3-1 - genetic disorders

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  • 8/2/2019 3-1 - Genetic Disorders


    Notes3-1 - Paediatrics

    Genetic Disorders & Dysmorphology

    Downs Syndrome

    Trisomy 21 - Inheritance of 3 x chromosome 21

    Risk Factors Maternal Age

    Family HistoryPresentation

    Antenatal - As a result of screening (Amniocentesis/Chorionic Villous Sampling)

    Perinatal - At birthSigns & Symptoms

    Brachycephaly Facies - Low set ears, Mongoloid slant/Epicanthic folds, Protruding Tongue, Flat Nasal Bridge

    Hands - Small hands, Single palmar crease, In-curved little finger

    HypotoniaAssociated Conditions

    Cardiological Defectso ASDs & VSDs - >50%o Persistent PDA - 7%o Tetralogy Of Fallot - 5% i.e. VSD, Overriding aortic root, RVOT Obstruction & RV

    Hypertophy Blue condition - Neonates present with severe cyanosis

    GI Defectso Oesophageal Atresia/Tracheo-Oesophageal Fistulao Duodenal Atresiao Also: Pyloric Stenosis, Meckels, Hirschsprungs, Imperforate Anus

    Orthopaedic Disorderso Hyperflexibilityo Atlanto-Axial Instability

    Deafness & Predisposition to ENT disorders e.g. Otitis Media

    Low IQ

    Opthalmological Disorders esp. Strabismus (Squint), Cataracts Hypothyroidism


    Risk Screeningo Triple Test - Conducted between 15 & 20 weeks - Only test currently on NHS

    Can also use double/quadruple factors Uses:

    Hormone Levels - -Feta Protein, hCG & Unconjugated Oestriol

    Maternal Age & Gestational Age +ve Screen = >1 in 150 risk of Downs

    o Nucchal Translucency - Conducted between 11 & 14 weeks NT suggests foetal heart failure - strongly assoc with chromosomal


    o Integrated Test - Conducted between 11 & 14 weeks Triple Test + NT - Sensitivity & Specificity

    Diagnostic Testingo Amniocentesis - 12-18 weeks, >99% accuracy, 1% Miscarriage risk

    Placental biopsy taken & karyotyped (i.e. chromosomes examined)

    Turner Syndrome

    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

    Epidemiology Female Only

    1 in 2500 live female births (95% of Turners spontaneously abort) Presentation

    Prenatally - via screening

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    Infancy - Due to lymphoedema & neck webbing

    Childhood/Adolescence - Due to short stature & delayed puberty/menarcheClinical Features

    Lymphoedema of hands & feet during neonatal period Congenital Short Stature - Due to Growth Hormone levels

    Neck Webbing or thick neck

    Ovarian Dysgenesis resulting in:o Delayed Pubertyo Amenorrhoeao Infertility

    Widely spaced nipples, wide carrying angle, spoon shaped nails N.B. Most havenormal IQ

    Associated Conditions Cardiological Defects esp. Coarctation of the Aorta


    Renal Abnormalities Otitis Media

    Treatment Growth Hormone replacement

    Oestrogen Therapy during puberty, to produce secondary sexual characteristicsScreening May be picked up on antenatal USS, due to:

    o Oedema of hands, neck or feet, or Cystic Hygroma - Large lymph cyst in neck

    Cystic Fibrosis

    Autosomal Recessive Disordero Produces defective CFTR protein - Cystic Fibr. Transmembrane conductance Regulator

    Epidemiology Caucasian - Most common in caucasians, less in other ethnic groups


    Defective CFTR results in diffusion of Cl-out of cells, & therefore Na

    +leaves cell also

    o Th. Osmosis of Waterout of cell, due to [ion]intracellular

    Results in thick mucous, producing:o Chronic respiratory infection (Staph A, Haem Inf, P Aeruginosa) & bronchiectasiso Thick neonatal intestinal secretions meconium ileuso Pancreatic duct blockage pancreatic enzyme deficiency & malabsorptiono Biliary cirrhosis

    Infertility (men only) - in males due to absence of vas deferens (but ICSI may be used) Presentation

    Usually in infancy - as screened for in Guthrie (heel prick) testo Genetic & sweat testing then used to confirm diagnosis

    Clinical Features

    Respiratoryo Bronchiectasis - Persistent productive cough, hyperinflation, coarse creps/wheezeo Recurrent infection/pneumonia

    Pseudomonas Aerigunosais most common chronic infection

    Burkholderia also common Staph Aureus & Haemophilus Influenza common in infancy

    GIo Meconium Ileus (10-20%) - Vomiting, abdo distension, failure to feed in first few days

    Virtually all Mec Ileus sufferers have CFo Pancreatic Insufficiency - Steatorrhoea

    Resulting in Malabsorption & Failure To ThriveDiagnosis

    Sweat Test - Shows elevated [Cl-]sweat(>60mmol/L, where normal range is 10-40)

    o Sweating stimulated with pilocarpine, and sweat collected in capillary tube/filter paper Management

    Respiratoryo Monitoring - Regular Spirometryo

    Chest Physiotherapy - 2x dailyo Prophylactic ABX - Oral Flucloxacillin & inhaled anti-pseudomonas agents

    Prompt IV ABX in exacerbations

  • 8/2/2019 3-1 - Genetic Disorders


    o Nebulised Saline - To clear secretionso Portacathmay be implanted, allowing IV access in those with recurrent exacerbations

    Nutritiono Enzyme Replacemento High Calorie Diet - 150% normal calorie intake


    Postnatal screening for CF in Guthrie (heel prick) test

    Duchenne Muscular Dystrophy X-Linked Recessive - Th. males only (virtually)

    o N.B. 1/3 are new mutationsEpidemiology

    1 in 4000 malesPathophysiology

    Genetic problem producing flawed dystrophin-glycoprotein complexo Responsible for anchoring of muscle fibres to cell membranes/surrounding tissue

    Presentation After neonatal screening

    In childhood (Average age of diagnosis = 5 y.o.)o Waddling gait & trouble climbing stairso Slowness/Clumsiness compared to peerso Gowers Sign - Have to turn prone to stand

    Course Appear normal at birth, progressive decline Wheelchair bound by early teens, die inearly 20s from respiratory failure

    Associated Conditions

    Cardiomyopathy, Respiratory muscle weakness


    Learning Difficulties - in sizeable numberInvestigations

    Creatinine Kinase DNA Testing

    Muscle Biopsy

    Treatment Steroids - Prolong ambulance (walking) - method unknown

    Physio, OT, Ventilation etc.N.B. Beckers MD - Slower progressing version of MD

    Haemophilia X-Linked Recessive - Th. males only (virtually)

    o ~1/3 sporadically appear with no FHEpidemiology

    1 in 5000 males (Haemophilia A), 1 in 30,000 (Haemophilia B) Pathophysiology

    Haemophilia A - Factor 8 Deficiencyo Factor 8 circulates bound to vWF, and only dissociates when activated by thrombin

    vWF deficiency leads to F8 deficiency, as factor 8 quickly inactivated when notbound to vWF. FVIII deficiency also reduces vWF efficacy

    Haemophilia B (a.k.a. Christmas Disease) - Factor 9 Deficiency

    Produces delayed bleeding - as platelet plug forms, but this is not then reinforced by fibrin Presentation

    Onset- Usually at9 monthsonwards -i.e. where child begins to stand/fall-overo 40% in neonatal period with ICH, post-circumcision bleeding etc.

    Delayed Bleeding - May be spontaneous (severe disease), after trauma (moderate)o Into joints & muscleso Ecchymoses

    N.B. Disease severity rated by factor 8 levels -

  • 8/2/2019 3-1 - Genetic Disorders


    APTT - May be raised (F8 not involved in PT/TT pathways)

    Factor 8/9 LevelsManagement

    Acute- Give IV F8/F9 concentrate to circulating level up to at least 30% (more if bleed severe) o Plasma products used if not

    Prophylaxis- F8/9 given to severe sufferers - aim to levels to >2%

    N.B. F8/F9 antibodies develop in ~10%, require doses or F8a use DDAVP (Desmopressin) given to mild A pts

    ADH analogue, stimulates vWF & F8 production (doesnt stimulate F9) Avoid -IM Injections, NSAIDs


    See 212 - Thalassaemia & Sickle-Cell Anaemia

    X Linked Mental Retardation

    Predominantly affect males, but females with one faulty X-linked allele may have mild symptoms

    Multiple syndromes, with >200 genes implicated Accounts for ~15% of mental retardation in males

    Fragile X Syndrome

    X-linked trinucleotide repeat occurs, with anticipation through generations Features include:

    o Moderate - Severe Learning Difficultieso Facies - Sticky Out Ears, Long face, Prominent jaw & broad forehead (prominent in

    adults)o Macrocephalyo Macro-orchidismo Mitral valve prolapsed, joint laxity, autism, ADHD


    Rare - 1 in 10-15,000

    Enzyme Deficiency - Results in inability to metabolise phenylalanineo Th. build up of toxic phenylalanine & mental retardation

    Presentationo Via screening (Guthrie/Heel Prick Test)o At 6-12 months of age

    Developmental Delay

    Treatmento Phenylalanine dietary restriction - But enough needed for growtho Blood level monitoring

    Screeningo Screened for in Guthrie (Heel prick) Test


    The study of abnormal formDysmorpological Mechanisms

    Malformation -A structure within the foetus doesnt develop properly (e.g. spina bifida, cleftpalate)

    Deformation - An abnormal intrauterine mechanical forcedisrupts a normally formed structure

    Disruption - Destruction of a normally formed structure (e.g. amniotic bands causing limbreduction defects)

    Dysplasia - Abnormal cellular organisation/function of specific tissue types

    Sequences - Where one morphological abnormality leads to multiple further abnormalities (e.g.Potters Syndome - Renal agenesis leads to fo