Notes 3-1 - Paediatrics Genetic Disorders & Dysmorphology Downs Syndrome Trisomy 21 - Inheritance of 3 x chromosome 21 Risk Factors Maternal

al Age Family History Presentation Antenatal - As a result of screening (Amniocentesis/Chorionic Villous Sampling) Perinatal - At birth Signs & 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 Hypotonia Associated Conditions Cardiological Defects o 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 Defects o Oesophageal Atresia/Tracheo-Oesophageal Fistula o Duodenal Atresia o Also: Pyloric Stenosis, Meckels, Hirschsprungs, Imperforate Anus Orthopaedic Disorders o Hyperflexibility o Atlanto-Axial Instability Deafness & Predisposition to ENT disorders e.g. Otitis Media Low IQ Opthalmological Disorders esp. Strabismus (Squint), Cataracts Hypothyroidism Screening Risk Screening o 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 abnormalities o Integrated Test - Conducted between 11 & 14 weeks Triple Test + NT - Sensitivity & Specificity Diagnostic Testing o Amniocentesis - 12-18 weeks, >99% accuracy, <1% Miscarriage risk Amniotic fluid sample (containing foetal cells) taken & karyotyped o Chorionic Villus Sampling - 11-13 weeks, ~97% 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

 Infancy - Due to lymphoedema & neck webbing Childhood/Adolescence - Due to short stature & delayed puberty/menarche Clinical 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 Puberty o Amenorrhoea o Infertility Widely spaced nipples, wide carrying angle, spoon shaped nails N.B. Most have normal IQ Associated Conditions Cardiological Defects esp. Coarctation of the Aorta Hypothyroidism Renal Abnormalities Otitis Media Treatment Growth Hormone replacement Oestrogen Therapy during puberty, to produce secondary sexual characteristics Screening 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 Disorder o Produces defective CFTR protein - Cystic Fibr. Transmembrane conductance Regulator Epidemiology Caucasian - Most common in caucasians, less in other ethnic groups Pathophysiology Defective CFTR results in diffusion of Cl- out of cells, & therefore Na+ leaves cell also o Th. Osmosis of Water out of cell, due to [ion]intracellular Results in thick mucous, producing: o Chronic respiratory infection (Staph A, Haem Inf, P Aeruginosa) & bronchiectasis o Thick neonatal intestinal secretions meconium ileus o Pancreatic duct blockage pancreatic enzyme deficiency & malabsorption o 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) test o Genetic & sweat testing then used to confirm diagnosis Clinical Features Respiratory o Bronchiectasis - Persistent productive cough, hyperinflation, coarse creps/wheeze o Recurrent infection/pneumonia Pseudomonas Aerigunosa is most common chronic infection Burkholderia also common Staph Aureus & Haemophilus Influenza common in infancy GI o Meconium Ileus (10-20%) - Vomiting, abdo distension, failure to feed in first few days Virtually all Mec Ileus sufferers have CF o Pancreatic Insufficiency - Steatorrhoea Resulting in Malabsorption & Failure To Thrive Diagnosis 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 Respiratory o Monitoring - Regular Spirometry o Chest Physiotherapy - 2x daily o Prophylactic ABX - Oral Flucloxacillin & inhaled anti-pseudomonas agents Prompt IV ABX in exacerbations

o Nebulised Saline - To clear secretions o Portacath may be implanted, allowing IV access in those with recurrent exacerbations Nutrition o Enzyme Replacement o High Calorie Diet - 150% normal calorie intake Screening 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 mutations Epidemiology 1 in 4000 males Pathophysiology Genetic problem producing flawed dystrophin-glycoprotein complex o 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 stairs o Slowness/Clumsiness compared to peers o Gowers Sign - Have to turn prone to stand Course Appear normal at birth, progressive decline Wheelchair bound by early teens, die in early 20s from respiratory failure Associated Conditions Cardiomyopathy, Respiratory muscle weakness Scoliosis Learning Difficulties - in sizeable number Investigations 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 FH Epidemiology 1 in 5000 males (Haemophilia A), 1 in 30,000 (Haemophilia B) Pathophysiology Haemophilia A - Factor 8 Deficiency o 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 not bound 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 at 9 months onwards -i.e. where child begins to stand/fall-over o 40% in neonatal period with ICH, post-circumcision bleeding etc. Delayed Bleeding - May be spontaneous (severe disease), after trauma (moderate) o Into joints & muscles o Ecchymoses N.B. Disease severity rated by factor 8 levels - <1% of normal = severe disease (bleeding into joints/muscles occurs spontaneously), 1-5% = moderate (bleeding after minor trauma), 5-40% = mild (bleeding after surgery) Complications include chronic arthropathy due to joint bleeding Investigations Bleeding Time - Will be Raised due to vWF efficacy & th. slow platelet plug formation

 APTT - May be raised (F8 not involved in PT/TT pathways) Factor 8/9 Levels Management 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 Haemoglobinopathies 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 Difficulties o Facies - Sticky Out Ears, Long face, Prominent jaw & broad forehead (prominent in adults) o Macrocephaly o Macro-orchidism o Mitral valve prolapsed, joint laxity, autism, ADHD Phenylketonuria Rare - 1 in 10-15,000 Enzyme Deficiency - Results in inability to metabolise phenylalanine o Th. build up of toxic phenylalanine & mental retardation Presentation o Via screening (Guthrie/Heel Prick Test) o At 6-12 months of age Developmental Delay Treatment o Phenylalanine dietary restriction - But enough needed for growth o Blood level monitoring Screening o Screened for in Guthrie (Heel prick) Test Dysmorphology Dysmorphology The study of abnormal form Dysmorpological Mechanisms Malformation - A structure within the foetus doesnt develop properly (e.g. spina bifida, cleft palate) Deformation - An abnormal intrauterine mechanical force disrupts a normally formed structure Disruption - Destruction of a normally formed structure (e.g. amniotic bands causing limb reduction 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 foetal compression & pulmonary hypoplasia)