3-1 - Genetic Disorders

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<ul><li><p>8/2/2019 3-1 - Genetic Disorders</p><p> 1/4</p><p>Notes3-1 - Paediatrics</p><p>Genetic Disorders &amp; Dysmorphology</p><p>Downs Syndrome</p><p> Trisomy 21 - Inheritance of 3 x chromosome 21</p><p>Risk Factors Maternal Age</p><p> Family HistoryPresentation</p><p> Antenatal - As a result of screening (Amniocentesis/Chorionic Villous Sampling)</p><p> Perinatal - At birthSigns &amp; Symptoms</p><p> Brachycephaly Facies - Low set ears, Mongoloid slant/Epicanthic folds, Protruding Tongue, Flat Nasal Bridge</p><p> Hands - Small hands, Single palmar crease, In-curved little finger</p><p> HypotoniaAssociated Conditions</p><p> Cardiological Defectso ASDs &amp; VSDs - &gt;50%o Persistent PDA - 7%o Tetralogy Of Fallot - 5% i.e. VSD, Overriding aortic root, RVOT Obstruction &amp; RV</p><p>Hypertophy Blue condition - Neonates present with severe cyanosis</p><p> GI Defectso Oesophageal Atresia/Tracheo-Oesophageal Fistulao Duodenal Atresiao Also: Pyloric Stenosis, Meckels, Hirschsprungs, Imperforate Anus</p><p> Orthopaedic Disorderso Hyperflexibilityo Atlanto-Axial Instability</p><p> Deafness &amp; Predisposition to ENT disorders e.g. Otitis Media</p><p> Low IQ</p><p> Opthalmological Disorders esp. Strabismus (Squint), Cataracts Hypothyroidism</p><p>Screening</p><p> Risk Screeningo Triple Test - Conducted between 15 &amp; 20 weeks - Only test currently on NHS</p><p> Can also use double/quadruple factors Uses:</p><p> Hormone Levels - -Feta Protein, hCG &amp; Unconjugated Oestriol</p><p> Maternal Age &amp; Gestational Age +ve Screen = &gt;1 in 150 risk of Downs</p><p>o Nucchal Translucency - Conducted between 11 &amp; 14 weeks NT suggests foetal heart failure - strongly assoc with chromosomal</p><p>abnormalities</p><p>o Integrated Test - Conducted between 11 &amp; 14 weeks Triple Test + NT - Sensitivity &amp; Specificity</p><p> Diagnostic Testingo Amniocentesis - 12-18 weeks, &gt;99% accuracy, 1% Miscarriage risk</p><p> Placental biopsy taken &amp; karyotyped (i.e. chromosomes examined)</p><p>Turner Syndrome</p><p> 45 X - i.e. Turners pts have 45 chromosomes, one of which is an unpaired X. o 50% of Turners pts actually have 46 chromosomes, but only have part of the second X </p><p>Epidemiology Female Only</p><p> 1 in 2500 live female births (95% of Turners spontaneously abort) Presentation</p><p> Prenatally - via screening</p></li><li><p>8/2/2019 3-1 - Genetic Disorders</p><p> 2/4</p><p> Infancy - Due to lymphoedema &amp; neck webbing</p><p> Childhood/Adolescence - Due to short stature &amp; delayed puberty/menarcheClinical Features</p><p> Lymphoedema of hands &amp; feet during neonatal period Congenital Short Stature - Due to Growth Hormone levels</p><p> Neck Webbing or thick neck</p><p> Ovarian Dysgenesis resulting in:o Delayed Pubertyo Amenorrhoeao Infertility</p><p> Widely spaced nipples, wide carrying angle, spoon shaped nails N.B. Most havenormal IQ</p><p>Associated Conditions Cardiological Defects esp. Coarctation of the Aorta</p><p> Hypothyroidism</p><p> Renal Abnormalities Otitis Media</p><p>Treatment Growth Hormone replacement</p><p> Oestrogen Therapy during puberty, to produce secondary sexual characteristicsScreening May be picked up on antenatal USS, due to:</p><p>o Oedema of hands, neck or feet, or Cystic Hygroma - Large lymph cyst in neck</p><p>Cystic Fibrosis</p><p> Autosomal Recessive Disordero Produces defective CFTR protein - Cystic Fibr. Transmembrane conductance Regulator</p><p>Epidemiology Caucasian - Most common in caucasians, less in other ethnic groups </p><p>Pathophysiology</p><p> Defective CFTR results in diffusion of Cl-out of cells, &amp; therefore Na</p><p>+leaves cell also</p><p>o Th. Osmosis of Waterout of cell, due to [ion]intracellular</p><p> Results in thick mucous, producing:o Chronic respiratory infection (Staph A, Haem Inf, P Aeruginosa) &amp; bronchiectasiso Thick neonatal intestinal secretions meconium ileuso Pancreatic duct blockage pancreatic enzyme deficiency &amp; malabsorptiono Biliary cirrhosis</p><p> Infertility (men only) - in males due to absence of vas deferens (but ICSI may be used) Presentation</p><p> Usually in infancy - as screened for in Guthrie (heel prick) testo Genetic &amp; sweat testing then used to confirm diagnosis </p><p>Clinical Features</p><p> Respiratoryo Bronchiectasis - Persistent productive cough, hyperinflation, coarse creps/wheezeo Recurrent infection/pneumonia</p><p> Pseudomonas Aerigunosais most common chronic infection</p><p> Burkholderia also common Staph Aureus &amp; Haemophilus Influenza common in infancy</p><p> GIo Meconium Ileus (10-20%) - Vomiting, abdo distension, failure to feed in first few days</p><p> Virtually all Mec Ileus sufferers have CFo Pancreatic Insufficiency - Steatorrhoea</p><p> Resulting in Malabsorption &amp; Failure To ThriveDiagnosis</p><p> Sweat Test - Shows elevated [Cl-]sweat(&gt;60mmol/L, where normal range is 10-40)</p><p>o Sweating stimulated with pilocarpine, and sweat collected in capillary tube/filter paper Management</p><p> Respiratoryo Monitoring - Regular Spirometryo</p><p> Chest Physiotherapy - 2x dailyo Prophylactic ABX - Oral Flucloxacillin &amp; inhaled anti-pseudomonas agents</p><p> Prompt IV ABX in exacerbations</p></li><li><p>8/2/2019 3-1 - Genetic Disorders</p><p> 3/4</p><p>o Nebulised Saline - To clear secretionso Portacathmay be implanted, allowing IV access in those with recurrent exacerbations</p><p> Nutritiono Enzyme Replacemento High Calorie Diet - 150% normal calorie intake</p><p>Screening</p><p>Postnatal screening for CF in Guthrie (heel prick) test</p><p>Duchenne Muscular Dystrophy X-Linked Recessive - Th. males only (virtually)</p><p>o N.B. 1/3 are new mutationsEpidemiology</p><p> 1 in 4000 malesPathophysiology</p><p> Genetic problem producing flawed dystrophin-glycoprotein complexo Responsible for anchoring of muscle fibres to cell membranes/surrounding tissue</p><p>Presentation After neonatal screening</p><p> In childhood (Average age of diagnosis = 5 y.o.)o Waddling gait &amp; trouble climbing stairso Slowness/Clumsiness compared to peerso Gowers Sign - Have to turn prone to stand</p><p>Course Appear normal at birth, progressive decline Wheelchair bound by early teens, die inearly 20s from respiratory failure</p><p>Associated Conditions</p><p> Cardiomyopathy, Respiratory muscle weakness</p><p> Scoliosis</p><p> Learning Difficulties - in sizeable numberInvestigations</p><p> Creatinine Kinase DNA Testing</p><p> Muscle Biopsy</p><p>Treatment Steroids - Prolong ambulance (walking) - method unknown</p><p> Physio, OT, Ventilation etc.N.B. Beckers MD - Slower progressing version of MD</p><p>Haemophilia X-Linked Recessive - Th. males only (virtually)</p><p>o ~1/3 sporadically appear with no FHEpidemiology</p><p> 1 in 5000 males (Haemophilia A), 1 in 30,000 (Haemophilia B) Pathophysiology</p><p> Haemophilia A - Factor 8 Deficiencyo Factor 8 circulates bound to vWF, and only dissociates when activated by thrombin</p><p>vWF deficiency leads to F8 deficiency, as factor 8 quickly inactivated when notbound to vWF. FVIII deficiency also reduces vWF efficacy</p><p> Haemophilia B (a.k.a. Christmas Disease) - Factor 9 Deficiency</p><p> Produces delayed bleeding - as platelet plug forms, but this is not then reinforced by fibrin Presentation</p><p> Onset- Usually at9 monthsonwards -i.e. where child begins to stand/fall-overo 40% in neonatal period with ICH, post-circumcision bleeding etc.</p><p> Delayed Bleeding - May be spontaneous (severe disease), after trauma (moderate)o Into joints &amp; muscleso Ecchymoses</p><p> N.B. Disease severity rated by factor 8 levels - </p></li><li><p>8/2/2019 3-1 - Genetic Disorders</p><p> 4/4</p><p> APTT - May be raised (F8 not involved in PT/TT pathways)</p><p> Factor 8/9 LevelsManagement</p><p> Acute- Give IV F8/F9 concentrate to circulating level up to at least 30% (more if bleed severe) o Plasma products used if not</p><p> Prophylaxis- F8/9 given to severe sufferers - aim to levels to &gt;2%</p><p> N.B. F8/F9 antibodies develop in ~10%, require doses or F8a use DDAVP (Desmopressin) given to mild A pts</p><p> ADH analogue, stimulates vWF &amp; F8 production (doesnt stimulate F9) Avoid -IM Injections, NSAIDs</p><p>Haemoglobinopathies</p><p> See 212 - Thalassaemia &amp; Sickle-Cell Anaemia</p><p>X Linked Mental Retardation</p><p> Predominantly affect males, but females with one faulty X-linked allele may have mild symptoms</p><p> Multiple syndromes, with &gt;200 genes implicated Accounts for ~15% of mental retardation in males</p><p>Fragile X Syndrome</p><p>X-linked trinucleotide repeat occurs, with anticipation through generations Features include:</p><p>o Moderate - Severe Learning Difficultieso Facies - Sticky Out Ears, Long face, Prominent jaw &amp; broad forehead (prominent in</p><p>adults)o Macrocephalyo Macro-orchidismo Mitral valve prolapsed, joint laxity, autism, ADHD</p><p>Phenylketonuria</p><p> Rare - 1 in 10-15,000</p><p> Enzyme Deficiency - Results in inability to metabolise phenylalanineo Th. build up of toxic phenylalanine &amp; mental retardation</p><p> Presentationo Via screening (Guthrie/Heel Prick Test)o At 6-12 months of age</p><p> Developmental Delay</p><p> Treatmento Phenylalanine dietary restriction - But enough needed for growtho Blood level monitoring</p><p> Screeningo Screened for in Guthrie (Heel prick) Test</p><p>DysmorphologyDysmorphology</p><p> The study of abnormal formDysmorpological Mechanisms</p><p> Malformation -A structure within the foetus doesnt develop properly (e.g. spina bifida, cleftpalate)</p><p> Deformation - An abnormal intrauterine mechanical forcedisrupts a normally formed structure</p><p> Disruption - Destruction of a normally formed structure (e.g. amniotic bands causing limbreduction defects)</p><p> Dysplasia - Abnormal cellular organisation/function of specific tissue types </p><p> Sequences - Where one morphological abnormality leads to multiple further abnormalities (e.g.Potters Syndome - Renal agenesis leads to foetal compression &amp; pulmonary hypoplasia)</p></li></ul>