Category Archives: Genetics

Radial dysplasia

Spectrum of congenital abnormalities of hand and forearm, from hypoplastic or absent thumb, to short arm with deviated, clubbed hand.

Commonly part of a congenital syndrome, so refer to a clinical geneticist.

  • VACTERL Association,
  • VATER syndrome,
  • Holt-Oram syndrome ( association of cardiopulmonary and limb defects),
  • TAR syndrome (thrombocytopenia-absent radius),
  • Fanconi anaemia.  


  • Spine x-rays,
  • renal ultrasound,
  • complete blood count,
  • echocardiography

Dravet syndrome

Previously Severe myoclonic epilepsy of infancy. Charlotte Dravet described in 70s. Characterised by:

  • Refractory epilepsy
  • Onset in infancy
  • Associated neurodevelopmental problems

Due to defect in SCN1A gene on chromosome 2q24 (a sodium channel), usually de novo. Many mutations, don’t predict severity, unfortunately.

Accounts for about 7% of epilepsy presenting in first 3 years of life.

Onset around 5-8 months, often with febrile illness so can look like typical febrile convulsion. But often prolonged. Neurodevelopmental problems come later…

Later though, multiple seizure types. Hypotonia, ataxia, spasticity all seen. Dysautomnia can be a feature. ADHD and autistic traits common later.

EEG can be normal, or vary over time, with multifocal or generalised changes, photosensitivity too.

Sickle cell disease

Autosomal recessive genetic disorder caused by a single nucleotide mutation of the haemoglobin ß-unit, from glutamic acid to valine. The resulting mutant haemoglobin S (HbS) is prone to distortion in cooler or hypoxic conditions, turning into a sickle shape. This damages the erythrocyte causing haemolysis.

The gene is more common among Africans and is occasionally seen in races from the Middle East and South Asia. Its existence is due to protection from malaria seen in sickle cell trait (the heterozygote form), due to shortened red cell lifespan.

You can of course get combinations of sickle cell with other genetic haemoglobin disorders.

Triggers for sickling include cold environment, acidosis, hypoxia and hyperviscosity eg dehydration. Blood flow in capillaries is impaired by the damaged red cells, which leads to a vicious cycle of increased tissue acidosis and hypoxia. Infarction may occur.


Can be diagnosed even in newborns by hemoglobin electrophoresis.

Screening programmes exist in some countries, so that prophylactic oral penicillin can get started early, preventing sepsis.


Presents in infancy or early childhood. The neonate with its high proportion of Haemoglobin F does not get symptoms until there is enough abnormal haemoglobin A produced for red cells to start to sickle.

Acute Crisis

  • Pain
  • Chest syndrome
  • Aplastic crisis
  • Gut crisis
  • Stroke
  • Priapism
  • Sepsis (may precipitate crisis or complicate it)


Pain can be widespread, but particularly involves bones, the spine, the chest.

Acute Chest syndrome

Can mimic pneumonia, with unilateral or bilateral signs of consolidation, pleuritic pain, and hypoxia. Pain is in chest wall, thoracic spine and upper abdomen. Leads to hypoventilation, causing vicious cycle of atelectasis and subsequently worse sickling. High mortality, so low threshold of suspicion.

  • Hypoxia should be managed aggressively, with respiratory support if necessary.
  • Antibiotics in infection contributing.
  • Avoid diuretics – signs may suggest pulmonary oedema, but likely to exacerbate hyperviscosity.

Aplastic Crisis

Usually secondary to Erythrovirus B19 (formerly known as parvovirus B19) infection, which can trigger transient bone marrow arrest. So sudden drop in haemoglobin with an absence of reticulocytes. Classic “slapped cheek” appearance may never become apparent. Can affect multiple members of a family simultaneously. Differential is spleen sequestration.

Abdominal crisis

Manifest as anorexia, abdominal pain, distension. Usually not diarrhoea or vomiting. Usually not rebound. Bowel sounds usually quiet.

  • Girdle or Mesenteric syndrome – ileus with vomiting. Associated with liver enlargement and bilateral basal consolidation.
  • Differential includes appendicitis, biliary colic or cholecystitis, ischaemic colitis.


Typically affects middle cerebral artery territory but may affect any region of the brain; may be transient or permanent. Seizures may occur. Predictive factors are:

  • Previous TIA/stroke
  • Chest syndrome
  • Hypertension
  • Family history of SCD related stroke
  • Low HbF and/or low total haemoglobin
  • Doppler velocities >200cm/sec in children

Differential is meningitis, subarachnoid haemorrhage (associated with multiple intracranial aneurysms).

Sequestration syndromes

  • Splenic sequestration – Seen in infants and young children. Precipitated by fever or dehydration. Symptoms are:
    • Abdominal pain/distension
    • Rapidly expanding spleen (may or may not be painful)
    • Shock, pallor due to drop in haemoglobin (but high reticulocytes cf aplastic crisis)
  • Management is by fluid resuscitation with blood (type specific/O negative if necessary).
  • Hepatic sequestration: similar to splenic, although less shock, and possibly jaundice along with enlarging liver.
  • Priapism: =sustained painful erection. Potentially leads to peripheral gangrene, else cavernosal fibrosis and hence impotence. A urological emergency. Management:
    1. Warm bath, hydration, analgesia
    2. Catheterize if unable to urinate
    3. Sedation eg diazepam
    4. Aspiration + irrigation – ideally within 4-6hrs of onset. Else shunt.
    5. Top-up transfusion may be considered if unstable with other sickle related problems (aiming for Hb 10-12g/dl).
  • Sepsis. Children are relatively immunocompromised due to functional hyposplenism from recurrent spleen infarction. This increases susceptibility to capsulated organisms eg pneumococcus, salmonella, haemophilus.
    • Yersinia is a particular risk in children on desferrioxamine. Causes diarrhoea.


  • Analgesia, aiming to get rapid symptom control with IV bolus doses of opiates eg morphine, diamorphine ideally within 30 minutes of admission, followed by infusion or regular oral doses. Paracetamol and non-steroidal anti-inflammatories may be synnergistic.
  • Oxygen, esp for acute chest syndrome. Debatable if effective for other problems.
  • Hydration, even hyperhydration eg 150% normal daily requirements, IV if necessary. Impairment of renal concentrating power may contribute to dehydration.
  • Warm environment
  • Identification and treatment of infection. Give treatment doses of penicillin (else erythromycin) even if no specific agent identified.
    • Treat with IV antibiotics if severe symptoms/signs
    • Add macrolide eg clarithromycin if chest symptoms
    • Treat empirically for Yersinia with ciprofloxacin if diarrhoea on desferrioxamine.
  • Folic acid (should be on already)


Although anaemia is common in SCD, repeated transfusions lead to the possible complications of:

  • Allo-immunization
  • Iron overload

Hence top up transfusion is only used for acute symptomatic anaemia eg cardiac failure, severe sequestration or pre-operatively. Do not transfuse above Hb 11g/dl. Regular transfusions have a prophylactic role – see on-going treatment below.

Hyperhaemolysis is a life threatening complication of red cell transfusion in sickle cell disease. Can be acute (within 7 days of transfusion) or delayed. Affects not just transfused but autologous cells so Hb can drop below previous level. Fever, haemogobinuria as usual; negative DAT, reticulocytopenia seen (cf parvo). Cover subsequent transfusion with IVIG and steroids; use erythropoietin to maintain. For elective surgery, prophylactic postop CPAP has been used without transfusion. Risk factors poorly defined.

Exchange transfusion

Undertaken to rapidly reduce the percentage of sickle cells in the circulation where life-threatening eg severe chest syndrome, stroke, multi-organ failure. The aim is to reduce %HbS to <20%. Complications are common eg fluid overload, transfusion reaction.

Other Treatments

  1. Pneumococcal prophylaxis is essential for all children. Polysaccharide vaccine should be offered with repeat doses as per Green book.
  2. Folic acid
  3. Hepatitis B immunization
  4. Splenectomy for recurrent splenic sequestration.

On-going treatment

Consider for:

  • Recurrent or stuttering priapism (etilefrine orally is another option here)
  • Stroke/TIA
  • Chronic organ damage eg renal failure
  • Failure to thrive
  • Intractable crises


  • Regular transfusions. The aim is to keep %HbS <25%. Compared with exchange transfusion, regular transfusions are just as good at reducing complications, are less challenging in terms of vascular access, involve less donor exposure, but cause more iron accumulation.
  • Hydroxyurea. Reduces frequency of crises and transfusion requirements, improves growth. Trials ongoing. Long term risks need to be clarified (toxicity, mutagenicity, teratogenicity).
  • Bone marrow transplant

Iron overload and chelation therapy

Iron overload can be monitored by means of Ferritin levels. Chelation therapy should commence at ferritin levels of 1000mcg/l, with desferrioxamine (desferal) the chelator of choice. Treatment should include vitamin C. Ophthalmological, audiological and cardiological review is necessary.

Cobalamin related metabolic disorders

Amino acid homocysteine is converted to methionine (“remethylated”) – cobalamin is involved in some of these processes, folate metabolism also important.

Various disorders.

Variety of presentations, at different ages:

  • Neurological (central and peripheral)
    • Feeding difficulties, apnoea in babies
    • Seizures
    • Subacute combined degeneration of spinal cord (peripheral neuropathy, ataxia, incontinence)
    • Acute and/or chronic encephalopathy – hypotonia, regression
    • Neuropsychiatric problems
  • vascular problems (stroke/embolism)
  • bone marrow (megaloblastic anaemia, cytopenia) – folate related
  • Atypical HUS
  • Glomerulopathy


  • High homocysteine, usually
  • Vitamin B12 and folate, for differential
  • Methylmalonic acid (in urine)
  • Acylcarnitine
  • Methionine (usually goes low)


Start intramuscular B12 (hydroxocobalamin) as soon as samples collected, to prevent end organ damage.

Betaine should be started if high homocysteine with low methionine found, helps push conversion to methionine.


Autosomal recessive condition of high homocysteine in blood and urine, causing similar neurological problems, thrombosis, Marfanoid appearance, downward subluxing lenses.

Needs low methionine diet. Betaine supplements help.

Cystic Fibrosis

The most common inherited genetic condition in N European populations, with carrier rate of 1 in 20. Incidence is therefore around 1 in 4000 births. Most common gene defect is deletion at delta F508 of CFTR (CF transmembrane conductance regulator) gene.


  • family history
  • congenital intestinal atresia
  • meconium ileus
  • distal intestinal obstruction syndrome
  • faltering growth (in infants and young children)
  • undernutrition
  • recurrent and chronic pulmonary disease, such as:
    • recurrent lower respiratory tract infections
    • clinical or radiological evidence of lung disease (in particular bronchiectasis)
    • persistent chest X-ray changes
    • chronic wet or productive cough
  • chronic sinus disease
  • obstructive azoospermia (in young people and adults)
  • acute or chronic pancreatitis
  • malabsorption
  • rectal prolapse (in children)
  • pseudo-Bartter syndrome.

Median predicted life expectancy is now nearly 50 years, but this doesn’t take into account the new CFTR modulators. Management has evolved slowly, with revolutionary improvements including high calorie diets/feeding, pancreatic enzyme replacement, specialist CF centres and CF newborn screening.


  • Regular prophylactic antibiotics (usually starting with oral flucloxacillin) introduced at early stage. Later on may require regular courses of IV antibiotics.
  • Azithromycin given on Mondays, Wednesdays and Fridays – but for anti-inflammatory properties as much as antibacterial.
  • Creon is the name for pancreatic enzyme supplements, taken with each meal.
  • Fat soluble vitamins.
  • Nebulised DNAse and hypertonic saline to help with chest physiotherapy

New treatments

CFTR modulators treat the basic defect. Lead to significantly improved pulmonary function, decreased respiratory infections and improved nutrition.

Combination elexacaftor, tezacaftor and ivacaftor, will be suitable for approximately 90% of all people with CF. But expensive, with many countries unwilling or unable to fund them.

CFTR phenotypes vary. Class I–III variants are most severe, with minimal or no CFTR function. Class IV–VI variants are where CFTR is produced and reaches apical membrane but doesn’t work normally, so milder phenotype.

Ivacaftor reduces hospital admission, rates of respiratory Pseudomonas and Aspergillus infection, and halves rate of decline in FEV1 %, suggesting at least 5 years survival benefit.


Angelman syndrome

Caused (mostly) by absence of maternal contribution to a region of the 15q chromosome.  Paternal uniparental disomy is one way this can happen, although mostly there is de novo maternal deletion.  The same region is also responsible for Beckwith-Wiedemann syndrome, but this syndrome is the result of a paternal deletion.

Characteristically “happy puppet” –

  • severe speech and language delay
  • learning disability and epilepsy
  • Movement disorder esp ataxia, also tremor, hyperreflexia
  • open mouthed expression, large mandible
  • Excitability, paroxysmal laughter


Hereditary spherocytosis

One of the genetic red blood cell abnormalities that protects against malaria (cf sickle cell), as haemolysis shortens life span and potential for parasite reproduction.

Phenotype (severity) consistent within family, but very different between families. FH may be vague eg splenectomy, jaundice rather than awareness of underlying diagnosis…


Anaemia, jaundice and splenomegaly classically. Splenomegaly is usually mild and there is no increased risk of rupture. Neonatal jaundice can be severe but does not predict severe disease! Severe cases (assessed when well, not during crises, only about 5%) can be transfusion dependent in first years of life (erythropoietin helpful) but not usually afterwards.

May present with parvovirus aplastic crisis (not just red cells; white cells and platelets often drop too) – only happens once.

Diagnosis by spherocytes on film, reduced MCV, high reticulocytes (but retics do not go up during aplastic crisis), unconj hyperbilirubinaemia, splenomegaly. There are other causes of spherocytes, and they can be seen in normal neonatal blood films.

Differential is autoimmune haemolytic anaemia, which is associated with acute viral infection (direct Coombs test usually positive). Osmotic fragility test does not distinguish, can be false negative in iron deficiency, and is unreliable in the first few months of life. New EMA dye binding test takes 2 hours and is 92% sensitive. Gene tests don’t add much.

Other problem is gallstones. High reticulocyte count predicts.

Folate probably only necessary for severe cases.


Most children are asymptomatic, but severe cases can have growth failure, lethargy, heart failure and leg ulcers. Should be delayed until at least 5 yrs, potentially laparascopic and/or partial. Do cholecystectomy at same time if symptomatic. Platelets rise to abnormally high levels after splenectomy, but no apparent increase in thrombosis.

[Arch Dis Child PMID 15321852]