Chapter 18: Genetic conditions

The family doctor has an important role to play in the exciting and rapidly expanding world of medical genetics. The role includes routine diagnosis, early detection, and community and ethical guidance. Virtually all of the three billion nucleotides of the human genome have been sequenced and the knowledge of their organisation into the known 30 000–35 000 functional units or genes continues to become more sophisticated.²

The genome project has commenced mapping out ‘single nucleotide polymorphisms’ (SNPs) as signposts throughout the genome to assist in locating disease-associated genes and studying variations between individuals.³ Any two unrelated individuals differ by one base per every thousand or so—these as SNPs—and it is believed that SNPs contribute to the risk of common disease rather than directly cause disease. If we carry the wrong set of SNPs, we can be predisposed to various diseases.

Genetic testing is now available for many common hereditary disorders, such as the HFE genes for haemochromatosis, presymptomatic DNA tests are available for the hereditary neurological disorders, such as Huntington disease, and predictive DNA testing is available for some forms of hereditary cancer, such as breast and colon cancer, and in the future for cardiovascular disease and diabetes.⁴ Also in the future, pharmacogenetics, which predicts genetically determined responses to pharmaceuticals, will greatly assist rational prescribing, and gene therapy is a futuristic treatment modality.⁵

An important recent development in gene expression has been advances in DNA technology, with the detection of fetal DNA in maternal plasma, thus allowing an excellent screening test for Down syndrome.⁶

Epigenetics

Epigenetics, meaning ‘on top of’ traditional genetic inheritance, is a study of changes in genetic expression or cellular phenotype caused by mechanisms other than changes in the DNA sequence. These factors, which include environment, lifestyle, nutrition and psychosocial influences, can influence the outcomes of chronic illness such as cancer, diabetes, autoimmune disorders and ageing. The incurred changes are heritable. This is an expanding development.

A summary of the prevalence of genetic disease is presented in TABLE 18.1.

The list of inherited disorders continues to grow as evidence supports intuition that certain conditions are hereditary. It is important for the family doctor to be aware of this potential. We are familiar with the more common classic disorders, such as cystic fibrosis, thalassaemia, Down syndrome and haemochromatosis, but it is incumbent on us to be conversant with the genetic basis of diseases such as cancer, particularly breast, ovarian and bowel cancer, in addition to the childhood chromosomal/microdeletion syndromes, various inborn errors of metabolism and the everemerging rare mutations, such as the mitochondrial disorders.

The genogram is a valuable pedigree chart that usually covers at least three generations of a family tree. It is a simple and disciplined means of gathering data about an individual couple or family to determine inheritance patterns. The data have to be gathered with tact and care. A useful strategy is to encourage patients to develop their own family genogram using charts as templates (resource: Centre for Genetic Education, NSW Health, www.genetics.edu.au).

An example including the use of symbols is shown in FIGURE 18.1.

Specific important genetic disorders

Haemochromatosis

Hereditary haemochromatosis (HHC), which is a disorder of iron overload, is the most common serious single gene genetic disorder in our population.

It is a common condition in which the total body iron concentration is increased to 20–60 g (normal 4 g). The excess iron is deposited in and can damage several organs:

• liver—cirrhosis (10% develop cancer)

• pancreas—‘bronze’ diabetes

• skin—bronze or leaden grey colour

• heart—restrictive cardiomyopathy

• pituitary—hypogonadism, impotence

• joints—arthralgia (especially hands), chondrocalcinosis

It is usually hereditary (autosomal recessive = AR) or may be secondary to chronic haemolysis and multiple transfusions.

Note: Hereditary haemochromatosis is the genetic condition; haemosiderosis is the secondary condition.

Being an autosomal recessive disorder, the patient must inherit two altered (mutated) copies of the gene (see FIG. 18.2 for a thalassaemia example). It is a problem mainly affecting Caucasians, usually from middle age onwards. About 1 in 10 people are silent carriers of one mutated gene, while 1 in 200 are homozygous and are at risk of developing haemochromatosis. These people can have it to a variable extent (the penetrance factor), and some are asymptomatic while others have a serious problem. It is rare for symptoms to manifest before the third decade.⁹

The two common identified specific mutations in the HFE gene are C282Y and H63D (another is S65C):

• homozygous C282Y—high risk for HHC

• homozygous H63D—unlikely to develop clinical HHC

• heterozygous C282Y and H63D—milder form of HHC

The key diagnostic sensitive markers are serum transferrin saturation and the serum ferritin level. The serum iron level is not a good indicator. An elevated ferritin level is not diagnostic of HHC but is the best serum marker of iron overload.

Most patients are asymptomatic but may have extreme lethargy, abdominal discomfort, signs of chronic liver disease, polyuria and polydipsia, arthralgia, erectile dysfunction, loss of libido and joint signs.

Signs: look for hepatomegaly, very tanned skin, cardiac arrhythmias, joint swelling, testicular atrophy.

• Increased serum transferrin saturation >45%

• Increased serum ferritin level (see CHAPTER 22)

• CT, MRI or FerriScan—increased iron deposition in liver

• Liver biopsy (if liver function test enzymes are abnormal or ferritin >1000 mcg/L or hepatomegaly)—FerriScan now preferred

• Genetic studies: HFE gene—a C282Y and/or H63D mutation

• Screen first-degree relatives (serum ferritin levels and serum transferrin saturation in older relatives and genetic testing in younger ones). No need to screen before adulthood.

Note: Full blood count (FBE) and erythrocyte sedimentation rate are normal.

• Refer for specialist care

• Weekly venesection 500 mL (250 mg iron) until serum iron stores are normal (may take at least 2 years), then every 3–4 months to keep serum ferritin level <100 mcg/L (usually 40–80 mcg/L), serum transferrin saturation <50%, and iron levels normal

• Desferrioxamine can be used but not as effective as venesection

• Normal, healthy low-iron diet

• Avoid or limit alcohol

• Avoid iron tablets and vitamin C

• Life expectancy is normal if treated before cirrhosis or diabetes develops

Thalassaemia

The thalassaemias, the most common human single-gene disorders in the world, are a group of hereditary disorders characterised by a defect in the synthesis of one or more of the globin chains (α or β)—there are two of each (α2, β2). This causes defective haemoglobin synthesis leading to hypochromic microcytic anaemia. α-thalassaemia is usually seen in people of Asian origin while β-thalassaemia is seen in certain ethnic groups from the Mediterranean, the Middle East, South-East Asia and the Indian subcontinent. However, in our multicultural communities one cannot assume a person's origins. It is recommended that all women of child-bearing age be screened for thalassaemia. The thalassaemias are described as ‘trait’ when there are laboratory features without clinical expression.

Genetic profile⁸

α-thalassaemia is usually due to the deletion of one or more of the four genes for α-globin, the severity depending on the number of genes deleted: deletion of all four genes—α-thalassaemia (hydrops fetalis); of three genes—haemoglobin H disease, which results in lifelong anaemia of mild-to-moderate degree; of one or two genes—a symptomless carrier.

In β-thalassaemia, the β-chains are produced in decreased quantity rather than having large deletions. People who have two mutations (one in each β-globin gene) have β-thalassaemia major.

• β-thalassaemia minor—a single mutation (heterozygous)—the carrier or trait state

• β-thalassaemia major—two mutations (homozygous)—the person who has the disorder

Inheritance is illustrated in FIGURE 18.2. If both parents are carriers, there is a 1 in 4 chance that their child will have the disorder.

Clinical features

Carriers are clinically asymptomatic and do not need treatment apart from counselling. Patients with thalassaemia major present with symptoms of severe anaemia (haemolytic anaemia). Without treatment, children with thalassaemia major are lethargic and inactive, show a failure to thrive or to grow normally, and delayed puberty, hepatosplenomegaly and jaundice. Signs usually appear after 6 months and death from cardiac failure used to be common but with regular blood transfusions and iron-chelating treatment people can now live in good health.

Diagnosis⁹

• FBE: in most carriers the mean corpuscular haemoglobin/mean corpuscular volume is low but can be normal. There is usually mild hypochromic microcytic anaemia but this is severe with the homozygous type.

• Haemoglobin electrophoresis: measures relative amounts of normal adult haemoglobin (HbA) and other variants (e.g. HbA₂, HbF). This will detect most carriers.

• Serum ferritin level: helps distinguish from iron deficiency, which has a similar blood film.

• DNA analysis: for mutation detection (mainly used to detect or confirm carriers).

Treatment for thalassaemia major

Treatment is based on a regular blood transfusion schedule for anaemia. Avoid iron supplements. Folate supplementation and a low-iron diet are advisable. Excess iron is removed by iron chelation (e.g. desferrioxamine). Allogenic bone marrow transplantation has been used with success.¹⁰ Splenectomy may be appropriate.

Cystic fibrosis⁹

Cystic fibrosis is the result of a defect in an ion channel protein, the cystic fibrosis transmembrane receptor, which is found in the membranes of cells lining the exocrine ducts. The defect affects the normal transport of chloride ions, leading to a decreased sodium and water transfer, thus causing viscid secretions that affect the lungs, pancreas and gut.

Genetic profile^7,11

• The most common AR paediatric illness

• About 1 in 2500 Caucasians affected

• About 1 in 20–25 are carriers

• A mutation (δ-F508) of chromosome 7 is the most common of some 500 possible mutations of the gene. This deletes a single phenylalanine residue from a 1480-aminoacid chain.

Clinical features

• General: malaise, failure to thrive, exercise intolerance

• Chronic respiratory problems: cough, recurrent pneumonia, bronchiectasis, sinus tenderness, nasal polyps

• Gastrointestinal: malabsorption, pale loose bulky stools, jaundice (pancreatic effect), meconium ileus (10% of newborn babies)

• Infertility in males (atrophy of vas deferens)

• Pancreatic insufficiency

• Early mortality but improving survival rates (mean age now 31 years)

Diagnosis

• Screening for immunoreactive trypsin/trypsinogen in newborns detects 75%

• Sweat test for elevated chloride and sodium levels

• DNA testing for carriers identifies only the most common mutations (70–75%)

Treatment

• Early diagnosis and multidisciplinary team care are important

• Physiotherapy for drainage of airway secretions

• Hypertonic saline solution (by nebuliser) preceded by a bronchodilator

• Treatment of infections: therapeutic and prophylactic antibiotics

• Oral pancreatic enzyme replacement

• Dietary manipulation

• Lung and liver transplantation are considerations

There is currently no cure for cystic fibrosis; treatment is based on correcting the nutritional deficiencies and minimising chest infections.

Neurofibromatosis

• NF1—peripheral neurofibromatosis (von Recklinghausen disorder)

• NF2—central type, bilateral acoustic neuromas (schwannomas) (rare)

The gene for NF1 is carried on chromosome 17 and NF2 on chromosome 22. Diagnostic genetic testing is not routinely available. Diagnosis is by clinical examination.

Clinical features of NF1⁸

• Six or more café-au-lait spots (increasing with age)

• Freckling in the axillary or inguinal regions

• Flesh-coloured cutaneous tumours (appear at puberty)

• Hypertension

• Eye features (iris hamartomas)

• Learning difficulty

• Musculoskeletal problems (e.g. scoliosis, fibrous dysplasia, pseudoarthrosis)

• Optic nerve gliomas

General rule

• One-third asymptomatic, only have skin stigmata

• One-third minor problems, mainly cosmetic

• One-third significant problems (e.g. neurological tumours)

Management

• No special treatment available

• Surgical excisions of neurofibromas as appropriate

• Refer to a special clinic, including neurofibroma clinic

• Careful surveillance—report new symptoms

• Yearly examination for children and adults, including blood pressure, neurological, skeletal and ophthalmological examination

Duchenne muscular dystrophy (DMD)

DMD is a progressive proximal muscle weakness disorder with replacement of muscle by connective tissue. Becker muscular dystrophy is a less severe variant. Early diagnosis is important. First signs are delayed motor development, speech and language.

Genetic profile

DMD is an X-linked recessive condition. It is caused by a mutation in the gene coding for dystrophin, a protein found inside the muscle cell membrane.

Clinical features⁸

• Usually diagnosed from 2–5 years

• Weakness in hip and shoulder girdles

• Walking problems: delayed onset or starting in boys aged 3–7

• Waddling gait, falls, difficulty standing and climbing steps

• Pseudohypertrophy of muscles, especially calves

• Most in wheelchair by age 10–12

• ± Intellectual retardation/learning difficulties

• Most die of respiratory problems by age 25

• Gowers sign: patient uses ‘trick’ method by using hands to climb up his or her legs when rising to an erect position from the floor

Diagnosis (initiate at first suspicion)

• Elevated serum creatinine kinase level

• Electromyography

• Direct dystrophin gene testing

• Muscle biopsy

Treatment

• Counselling, especially genetic counselling, education, screening (especially mother)

• No specific treatment available; support; corticosteroids delay progression

Spinal muscular atrophy (SMA)

Claimed to be the leading genetic cause of infant death, SMA includes several types, all manifesting as progressive muscle wasting and leading to early death in the more severe types.

Genetic profile

SMA is autosomal recessive and due to mutation in SMN1 gene on chromosome. Prevalence 1 in 6000-10 000; carriers 1 in 40.

Clinical features

• muscle weakness, poor tone and floppiness

• feeding difficulties and feeble cry in babies

• weak swallowing, coughing and breathing

• normal intelligence and sensory modalities

Diagnosis is by DNA screening at birth and EEG studies. There is no cure at present and treatment is supportive. Intrathecal injections of nusinersen are available.

Dystrophia myotonica

Genetic profile: AD disorder.

Clinical features

• Typically presents 20–30 years as myotonia (tonic muscle spasm)

• Muscle weakness, esp. hands, legs, face, neck

• Slow relaxation of hand grip

• ‘Hatchet face’—long haggard look with atrophy of facial muscles

• Frontal baldness in men

• Cataracts

• Mental impairment

• Cardiac disturbances, e.g. cardiomyopathy

• Endocrine abnormalities, e.g. diabetes

Investigation: electromyography.

Familial periodic paralysis

See CHAPTER 33.

Inherited adult onset neurological disorders^11,12

These disorders have the following common features.

• They are serious and usually eventually fatal.

• Onset is in adulthood.

• They are currently incurable.

• They affect successive generations.

• Most are inherited from a parent in an autosomal dominant fashion.

• Specific genetic testing is usually available.

Examples of inherited adult onset neurological conditions are:

• Huntington disease

• Creutzfeldt–Jakob disease and other prion diseases

• familial Alzheimer disease

• familial epilepsy

• familial motor neurone disease

• Friedreich ataxia

• hereditary peripheral neuropathies (Charcot–Marie–Tooth disease)

• mitochondrial disorders

• hereditary spastic paraparesis

• muscular dystrophies

• myotonic dystrophy

• spinal muscular atrophy

• spinocerebellar ataxias

A minority of these conditions are due primarily to a dominantly inherited genetic alteration (mutation), e.g. Huntington disease, and are usually more accessible to genetic testing. Some gene alterations (polymorphism) may be associated with a higher risk of developing certain neurological conditions. Testing for polymorphisms is more complex. If concerned about a hereditary basis, GPs should refer their patients with these disorders to a neurologist or a neurogenetics clinic.

Huntington disease⁹

Genetic profile

• Inherited as an AD disorder.

• The responsible mutant gene has been located on the short arm of chromosome 4.

• One genetic mutation accounts for the vast majority of cases, which means that there is an accurate diagnostic test.

• Both sexes are equally affected.

Clinical features

• Insidious onset and progression of chorea

• Onset most often between 35 and 55 years

• Mental changes—change in behaviour (can be as early as childhood or in very late life), intellectual deterioration leading to dementia

• Family history present in the majority

• Motor symptoms: flicking movements of arms, lilting gait, facial grimacing, ataxia, dystonia

• Usually a fatal outcome 15–20 years from onset

Treatment

• There is no cure or specific treatment

• Supportive treatment with agents such as haloperidol

Genetic testing and counselling

This is available, sensitive and important because offspring have a 1 in 2 risk and the onset may be late—after childbearing years. It is appropriate to refer to expert centres for those seeking it. Of interest is that only 20% have undergone testing since it became available, indicating that those at risk generally prefer the uncertainty of not knowing the reality.

Familial Alzheimer disease (FAD)

Early onset familial Alzheimer disease (EoFAD), which accounts for less than 1% of all Alzheimer disease, is defined as the presence of two or more affected people with onset age <65 years in more than one generation of a family, with postmortem pathologically proven Alzheimer disease in at least one person. Mutations in any one of three different forms (alleles) of the susceptible APOE gene are known to cause FAD.^9,13

Parkinson disease

Most cases are sporadic, and the majority of cases with a family history do not have a clear inheritance pattern and could be the result of several factors including a genetic predisposition or simply a chance aggregation. Consider referral to a neurogenetics clinic for families with unusual features, such as familial aggregation and/or early onset Parkinson disease.

Motor neurone disease (MND) (amyotrophic lateral sclerosis)

Five to 10% of motor neurone disease is inherited, with an autosomal dominant inheritance pattern. Inherited MND shows familial aggregation and an earlier age of onset than average (40s or younger); otherwise clinical features are essentially the same as the sporadic form (see CHAPTER 33). If more than one family member presents with MND consider referral to a neurogenetic clinic.

Mitochondrial disorders

Mitochondrial disease is usually caused by mutations of the genes or DNA. Since mitochondria are the ‘power plants of the cells’, disorders cannot convert food into energy so high energy tissues such as muscle and the brain are particularly at risk. The variety of disorders include neuromuscular diseases (referred to as mitochondrial myopathies), Leber's hereditary optic neuropathy, varieties of Parkinson disease, myoclonic epilepsy, chronic progressive external ophthalmoplegia, and the deadly MELAS syndrome (myopathy, encephalopathy, lactic acidosis and strokelike episodes). Suspected cases should be referred for diagnosis which includes muscle testing. Treatment is supportive.

The epilepsies comprise a group of disorders with differing genetic components and the inheritance or genetic contribution relates to each specific disorder. Further studies on this subject are in progress. If there are two or more individuals in a family with epilepsy, referral for advice about the nature and inheritance about their form of epilepsy may be appropriate.

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).

HEREDITARY HAEMOGLOBINOPATHIES, HAEMOLYTIC DISORDERS, AND BLEEDING AND CLOTTING DISORDERS^9,14

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.

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.

Sickle cell disorders

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.

• Heterozygous state for HbS = sickle cell trait

• Homozygous state = sickle cell anaemia/disease

Sickle cell anaemia

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.

Features of infarctive sickle crises include:

• bone pain (usually limb bones)

• abdominal pain

• chest—pleuritic pain

• kidney—haematuria

• spleen—painful infarcts

• precipitated by cold, hypoxia, dehydration or infection

Hb electrophoresis is needed to confirm the diagnosis.

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.

Sickle cell trait

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.

Hereditary spherocytosis

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.

Bleeding disorders

In inherited bleeding deficiency disorders, there are deficiencies of vital factors (see CHAPTER 39). The common significant disorders are:

• 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

Others to consider are:

• hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu disease)

• inherited thrombocytopenia

Thrombophilia

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:

• factor V Leiden gene mutation (activated protein C resistance)

• prothrombin gene mutation

• protein C deficiency

• protein S deficiency

• antithrombin deficiency

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.

CHROMOSOMAL/MICRODELETION SYNDROMES (CHILDHOOD EXPRESSION)⁹

The following disorders, whose clinical features manifest in children, present with developmental and intellectual disability.

Down syndrome¹⁵

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.

Facts

• 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

Associated disorders

• 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

Management

• 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

Edward syndrome⁹

Trisomy 18

Clinical features

These include:

• 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

Prognosis is poor—about one-third die in first month, <10% live beyond 12 months.

Prenatal diagnosis is available.

Patau syndrome⁹

Trisomy 13

Clinical features

These include:

• incidence 1 in 7000 (approx.)

• microcephaly

• brain and heart malformation

• cleft lip/palate

• polydactyly

• neural tube defect

Prognosis is poor—50% die within first month.

Fragile X syndrome (FXS)¹⁵

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.

Facts

• 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

Diagnosis

• Cytogenetic testing (karyotyping)

• DNA test (specific for full mutation as well as carriers)

Associated disorders¹⁶

• 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

Management

• 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

Prader–Willi syndrome

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.

Clinical features

• 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

Management

• Early diagnosis and referral

• Multidisciplinary approach

• Expert dietetic control

With proper care and support, longevity into the eighth decade is a reality.¹⁴

Williams syndrome

Williams syndrome (idiopathic hypercalcaemia or elfin face syndrome) is due to a microdeletion on chromosome 7, a deletion in the elastin gene.

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.

Marfan syndrome⁹

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.

Genetic profile

• Mutations in the fibrillin gene on chromosome 15

• Autosomal dominant

• Prevalence about 5 per 100 000

• No specific laboratory test to date

Clinical features

• 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

Management

• 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

Tuberous sclerosis (epiloia)

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.

The above triad of features is classic but not applicable to all cases.

Noonan syndrome¹⁵

This is an AD disorder with mutation of chromosome 11. It has been described as a male Turner syndrome but affects both sexes.

Clinical features¹⁵

• 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

Treatment

• Refer to genetic service

• Evaluation of cardiac status

• Consider vision, hearing, clotting status, possible epilepsy

Angelman syndrome

Genetic profile

• Abnormal chromosome 15

Clinical features (a wide spectrum)

• Hand flapping

• ‘Puppet’-like ataxia

• Frequent laughter/smiling

• Microcephaly by age 2 years

• Developmental delay

• Speech impairment

• Seizures

• Cannot live independently

Diagnosis based on clinical features and genetic studies.

Treatment with minocycline is promising.

Progeria

Sporadic mutation of LMA gene that codes for a protein leads to early cell death.

Accelerated ageing—manifests in early childhood causing premature death (median age 12 years) from vascular disease. No known treatment.

SEX CHROMOSOME ABNORMALITIES

Klinefelter syndrome⁹

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.

Genetic profile

• XXY genotype

• The extra X chromosome is usually of maternal origin

• About 30 or more variants of the disorder

Clinical features

Marked variation but usually:

• tall men with long limbs

• small firm testes ≤2 cm (10 ml)

• infertility (azoospermia)

There may be:

• 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

Diagnosis

Increased gonadotrophin, low to normal testosterone

Treatment

• Transdermal testosterone

Turner syndrome (gonadal dysgenesis)

This is due to only one X chromosome, occurring in 1 in 4000 live female newborns; 99% of conceptions are miscarried.¹⁵

Genetic profile

• 45 chromosomes of XO karyotype (typical Turner's karyotype in 50% of cases)

• Many are mosaics (e.g. 45X/46XX chromosomes)

• Phenotypes vary

Clinical features of typical XO karyotype

• 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)

Mental deficiency is rare.

Treatment

• Hormone-based (e.g. growth hormone, hormone replacement therapy)

These are uncommon chromosomal disorders of sexual development (DSD) in which the appearance of the external genitalia is either ambiguous or at variance with the individual's chromosomal sex. The inappropriate term ‘hermaphrodite’ should be avoided.

The conditions include:

• mixed gonadal dysgenesis

• ovotesticular disorder DSD

• 46, XX DSD (androgenised females)

• 46, XY DSD (underandrogenised males)

The latter may be caused by inadequate production of androgen or inadequate response to androgen, which includes the ‘androgen insensitivity syndrome’. This syndrome, made prominent through athletes with a male genotype but female phenotype, results from a mutation of the gene encoding the androgen receptor.

Congenital adrenal hyperplasia

See CHAPTER 23.

FETAL ALCOHOL SYNDROME (FAS)¹⁸

FAS is the most severe form of the fetal alcohol spectrum disorders. These are caused by the tetrogenic effects of alcohol (not a chromosomal abnormality) and is estimated to involve 2 in 1000 live births. The phenotype varies with the dosage and gestational timing of the alcohol exposure.¹⁶ Caution is needed not to overdiagnose.

Clinical features of FAS

See FIGURE 18.3.

• Markedly underweight until puberty

• Learning difficulties

• Microcephaly

• Characteristic facies (needs 2 of ^*)

  • – shortened palpebral fissures^*

  • – long, smooth featureless philtrum^*

  • – thin upper lip^*

  • – upturned nose

• Hyperactivity

• Congenital heart disease often seen

• Skeletal abnormalities

Diagnosis based on alcohol history in pregnancy.

Management

• By preventive strategies with community education about the harmful effects of drinking, especially in early pregnancy

OTHER TYPES OF HEREDITARY DISORDERS

The many examples include familial hypercholesterolaemia (AD) and the AR disorders for which genetic testing is available, namely Gaucher disease, Tay–Sachs disease, glycogen storage disease, phenylketonuria, galactosaemia, homocystinuria, the porphyrias, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and the mitochondrial disorders.

Glucose-6-phosphate dehydrogenase deficiency

G-6-PD deficiency is a common disorder affecting over 400 million people worldwide. It is the most common red-cell enzyme defect that causes episodic haemolytic anaemia because of the decreased ability of red blood cells to cope with oxidative stresses. It is an X-linked recessive inherited disorder with a high prevalence among people of African, Mediterranean or Asian ancestry. In some countries such as Malaysia there is a national screening program. Consider the disorder in male black people (see CHAPTER 135).

The important clinical features are:

• asymptomatic in many

• neonatal jaundice—infants at risk should be observed after delivery (at least 5 days)

• episodic acute haemolytic anaemia—triggered by antioxidants and infections, and drugs, especially antimalarials, sulphonamides, nitrofurantoin, quinolones, traditional medicines, vitamins C and K, high dose aspirin, fava (broad) beans and naphthalene (e.g. moth balls)

There is no specific treatment. Known precipitants should be avoided. Avoid penicillin and probenecid.

Diagnosis is by G-6-PD assay and a blood film during an attack.

Hereditary haemorrhagic telangectasia

This is an autosomal dominant disorder of the development of vasculature. A strong family history aids diagnosis.

Key features:

• mucocutaneous telangiectasia (Osler–Weber–Rendu syndrome)

• recurrent epistaxis in children and adolescents

• visceral arteriovenous malformations, e.g. GIT, lips

• diagnosis is clinical, aided by imaging to detect AVMs

Gaucher disease

Gaucher disease, which is due to a deficiency of the lysosomal enzyme glucocerebrosidase, leads to anaemia and thrombocytopenia as a result primarily of hypersplenism. There is chronic bone pain and ‘crises’ of bone pain. Consider it in children with fatigue, bone pain, delayed growth, epistaxis, easy bruising and hepatosplenomegaly. Replacement enzyme therapy is available.

Galactosaemia⁹

Galactosaemia is an inborn error of metabolism in which the body is unable to metabolise galactose to glucose. There are three clinical syndromes caused by differing enzyme deficiencies, one of which is galactose-1-phosphate uridyl transferase, which causes the classic syndrome. It is an autosomal recessive disorder with an incidence of about 1 in 60 000 births. As lactose is the major source of galactose, the infant becomes anorexic and jaundiced within a few days or weeks of taking breast milk or lactose-containing formula. It can be rapidly fatal. Management is with a galactose (mainly lactose)-free formula such as soy with added calcium and vitamins.

Phenylketonuria (PKU)⁹

This autosomal recessive disorder of the catabolism of the amino acid, phenylalanine, is caused by a deficiency of phenylalanine hydroxylase activity, leading to an elevation of plasma phenylalanine, which if untreated can cause intellectual disability (often very severe) and other neurological symptoms, such as seizures. Neonatal screening for high blood phenylalanine levels (the Guthrie test) is performed routinely.

Treatment aims to limit phenylalanine intake so that essential amino acid needs are met but not exceeded. Diet therapy must commence as soon as possible. Females who have been treated for PKU need pre-pregnancy counselling and dietary management during pregnancy to prevent damage to the fetus by high phenylalanine levels.

The porphyrias

The three most common porphyrias are acute intermittent porphyria, porphyria cutanea tarda (the commonest) and erythropoietic protoporphyria, which are caused by deficiencies of the third, fifth and eighth enzymes, respectively, of the haem biosynthesis pathway. Their clinical features are quite different.

Acute intermittent porphyria

This autosomal dominant disorder is the most serious of the porphyrias although it remains clinically silent in the majority of patients who carry the trait. It is due to a deficiency of porphobilinogen (PBG) deaminase.

Clinical features

• Recurrent unexplained abdominal pain crises

• Usually young women (teens or 20s)

• Recurrent psychiatric illnesses, abnormal behaviour

• Acute peripheral or nervous system dysfunction (e.g. peripheral neuropathy, hypotonia)

• PBG in urine during attack

• Hyponatraemia

• Attacks precipitated by various drugs (e.g. anti-epileptics, alcohol, sulphonamides, barbiturates)

Diagnosis

• Urine PBGs (high) and serum sodium (very low) during ‘attack’

• Erythrocyte PBG deaminase testing to screen relatives

Treatment

• Eliminate triggers and avoid ‘unsafe’ drugs

• High-carbohydrate diet, glucose oral or IV for attacks

• IV haemetin (haemarginate)

Glycogen storage disease (liver glycogenoses)

This is a group of inherited disorders caused by a deficiency of one or more enzymes involved in glycogen breakdown, leading to the deposition of abnormal amounts of glycogen in tissues, especially the liver. The best-known type is 1A (von Gierke disorder), an autosomal recessive disorder due to deficiency of glucose-6-phosphatase (G-6-P). It is seen in several ethnic groups. It typically causes growth retardation, hepatomegaly, renomegaly, hypoglycaemia (can be severe), lactic acidosis and hyperlipidaemia. Children have characteristic morphological features—short, doll-like facies with fat cheeks, thin extremities and large abdomen (hepatomegaly).

Diagnosis is by abnormal plasma lactate and lipid levels, liver biopsy and recently by gene analysis for the G-6-P gene.

Treatment is aimed to prevent hypoglycaemia and lactic acidosis via frequent carbohydrate feedings, such as uncooked cornstarch and overnight nasogastric glucose infusion. The prognosis is poor.

Tay–Sachs disease

About 1 in 25 Ashkenazi Jews is a carrier of Tay–Sachs disease (gangliosidosis), an AR disorder caused by a total deficiency of hexosaminidase A resulting in an accumulation of gangliosides in the brain.

The infantile form is fatal by age 3 or 4 with early progressive loss of motor skills, dementia, blindness, macrocephaly and cherry-red retinal spots. The juvenile onset form presents with dementia and ataxia, with death at age 10–15. The adult form has progression of neurological symptoms following clumsiness in childhood and motor weakness in adolescence. Carrier testing is available and prenatal diagnosis is available.

SINGLE GENE CARDIAC DISORDERS

Includes:

• cardiomyopathies

• arrhythmia syndromes, e.g. long QT syndrome

• sudden cardiac death families

Congenital long QT syndrome

This is an autosomal dominant condition with predisposition to ventricular arrhythmias, syncopal/fainting spells and sudden death, particularly during exercise. Confirm or exclude by ECG when suspected—interval 0.5–0.7 seconds. Management includes sports restrictions, beta blockers and pacemaker or AICD.

Hypertrophic cardiomyopathy

This is an AD disorder with several genetic mutations. It is the most common cause of sudden cardiac death among athletes.

Clinical features

• Fatigue

• Exertional dyspnoea and chest pain

• Palpitations

• Dizziness/syncope

Diagnosis by ECG (LV hypertrophy) and doppler echocardiography.

Insertion of AICD may prevent sudden death.

Familial hyperlipoproteinaemia¹⁹

There are several types of genetic disorder of lipid metabolism including the better-known familial hypercholesterolaemia and familial combined hyperlipidaemia. The former is identified by elevated cholesterol, corneal arcus juvenalis, tendon xanthomas in the patient or their first- and second-degree relatives and also by a DNA mutation. Homozygous patients present with atherosclerotis disease in childhood and early death from myocardial infarction. Heterozygotes may develop the disorder in their 30s or 40s.

This is common, being 1 in 500 Caucasians, 1 in 70 in Lebanese and Afrikaners. Eighty per cent are undiagnosed and missing out on preventive treatments. GPs have an important role in screening people with premature ischaemic heart disease to look for phenotype characteristics of the condition.

Familial cancer²⁰

The majority of cancer is not inherited; rather it is acquired because of genetic mutations in several genes of a cell in a specific tissue during an individual's lifetime. Twenty to twenty-five individuals in a population of 1000 have a family history of bowel or breast cancer.⁹

However, some people carry inherited genetic mutations from conception that predispose them to developing certain cancers, particularly colorectal, breast and ovarian cancer, at a relatively young age. Up to 5% of some cancers are considered familial and the genetic basis of some of these is now understood. Most are AD with 50% of offspring being affected.

The three most significant familial cancer inherited susceptibility syndromes are:

• hereditary breast–ovarian cancer syndrome (BRCA₁ and BRCA₂ genes)

• hereditary non-polyposis colorectal cancer (HNPCC)

• familial adenomatous polyposis (FAP)

Features of breast–ovarian cancer syndrome^8,9

• Mutations in either of the two genes—BRCA₁ and BRCA₂—result in a strong predisposition for both breast and ovarian cancer

• Mutations present in about 1 in 800 of the general population (male and female), who are carriers

• Dominant inheritance

• The risk of developing breast cancer is 10-fold and 40–80% of cases occur before the age of 70 years¹⁷

• The prognosis in these women is the same as for sporadic cases

• Early age of onset of breast cancer

• Male breast cancer (6% in males with BRCA₂ gene mutation)

• Coexistence of ovarian and breast cancer in the same family

• Carriers of mutations may be at an increased risk of prostate cancer, pancreatic cancer and colorectal cancer, although this is controversial for the latter two

Risk indicators for familial breast–ovarian cancer

• Two first-degree or second-degree relatives on one side of the family with cancer

• Individuals with age of onset of cancer <50 years

• Individuals with bilateral or multifocal breast cancer

• Individuals with ovarian cancer

• Breast cancer in a male relative

• Jewish ancestry

Colorectal cancer²⁰

Both sexes have a risk of approximately 5% of developing bowel cancer in their lifetime. In some this risk is increased due to an inherited predisposition.

The two key disorders are HNPCC and FAP.

Lynch syndrome (hereditary non-polyposis colorectal cancer)

• Caused by a defect in one of the genes responsible for DNA mismatch repair

• Affects 1 in 1000 individuals

• Autosomal dominant

• Early age of onset

• Increased risk of certain extracolonic cancers, including endometrial, stomach, ovary and kidney tract cancers

• Screening should occur every 1–2 years from 25 years of age or 5 years earlier than affected family member developed it

Familial adenomatous polyposis

• Less common than HNPCC; affects about 1 in 10 000

• Caused by a mutation in the APC gene

• Usually hundreds or thousands of polyps

• Eventually almost 100% of cases develop colon cancer without prophylactic colectomy

• Median age of diagnosis 40 years

• Small increased risk of other cancers (e.g. thyroid, cerebral)

• Screening should occur annually from between 12–15 and 30–35 years of age, and then every 3 years

Individuals at risk

For Lynch syndrome (HNPCC):

• Three or more close relatives with bowel cancer

• Two or more close relatives with bowel cancer and:

  • – more than one bowel cancer in same relative

  • – onset of bowel cancer before 50 years

  • – a relative with endometrial cancer or ovarian cancer

(Refer: www.ncbi.nlm.nih.gov/pubmed/14970275.)

For FAP:

• A relative with bowel cancer with polyposis

• Individuals with multiple polyposis

Other cancers where family history is significant

• Melanoma: an inherited mutation in certain genes (e.g. BRAF gene) is considered to be involved in up to 5% of melanomas.

• Prostate: family history is a risk factor; some genes are susceptible.

• Several other cancers can develop as a mutation, e.g. stomach, pancreas, kidney, thyroid, uterus (Cancer Council Australia, family cancer clinics helpline: 13 11 20).

The role of the GP in familial cancer²⁰

The GP has an important role in identifying potential high-risk patients and families and in addressing their concerns.

• Take a family history and involve at least three generations.

• Map a family tree: include any diagnosed breast, ovarian or colorectal cancers in any relative and any type of cancer in first-degree or second-degree relatives on either side of the family.

• Record the age of onset and site of cancer in first-degree relatives.

• Confirm reports of cancer from medical records.

• Assess risk (high, low or intermediate) using guidelines from your country's national cancer guidelines, e.g. the NHMRC guidelines in Australia.

• Reassure low-risk patients but provide general preventive and screening guidelines.

• Refer all patients at potentially high risk to a familial cancer clinic.

Services at these clinics involve:

• risk assessment

• genetic testing

• counselling, including pre- and post-testing

• surveillance advice

Management is based on early detection and potential prophylactic methods, for example:

• for breast cancer—regular imaging and clinical examination

• for ovarian cancer—transvaginal ultrasound and serum CA-125 detection

• for FAP and HNPCC—annual colonoscopy, faecal occult blood test

Patients at high risk will ask about prophylactic colectomy, mastectomy and oophorectomy, for which there are reasonable indications, but it is necessary to refer to a cancer geneticist for expert evaluation before such decisions are made.

The Human Genetics Society of Australia strongly advises against predictive or presymptomatic genetic testing of children for disease where there is no pre-emptive treatment in childhood. It should only be carried out in children if an effective treatment or preventive strategy is available. It raises issues of confidentiality, informed consent and harmful effects on self-esteem.⁹

Routine genetic testing is only advisable for high-risk individuals, such as those with a family history.

The ethical issues for adults are also considerable and for the individual the decision is difficult and requires considerable counselling via a clinical genetics service. This applies particularly to those at risk of Huntington disease and other adult-onset neurodegenerative conditions for which no preventive treatment exists.

Reproductive genetic screening²¹

The triple test is often used for sub-fertility screening. It tests for cystic fibrosis, fragile X syndrome and spinal muscular atrophy. A survey by the Murdoch Children's Research Institute identified one in 20 carriers in a study of prospective parents.

Newborn screening

With parental consent, blood from the infant's heel is usually screened for 25 conditions including cystic fibrosis, phenylketonuria (compare the Guthrie test), congenital hypothyroidism, galactosaemia and other rare disorders of metabolism. This test has the potential for global screening of disorders.

Approximately 2% of births are associated with congenital abnormalities, of which 1 in 7 are chromosomal, the most common of which is Down syndrome (trisomy 21). Antenatal screening tests that can now be performed for several conditions are mainly:

• screening tests for Down syndrome and other trisomies

• screening tests for thalassaemias/haemoglobinopathies

• second-trimester ultrasound scans for fetal abnormalities, such as neural tube defects (NTD) and abdominal wall defects (AWD)

Screening for Down syndrome

This has a live birth incidence of 1.4 per 1000 in Australia.¹⁹ The risk of conceiving a child with Down syndrome increases proportionally with age. For a woman aged 21, it is 1 in 1000, while for a woman aged 35, it is 1 in 275 and for a woman aged 45, it is 1 in 20.

The tests available to test for Down syndrome include the following:^5,23

1. combined first-trimester screening tests (maternal serum screening/MSST; free fetal DNA at 10–12 weeks gestation; nuchal transparency ultrasound at 11–14 weeks)

2. second trimester MSST (4 analytes): alpha fetoprotein, oestriol, free beta hCG, inhibin A. A final risk is calculated by a computer program which combines other factors such as EDD age and age of gestation

3. non-invasive prenatal test (NIPT) from 10 weeks maternal serum. This anuploidy test usually covers three trisomies: 21 Down syndrome, 18 Edward syndrome, 13 Patau syndrome. It has the potential to screen multiple disorders

4. diagnostic tests (chorionic villus sampling, amniocentesis). The most reliable method is obtaining fetal tissue by these last means but there is a significant risk of miscarriage (1 in 100 for chorionic villus sampling and 1 in 200 for amniocentesis)

Consanguinity is the situation where a couple shares one or more common ancestors. Consanguineous relationships occur in most societies and in some cultures are associated with particular advantages and religious traditions.⁸

The concern about the issue has been questioned by a study in the Journal of Genetic Counselling, which suggested ‘aside from a thorough history, there is no need to offer genetic testing on the basis of consanguinity alone’. In a comment on this study which indicated that ‘cousins run few risks in mating’, the author pointed out that people like Charles Darwin, Queen Victoria and Albert Einstein married first cousins, and Darwin's children, in particular, were brilliant. In parts of Saudi Arabia 39% of all marriages are between first cousins.²⁴ On the other hand, there are substantiated records of problems with inherited disorders. Twenty-four US states ban the marriage of first cousins and the Catholic Church, with 2000 years of experience, has opposed cousin marriages for over 1000 years.

First cousins share a pair of grandparents and are statistically at an increased risk for autosomal recessive conditions. The baseline risk that any couple will have a baby with a birth defect is 3–4%.⁸ In addition, empirical data show that for first cousin marriage there is an additional 4% risk of having a child with a birth defect—this includes malformations such as intellectual impairment and many rare autosomal recessive disorders. So the combined risk is 8% irrespective of a positive family history, which is an important consideration in counselling these people.⁸

For siblings the risk of increase in birth defects is 30% and 19% for second cousins.

• Dark black urine on exposure = alkaptonuria

• Red urine on exposure = porphyria

• Blue diapers = tryptophan malabsorption syndrome

• Maple syrup odour (urine and perspiration) = maple syrup urine disease (AR) (an amino acid metabolic disorder)

• Mousy body odour = phenylketonuria

• ‘Fish-like’ mouth with micrognathia = Turner syndrome

• ‘Chipmunk’ facies = thalassaemia major

• ‘Doll-like’ facies = glycogen storage disease (G-6-P deficiency)

• Elfin face = Williams syndrome

• Butterfly-like facial rash in children = tuberous sclerosis

• Weak suction + delayed sitting and crawling = Prader–Willi syndrome

• ‘Happy puppet’ features = Angelman syndrome

• Characteristic eyes: wide-spaced, down-slanting openings, ptosis = Noonan syndrome

• Long fingers and limbs = Marfan syndrome

• High-pitched meowing cry, low-set ears, mental retardation = ‘cat-cry’ syndrome (maladie du cri du chat)

• Blue sclera = osteogenesis imperfecta