Drs Rosalyn Jewell, Schaida Schirwani, and Jude Hayward look at the role of GPs in identifying and managing FH, ADPKD, Down syndrome, and AAT deficiency

jewell ros

Dr Rosalyn Jewell

Read this article to learn more about:

  • the diagnosis and management of familial hypercholesterolaemia, autosomal dominant polycystic kidney disease, Down syndrome, and alpha-1-antitrypsin deficiency
  • assessing and monitoring patients with genetic conditions, and when to refer
  • advising patients and their families.

GP commissioning messages

G eneral practitioners play an important role in identifying patients with, or at risk of, common genetic conditions, and in their long-term care. This two-part article series does not aim to provide a comprehensive overview of common genetic conditions, but instead to highlight key management issues relevant to primary care.

Part 1 covers familial hypercholesterolaemia (FH), autosomal dominant polycystic kidney disease (ADPKD), Down syndrome, and alpha-1 antitrypsin (AAT) deficiency. Part 2 (to feature in the October 2016 issue of Guidelines in Practice) covers neurofibromatosis type 1, breast cancer, hereditary haemochromatosis, cystic fibrosis, and conditions with multifactorial inheritance.

Box 1: Terms used in this text1

  • First-degree relative: a person's sibling, parent, or child
  • Second-degree relative: a person's grandparent, grandchild, aunt, uncle, nephew, niece, or half sibling.

Familial hypercholesterolaemia

Familial hypercholesterolaemia is an autosomal dominant condition characterised by severely elevated levels of cholesterol from birth, which may lead to premature coronary heart disease (CHD). First-degree relatives (see Box 1, below)1 have a 50% chance of being affected by the condition. The estimated prevalence of FH is 1 in 500 and it is massively underdiagnosed. More than 50% of males will have developed CHD by the age of 50 years and 30% of females by the age of 60.2

Mr C, a 45-year-old man, attends for a vascular check, and his results include a total cholesterol of 8.4 mmol/l and an LDL cholesterol of 5.3 mmol/l.


The Simon Broome criteria are used to make a clinical diagnosis of FH (see Box 2, below).3

Box 2: Simon Broome criteria for a diagnosis of familial hypercholesterolaemia3

Definitive FH

  • high cholesterol levels (pre-treatment or highest on treatment):
    • adults over 16 years: total cholesterol levels >7.5 mmol/l or LDL-C >4.9 mmol/l
    • child less than 16 years of age: total cholesterol levels >6.7 mmol/l or LDL-C >4.0 mmol/l
  • plus at least one of the following:
    • tendon xanthomas on examination, or in first- or second-degree relative or
    • DNA-based evidence of an LDL-receptor mutation, familial defective apo B-100, or PCSK9 mutation.

Possible FH

  • high cholesterol levels as defined above
    • plus at least one of the following:
      • family history of myocardial infarction at:
        • age 60 years or younger in a first-degree relative
        • age 50 years or younger in a second-degree relative
      • family history of elevated total cholesterol as follows:
        • greater than 7.5 mmol/l in adult first- or second-degree relative or greater than 6.7 mmol/l in child or sibling aged younger than 16 years.

FH=familial hypercholesterolaemia; LDL-C=low-density lipoprotein cholesterol

Management responsibilities for primary care2

Statins are initial treatment, with a target of reducing low-density lipoprotein cholesterol (LDL-C) by more than 50% of baseline. If this target is not achieved by treatment with high-intensity statins and ezetimibe then specialist referral is appropriate. Lifestyle advice should be part of medical management.

People with features of possible CHD that are not immediately life-threatening should be offered urgent referral to cardiology. Standard CHD risk calculators should not be used, as they will underestimate risk in individuals with FH.

Referral to a specialist with expertise in FH should be offered to those with FH to confirm diagnosis and initiate cascade testing. In many areas, DNA testing is not available and so, at the very least, all first- and second-degree relatives should be advised to have total cholesterol and low-density lipoprotein (LDL-C) levels checked. Cholesterol levels for diagnosis in relatives of an index case are clarified in NICE Clinical Guideline (CG) 71.2

Children with one affected parent should be referred to a specialist clinic by the age of 10 years or at the earliest opportunity thereafter. If both parents are affected then refer by the age of 5 years.

Ongoing assessment and monitoring

On annual review:2

  • ask about any symptoms suggestive of CHD, consider a baseline ECG, check smoking status
  • check fasting LDL-C levels
  • review medications and ask about side-effects
  • record the progress of cascade testing and update the family history with any changes in CHD status of family members
  • consider changes in lifestyle and lipid-modifying drug medication that would achieve recommended LDL-C levels.

Recommendations for women and girls with familial hypercholesterolaemia

NICE CG71 recommends that women are given advice and support to include the following:2

  • when first considering lipid-modifying therapy, discuss the risks for future pregnancy and the fetus. Revisit at least yearly
  • combined oral contraceptive pills are not contraindicated in FH, but given the small increased risk of cardiovascular events, alternative methods should be considered
  • women should be advised that lipid-modifying therapy be stopped 3 months before planning to conceive
  • women who conceive while on lipid-modifying therapy should be advised to stop the medication immediately and offered urgent referral to an obstetrician for appropriate fetal assessment
  • organise shared-care including cardiology and obstetric input for women who are considering pregnancy or who are pregnant
  • do not measure serum cholesterol routinely during pregnancy
  • pregnant women with FH require advice on potential risks and benefits of restarting lipid-modifying drug therapy in pregnancy and when breastfeeding. Bile acid sequestrants (resins) are the only lipid-modifying drug therapy that should be considered during lactation.

Autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystemic and progressive disorder. The prevalence of the disease has been previously quoted as around 1 in 800,4 but more recent studies suggest a prevalence closer to 1 in 3000 people in the European Union.5 It is highly penetrant, and there is up to a 50% risk of developing end-stage renal disease by the age of 60 years.6 It is characterised by the following:

  • renal manifestations:
    • renal cysts
    • urinary tract infection (UTI), haematuria, and loin pain secondary to renal cysts
    • hypertension
    • end-stage renal disease in 50% of individuals by the age of 60 years
  • extra-renal manifestations:
    • cysts in other organs including the liver, pancreas, and spleen7
    • intracranial aneurysms and other vascular problems such as mitral valve prolapse, aortic root dilatation, or dissection.

Mrs R, a 38-year-old woman, has had a renal ultrasound scan as an investigation for persistent loin pain. The results show bilateral renal cysts, and also four hepatic cysts.


In an individual with a family history of ADPKD in a first-degree relative, diagnosis of ADPKD can be confirmed if imaging criteria are met (see Table 1, below).6–8 If the ultrasound findings are equivocal, then computerised tomography or magnetic resonance imaging may occasionally be indicated.

Table 1: Ultrasound diagnostic criteria for individuals at 50% risk of autosomal dominant polycystic kidney disease8
Age (years)Minimum number of renal cysts for diagnosis
15–39Three uni or bilateral cysts
40–59Two cysts in each kidney
≥60Four cysts in each kidney
Positive predictive value (PPV) is 100%, sensitivity variable depending on age and genotype

General management

Care and monitoring of patients with ADPKD would usually be undertaken jointly by primary care and renal teams. The mainstay of management in primary care is control of hypertension, and prevention and detection of other complications.

Referral to a geneticist is indicated for counselling of the patient and cascade screening of the family. Genetic testing in ADPKD is complex, and usually indicated only if there is diagnostic doubt, for reproductive reasons, or to exclude the condition in a family member being considered as a potential kidney donor.9

Pregnant women should be referred to an obstetrician. Oestrogens appear to provoke growth of liver cysts, so oestrogen-containing contraceptives and hormone replacement therapy should be avoided9,10

Magnetic resonance angiography is used to detect aneurysms in patients with ADPKD where there is a family history of aneurysm, preparation for major surgery, or a high-risk occupation (e.g. pilot).6,9

Screening echocardiography is used for individuals with heart murmur or for those with a family history of a first-degree relative with a thoracic aortic dissection.6

Long-term administration of nephrotoxic drugs (e.g. non-steroidal anti-inflammatory drugs) and smoking should be avoided.6

Tolvaptan is a selective vasopressin antagonist that has been approved for use by NICE (2015) to slow growth of kidney cysts in those with chronic kidney disease at stage 2 or 3 at start of treatment, and with evidence of rapidly progressive kidney disease.11

Mrs R's 35-year-old brother then comes to see you asking to 'be tested' for the condition.

First-degree relatives of patients with ADPKD are at 50% risk of having the condition. The initial evaluation of at-risk relatives over age 18 years should be renal ultrasound. If the pathogenic variant in the family is known, predictive genetic testing may be appropriate. Prior to screening, at-risk relatives should be counselled on the condition and implications for insurance and employability in future. Normal kidneys on an ultrasound in an individual age 30–39 years or only one renal cyst in an individual age 40 years or older can effectively exclude ADPKD.6–8

At present, screening asymptomatic at-risk children is not recommended.9 However, hypertension can start in childhood, so blood pressure should be monitored from the age of 5 years, with an interval of 3 years when no hypertension is found.9

Down syndrome

Down syndrome, or trisomy 21, is usually caused by non-disjunction during meiosis leading to three copies of chromosome 21. The risk of this occurring increases with maternal age. In some cases, mosaic trisomy 21 occurs where not all of the patient's cells have three copies of chromosome 21. In 2–4% of cases, trisomy 21 is caused by a Robertsonian translocation. This is important as it could mean a higher chance of recurrence in a future pregnancy if inherited from a parent. If this is the cause, it will be stated clearly on the karyotype report including the need to test parental samples. There is a 1 in 2 (50%) risk that each child of a women with Down syndrome will also have the condition. Fertility in men with Down syndrome is rare.12,13

Mr T, a 35-year-old man with Down syndrome, attends for his annual learning disabilities review.


There is evidence that a significant proportion of adults with Down syndrome receive inadequate surveillance.14 Annual review should include the health checks offered to all patients with learning disability, particularly body mass index and urinalysis. There are, however, other conditions over-represented in these individuals, for example dementia and coeliac disease, which GPs should be alert to. The Down Syndrome Medical Interest Group and Down's Syndrome Association have produced annual review guidelines.15,16

Alpha-1-antitrypsin deficiency

Alpha-1 antitrypsin (AAT) is a protease inhibitor that inhibits neutrophil elastase. The lack of this inhibition, associated with the effects of cigarette smoke, can lead to pulmonary emphysema. Accumulation of mutant AAT Z proteins in the endoplasmic reticulum of hepatocytes appears to cause liver disease in alpha-1-antitrypsin deficiency.17

A PiZZ genotype is consistent with a clinical diagnosis of AAT deficiency. The common PiMM genotype is found in around 95% of Caucasian people and is associated with normal AAT levels. Alpha-1 antitrypsin deficiency is found in those with PiZZ and PiSS genotypes (0.02–0.06% and 0.01–2.00% of European populations have these genotypes, respectively). The PiSS genotype is associated with AAT levels approximately 60% of normal, those with PiZZ have much lower levels. There are also rare null variants associated with no detectable AAT in the plasma.17

Alpha-1 antitrypsin deficiency is a recessive disorder with 2–5% of the European population being a carrier for the Z allele and 4–11% a carrier for the S allele.17

The key groups where AAT deficiency should be considered are those with early onset emphysema (<=45 years) or those without a risk factor for emphysema and otherwise unexplained liver disease (including in neonates and the elderly).17

Mr H, a 50-year-old man, attends as his brother has recently been found to have AAT deficiency during investigations for chronic obstructive pulmonary disease. Mr H is concerned about his risks and risks to his children.

Mr H is at a 25% risk of having the same genotype as his brother and at risk of clinically relevant respiratory and liver disease. Genotyping and measurement of AAT levels in Mr H are therefore indicated in primary care. Advice should be provided regarding cessation of smoking.

Genotyping shows that Mr H has a PiMZ genotype with normal AAT levels and so is at a lower risk of developing respiratory or liver disease.

Extensive guidance on the diagnosis and management of those with AAT deficiency is available from the American Thoracic Society and European Respiratory Society.17

The genotype of Mr H's children will depend on his partner's status. Genetic testing can be arranged via primary care.

GP commissioning messages

written by Dr David Jenner, GP, Cullompton, Devon

  • FH is common and underdiagnosed and is a major cause of preventable CVD
  • GPs should be made aware of the Simon Broome criteria and there should be clear local pathways for referral for suspected FH:
    • commissioners should ensure the availability of the specific DNA test for diagnosis and cascade testing
  • A genetic counselling service should be available for direct referral from primary care for people with genetic conditions and people who are identified as being at risk
  • It would be helpful for GPs to have ready access to guidelines for the identification and management of various rare genetic conditions. These could be made available via a 'referral and formulary app' that allows rapid update and accessibility to multiple local guidelines; some CCGs have already adopted this type of app.

FH=familial hypercholesterolaemia; CVD=cardiovascular disease


  1. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Dictionary of genetics terms. Available at: www.cancer.gov/publications/dictionaries/genetics-dictionary
  2. NICE. Identification and management of familial hypercholesterolaemia. Clinical Guideline 71. NICE, 2008. Available at: www.nice.org.uk/guidance/CG71
  3. Heart UK. Diagnostic criteria for familial hypercholesterolaemia using Simon Broome register. Available at: heartuk.org.uk/files/uploads/documents/HUK_AS04_Diagnostic.pdf
  4. Dalgaard O. Bilateral polycystic disease of the kidneys; a follow-up of two hundred and eighty-four patients and their families. Acta Med Scand Suppl 1957; 158 (328): 1–255.
  5. Willey C, Blais J, Hall A et al. Prevalence of autosomal dominant polycystic kidney disease in the European Union. Nephrol Dial Transplant, 2016, Epub 19 Jun. Available at: ndt.oxfordjournals.org/content/early/2016/06/19/ndt.gfw240.full.pdf+html
  6. Harris P, Torres V. Polycystic kidney disease, autosomal dominant. In: Pagon R, Adam M, Ardinger H et al, editors. GeneReviews®. Seattle (WA): University of Washington, Seattle, 2002: 1993–2016. Available at: www.ncbi.nlm.nih.gov/books/NBK1246/
  7. Mosetti M, Leonardou P, Motohara T et al. Autosomal dominant polycystic kidney disease: MR imaging evaluation using current techniques. J Magn Reson Imaging 2003; 18 (2): 210–215.
  8. Pei Y, Obaji J, Dupuis A et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol 2009; 20: 205–212. Available at: doi.org/10.1681/ASN.2008050507
  9. Chapman A, Devuyst O, Eckardt K et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a kidney disease: improving global outcomes (KDIGO) controversies conference. Kidney Int 2015, 88 (1): 17–27.
  10. Alvaro D, Mancino M, Onori P et al: Estrogens and the pathophysiology of the biliary tree. World J Gastroenterol 2006; 12: 3537–3545. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC4087569/
  11. NICE. Tolvaptan for treating autosomal dominant polycystic kidney disease. NICE Technology Appraisal 358. NICE, 2015. Available at: www.nice.org.uk/ta358
  12. Asim A, Kumar A, Muthuswamy S et al. Down syndrome: an insight of the disease. J Biomed Sci 2015, 22: 41. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC4464633
  13. Firth H, Hurst J, Bobrow M. Down syndrome (trisomy 21). In: Hall JG, editor. Oxford Desk Reference Clinical Genetics. Oxford: Oxford University Press, 2005: 524–525.
  14. Henderson A, Lynch S, Wilkinson S, Hunter M. Adults with Down’s syndrome: the prevalence of complications and health care in the community. BJGP 2007; 57: 50–55.
  15. Down's Syndrome Medical Interest Group. Guidance for essential medical surveillance. Available at: www.dsmig.org.uk/information-resources/guidance-for-essential-medical-surveillance/ (accessed 11 August 2016).
  16. Down's Syndrome Association. For professionals: annual health check information for GPs. Available at: www.downs-syndrome.org.uk/for-professionals/health-medical/annual-health-check-information-for-gps/ (accessed 11 August 2016).
  17. American Thoracic Society/European Respiratory Society Task Force. American Thoracic Society/European Respiratory Society statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003; 168 (7): 818–900. Available at: www.atsjournals.org/doi/pdf/10.1164/rccm.168.7.818G

Common genetic conditions: a guide for GPs—part 1