3-1 - genetic disorders

8/2/2019 3-1 - Genetic Disorders

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Notes3-1 - Paediatrics

Genetic Disorders & Dysmorphology

Down’s 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 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 Fistulao Duodenal Atresiao Also: Pyloric Stenosis, Meckel’s, Hirschsprung’s, 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

Screening

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

Can also use double/quadruple factors Uses:

Hormone Levels - α-Feta Protein, βhCG & Unconjugated Oestriol

Maternal Age & Gestational Age +ve Screen = >1 in 150 risk of Down’s

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

Amniotic fluid sample (containing foetal cells) taken & karyotypedo 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. Turner’s pts have 45 chromosomes, one of which is an unpaired X. o 50% of Turner’s 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

Respiratoryo Monitoring - Regular Spirometryo

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

Prompt IV ABX in exacerbations



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

Nutritiono 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 Gower’s 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 numberInvestigations

↑ Creatinine Kinase DNA Testing

Muscle Biopsy

Treatment Steroids - Prolong ambulance (walking) - method unknown

Physio, OT, Ventilation etc. N.B. Becker’s 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 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 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 (doesn’t 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

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

DysmorphologyDysmorphology

‘The study of abnormal form’ Dysmorpological Mechanisms

Malformation - A structure within the foetus doesn’t develop properly (e.g. spina bifida, cleftpalate)

Deformation - An abnormal intrauterine mechanical force disrupts 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.Potter’s Syndome - Renal agenesis leads to foetal compression & pulmonary hypoplasia)

3-1 - genetic disorders

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