congenital hypothyroid Increased risk of tumours inc leukaemia, and lymphoma. Others Blooms AR High frequency breakage & rearrangements of chromosomes à increased risk of cancer with early onset (<25yrs) Features Short stature, facial photosensitive rash, high pitched voice Face –long narrow face, small jaw, prominent nose & ears Skin changes – including café-au-lait patches & telangiectasia Moderate immune deficiency à chest & ear infections Subfertility Cockaynes AR - Various ages of onset DNA repair mechanism defect Growth failure, photosensitive & premature aging Angelman 15q12 maternal deletion (if paternal à prader willi) Features Developmental delay – with little / no verbal communication Ataxia à jerky movements esp hand flapping Happy demeanour (happy puppet syndrome) Also - sleep disturbance & seizures with characteristic EEG with large amplitude slowspike patterns Prader-Willi Syndrome Loss of paternal genes at 11-13q of Ch15 (or maternal disomy) Loss of proteins à hypothalamic dysfunction à hyperphagia, hypogonadism, temper tantrums, hypotonia, learning disability (IQ approx 70) ALMOND shaped eyes Small hands and feet Presentation – decreased fetal movements, floppy baby with poor suck, delay in gross motor milestones, hyperphagia starts approx 2-3 yrs, moderate short stature (low GH) Males - bilateral cryptorchidism with absent or incomplete puberty Females – complete but delayed development with oliogomenorrhoea Rx – diet, physio, SALT, GH to increase height, testosterone for males NB: increased risk of sleep apnoea, respiratory failure and DM II Genetic Dyslipidaemias 2/3 = familial combined hyperlipidaemia AD Assoc with obesity, insulin resistance, hyperinsulinaemia, glucose intolerance & increased urea 1/5 = familial hypercholesterolaemia AD on Chr 19 Defect in LDL receptor Can exist in homozygous and heterozygous forms Tendon xanthomatas are pathognomic Lawrence-Moon-Biedl Syndrome Mild – moderate mental retardation Retinitis pigmentosa Obesity Digital anomalies e.g. syndactly Hurlers Syndrome Deficiency of enzyme required for breakdown of GAGs Coarse facial features, skeletal & cardiac anomalies, physical & mental retardation Life expectancy 10 yrs