Category Archives: Genetics

Ehlers-Danlos syndrome

General paediatrics, Genetics, Orthopaedic, Rheumatology

Covers a spectrum of problems, classified by Beighton (as in hypermobility, Marfans etc). “Vast genetic heterogeneity and phenotypic variability” – 2017 proposed classification includes 13 subtypes!

Classically:

  • joint laxity (hypermobility),
  • skin hyperextensibility,
  • tissue fragility (easy bruising, skin splitting, hernias, prolapses).

Stretchy skin can feel soft and doughy.  Associated with atrophic scars (that look like bad healing).

Mild myopathy seen.

  • Type 1 is severe, commonly born prematurely due to premature rupture of membranes, joint and skin laxity are gross with frequent orthopaedic problems. History of hernia repair? Aortic root dilatation and mitral valve prolapse have been reported but evidence on prognosis is still conflicting.
  • Type 2 is milder and so often underdiagnosed.
  • Type 3 is benign joint hypermobility without skin problems!
  • Type 4 is the rare but severe form where risk of arterial rupture, mostly between ages 20-40. Autosomal dominant so may be history, sometimes characteristic facies. Abnormal bruising is characteristic and the skin is unusually translucent but paradoxically it is not especially hyperextensible, and hypermobility may not be very obvious (perhaps only in fingers)! Problems rarely present before age 20 so important to pick up. Arterial rupture can affect anywhere – aneurysm or bizarre fistula may precede, else trauma or surgery may be a trigger. Bowel rupture is often seen although not usually lethal, pregnancies can be affected by uterine rupture +/- haemorrhage.

Sheffield does genetic testing.

Wilson’s disease

Gastro, General paediatrics, Genetics, Neurology

= hepatolenticular degeneration. Autosomal recessive condition with copper accumulation due to impairment of biliary excretion. Leads to cirrhosis, via a stage indistinguishable from chronic active hepatitis, plus neurological disease. Caused by mutations of the ATP7B gene that codes for a copper transporting ATPase – over 300 mutations known, varying geographically.

Clinical Presentation

Usually presents in late teens but has been described as young as 3yrs. Neurological presentation tends to be older (by 5 years) although they usually have subclinical liver disease. Hepatic disease varies from elevated aminotransferases, through chronic liver disease to fulminant hepatic failure (often with Coombs negative haemolytic anaemia), about 5% of presentations.

Basal ganglia involvement leads to movement disorders viz:

  • Tremor
  • Chorea
  • Parkinsonism
  • Gait disturbances
  • Dysarthria

Other neurological signs are:

  • Psychiatric symptoms
  • Depression
  • Neuroses
  • Personality changes
  • Psychosis

It can also cause:

  • Epilepsy
  • Sunflower cataracts
  • Aminoaciduria
  • Renal stones
  • Osteomalacia with spontaneous fractures

Diagnosis

Can be tricky given multisystem disorder and limited sensitivity/specificity of tests. Heterozygotes may also have borderline results. If typical presentation then diagnosis can be made on basis of:

  • Kayser-Fleischer rings
  • Low serum ceruloplasmin levels (<0.2g/L)
  • Genetic screening of limited utility due to number of known mutations

May require extensive tests of copper metabolism especially with severe hepatic presentation, where up to 50% can have normal ceruloplasmin (an acute phase reactant) eg

  • Non-caeruloplasmin-bound serum copper
  • 24-h urinary copper excretion – can be abnormal in other chronic liver diseases, however. Excretion of >25micromol/24hr after penicillamine is a diagnostic test in children.
  • Liver copper content (>250mcg/g dry weight) – best test when others ambiguous.

In fulminant hepatic failure the following features may suggest diagnosis:

  • Haemolysis (Coombs negative)
  • Alkaline phosphatase surprisingly low viz ALP:Bilirubin ratio of less than 1 has 86% sensitivity and 50% specificity in children

Treatment

  • Diet – chocolate, liver, nuts, mushrooms, and shellfish are high in copper
  • Zinc – reduces copper absorption from gut. Monotherapy is an option for maintenance therapy.
  • Chelation
    • D-penicillamine – but note side effects, and some patients with neurological disease deteriorate on starting treatment
    • Trientine – perhaps less side effects
  • Liver transplantation – curative, except for long-standing neurological disease. Indicated for fulminant hepatic failure.

Monitoring

  • Neurological function
  • Liver function tests
  • 24hr urinary copper excretion (aim for less than 2 micromol/d)
  • Non-ceruloplasmin bound copper of 50-150mcg/L

Marfans syndrome

Cardiology, General paediatrics, Genetics,

Chromosome 15, fibrillin 1 gene (FBN1) locus but lots of different mutations.  Variable penetrance, about a quarter de ovo.

Fibrillin is part of connective tissue, different from collagen, despite clinical overlap with Ehlers-Danlos etc.

Neonatal cases can occur, always severe, with cardiac abnormalities and contractures.

Clinical diagnosis – Beighton (he of benign hypermobility score fame) published Berlin criteria, later came Ghent criteria –

  • family history important, else
  • involvement of the skeleton, plus
  • at least 2 other systems, with a minimum of 1 major manifestation (ectopia lentis, aortic dilatation/dissection, or dural ectasia). 

Skeletal – Tall, disproportionate arm span (>1.05x height – 8cm wider than tall at 160cm) and digits, anterior chest deformity, hypermobility (joint laxity), scoliosis/lordosis, high arched palate and crowded teeth.

Eyes – Myopia, corneal flatness, subluxation of lens (ectopia lentis).

Cardiac – MVP, MR, AR and aortic root dilatation (chart of normal measurements available).  Cardiac examination is often normal despite abnormal echo findings! Aortic aneurysm and dissection can be life threatening.

Pulmonary blebs affect some people, recurrent pneumothorax.  Dural ectasia (widening of lumbosacral spinal canal) on CT is very common, hence why a major manifestation, although symptoms unusual.

Life expectancy is reduced, particularly in males. [Omim]

Ethics of genetic testing in childhood

Ethics, General paediatrics, Genetics

Difficult to determine the psychosocial harms and benefits of testing in childhood.  A systematic review (Genetics in Medicine, 2015,   doi:10.1038/gim.2015.181) found that serious adverse psychological outcomes were uncommon, and most studies reported no significant increase in mean anxiety, depression, and distress scores.  However, some children experienced intrafamilial distress, discrimination, and guilt/regret. Some children were more concerned about their own health or their family members’ health.  It wasn’t very easy to anticipate adverse impact.

Objections-

  • No direct or medical benefit? Duty to protect the future autonomy of the child, i.e. preserving the right for the child to make her/his own decision to be tested or not.
  • Possible psychosocial harm from knowing diagnosis? Existing guidelines are often based on assumptions rather than empirical evidence of such harm, viz possible lessened self esteem, distortion of the family’s perception of the child, altered upbringing, discrimination and increased anxiety both of parent and child.

On the other hand, it has been argued that parents have the right to make decisions on behalf of their children because they have primary responsibility for their child and they know their child best.

Similarly, not testing may mean that the child loses the opportunity to grow up with and adapt to genetic knowledge during his/her formative years. Plus, parental anxiety, difficulty of living with uncertainty.

The authors of the systematic review highlighted the lack of data regarding genetic testing for conditions that may not be treatable/modifiable, and the dearth of longitudinal studies. So they conclude that caution remains essential for the ethical integration of genetic testing in children.

British society for human genetics, 2013 report into testing children. http://www.ethox.org.uk/Documents%20and%20images/GTOC_2010_BSHG.pdf

Alpha 1 Antitrypsin deficiency

Gastro, General paediatrics, Genetics, Respiratory,

Similar incidence to CF in white populations. Protease inhibitor (PI), counteracts neutrophil elastase. Alleles include PiZ (defective), PiM (normal), PiNull (non functioning). Protein phenotype then described as Z, M, MZ, or None

  • Double Null – very high risk of COPD but no liver disease!
  • ZZ have high risk of COPD and liver disease.
  • SZ also seen, risk of COPD.

The risk of emphysema is increased in males, in asthma and especially in smokers.

PiMZ genotype does not appear to predispose to chronic liver disease (in case control study). On the other hand, patients with decompensated liver disease (of any cause) were significantly more likely to have PiMZ, and particularly in HCV or NAFLD PiMZ was associated with more severe liver disease and need for liver transplantation. Suggests that if you have some other cause for liver disease, PiMZ will do less well.

J Pediatr Gastroenterol Nutr. 2006 Jul;43 Suppl 1:S30-5. [pmid:16819398]

About 10% of children with Z phenotype have prolonged (obstructive) jaundice as babies, most have abnormal LFTs at some point in first year of life. Only 2% progress to liver failure requiring transplantation, however. Risk of hepatocellular carcinoma higher, not surprisingly.

Augmentation therapy with IV AAT approved by FDA, expensive. May slow decline in lung function but not great evidence yet. No intended to treat liver disease.

Screening is really only useful in aggressive smoking and alcohol advice. Non-alcoholic fatty liver disease seems to worsen other causes of liver disease so avoidance of obesity seems important too.

Necrotizing panniculitis associated with AAT deficiency, seems to respond rapidly to AAT treatment.

 

Riley Day Familial dysautonomia

Cardiology, General paediatrics, Genetics, Neurology

Seen virtually exclusively in Ashkenazi Jews. Subtype of hereditary
sensory and autonomic neuropathy (cf HSMN).

From birth, absence of tears, poor tone and suck, blotchy skin rashes.
Insensitivity to pain can lead to accidental self mutilation. Speech,
motor development and growth all impaired, but intelligence normal.

Autonomic crises occur, triggered by physical or emotional stress –
sweating, high blood pressure, blotchy rash, vomiting.