Category Archives: Genetics

Bartter’s syndrome

Abnormal renal excretion, leading to low potassium.

Presents in early childhood with failure to thrive. Could also be constipation, muscle cramps and weakness (potassium needed for membrane potential, so these are all neuromuscular) and non-specific dizziness and fatigue.

Characteristic hypokalemic, hypochloremic metabolic alkalosis. High plasma renin activity and high aldosterone concentration seen.

Gitelman syndrome is similar, less severe (distal tubule, rather than ascending limb of loop of Henle) – less failure to thrive, in fact often asymptomatic detected incidentally. Might present with nocturia/polyuria.

Urinary calcium excretion distinguishes the two syndromes. Bartter’s waste calcium (more severe, after all), Gitelman retain.

Treatment is with supplementation.

Decompensation can be precipitated by diarrhoea or vomiting. Acute treatment can include potassium-sparing diuretics (spironolactone), cyclo-oxygenase inhibitors and renin-angiotensin blockers.

Pseudo-Bartter’s is due to CF.

Fragile X

Cause of developmental delay.

FMR1 gene is on X chromosome, obviously, and is a trinucleotide repeat disorder (along with Friedrich’s ataxia, myotonic dystrophy, Huntington disease etc), so inheritance is interesting.

Dads can carry gene, but only pass it on to their daughters (who will all get it).

Mums will carry gene on 1 chromosome, so sons and daughters can both get it, but 50:50 chance.

As with other trinucleotide repeat disorders, gene expands with each generation, so risk of disease increases from 1 generation to the next, and this is somewhat predictable: intermediate gene (so 45-54 copies) won’t expand to cause disease (200+ copies) in 1 generation, but premutation gene (55-199) copies probably will.


  • Moderately severe learning disability
  • Facial features – long face, midface hypoplasia, large lips and jaw, small ears
  • Macro-orchidism

Females less severely affected, of course.


Muscle breakdown with release of products into blood stream that can cause acute renal failure.

Typically occurs with crush injuries, sometimes seen with extreme endurance sports.

Can be infectious.

Recurrent seen with fatty acid oxidation disorders and Lipin 1 mutations.

Lipin 1 mutations

Autosomal recessive – heterozygotes may have exercise induced muscle symptoms or be prone to drug induced myopathy.

Basal CK high but spikes to over 100 000 with decompensation (infection, exercise, anaesthetic).

Treat crises with carbohydrates/intralipid.

Muckle-Wells Syndrome

A Cryopyrin disorder, found in Northern Europeans. Cryopyrin triggers an IL-1 dominated inflammatory response, and is coded for by the Cold-Induced Autoinflammatory Syndrome 1 (CIAS1) gene, also known as the NLRP3, NALP3 or PYPAF1 gene.

Attacks of periodic fever are very brief eg 1-2 days – apart from fever, an urticarial rash is sometimes seen, limb pain/arthralgia occurs. Abdominal pain and arthritis occur rarely. Sensorineural hearing loss is characteristic.

Amyloidosis affects 25%, which is high cf other periodic syndromes.

Diagnosis is by genetics.

Steroids are often used but benefit is inconsistent; interleukin 1 (IL-1) receptor antagonist Anakinra shows promise.

Familial cold autoinflammatory syndrome (FCAS) is a similar condition, also related to Cryopyrins. Cold induced obviously, but without the deafness, and amyloidosis is rare.

NOMID/CINCA are also related – the names say it all: Neonatal onset multisystem inflammatory disorder, and chronic infantile neurological cutaneous and articular syndrome. Papilloedema and uveitis potentially leading to blindness occur; there is epiphyseal bone formation; hepatosplenomegaly; and a chronic meningitis with deafness. There is no known treatment, sadly.

Behcet’s syndrome

Recurrent fever and aphthous stomatitis, mostly. However, there is no regular periodicity of the symptoms, and episodes of fever may last for weeks.

Traditionally associated with Mediterranean or Eurasia but in UK mostly white Caucasian.

Other features –

  • arthritis,
  • genital ulcers,
  • iridocyclitis and optic neuritis, even blindness
  • skin rashes (classically erythema nodosum or pustulosis),
  • disabling vascular (thrombosis, superficial phlebitis) and central nervous system complications may occur.

BPSU study found 1 case every 2 weeks in the UK. Median age of onset was 6yrs – but diagnosis 11yrs!

Colchicine as regular preventive treatment, else immunosuppressive treatment. Topical steroids or short courses oral steroids.

Hereditary haemorrhagic telangiectasia

=Osler-Weber-Rendu disease.

Autosomal dominant with high penetrance. 

Not a problem in early life.  Usually presents with recurrent nose bleeds.  Red spots on lips, tongue and fingertips, not so obvious in young children. But potential for GI and pulmonary haemorrhage, pulmonary/liver/brain AVMs.  Migraine common.

Iron deficiency a problem, of course!

Screening for AVMs done from age 16. Annual full blood count. Beware nasogastric interventions!

Rett Syndrome

Exclusively females (lethal in males? Or rate of germ cell mutations higher in male germ cells?).  Virtually always sporadic – so not exactly X linked dominant.

MECP2 gene on X chromosome.

Developmental arrest at 6-18 months, then regression, loss of speech, stereotypies esp hands.

Often epilepsy, then complications of severe neurodisability eg chronic lung issues.

Not degenerative however – can live into middle life.


=Asymmetric overgrowth of one limb, or one side of the body, or just one side of the face.

Can be associated asymmetric overgrowth of internal organs.

Can be an isolated finding (of unknown cause) or associated with syndromes such as Beckwith-Wiedmann, Klippel-Trenaunay-Weber, or McCune-Albright syndromes.

Essentially a cosmetic problem. But increased risk of tumours, including Wilm’s tumour, adrenal cell carcinoma, hepatoblastoma and small bowel sarcoma.

Risk of tumour development in isolated hemihyperplasia is about 1 in 20 or approximately 5%. Given that oldest reported case was 6yrs and shortest interval between tumour presentation and ultrasound was 5 months, suggested hat till age of 6 years these children should have abdominal ultrasound scans at three monthly intervals.

Fanconi anaemia

Autosomal recessive condition characterized by severe hypoplasia or aplasia of the bone marrow (so anaemia, low white cells and thrombocytopenia). Clue is congenital hand defect, but lower limb, head/eye/ear/genital abnormalities also common.

Majority also have cafe au lait spots.

It is possible to diagnose Fanconi anemia before bone marrow failure occurs, with potential to find bone marrow match.

Diagnosis is by Chromosomal breakage studies.

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