Neurocutaneous disorders

Neurofibromatosis type 1 (NF1), initially described by
von Recklinghausen, is one of the most common single gene
disorders, with an incidence of around 1 in 3000. The main
diagnostic features of NF1 are café-au-lait patches, peripheral
neurofibromas and lisch nodules. Café-au-lait patches are
sometimes present at birth, but often appear in the first few
years of life, increasing in size and number. A child at risk who
has no café-au-lait patches by the age of five is extremely
unlikely to be affected. Freckling in the axillae, groins or base
of the neck is common and generally only seen in people with
NF1. Peripheral neurofibromas usually start to appear around
puberty and tend to increase in number through adult life.
The number of neurofibromas varies widely between different
subjects from very few to several hundred. Lisch nodules
(iris hamartomas) are not visible to the naked eye but can be
seen using a slit lamp. Minor features of NF1 include short
stature and macrocephaly. Complications of NF1 are listed
in the box and occur in about one third of affected
individuals. Malignancy (mainly embryonal tumours or
neurosarcomas) occur in about 5% of affected
individuals. Learning disability occurs in about one
third of children, but severe mental retardation in
only 1 to 2%.

The gene for NF1

The gene for NF1 was localised to chromosome 17 in 1987
and cloned in 1990. The gene contains 59 exons and encodes
of protein called neurofibromin, which appear to be involved
in the control of cell growth and differentiation. Mutation
analysis is not routine because of the large size of the gene and
the difficulty in identifying mutations. Prenatal diagnosis by
linkage analysis is possible in families with two or more affected
individuals. NF1 has a very variable phenotype and prenatal
testing does not predict the likely severity of the condition. Up
to one third of cases arise by a new mutation.

Neurofibromatos

Neurofibromatos is type 2 (NF2) is a disorder distinct from
NF1. It is characterised by schwannomas (usually bilateral) and
other cranial and spinal tumours. Café-au-lait patches and
peripheral neurofibromas can also occur, as in NF1. Survival is
reduced in NF2, with the mean age of death being around 32
years. NF2 follows autosomal dominant inheritance with about
50% of cases representing new mutations. The NF2 gene, whose
protein product has been called merlin, is a tumour suppressor
gene located on chromosome 22. Mutation analysis of the NF2
gene contributes to confirmation of diagnosis in clinically
affected individuals and enables presymptomatic testing of
relatives at risk, identifying those who will require annual
clinical and radiological screening.

Tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant
disorder with a birth incidence of about 1 in 6000. TSC is very
variable in its clinical presentation. The classical triad of mental
retardation, epilepsy and adenosum sebaceum are present in
only 30% of cases. TSC is characterised by hamartomas in
multiple organ systems, commonly the skin, CNS, kidneys,
heart and eyes. The ectodermal manifestations of the condition
are shown in the table. CNS manifestations include cortical
tumours that are associated with epilepsy and mental
retardation, and subependymal nodules that are found in 95%
of subjects on MRI brain scans. Subependymal giant cell
astrocytomas develop in about 6% of affected individuals. TSC
is associated with both infantile spasms and epilepsy occurring
later in childhood. Learning disability is frequently associated.
Attention deficit hyperactivity disorder is associated with TSC
and severe retardation occurs in about 40% of cases. Renal
angiomyolipomas or renal cysts are usually bilateral and
multiple, but mainly asymptomatic. Their frequency increases
with age. Angiomyolipomas may cause abdominal pain, with or
without haematuria, and multiple cysts can lead to renal failure.
There may be a small increase in the risk of renal carcinoma in
TSC. Cardiac rhabdomyomas are detected by echocardiography
in 50% of children with TSC. These can cause outflow tract
obstruction or arrhythmias, but tend to resolve with age.
Ophthalmic features of TSC include retinal hamartomas,
which are usually asymptomatic.

TSC follows autosomal dominant inheritance

TSC follows autosomal dominant inheritance but has very
variable expression both within and between families. Fifty
per cent of cases are sporadic. First degree relatives of an
affected individual need careful clinical examination to detect
minor features of the condition. The value of other
investigations in subjects with no clinical features is not of
proven benefit.

Two genes causing TSC

genes causing TSC have been identified: TSC1 on
chromosome 9 and TSC2 on chromosome 16. The products of
these genes have been called hamartin and tuberin respectively.
Current strategies for mutation analysis do not identify the
underlying mutation in all cases. However, when a mutation is
detected, this aids diagnosis in atypical cases, can be used to
investigate apparently unaffected parents of an affected child,
and enables prenatal diagnosis. Mutations of both TSC1 and
TSC2 are found in familial and sporadic TSC cases. There is no
observable difference in the clinical presentation between TSC1
and TSC2 cases, although it has been suggested that intellectual
disability is more frequent in sporadic cases with TSC2 than
TSC1 mutations.

Connective tissue disorders

Marfan syndrome is an autosomal dominant disorder affecting
connective tissues caused by mutation in the gene encoding
fibrillin 1 (FBN1). The disorder has an incidence of at least 1 in
10 000. It arises by new mutation in 25–30% of cases. In some
familial cases, the diagnosis may have gone unrecognised in
previously affected relatives because of mild presentation and
the absence of complications.

The main features of Marfan syndrome

The main features of Marfan syndrome involve the skeletal,
ocular and cardiovascular systems. The various skeletal features
of Marfan syndrome are shown in the box. Up to 80% of
affected individuals have dislocated lenses (usually bilateral)
and there is also a high incidence of myopia. Cardiovascular
manifestations include mitral valve disease and progressive
dilatation of the aortic root and ascending aorta. Aorta
dissection is the commonest cause of premature death in
Marfan syndrome. Regular monitoring of aortic root
dimension by echocardiography, medical therapy
(betablockers) and elective aortic replacement surgery have
contributed to the fall in early mortality from the condition
over the past 30 years.

Clinical diagnosis

Clinical diagnosis is based on the Gent criteria, which
require the presence of major diagnostic criteria in two systems,
with involvement of a third system. Major criteria include any
combination of four of the skeletal features, ectopia lentis,
dilatation of the ascending aorta involving at least the sinus of
Valsalva, lumbospinal dural ectasia detected by MRI scan, and a
first degree relative with confirmed Marfan syndrome. Minor
features indicating involvement of other symptoms include
striae, recurrent or incisional herniae, and spontaneous
pneumothorax.

Clinical features of Marfan syndrome

Clinical features of Marfan syndrome evolve with age and
children at risk should be monitored until growth is completed.
More frequent assessment may be needed during the pubertal
growth spurt. Neonatal Marfan syndrome represents a
particularly severe form of the condition presenting in the
newborn period. Early death from cardiac insufficiency is
common. Most cases are due to new mutations, which are
clustered in the same region of the FBN1 gene. Adults with
Marfan syndrome need to be monitored annually with
echocardiography. Pregnancy in women with Marfan syndrome
should be regarded as high risk and carefully monitored by
obstetricians and cardiologists with expertise in management of
the condition.

Marfan syndrome

Marfan syndrome was initially mapped to chromosome 15q
by linkage studies and subsequently shown to be associated with
mutations in the fibrillin 1 gene (FBN1). Fibrillin is the major
constituent of extracellular microfibrils and is widely
distributed in both elastic and non-elastic connective tissue
throughout the body. FBN1 mutations have been found in
patients who do not fulfil the full diagnostic criteria for
Marfan syndrome, including cases with isolated ectopia lentis,
familial aortic aneurysm and patients with only skeletal
manifestations. FBN1 is a large gene containing 65 exons. Most
Marfan syndrome families carry unique mutations and more
than 140 different mutations have been reported. Screening
new cases for mutations is not routinely available, and
diagnosis depends on clinical assessment. Mutations in the
fibrillin 2 gene (FBN2) cause the phenotypically related
disorder of contractural arachnodactyly (Beal syndrome)
characterised by dolichostenomelia (long slim limbs) with
arachnodactyly, joint contractures and a characteristically
crumpled ear.

Cardiac and respiratory disorders

Cystic fibrosis (CF) is the most common lethal autosomal
recessive disorder of childhood in Northern Europeans. The
incidence of cystic fibrosis is approximately 1 in 2000, with 1 in
22 people in the population being carriers. Clinical
manifestations are due to disruption of exocrine pancreatic
function (malabsorption), intestinal glands (meconium ileus),
bile ducts (biliary cirrhosis), bronchial glands (chronic
bronchopulmonary infection with emphysema), sweat glands
(abnormal sweat electrolytes), and gonadal function (infertility).
Clinical presentation is very variable and can include any
combination of the above features. Some cases present in the
neonatal period with meconium ileus, others may not be
diagnosed until middle age. Presentation in childhood is usually
with failure to thrive, malabsorption and recurrent pneumonia.
Approximately 15% of patients do not have pancreatic
insufficiency. Congenital bilateral absence of the vas deferens is
the usual cause of infertility in males with CF and can occur in
heterozygotes, associated with a particular mutation in intron 8
of the gene.

cystic fibrosis

cystic fibrosis is due to mutations in the cystic fibrosis
conductance regulator (CFTR) gene which is a chloride ion
channel disease affecting conductance pathways for salt and
water in epithelial cells. Decreased fluid and salt secretion is
responsible for the blockage of exocrine outflow from the
pancreas, accumulation of mucus in the airways and defective
reabsorption of salt in the sweat glands. Family studies localised
the gene causing cystic fibrosis to chromosome 7q31 in 1985
and the use of linked markers in affected families enabled
carrier detection and prenatal diagnosis. Prior to this, carrier
detection tests were not available and prenatal diagnosis, only
possible for couples who already had an affected child, relied
on measurement of microvillar enzymes in amniotic fluid – a
test that was associated with both false positive and false
negative results.

Conventional treatment of CF

Conventional treatment of CF involves pancreatic enzyme
replacement and treatment of pulmonary infections with
antibiotics and physiotherapy. These measures have
dramatically improved survival rates for cystic fibrosis over the
last 20 years. Several gene therapy trials have been undertaken
in CF patients aimed at delivering the normal CFTR gene to
the airway epithelium and research into this approach is
continuing.

Cardiomyopathy

Cardiomyopathy
Several forms of cardiomyopathy are due to single gene defects,
most being inherited in an autosomal dominant manner. The
term cardiomyopathy was initially used to distinguish cardiac
muscle disease of unknown origin from abnormalities
secondary to hypertension, coronary artery disease and valvular
disease.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HOCM) has an incidence
of about 1 in 1000. Presentation is with hypertrophy of the left
and/or right ventricle without dilatation. Many affected
individuals are asymptomatic and the initial presentation may
be with sudden death. In others, there is slow progression of
symptoms that include dyspnoea, chest pain and syncope.
Myocardial hypertrophy may not be present before the
adolescence growth spurt in children at risk, but a normal
two-dimensional echocardiogram in young adults will virtually
exclude the diagnosis. Many adults are asymptomatic and are
diagnosed during family screening. Atrial or ventricular
arrhythmias may be asymptomatic, but their presence indicates
an increased likelihood of sudden death. Linkage analysis and
positional cloning has identified several loci for HOCM.
The genes known to be involved include those encoding for
beta myosin heavy chain, cardiac troponin T, alpha
tropomyosin and myosin binding protein C. These are
sarcomeric proteins known to be essential for cardiac muscle
contraction. Mutation analysis is not routine, but mutation
detection allows presymptomatic predictive testing in family
members at risk, identifying those relatives who require
follow up.

Dilated cardiomyopathies

Dilated cardiomyopathies demonstrate considerable
heterogeneity. Autosomal dominant inheritance may account
for about 25% of cases. Mutations in the cardiac alpha actin
gene have been found in some autosomal dominant families
and an X-linked form (Barth syndrome) is associated with
skeletal myopathy, neutropenia and abnormal mitochondria
due to mutations in the X-linked taffazin gene.
Dystrophinopathy, caused by mutations in the X-linked gene
causing Duchenne and Becker muscular dystrophies can
sometimes present as isolated cardiomyopathy in the absence of
skeletal muscle involvement.

Restrictive cardiomyopathy

Restrictive cardiomyopathy may be due to autosomal
recessive inborn errors of metabolism that lead to
accumulation of metabolites in the myocardium, to autosomal
dominant familial amyloidosis or to autosomal dominant
familial endocardial fibroelastosis.

Haemophilia

The term haemophilia has been used in reference to
haemophilia A, haemophilia B and von Willebrand disease.
Haemophilia A is the most common bleeding disorder
affecting 1 in 5000 to 1 in 10 000 males. It is an X-linked
recessive disorder due to deficiency of coagulation factor VIII.
Clinical severity varies considerably and correlates with residual
factor VIII activity. Activity of 1% leads to severe disease that
occurs in about half of affected males and may present at birth.
Activity of 1–5% leads to moderate disease, and 5–25% to mild
disease that may not require treatment. Affected individuals
have easy bruising, prolonged bleeding from wounds, and
bleeding into muscles and joints after relatively mild trauma.
Repeated bleeding into joints causes a chronic inflammatory
reaction leading to haemophiliac arthropathy with loss of
cartilage and reduced joint mobility. Treatment using human
plasma or recombinant factor VIII controls acute episodes and
is used electively for surgical procedures. Up to 15% of treated
individuals develop neutralising antibodies that reduce the
efficiency of treatment.

The factor VIII gene

The factor VIII gene (F8C) is located on the X chromosome
at Xq28. Mutation analysis is used effectively in carrier
detection and prenatal diagnosis. A range of mutations occur in
the factor VIII gene with point mutations and inversion
mutations predominating. The mutation rate in males is much
greater than in females so that most mothers of isolated cases
are carriers. This is because they are more likely to have
inherited a mutation occurring during spermatogenesis
transmitted by their father, than to have transmitted a new
mutation arising during oogenesis to their sons.

Haemophilia B

Haemophilia B is less common than haemophilia A and
also follows X-linked recessive inheritance, and is due to
mutations in the factor IX gene (F9) located at Xq27.
Mutations in this gene are usually point mutations or small
deletions or duplications.