People have the right to be involved in discussions and make informed decisions about their care, as described in your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
See also the section on information needs and support.
1.1.1 Suspect familial hypercholesterolaemia (FH) as a possible diagnosis in adults with:
1.1.2 Systematically search primary care records for people:
younger than 30 years, with a total cholesterol concentration greater than 7.5 mmol/l and
30 years or older, with a total cholesterol concentration greater than 9.0 mmol/l
as these are the people who are at highest risk of FH. 
1.1.3 For people with a personal or family history of premature coronary heart disease (an event before 60 years in an index individual or first-degree relative), but whose total cholesterol is unknown, offer to measure their total cholesterol. 
1.1.4 Healthcare professionals should exclude secondary causes of hypercholesterolaemia before a diagnosis of FH is considered. 
1.1.5 Use the Simon Broome criteria (see appendix F of the full guideline) or Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH in primary care settings. This should be done by a healthcare professional competent in using the criteria. 
1.1.6 Refer the person to an FH specialist service for DNA testing if they meet the Simon Broome criteria for possible or definite FH, or they have a DLCN score greater than 5. 
1.1.8 Healthcare professionals should consider a clinical diagnosis of homozygous FH in adults with a low-density lipoprotein cholesterol (LDL‑C) concentration greater than 13 mmol/l and in children/young people with an LDL‑C concentration greater than 11 mmol/l. All people with a clinical diagnosis of homozygous FH should be offered referral to a specialist centre. 
1.1.9 To confirm a diagnosis of FH, healthcare professionals should undertake two measurements of LDL‑C concentration because biological and analytical variability occurs. 
1.1.10 When considering a diagnosis of FH, healthcare professionals with expertise in FH should use standardised pedigree terminology to document, when possible, at least a three-generation pedigree. This should include relatives' age of onset of coronary heart disease, lipid concentrations and smoking history. For deceased relatives, the age and cause of death, and smoking history should be documented. If possible, the index individual should verify this information with other family members. 
1.1.11 Ultrasonography of the Achilles tendon is not recommended in the diagnosis of FH. 
1.1.12 Coronary heart disease risk estimation tools, such as QRISK2 and those based on the Framingham algorithm, should not be used because people with FH are already at a high risk of premature coronary heart disease. [2008, amended 2017]
1.1.13 Inform all people who have an identified mutation diagnostic of FH that they have an unequivocal diagnosis of FH even if their LDL‑C concentration does not meet the diagnostic criteria (see recommendation 1.1.5). [2008, amended 2017]
1.1.14 In a family where a DNA mutation is identified, not all family members may have inherited the mutation. When DNA testing has excluded FH in a member of a family, healthcare professionals should manage the person's coronary heart disease risk as in the general population (see NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification). 
1.1.15 In children aged 0–10 years at risk of FH because of 1 affected parent, offer a DNA test at the earliest opportunity. If testing of a child at risk has not been undertaken by the age of 10 years, offer an additional opportunity for a DNA test. 
1.1.16 In children at risk of homozygous FH because of two affected parents or because of the presence of clinical signs, for example, cutaneous lipid deposits (xanthomata), LDL‑C concentration should be measured before the age of 5 years or at the earliest opportunity thereafter. If the LDL‑C concentration is greater than 11 mmol/l then a clinical diagnosis of homozygous FH should be considered. 
1.2.2 Healthcare professionals should offer all people with FH a referral to a specialist with expertise in FH for confirmation of diagnosis and initiation of cascade testing. 
1.2.3 Healthcare professionals with expertise in FH should explain what is meant by cascade testing, and discuss its implications with all people with FH. 
1.2.4 Healthcare professionals should be aware of the latest guidance on data protection when undertaking cascade testing. 
Recommendations 18.104.22.168 to 22.214.171.124 have been adapted from NICE's technology appraisal guidance on ezetimibe for treating primary (heterozygous-familial and non-familial) hypercholesterolaemia.
126.96.36.199 When offering lipid-modifying drug therapy to adults with FH, healthcare professionals should inform the person that this treatment should be lifelong. .
188.8.131.52 Offer a high-intensity statin with the lowest acquisition cost as the initial treatment for all adults with FH and aim for at least a 50% reduction in LDL‑C concentration from the baseline measurement. 
184.108.40.206 The dose of statin should be increased to the maximum licensed or tolerated dose to achieve a recommended reduction in LDL‑C concentration of greater than 50% from baseline (that is, LDL‑C concentration before treatment). 
220.127.116.11 Ezetimibe monotherapy is recommended as an option for treating primary heterozygous‑familial hypercholesterolaemia in adults in whom initial statin therapy is contraindicated. 
18.104.22.168 Ezetimibe monotherapy is recommended as an option for treating primary heterozygous‑familial hypercholesterolaemia in adults who cannot tolerate statin therapy (as defined in recommendation 22.214.171.124). 
126.96.36.199 Ezetimibe, co‑administered with initial statin therapy, is recommended as an option for treating primary (heterozygous‑familial) hypercholesterolaemia in adults who have started statin therapy when:
serum total or low‑density lipoprotein (LDL) cholesterol concentration is not appropriately controlled (as defined in recommendation 188.8.131.52) either after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy (as defined in recommendation 184.108.40.206) and
a change from initial statin therapy to an alternative statin is being considered. 
220.127.116.11 When prescribing ezetimibe co-administered with a statin, ezetimibe should be prescribed on the basis of lowest acquisition cost. 
18.104.22.168 For the purposes of this guidance, appropriate control of cholesterol concentrations should be based on individualised risk assessment according to national guidance on managing cardiovascular disease in the relevant populations. 
22.214.171.124 For the purposes of this guidance, intolerance to initial statin therapy is defined as the presence of clinically significant adverse effects that represent an unacceptable risk to the patient or that may reduce compliance with therapy. 
126.96.36.199 Healthcare professionals should offer adults with FH a referral to a specialist with expertise in FH if treatment with the maximum tolerated dose of a high-intensity statin and ezetimibe does not achieve a recommended reduction in LDL‑C concentration of greater than 50% from baseline (that is, LDL‑C concentration before treatment). 
188.8.131.52 Healthcare professionals should offer adults with FH a referral to a specialist with expertise in FH for consideration for further treatment if they are assessed to be at very high risk of a coronary event, that is, if they have any of the following.
184.108.40.206 For recommendations on managing primary heterozygous familial hypercholesterolaemia in people whose LDL‑C levels are not adequately controlled despite maximal tolerated lipid-lowering therapy, see the NICE technology appraisal guidance on alirocumab and evolocumab. 
220.127.116.11 Adults with FH with intolerance or contraindications to statins or ezetimibe should be offered a referral to a specialist with expertise in FH for consideration for treatment with either a bile acid sequestrant (resin) or a fibrate to reduce their LDL‑C concentration. [2008, amended 2017]
18.104.22.168 The decision to offer treatment with a bile acid sequestrant (resin) or a fibrate in addition to initial statin therapy should be taken by a specialist with expertise in FH. [2008, amended 2017]
22.214.171.124 Healthcare professionals should exercise caution when adding a fibrate to a statin because of the risk of muscle-related side effects (including rhabdomyolysis). Gemfibrozil and statins should not be used together. [2008, amended 2017]
126.96.36.199 Healthcare professionals should offer all children and young people diagnosed with, or being investigated for, a diagnosis of FH a referral to a specialist with expertise in FH in children and young people. This should be in an appropriate child/young person-focused setting that meets the standards within the National service framework for children, young people and maternity services. 
188.8.131.52 Lipid-modifying drug therapy for a child or young person with FH should usually be considered by the age of 10 years. The decision to defer or offer lipid-modifying drug therapy for a child or young person should take into account:
the age of onset of coronary heart disease within the family, and
the presence of other cardiovascular risk factors, including their LDL‑C concentration. 
184.108.40.206 When offering lipid-modifying drug therapy for children or young people, healthcare professionals should inform the child/young person and their parent/carer that this treatment should be lifelong. 
220.127.116.11 Offer statins to children with FH by the age of 10 years or at the earliest opportunity thereafter. 
18.104.22.168 For children and young people with FH, consider a statin that is licensed for use in the appropriate age group. 
22.214.171.124 Statin therapy for children and young people should be initiated by a healthcare professional with expertise in treating children and young people with FH, and in a child-focused setting. [2008, amended 2017]
126.96.36.199 Statin therapy for children and young people with FH should usually be prescribed at the doses specified in the 'British national formulary (BNF) for children'. 
188.8.131.52 In exceptional instances, for example, when there is a family history of coronary heart disease in early adulthood, healthcare professionals with expertise in FH in children and young people should consider offering:
a higher dose of statin than is licensed for use in the appropriate age group, and/or
more than one lipid-modifying drug therapy, and/or
lipid-modifying drug therapy before the age of 10 years. 
184.108.40.206 In children and young people with homozygous FH, LDL‑C concentration may be lowered by lipid-modifying drug therapy and this should be considered before LDL apheresis (see section 1.3.3). 
220.127.116.11 In children and young people with FH who are intolerant of statins, healthcare professionals should consider offering other lipid-modifying drug therapies capable of reducing LDL‑C concentration (such as bile acid sequestrants [resins], fibrates or ezetimibe). 
18.104.22.168 Routine monitoring of growth and pubertal development in children and young people with FH is recommended. 
22.214.171.124 Decisions about the choice of treatment should be made following discussion with the adult or child/young person and their parent/carer, and be informed by consideration of concomitant medication, comorbidities, safety and tolerability. 
126.96.36.199 Healthcare professionals should consider offering fat-soluble vitamin (vitamins A, D and K) and folic acid supplementation for adults or children/young people with FH who are receiving long-term treatment with bile acid sequestrants (resins). 
188.8.131.52 Healthcare professionals should offer people with FH a referral to a specialist with expertise in FH if they are experiencing side effects that compromise concordance with lipid-modifying drug therapy. 
184.108.40.206 When the decision has been made to offer adults or children/young people with FH treatment with a statin, baseline liver and muscle enzymes (including transaminases and creatine kinase, respectively) should be measured before initiation of therapy. However, people with raised liver or muscle enzymes should not routinely be excluded from statin therapy. 
220.127.116.11 Routine monitoring of creatine kinase is not recommended in asymptomatic adults or children/young people with FH who are receiving treatment with a statin. 
18.104.22.168 Healthcare professionals should regard lifestyle advice as a component of medical management, and not as a substitute for lipid-modifying drug therapy. 
22.214.171.124 All people with FH should be offered individualised nutritional advice from a healthcare professional with specific expertise in nutrition. 
126.96.36.199 People with FH should be advised to consume a diet in which:
total fat intake is 30% or less of total energy intake
saturated fats are 10% or less of total energy intake
intake of dietary cholesterol is less than 300 mg/day
saturated fats are replaced by increasing the intake of monounsaturated and polyunsaturated fats.
It may be helpful to suggest they look at Live Well for further practical advice. 
188.8.131.52 Healthcare professionals should advise people with FH to eat at least five portions of fruit and vegetables a day, in line with national guidance for the general population. Examples of what constitutes a portion can be found at Live Well. 
184.108.40.206 Healthcare professionals should advise people with FH to consume at least two portions of fish a week (one of which should be oily fish). Pregnant women with FH should be advised to limit their oily fish to two portions a week. Further information and advice on healthy cooking methods can be found at Live Well. 
220.127.116.11 Healthcare professionals should advise people with FH that if they wish to consume food products containing stanols and sterols these need to be taken consistently to be effective. 
18.104.22.168 People with FH should not routinely be recommended to take omega-3 fatty acid supplements. For people with FH who have already had a myocardial infarction (MI), refer to the NICE guideline on myocardial infarction. 
22.214.171.124 Healthcare professionals should advise people with FH to undertake physical activity in line with national guidance for the general population (see the UK Chief Medical Officers' physical activity guidelines for more information). 
126.96.36.199 Healthcare professionals should encourage people who are unable to perform moderate-intensity physical activity because of comorbidity, medical conditions or personal circumstances to exercise at their maximum safe capacity (see the UK Chief Medical Officers' physical activity guidelines for more information). 
188.8.131.52 Recommended types of physical activity include those that can be incorporated into everyday life, such as brisk walking, using stairs and cycling (see the UK Chief Medical Officers' physical activity guidelines for more information). 
184.108.40.206 Healthcare professionals should offer people with FH who are overweight or obese appropriate advice and support to achieve and maintain a healthy weight in line with NICE's guideline on obesity prevention. 
220.127.116.11 As for the general population, alcohol consumption for adult men with FH should be limited to up to 3–4 units a day, and for adult women with FH up to 2–3 units of alcohol a day. Binge drinking should be avoided. Further information can be found at Live Well. 
18.104.22.168 People with FH, especially children, who do not smoke should be strongly discouraged from starting because of their already greatly increased risk of coronary heart disease. 
22.214.171.124 People with FH who smoke should be advised that, because of their already greatly increased risk of coronary heart disease, they should stop. 
126.96.36.199 Healthcare professionals should offer people who want to stop smoking support and advice, and referral to an intensive support service, in line with the NICE guidance on smoking cessation. 
188.8.131.52 People with FH who are unwilling or unable to accept a referral to an intensive support service should be offered pharmacotherapy in line with NICE guidance on nicotine replacement therapy and bupropion, and varenicline. See NICE guidance on smoking cessation, including NICE's technology appraisal guidance on varenicline for smoking cessation. 
184.108.40.206 Healthcare professionals should consider offering LDL apheresis for the treatment of adults and children/young people with homozygous FH (see recommendations 1.1.8 and 1.1.16). The timing of initiation of LDL apheresis should depend on factors such as the person's response to lipid-modifying drug therapy and presence of coronary heart disease. 
220.127.116.11 In exceptional instances (such as when there is progressive, symptomatic coronary heart disease, despite maximal tolerated lipid-modifying drug therapy and optimal medical and surgical therapy), healthcare professionals should consider offering LDL apheresis for the treatment of people with heterozygous FH. This should take place in a specialist centre on a case-by-case basis and data recorded in an appropriate registry. 
18.104.22.168 Healthcare professionals should recommend arterio-venous fistulae as the preferred method of access for people with FH who are offered treatment with LDL apheresis. People should be counselled about possible benefits and complications of this procedure. 
22.214.171.124 Routine monitoring of the person's iron status should be carried out and iron supplementation initiated as required for people with FH who are receiving treatment with LDL apheresis. 
126.96.36.199 Angiotensin-converting enzyme (ACE) inhibitors should not be used in people with FH who are being treated with LDL apheresis. Instead, ACE inhibitors should be substituted with angiotensin-receptor blocking agents. 
188.8.131.52 People with FH who are receiving blood pressure-lowering drug therapy should have this reviewed and considered for discontinuation on the morning of the day of LDL apheresis. 
184.108.40.206 People with FH who are taking warfarin should have this discontinued approximately 4 days before LDL apheresis and substituted with low molecular weight heparin. 
220.127.116.11 People with FH who are receiving anti-platelet therapy should have this continued if they are receiving treatment with LDL apheresis. 
18.104.22.168 Healthcare professionals should consider offering liver transplantation as an option for the treatment of people with homozygous FH after treatment with lipid-modifying drug therapy and LDL apheresis. 
22.214.171.124 The decision to refer for liver transplantation should take place in partnership with the patient and/or their relatives in an appropriate specialist setting, following a discussion of the benefits and potential harms of undertaking or declining transplantation. 
126.96.36.199 During the assessment and communication of familial risk, people should receive clear and appropriate educational information about FH, the process of family testing, DNA testing and the measurement of LDL‑C concentration. 
188.8.131.52 A healthcare professional with expertise in FH should provide information to people with FH on their specific level of risk of coronary heart disease, its implications for them and their families, lifestyle advice and treatment options. 
184.108.40.206 Healthcare professionals with expertise in FH should encourage people with FH to contact their relatives to inform them of their potential risk and so that cascade testing can take place. 
220.127.116.11 When considering cascade testing, a healthcare professional with expertise in FH should offer to facilitate the sharing of information about FH with family members. 
18.104.22.168 Healthcare professionals should offer people with FH and their families written advice and information about patient support groups. 
22.214.171.124 When lipid-modifying drug therapy is first considered for women and girls, the risks for future pregnancy and the fetus while taking lipid-modifying drug therapy should be discussed. This discussion should be revisited at least annually. 
126.96.36.199 Healthcare professionals should give women and girls with FH specific information tailored to their needs and should offer a choice of effective contraceptive methods. 
188.8.131.52 Combined oral contraceptives (COCs) are not generally contraindicated for women and girls being treated with lipid-modifying drug therapy. However, because there is a potential small increased risk of cardiovascular events with the use of COCs, healthcare professionals should consider other forms of contraception. Prescribers should refer to the summary of product characteristics of COCs and the relevant lipid-modifying drugs for their specific contraindications. 
184.108.40.206 Healthcare professionals should be aware that, in general, there is no reason to advise against pregnancy or breastfeeding in women with FH. 
220.127.116.11 Healthcare professionals should advise women with FH that lipid-modifying drug therapy should not be taken if they are planning to conceive or during pregnancy, because of the potential risk of fetal abnormality. Women should be advised that lipid-modifying drug therapy should be stopped 3 months before they attempt to conceive. 
18.104.22.168 Women with FH who conceive while taking statins or other systemically absorbed lipid-modifying drug therapy should be advised to stop treatment immediately and they should be offered an urgent referral to an obstetrician for a fetal assessment. Women should be fully informed about the nature and purpose of the assessment. 
22.214.171.124 Women with FH who have conceived while taking statins or other systemically absorbed lipid-modifying drug therapy and have had a fetal assessment should be given time, opportunity and full information to consider their options (including the advantages and disadvantages) of continuing with their pregnancy. 
126.96.36.199 Shared-care arrangements, to include expertise in cardiology and obstetrics, should be made for women with FH who are considering pregnancy or are pregnant. Such care should include an assessment of coronary heart disease risk, particularly to exclude aortic stenosis. This is essential for women with homozygous FH. 
188.8.131.52 Serum cholesterol concentrations should not be measured routinely during pregnancy. 
184.108.40.206 Women with FH who are pregnant should be advised on the potential risks and benefits of re-starting lipid-modifying drug therapy for the mother and breastfed infant. Resins are the only lipid-modifying drug therapy that should be considered during lactation. 
220.127.116.11 All people with FH should be offered a regular structured review that is carried out at least annually. 
18.104.22.168 A baseline electrocardiogram (ECG) should be considered for adults with FH. 
22.214.171.124 Healthcare professionals should record the progress of cascade testing among the relatives of a person with FH as part of the structured review. This should include at least the first- and second-degree relatives- and, when possible, third-degree biological relatives. If there are still relatives who have not been tested, further action should be discussed. 
126.96.36.199 Healthcare professionals should update the family pedigree of a person with FH and note any changes in the coronary heart disease status of their relatives as part of the structured review. This should include at least the first- and second- and, when possible, third-degree biological relatives. 
188.8.131.52 Structured review should include assessment of any symptoms of coronary heart disease and smoking status, a fasting lipid profile, and discussion about concordance with medication, possible side effects of treatment the patient may be experiencing, and any changes in lifestyle or lipid-modifying drug therapy that may be required to achieve the recommended LDL‑C concentration (see the section on management). 
184.108.40.206 Healthcare professionals should offer people with FH an urgent referral to a specialist with expertise in cardiology for evaluation if they have symptoms or signs of possible coronary heart disease which are not immediately life-threatening. A low threshold for referral is recommended. 
220.127.116.11 A person with FH with symptoms or signs of possible coronary heart disease which are immediately life-threatening (for example, acute coronary syndrome) should be referred to hospital as an emergency in line with advice for the general population. 
18.104.22.168 Healthcare professionals should consider offering people with FH a referral for evaluation of coronary heart disease if they have a family history of coronary heart disease in early adulthood, or two or more other cardiovascular risk factors (for example, they are male, they smoke, or they have hypertension or diabetes). 
22.214.171.124 In asymptomatic children and young people with heterozygous FH, evaluation of coronary heart disease is unlikely to detect clinically significant disease and referral should not be routinely offered. 
For the purposes of this guideline, 'adults' includes all persons with familial hypercholesterolaemia (FH; heterozygous or homozygous) who are 16 years and older.
Cascade testing is a mechanism for identifying people at risk of a genetic condition by a process of family tracing. For FH the test employed is a DNA test where a disease-causing mutation has been identified in the index individual/proband.
For the purposes of this guideline, 'children' refers to persons younger than 10 years; 'young people' refers to persons from 10 years of age up to the age of 15 years. The definitions used here are not prescriptive and healthcare professionals are expected to exercise their judgement and consider the wishes of the patients, and their families or carers when interpreting these terms in individual instances.
Child-focused refers to valuing the child's view and validating their voice in making decisions impacting their lives. A child-focused facility or space is one designed from the viewpoint of the service recipients.
An event is defined as angina, acute coronary syndrome, myocardial infarction, need for coronary artery bypass grafting, need for percutaneous coronary intervention or definite coronary artery disease on coronary angiography.
A method of assessing whether a person has FH. It is based on personal and family medical history, clinical signs, LDL‑C concentration and DNA testing. A score is attributed to each component; the higher the score, the higher the likelihood of the person having FH.
The structure and relationships within the family that relates information about diseases in family members.
High LDL‑C concentration in the blood caused by an inherited mutation from one parent only. People with FH are at increased risk of cardiovascular disease.
Statins are classified as high intensity if they produce average reductions in LDL-C greater than 40%. See appendix A of NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification.
Very high LDL‑C concentration in the blood caused by an inherited mutation from both parents. When a person inherits exactly the same affected gene from both parents this is called truly 'homozygous' FH. When the mutations in the LDL receptor gene (or equivalent) are different, this state is called 'compound heterozygous'. In general, the overall effect in both states is similar, in that LDL‑C concentrations are very high. Both groups of patients have the same clinical pattern and high risk of cardiovascular disease.
For clinical purposes, both homozygous FH and compound heterozygous FH can be regarded as behaving in a similar manner. Therefore, for the purposes of this guideline the term 'homozygous FH' is used to also encompass compound heterozygous FH.
The original patient who is the starting point for follow-up of other members of a family when investigating for possible causative genetic factors of the presenting condition.
These terms refer to the measurement of total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL‑C), and LDL‑C. LDL‑C is not usually measured directly but calculated from the TC, TGs and HDL‑C, ideally using a fasting sample.
Such tests are usually done in a clinical biochemistry laboratory.
An identified change in the DNA sequence of a gene that is predicted to damage the normal function of the gene and so cause disease.
A method of characterising the relatives of an index individual/case and their family relationship as well as problems or illnesses within the family. This information, often represented graphically as a family tree, facilitates analysis of inheritance patterns. Study of a trait or disease begins with the affected person (the index individual). The pedigree is drawn as the relatives are described. One begins with the siblings of the index individual and proceeds to the parents; relatives of the parents, including brothers, sisters, nephews, nieces, grandparents, and so on. At least three generations are usually included. Illnesses, hospitalisations, causes of death, miscarriages, abortions, congenital anomalies, and any other unusual features are recorded.
For the purpose of this guideline, this refers to a coronary event that has occurred before 60 years of age in an index individual or first-degree relative.
The affected (index) individual through whom a family with a genetic disorder is ascertained.
A person's biological grandparent, grandchild, uncle, aunt, niece, nephew, half sister or half brother.
Causes of hyperlipidaemia other than familial, including uncontrolled diabetes mellitus, obesity, excess alcohol consumption, untreated hypothyroidism and some medications, for example, thiazide diuretics and ciclosporin.
The definition of a specialist centre is not rigid and is based on a combination of patient treatment services, numbers and ages of people attending there, the presence of a multi-disciplinary team (which may include, for example, physicians, lipidologists, specialist nurses, pharmacists and dietitians), the ability to manage the more unusual manifestations of the condition and the additional functions such as research, education and standard setting. Care is supervised by expert healthcare professionals but shared with local hospitals and primary care teams. Although details of the model may vary between patients and areas, the key is that specialist supervision oversees local provision with the patient seen at diagnosis for initial assessment and then at least annually for review.
A clinically detectable nodularity and/or thickening of the tendons caused by infiltration with lipid-laden histiocytes (macrophages in connective tissue).
A distinctive feature of FH that most frequently affects the Achilles tendons but can also involve tendons on the back of the hands, elbows and knees.
A person's biological great grandparent, great grandchild, great aunt, great uncle, first cousin, grand nephew or grand niece.