Drs Rosalyn Jewell, Schaida Schirwani, and Jude Hayward discuss key aspects of genetic conditions, including breast cancer and cystic fibrosis, that GPs should be aware of 

schirwani schaida

Dr Schaida Schirwani

Read this article to learn more about:

  • the diagnosis and management of neurofibromatosis type 1, breast cancer, hereditary haemochromatosis, cystic fibrosis, and conditions with multifactorial inheritance
  • a typical patient presentation through example case studies
  • when testing of first- and second-degree relatives is appropriate.

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 2 covers neurofibromatosis type 1 (NF1), breast cancer, hereditary haemochromatosis, cystic fibrosis, and conditions with multifactorial inheritance. Part 1 focuses on familial hypercholesterolaemia, autosomal dominant polycystic kidney disease, Down syndrome, and alpha-1 antitrypsin deficiency.

Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a common neuro-cutaneous condition with a birth incidence of 1 in 2500–3000.1 The complications are diverse and disease expression varies, even within the same family. The condition is inherited in a dominant manner, which means that children of an individual with NF1 will have a 50% risk of having the same condition. The diagnosis of NF1 is usually clinical, based on the presence of two or more diagnostic criteria (see Box 1, below).

Some 10% of the general population will have one or more café-au-lait patches.1

Box 1: Diagnostic criteria for neurofibromatosis type 11

  • Six or more café-au-lait macules (>0.5 cm in children or >1.5 cm in adults)
  • Two or more cutaneous or subcutaneous neurofibromas or one plexiform neurofibroma
  • Axillary or groin freckling aa Optic pathway glioma
  • Two or more Lisch nodules (iris hamartomas seen on slit lamp examination)
  • Bony dysplasia (sphenoid wing dysplasia, bowing of long bone +/- pseudarthrosis)
  • First-degree relative with neurofibromatosis type 1.

For terms used in this article see Box 2, below

Box 2: Terms used in this text

  • 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.
Miss K brings her 2-year-old daughter to see you as she has noticed several brown 'birthmarks' continuing to appear over her daughter's back and arms.

Management of neurofibromatosis type 1

The mainstay in the management of NF1 is patient education, monitoring for disease manifestations that occur at specific ages, and symptomatic treatment of complications if indicated.1 (see Table 1, below for list of complications).

Table 1: Possible complications of neurofibromatosis type 11
  • Cutaneous and subcutaneous neurofibromas: refer for removal if unsightly or if they cause irritation or pain
  • Plexiform neurofibromas: refer to a specialist NF1 service, if sudden increase in size, change in texture, or unexplained pain as it may indicate malignant transformation.
Learning difficulties and behavioural problems
  • Children should have yearly developmental assessment under a paediatrician.
  • Consider renal artery stenosis (usually occurs at age less than 20 years or in pregnancy) or phaeochromocytoma.
Optic pathway glioma
  • Uncommon in adults. Often asymptomatic but it can present with various visual problems (e.g. visual field loss and abnormal colour vision).
Neurological problems
  • Headache on waking, vomiting in the morning, and altered consciousness are suggestive of raised intracranial pressure and require urgent assessment and referral
  • Malignant peripheral nerve sheath tumours present with persistent pain, new or unexplained neurological deficit, or sphincter disturbance
  • Epilepsy occurs in 6–7% of patients with NF1.
Psychological problems
  • Disfigurement as a result of neurofibromas may cause issues with self-image.
Considerations for women and family planning
  • Women with NF1 are at moderately increased risk of breast cancer. Refer to local breast screening centre for annual mammography from the age of 40 years, as per NICE guideline for Familial breast cancer2,3
  • For women with NF1, close liaison between an obstetrician and a neurofibromatosis clinician is advised1
  • Couples who are planning a pregnancy should be referred to clinical genetics for discussion of risks to offspring and prenatal options.1
Gastrointestinal problems
  • Abdominal pain, bloating, constipation, dyspepsia, bleeding, or anaemia may indicate a neurofibroma in the digestive tract or gastrointestinal stromal tumour (GIST) and should be investigated.
Bony problems
  • The majority of orthopaedic problems in NF1 are evident in childhood (e.g. tibial bowing, scoliosis). Non-ossifying fibromas can cause pathological fracture and pain in adults and need to be differentiated from malignant tumours1
  • There is increased risk of osteoporosis and greater incidence of vitamin D deficiency in adults with NF1. There is some evidence to support the importance of preventative treatment with vitamin D to improve bone mineral density.4
NF1=neurofibromatosis type 1

Children with NF1 should have annual follow up with a paediatrician until adulthood and an ophthalmologist until the age of 7 years. A new squint in a child with NF1 should be referred urgently to exclude optic glioma. Parents of an affected child should also be examined to establish whether they have NF1, as adults with NF1 require regular surveillance. Educating people with NF1 about their condition should start from adolescence.1

Miss K returns to see you after the appointment with the geneticist. She has also been diagnosed with NF1 and has come for a 'check-up'.

Annual follow up of adults with NF1 can take place within a specialist clinic or primary care. It should include:

  • blood-pressure measurement
  • referral for removal of any neurofibromas that have become troublesome
  • questions about and assessment for any signs and symptoms suggestive of the complications listed in Table 1 (above).

Breast cancer

Breast cancer is a common disease. Approximately 1 in 8 women in the UK will develop breast cancer during their lifetime.5 BRCA1 and BRCA2 mutations probably only account for around 2% of breast cancers overall, but may explain 15–20% of cases where there is a first-degree relative (for terms used in this article see Box 2, above) with breast cancer.6,7

Familial breast cancer is suspected in individuals with multiple family members affected by breast, ovarian, or related cancers.

Mrs Y is a 45-year-old woman who has a sister recently diagnosed with breast cancer at the age of 48 and her mother also had breast cancer some years ago. She is concerned about her risk.

When an individual with no personal family history of breast cancer presents with breast symptoms or has concerns about family history of breast cancer, a first- and second-degree family history of both the paternal and maternal side should be taken in primary care to assess risk according to guidance in NICE CG164 for Familial breast cancer.3

Important information includes the ages at which people were diagnosed with cancer, the site of tumours, whether there were multiple cancers (including bilateral breast cancer), and whether the family has Jewish ancestry in view of the higher incidence of specific BRCA mutations in this population.

A referral to secondary care should be offered to individuals without a personal history of breast cancer who meet the criteria shown in Box 3 (see below).3

Box 3: Criteria for people without a personal history of breast cancer who should be offered referral to secondary care3

  • One first-degree female relative diagnosed with breast cancer at younger than age 40 years or
  • One first-degree male relative diagnosed with breast cancer at any age or
  • One first-degree relative with bilateral breast cancer where the first primary was diagnosed at younger than age 50 years or
  • Two first-degree relatives, or one first-degree and one second-degree relative, diagnosed with breast cancer at any age or
  • One first-degree or second-degree relative diagnosed with breast cancer at any age and one first-degree or second-degree relative diagnosed with ovarian cancer at any age (one of these should be a first-degree relative) or
  • Three first-degree or second-degree relatives diagnosed with breast cancer at any age.

National Institute for Health and Care Excellence (2013, updated August 2015). Familial breast cancer: classifcation, care and managing breast cancer and related risks in people with a family history of breast cancer. NICE Clinical Guideline 164. Available from: www.nice.org.uk/cg164
NICE has not checked the use of its content in this article to confirm that it accurately reflects the NICE publication from which it is taken.

If there is only one first-or second-degree relative with breast cancer at an age older than 40 years, then the individual can be looked after by primary care.

Discussions with secondary care should occur if there is a complicated or uncertain family history, or if the individual is not eligible for secondary care referral but the family history reveals the following information:3

  • bilateral breast cancer
  • male breast cancer
  • ovarian cancer
  • Jewish ancestry
  • sarcoma in a relative younger than age 45 years
  • glioma or childhood adrenal cortical carcinomas
  • complicated patterns of multiple cancers at a young age
  • paternal history of breast cancer (two or more relatives with breast cancer on the father's side of the family).

Referral to a specialist genetics service may be indicated when a high-risk predisposing gene (e.g. BRCA1, BRCA2, or TP53) mutation is identified in the family.

NICE CG164 recommends that standard written information should be provided for patients with increased risk of breast cancer regarding:3

  • risk information about population level and family history levels of risk, including a definition of family history
  • the message that, if their family history alters, their risk may alter
  • breast awareness information
  • lifestyle advice regarding breast cancer risk, including information about:
    • HRT and oral contraceptives (women only)
    • lifestyle, including diet, alcohol, etc
    • breastfeeding, family size and timing (women only)
  • contact details of those providing support and information, including local and national support groups
  • people should be informed prior to appointments that they can bring a family member/friend with them to appointments
  • details of any trials or studies that may be appropriate...
  • advice to return to discuss any implications if there is a change in family history or breast symptoms develop.

Secondary care will assess eligibility for increased surveillance or chemoprevention and whether referral to the genetics service is required.

Hereditary haemochromatosis

Hereditary haemochromatosis is a common genetic condition, with a carrier frequency of approximately 1 in 10 and a prevalence of up to 1 in 260.8,9 It is an autosomal recessive condition.

A 52-year-old man, Mr J, tells you that he is 'tired all the time' and has also noticed some vague aches and pains. He volunteers that he is under a lot of stress at work, but is keen for blood tests.


A serum ferritin test should be considered. Early features of hereditary haemochromatosis are often non-specific, with generalised lethargy being a common presentation. Other symptoms include weakness, and joint and abdominal pains. Deposition of iron in major organs, including the liver, heart, pituitary gland, and pancreas, results in a bronzed appearance to the skin and serious complications such as cirrhosis and liver cancer, diabetes, cardiomyopathy and arrhythmias, loss of libido, and degenerative arthritis. These can be prevented and life expectancy improved by early diagnosis and treatment, and so referral to a haematologist should be initiated on diagnosis.

Important differential diagnoses of a raised serum ferritin are an acute phase reaction, chronic alcohol consumption, liver inflammation and necrosis (C-reactive protein and liver function tests should be performed) and hepatic steatosis. If these are excluded, a fasting serum transferrin saturation should be performed. Serum ferritin greater than 300 µg/l, or greater than 200 µg/l in premenopausal women or increased fasting transferrin saturation (>45% in females, and >50% in males) are suggestive of clinical haemochromatosis.8–10

Presentation is usually between the ages of 40 and 60 years, but may be later in women as menstruation reduces iron overload.

Genotyping for the two common mutations in the human haemochromatosis protein gene (C282Y and H63D) should be performed if fasting transferrin saturation is raised. This may be requested from primary care.8–10

Liver biopsy is no longer needed to diagnose haemochromatosis but could be considered if the patient has serum ferritin greater than 1000 μg/l, raised aspartate transaminase, hepatomegaly, or is aged over 40 years.8 Treatment is with regular venesection and avoidance of dietary sources containing large amounts of iron.8

Following his diagnosis with hereditary haemochromatosis, Mr J's 28-year-old daughter presents requesting 'a test'.

It is appropriate to offer testing to first-degree relatives of people with hereditary haemochromatosis, as penetrance is incomplete, meaning that only 10–33% of homozygotes for C282Y will develop haemochromatosis-related morbidity. Men are more likely to be affected than women (28% versus 1%).8

Alternatively, the partner of an affected person can be tested initially, and if they are not a carrier then their offspring are not at risk of developing the disease, although they will be carriers.

Siblings of patients with hereditary haemochromatosis should be genotyped and screened for iron overload as they are at a 1 in 4 (25%) chance of having the same genotype.

Testing consists of genotyping, serum ferritin and transferrin saturation. Homozygotes for C282Y and compound heterozygotes for C282Y/H63D should be monitored annually by serum iron studies and referred if the serum ferritin becomes raised.8 It is less clear whether patients homozygous for H63D mutations are at risk of iron overload, but yearly iron studies could be considered.10

Cystic fibrosis

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive condition in individuals of northern European ancestry, with an incidence of 1 in 2500 and carrier frequency of about 1 in 25 among Caucasians. The disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.11

Cystic fibrosis affects the respiratory tract, pancreas, intestine, hepatobiliary tract, and the male genital tract. Affected individuals produce secretions that are highly viscous, which results in multi-organ dysfunction. Lower respiratory tract infections and respiratory failure are the major causes of morbidity and mortality in individuals with CF. Pancreatic insufficiency and malabsorption occurs in the majority of individuals with CF. More than 95% of males with CF are infertile due to congenital absence of the vas deferens.12

Individuals with CF have mutations in both copies of their CFTR genes, one copy inherited from each asymptomatic parent carrying a mutation. Each child of two carriers has a 25% (1 in 4) chance of inheriting both mutations and developing CF.12

Mr A is a healthy 25-year-old man who has a younger sister with CF. He tells you that he is planning to start a family and worried that his future children may also have CF.

In the UK, all newborn babies are screened for CF. Therefore most cases are diagnosed soon after birth, but sometimes CF may not be diagnosed until later in life especially in children and adults who were not screened or those who carry rare mutations not tested for as part of the screening programme. People with CF produce higher levels of salt in their sweat than unaffected individuals, therefore where there is a clinical suspicion of CF, a sweat test should be undertaken to confirm the diagnosis.13

Carrier testing is offered to individuals with a family history of CF and their reproductive partners. Also, a relative of anyone found to be a carrier for CF will be offered testing. An asymptomatic sibling of an individual with CF is at a 2 in 3 chance of being a carrier for a mutation. GPs can refer individuals to the local genetics department for carrier testing.12,14

Mr A and his partner were found to be carriers of CF. What options may be available for them to consider?

Genetic counselling is offered to all couples and individuals who are found to be carriers for CF. If both members of a couple are found to be carriers for CF, each pregnancy is at a 25% risk of having CF.14

Antenatal testing is possible for pregnancies at increased risk of CF if the mutation status of the parents is known. Antenatal testing is performed by chorionic villus sampling at around 11 weeks' gestation, or amniocentesis at around the 16 weeks. To ensure that couples considering antenatal testing receive appropriate counselling and advice, a referral should be made to the local clinical genetics service prior to a pregnancy. If a couple at increased risk of having a child with CF present with a pregnancy, an urgent referral should be made to the local clinical genetics service or fetal medicine team for counselling. If a pregnancy is found to have biallelic CF mutation, the parents are given the options of continuing or ending the pregnancy.12,14

Preimplantation genetic diagnosis (PGD) is another option for parents who are carriers of mutations. In PGD, in vitro fertilisation (IVF) techniques are used to screen embryos at early stages for their mutation status. Selected embryos without biallelic mutation are implanted back into the womb. At present, PGD is only available in specialist centres and limited by funding and IVF success rate. Couples considering PGD should be referred to genetic services.15

The same principle of carrier and antenatal testing discussed for CF applies to certain other genetic conditions e.g. Gaucher disease, Tay-Sachs disease, thalassaemia, etc.

Conditions with multifactorial inheritance

Most of the conditions with a genetic basis seen in primary care will follow a multifactorial pattern of inheritance. Multifactorial inheritance occurs where there is interplay between environmental factors and genetic factors, either with contribution from a single gene or from several genes with lower penetrance. This includes many common diseases such as cancer, diabetes, coronary heart disease (CHD), multiple sclerosis, subarachnoid haemorrhage, and cleft palate.

Familial clustering of the disease is often present, as families share genes and environment.

A frequently quoted figure is that 1–5% of people with a multifactorial condition within the general population will have a single-gene disorder that is responsible, and it is important to identify these people as they are often at the highest risk. Important examples are breast cancer, type 2 diabetes, and CHD.

General practitioners have several important roles with regard to multifactorial conditions:

  • identifying individuals at risk of a condition as a result of their family history
  • advising on the risk of becoming affected, so for instance first-degree relatives of a person with multiple sclerosis are at approximately 2.5% absolute risk16
  • advising that even if a condition runs in the family, modifying lifestyle factors can reduce risk, for example in CHD
  • ensuring access to appropriate screening either through national screening programmes (e.g. by encouraging participation in the bowel screening programme) or referral to a geneticist
  • identifying the small but extremely important proportion of people who will have a single-gene disorder.

GP commissioning messages

written by Dr David Jenner, GP, Cullompton, Devon

  • Commissioners should consider:
    • placing aide-memoires and clinical pathways on local referral websites to guide GPs in dealing with (often rare) genetic conditions
    • agreeing on an 'advice and guidance' service with clinical genetics services to help GPs make appropriate referrals and avoid unnecessary ones
  • Transferrin saturation testing and genetic tests should be directly accessible to GPs through primary care, following a simple diagnostic pathway for the investigation of possible haemachromatosis
  • Breast cancer is so common that a family history is often positive:
    • guidance on when to refer for a significant family history should be agreed locally and made available to GPs
  • PbR cost non face-to-face outpatient £23a


PbR=payment by results

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  1. Ferner R, Huson S, Thomas N et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007; 44: 81–88.
  2. Sharif S, Moran A, Huson S et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet 2007; 44: 481–484.
  3. NICE. Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer. NICE, 2013 (updated August 2015). Available at: www.nice.org.uk/cg164
  4. Schnabel C, Jett K, Friedman J et al. Effect of vitamin D3 treatment on bone density in neurofibromatosis 1 patients: a retrospective clinical study. Joint Bone Spine 2013; 80 (3): 315–319.
  5. Cancer Research UK. Breast cancer incidence (invasive) statistics. Available at: www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/incidence-invasive (accessed 27 September 2016).
  6. Peto J, Collins N, Barfoot R et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 1999; 91 (11): 943–949.
  7. Turnbull C, Rahman N. Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet 2008; 9: 321–345.
  8. European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010; 53 (1): 3–22.
  9. Seckington R, Powell L. HFE-associated hereditary hemochromatosis. 2000, updated 2015. In: Pagon R, Adam M, Ardinger H et al, editors. GeneReviews® [internet]. Seattle (WA): University of Washington, Seattle; 1993–2016.
  10. King C, Barton D. Best practice guidelines for the molecular genetic diagnosis of type 1 (HFE-related) hereditary haemochromatosis. BMC Med Genet 2006; 7: 81.
  11. Massie J, Delatycki M. Cystic fibrosis carrier screening. Paediatr Respir Rev 2013; 14 (4): 270–275.
  12. Moskowitz S, Chmiel J, Sternen D et al. CFTR-Related Disorders. 2001, updated 2008. In: Pagon R, Adam M, Ardinger H, et al., editors. GeneReviews® [internet]. Seattle (WA): University of Washington, Seattle; 1993–2016.
  13. Cystic Fibrosis Trust. The sweat test in cystic fibrosis. Cystic Fibrosis Trust, 2016. Available from: www.cysticfibrosis.org.uk/life-with-cystic-fibrosis/publications/factsheets
  14. Cystic Fibrosis Trust. Family genetic testing: the family cascade screening programme for cystic fibrosis. Cystic Fibrosis Trust, 2015. Available from: www.cysticfibrosis.org.uk/life-with-cystic-fibrosis/publications/factsheets
  15. Girardet A, Viart V, Plaza S et al. The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus. Eur J Hum Genet 2016; 24 (4): 469–478.
  16. O'Gorman C, Lin R, Stankovich J, Broadley S. Modelling genetic susceptibility to multiple sclerosis with family data. Neuroepidemiology 2013; 40: 1–12. G

Common genetic conditions: a guide for GPs—part 1