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Serious psychotic and mood disorders can run in families, especially schizophrenia and bipolar disorder, which have a clear genetic component that appears to be complex and poorly understood (see TABLE 18.2). To date no genes causing schizophrenia have been identified, but large regions on some chromosomes have been associated with schizophrenia. Individuals with a first-degree relative with bipolar disorder or purely depressive (unipolar) disorder have an increased risk of a mood disorder, but the genetics are not understood. Tourette syndrome is another psychological disorder that has a hereditary basis through an autosomal dominant gene with variable expression (penetrance).
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HEREDITARY HAEMOGLOBINOPATHIES, HAEMOLYTIC DISORDERS, AND BLEEDING AND CLOTTING DISORDERS9,14
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The commonest haemoglobinopathies are the thalassaemias (see earlier in this chapter), which are caused by a deficiency in the quality of globin chains, whereas other haemoglobinopathies are caused by structural variations in the globin chain. These conditions include HbS (sickle cell), HbC, HbD, HbE, HbO and HbLepore.
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Other inherited conditions that can cause haemolytic anaemia are those with a red cell membrane defect and include hereditary spherocytosis, hereditary elliptocytosis and hereditary stomatocytosis.
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Sickle cell disorders
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The most important abnormality in the haemoglobin (Hb) chain is sickle cell haemoglobin (HbS), which results from a single base mutation of adenine to thymine leading to a substitution of valine for glutamine at position 6 on the β-globin chain. The defective Hb causes the red cells to become deformed in shape—‘sickled’. The sickled cells tend to flow poorly and clog the microcirculation, resulting in hypoxia, which compounds the sickling. Such attacks, which result in tissue infarction, are called ‘crises’. Sickling is precipitated by infection, hypoxia, dehydration, cold and acidosis, and may complicate operations. The autosomal recessive disorder occurs mainly in Africans (25% carry the gene), but it is also found in India, South-East Asia, the Middle East and southern Europe.
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This varies from being mild or asymptomatic to a severe haemolytic anaemia and recurrent painful crises. It may present in children with anaemia and mild jaundice. Children may develop digits of varying lengths from the hand-and-foot syndrome due to infarcts of small bones.
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Features of infarctive sickle crises include:
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bone pain (usually limb bones)
abdominal pain
chest—pleuritic pain
kidney—haematuria
spleen—painful infarcts
precipitated by cold, hypoxia, dehydration or infection
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Hb electrophoresis is needed to confirm the diagnosis.
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Long-term problems include chronic leg ulcers, susceptibility to infection, aseptic necrosis of bone (especially head of femur), blindness and chronic kidney disease. The prognosis is variable. Children in Africa often die within the first year of life. Infection is the commonest cause of death.
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People with this usually have no symptoms unless they are exposed to prolonged hypoxia, such as anaesthesia and flying in non-pressurised aircraft. The disorder is protective against malaria.
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Hereditary spherocytosis
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This is the commonest cause of inherited haemolytic anaemia in northern Europeans. It is an autosomal dominant disorder of variable severity, although in 25% of patients neither parent is affected, suggesting spontaneous mutation in some instances. Jaundice may present at birth or be delayed or occur not at all. Splenomegaly is a feature and splenectomy is considered to be the treatment of choice in severe cases. Maintenance of folic acid levels is important.
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In inherited bleeding deficiency disorders, there are deficiencies of vital factors (see CHAPTER 39). The common significant disorders are:
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haemophilia A (factor VIII deficiency)—X-linked recessive
haemophilia B (factor IX deficiency)—X-linked recessive
von Willebrand disease (deficiency of factor VIII:C + defective platelet factor)—autosomal dominant
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This should be considered in patients with a past and/or family history of DVT or other thrombotic episodes (see CHAPTER 131). There are several causes, including important inherited factors, which are:
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It is important to be aware of these factors, especially in people with a past history of unexplained thrombotic episodes. Prescribing the oral contraceptive pill (OCP) is an issue but preliminary screening for thrombophilias is not recommended. In factor V Leiden, the most common factor in this group, there is a 35-fold increased risk of thrombosis for those taking the OCP.
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CHROMOSOMAL/MICRODELETION SYNDROMES (CHILDHOOD EXPRESSION)9
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The following disorders, whose clinical features manifest in children, present with developmental and intellectual disability.
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Down syndrome (trisomy 21) is based on typical facial features (flat facies, slanting eyes, prominent epicanthic folds, small ears), hypotonia, intellectual disability and a single palmar crease.
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DxT typical facies + hypotonia + single palmar crease ➜ Down syndrome
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95% have extra chromosome of maternal origin (trisomy 21)
Remainder due to either unbalances, translocations or mosaicism
Prenatal screening tests include early ultrasound (nuchal lucency) and maternal serum screening in first trimester (serum maternal and fetal DNA). Karyotyping of chorionic villus sampling on amniocytes for pregnancies at risk is available.
Prevalence 1 in 650 live births
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Seizures (usually later onset)
Impaired hearing
Leukaemia
Hypothyroidism
Congenital anomalies (e.g. heart, duodenal atresia, Hirschsprung, TOF)
Alzheimer-like dementia (fourth–fifth decade)
Atlantoaxial instability
Coeliac disease
Diabetes
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Assess child's capabilities
Refer to agencies for assessment (e.g. hearing, vision, developmental disability unit)
Advise on sexuality, especially for females (i.e. menstrual management, contraception) as fertility must be presumed
Genetic counselling for parents
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incidence 1 in 2000 live births (approx.)
microcephaly
facial abnormalities, e.g. cleft lip/palate
malformations of major organs
malformations of hands and feet—clenched hand posture
neural tube defect
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Prognosis is poor—about one-third die in first month, <10% live beyond 12 months.
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Prenatal diagnosis is available.
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Prognosis is poor—50% die within first month.
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Fragile X syndrome (FXS)15
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FXS presents as a classic physical phenotype with large prominent ears, long narrow face, macro-orchidism and intellectual disability. It is the most common inherited cause known of developmental disability and should always be considered. The cause is the result of an increase in the size of a trinucleotide repeat in the FMR-I gene on the X chromosome (the number of sequences determines carrier or full mutant status). Any individual with significant development delay should be tested for FXS.
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DxT characteristic facies + intellectual disability + large testes ➜ FXS
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M:F ratio 2:1
Prevalence of full mutation 1 in 4000
Variable spectrum of characteristic features, making detection difficult in some cases
1 in 250 are pre-mutation carriers
Family history of intellectual disability
Affects all ethnic groups
Females may appear normal but may be affected
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Associated disorders16
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Intellectual disability (IQ <70)
Autism or autistic-like behaviour
Attention deficit in 10% (with or without hyperactivity)
Seizures (20%)
Connective tissue abnormalities
Learning disability and speech delay
Coordination difficulty
Primary ovarian insufficiency
Late onset tremor/ataxia syndrome
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Careful genetic appraisal and counselling
Assessment of child's capabilities
Multidisciplinary assessment, including developmental disability unit
Referral for integration of speech and language therapy, special education, behaviour management
Pharmacological treatment of any epilepsy, or attention or mood behaviour disorders
Medications may determine whether the child remains in the community or not
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Prader–Willi syndrome
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This uncommon disorder (1 in 10 000–15 000) has classic features, especially a bizarre appetite and eating habits, of which the GP should be aware. It is probable that there are many undiagnosed cases in the community. The most common cause is a deletion of the short arm of chromosome 15.
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DxT neonatal hypotonia + failure to thrive + obesity (later) ➜ Prader–Willi syndrome
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Hypotonic infants with weak suction and failure to thrive, then voracious appetite causing morbid obesity
Usually manifests at 3 years
Intellectual disability
Narrow forehead and turned-down mouth
Small hands and feet
Hypogonadism
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With proper care and support, longevity into the eighth decade is a reality.14
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Williams syndrome (idiopathic hypercalcaemia or elfin face syndrome) is due to a microdeletion on chromosome 7, a deletion in the elastin gene.
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Children have a distinctive elfin facial appearance, mild pre- and postnatal growth retardation, mild microcephaly and mild-to-moderate developmental delay. In the first 2 years of life, feeding problems, vomiting, irritability, hyperacusis, constipation and failure to thrive may lead to presentation, but children are rarely diagnosed at this stage.
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DxT ‘elfin’ face + intellectual disability + aortic stenosis ➜ Williams syndrome
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This is a systemic connective tissue disorder characterised by abnormalities of the skeletal, cardiovascular and ocular systems. It has variable expressions and is a potentially lethal disorder. If untreated, death in the 30s and 40s is common.
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DxT tall stature + dislocated lens and myopia + aortic root dilatation ➜ Marfan syndrome
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Mutations in the fibrillin gene on chromosome 15
Autosomal dominant
Prevalence about 5 per 100 000
No specific laboratory test to date
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Disproportionally tall and thin
Long digits—arachnodactyly
Kyphoscoliosis
Joint laxity (e.g. genu recurvatum)
Myopia and ectopic ocular lens
High arched palate
Aortic dilatation and dissection
Mitral valve prolapse
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Needs surveillance of eyes, heart and thoracic aorta
Echocardiography, possibly aortic root dilatation
Long-term beta blockade therapy reduces rate of dilatation
Consider prophylactic cardiovascular surgery
Genetic counselling for the family
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Tuberous sclerosis (epiloia)
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This is an autosomal dominant disorder due to mutations in one of two genes located on chromosomes 9 and 16. A feature is tube-like growths that affect multiple systems including the brain.
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DxT facial rash + intellectual disability + seizures ➜ tuberous sclerosis
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The above triad of features is classic but not applicable to all cases.
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This is an AD disorder with mutation of chromosome 11. It has been described as a male Turner syndrome but affects both sexes.
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DxT facies + short stature + pulmonary stenosis ➜ Noonan syndrome
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Characteristic facies—down-slanting palpebral fissures, widespread eyes, low-set ears ± ptosis
Short stature
Pulmonary valve stenosis
Webbed neck
Failure to thrive, usually mild
Abnormalities of cardiac conduction and rhythm
± Intellectual disability
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Refer to genetic service
Evaluation of cardiac status
Consider vision, hearing, clotting status, possible epilepsy
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Clinical features (a wide spectrum)
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Hand flapping
‘Puppet’-like ataxia
Frequent laughter/smiling
Microcephaly by age 2 years
Developmental delay
Speech impairment
Seizures
Cannot live independently
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Diagnosis based on clinical features and genetic studies.
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Treatment with minocycline is promising.
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Sporadic mutation of LMA gene that codes for a protein leads to early cell death.
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Accelerated ageing—manifests in early childhood causing premature death (median age 12 years) from vascular disease. No known treatment.
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SEX CHROMOSOME ABNORMALITIES
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Klinefelter syndrome9
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This is due to an extra X chromosome, resulting in a male phenotype and occurring in 1 in 800 live births. Approximately 2 out of 3 are never recognised.
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DxT lanky men + small testes + infertility ➜ Klinefelter syndrome
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Marked variation but usually:
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sparse facial hair
reduced libido
learning difficulties, especially reading
intellectual ability may range from normal to disability
gynaecomastia
increased risk of breast cancer and diabetes
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Increased gonadotrophin, low to normal testosterone
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Turner syndrome (gonadal dysgenesis)
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This is due to only one X chromosome, occurring in 1 in 4000 live female newborns; 99% of conceptions are miscarried.15
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DxT short stature + webbed neck + facies ➜ Turner syndrome
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Clinical features of typical XO karyotype
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Short stature—average adult height 143 cm
Primary amenorrhoea in XO patient; infertility
Webbing of neck
Typical facies: micrognathia, low hairline
Lymphoedema of extremities
Cardiac defects (e.g. coarctation of aorta)
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Mental deficiency is rare.
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