sickle cell disease

commonest genetic disorder in UK kids
1. prevalence= 1 in 2000 live births
collective name for haemoglobinopathies where HbS inherited
HbS forms due to mutation in codon 6 of beta-globin gene
1. so glutamine-> valine
commonest in kids w/ black parents from tropical Africa or Caribbean
also seen in Middle East & in low prev in most of world except N. Europe
3 main forms of sickle cell disease
1. sickle cell anaemia (HbSS)
  1. patients homozygous for HbS
    1. so practically all Hb is HbS
      1. have some small amounts of HbF & NO HbA
        cos they've sickle mutation in both beta-globin genes
2. HbSC disease (HbSC)
  1. inherit HbS from one parent & HbC from other
  2. HbC formed due to diff point mutation in beta-globin
    1. have NO HbA cos they've no normal beta-globin genes
  3. usually have nearly normal Hb level
  4. have fewer painful crises than HbSS
  5. may develop PROLIFERATIVE RETINOPATHY IN TEENS
    1. check eyes periodically
  6. prone to osteonecrosis of hips & shoulders
3. sickle beta-thalassaemia
  1. inherit HbS from 1 parent and beta-thalassaemia trait from other
    1. no normal beta-globin genes & most can't make HbA
      1. so similar sx to sickle cell anaemia
sickle trait
1. inherit HbS from 1 parent and normal beta-globin gene from other
  1. so 40% of Hb= HbS
2. asymptomatic
  1. only IDed on blood test
  2. rarely cause probs except under conditions of low O2 tension
    1. but general anaesthesia not a risk as long as trait known & hypoxia avoided
3. are HbS carriers
  1. can transmit HbS to kids
pathogenesis
1. in all forms of SCD
  1. HbS polymerises within RBCs
    1. -> rigid tubular spiral bodies which deform-> sickle shaped RBCs
      1. irreversible sickled RBCs have reduced lifespan & may be trapped in microcirculation
        -> vaso-occlusion-> ischaemia in organ or bone
        vaso-occlusion worsened by low O2 tension, dehydration & cold
2. clinical manifestations differ btw people
3. HbSS is most severe form
4. severity can be reduced depending on how much HbF is made
clinical features
1. anaemia
  1. all have moderate anaemia (Hb 6-10 g/dl)
    1. + clinically detectable jaundice from chronic haemolysis
2. infections
  1. all have increased susceptibility to encapsulated organisms
    1. pneumococci
    2. Haem influenzae
  2. increased incidence of osteomyelitis by Salmonella & other orgs
  3. greater susceptibility to infection due to
    1. hyposplenism 2dary to chronic sickling
    2. microinfarction of spleen in infancy
  4. risk of overwhelming sepsis greatest in early childhood
3. painful vaso-occlusive crises
  1. hand-foot syn
    1. presents in late infancy
    2. dactylitis
      1. swelling & pain of fingers +/- feet from vaso-occlusion
  2. commonest sites
    1. limb bones
    2. spine
  3. most serious crisis= acute chest syn
    1. can -> severe hypoxia
    2. may need mechanical ventilation & emergency transfusion
  4. avascular necrosis of femoral head
  5. acute vaso-occlusive crises ppted by
    1. exposure to cold
    2. dehydration
    3. excessive exercise/stress
    4. hypoxia
    5. infection
4. acute anaemia
  1. sudden drop in Hb from
    1. haemolytic crises
      1. sometimes assoc w/ infection
    2. aplastic crises
      1. Hb may fall dramatically
      2. parvovirus infection
        causes complete but temporary cessation of RBC prodn
    3. sequestration crises
      1. sudden splenic/hepatic enlargement, abdo pain & circulatory collapse
        due to build of sickled cells in spleen
5. priapism
  1. treat promptly w/ exchange transfusion
6. splenomegaly
  1. common in young kids, less freq in older kids
7. long-term probs
  1. short stature & delayed puberty
  2. stroke & cognitive probs
    1. 1 in 10 kids with SCD have a stroke
    2. 1 in 5 develop subtle neuro damage
      1. manifests as poor concn & school performance
  3. adenotonsillar hypertrophy
    1. -> sleep apnoea-> nocturnal hypoxaemia
      1. can cause vaso-occlusive crises &/or stroke
  4. cardiac enlargement
    1. from chronic anaemia
  5. heart failure
    1. from uncorrected anaemia
  6. renal dysfuncn
    1. may worsen enuresis cos of inability to conc urine
  7. pigment gallstones
    1. due to increased bile pigment prodn
  8. leg ulcers
    1. not common in kids
  9. psychosocial probs
    1. difficulties w/ education & behaviour worsened by time off school
Mx
1. prophylaxis
  1. full immunisation vs Hib, pneumococcal & meningoccocus infection
  2. daily oral penicillin throughout childhood
    1. to ensure full coverage of all pneumococcal subgroups
  3. once daily oral folic acid
    1. needed cos of increased demand for folic acid caused by chronic haemolytic anaemia
  4. minimise vaso-occlusive crises
    1. avoid exposure to
      1. cold
        dress kids warmly
        take extra care to keep warm after swimming or when playing out in winter
      2. dehydration
        give drinks esp before exercise
      3. excessive exercise
      4. undue stress
      5. hypoxia
2. Rx of acute crises
  1. oral/iv analgesia
    1. accord to need -may need opiates
  2. infection-Abx
  3. give O2 if O2 sats reduced
  4. exchange transfusion
    1. for acute chest syn, stroke or priapism
3. Rx of chronic crises
  1. for kids w/ recurrent admissions for painful v-o crises or acute chest syn
    1. give hydroxyurea
      1. increases HbF prodn
      2. protects vs further crises
      3. need to monitor for S/Es
        WBC suppression
  2. bone marrow transplant
    1. for kids unresponsive to hydroxyurea
    2. the only cure for SCD
    3. can only be safely done if kid has HLA-identical sibling who can donate bone marrow
      1. 90% cure rate, but 5% risk of fatal transplant-rel complications
prognosis
1. SCD is cause of premature death
  1. 50% of pts w/ most severe form die before 40 yrs old
  2. mortality rate during childhood =3%
    1. usually from bacterial infection
prenatal dx & screening
1. UK neonatal screening test
  1. Guthrie (test on dried blood spots)
    1. done in 1st week of life
2. early dx of SCD allows early starting of prophylaxis in early infancy
3. prenatal diag by chorionic villus sampling at end of T1

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