Essential Revision Notes in

Paediatrics for the MRCPCH

Third edition
Edited by
Dr R M Beattie BSc MBBS MRCP FRCPCH
Consultant Paediatric Gastroenterologist
Paediatric Medical Unit
Southampton General Hospital
Southampton
Dr Mike Champion BSc MBBS MRCP FRCPCH
Consultant in Paediatric Inherited Metabolic Disease
Evelina Children’s Hospital
Guy’s and St Thomas’ NHS Foundation Trust
London
 Contents

Contributors vii
Preface to the Third edition xi

CHAPTERS
1. Cardiology 1
Robert Tulloh
2. Child Development, Child Mental Health and Community Paediatrics 41
Joanne Philpot and Ruth Charlton
3. Child Protection and Safeguarding 85
Joanne Philpot and Ruth Charlton
4. Clinical Governance 95
Robert Wheeler
5. Clinical Pharmacology andToxicology 105
Steven Tomlin
6. Dermatology 125
Helen M Goodyear
7. Emergency Paediatrics 147
Serena Cottrell
8. Endocrinology and Diabetes 173
Heather Mitchell and Vasanta Nanduri
9. Ethics and Law 209
Vic Larcher and Robert Wheeler
10. Gastroenterology and Nutrition 229
Mark Beattie and Hemant Bhavsar
11. Genetics 275
Natalie Canham
12. Haematology and Oncology 299
Michael Capra
13. Hepatology 341
Nancy Tan and Anil Dhawan
14. Immunology 373
Pamela Lee and Bobby Gaspar

v
Contents

15. Infectious Diseases 407

Nigel Klein and Karyn Moshal
16. Metabolic Medicine 451
Mike Champion
17. Neonatology 485
Grenville F Fox
18. Nephrology 527
Christopher J D Reid
19. Neurology 567
Neil H Thomas
20. Ophthalmology 607
Ken K Nischal
21. Orthopaedics 637
Vel K Sakthivel
22. Respiratory 655
Rebecca Thursfield and Jane C Davies
23. Rheumatology 689
Nathan Hasson
24. Statistics 709
Angie Wade
25. Surgery 727
Merrill McHoney
Picture Permissions 761
Index 763

vi
 Chapter 11
Genetics
Natalie Canham

CONTENTS
3.4 Reverse transcription PCR
1. Chromosomes (rt-PCR)
1.1 Common sex chromosome 3.5 Next generation sequencing
aneuploidies 3.6 Exome sequencing
1.2 Common autosomal
chromosome aneuploidies 4. Trinucleotide repeat disorders
1.3 CGH microarray 4.1 Fragile X syndrome
1.4 MLPA
1.5 Qf-PCR 5. Mitochondrial disorders
1.6 FISH testing
1.7 Microdeletion syndromes 6. Genomic imprinting
1.8 Genetic counselling in
chromosomal disorders 7. Genetic testing
2. Mendelian inheritance 8. Important genetic topics
2.1 Autosomal dominant (AD) 8.1 Ambiguous genitalia
conditions 8.2 Cystic fibrosis
2.2 Autosomal recessive (AR) 8.3 Duchenne and Becker
conditions muscular dystrophies
2.3 X-linked recessive (XLR) 8.4 Neurofibromatosis (NF)
conditions 8.5 Tuberous sclerosis
2.4 X-linked dominant (XLD) 8.6 Marfan syndrome
conditions 8.7 Homocystinuria
2.5 Constructing a pedigree 8.8 Noonan syndrome
diagram (family tree) 8.9 Achondroplasia
8.10 Alagille syndrome
3. Molecular genetics 8.11 CHARGE syndrome
3.1 DNA (deoxyribonucleic acid) 8.12 VATER (VACTERL) association
3.2 RNA (ribonucleic acid) 8.13 Goldenhar syndrome
3.3 Polymerase chain reaction 8.14 Pierre Robin sequence
(PCR) 8.15 Potter sequence

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Essential Revision Notes in Paediatrics for MRCPCH

9. Fetal teratogens
9.1 Maternal illness
9.2 Infectious agents
9.3 Other teratogens

10. Prenatal testing

11. Non-invasive prenatal testing

12. Preimplantation genetic

diagnosis (PGD)

13. Genetic counselling

14. Further reading

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 Genetics

Genetics

1. CHROMOSOMES
Chromosomes are divided by the centromere into a
short ‘p’ arm (‘petit’) and a long ‘q’ arm. Acro-
Background
centric chromosomes (13, 14, 15, 21, 22) have the
Within the nucleus of somatic cells there are 22 centromere at one end and only a q arm.
pairs of autosomes and one pair of sex chromo-
Lyonization is the process in which, in a cell con-
somes. Normal male and female karyotypes are
taining more than one X chromosome, only one is
46,XY and 46,XX respectively. The normal chromo-
active. Selection of the active X chromosome is
some complement of 46 chromosomes is known as
usually random and each inactivated X chromo-
diploid. Genomes with only a single copy of every
some can be seen as a Barr body on microscopy.
chromosome or with three copies of each are
Genes are expressed only from the active X
known respectively as haploid and triploid. A kar-
chromosome.
yotype with too many or too few chromosomes,
where the total is not a multiple of 23, is called Mitosis occurs in somatic cells and results in two
aneuploid. Three copies of a single chromosome in diploid daughter cells with nuclear chromosomes
a cell are referred to as trisomy, whereas a single which are genetically identical both to each other
copy is monosomy. and the original parent cell.

Mitosis

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Essential Revision Notes in Paediatrics for MRCPCH

Meiosis occurs in the germ cells of the gonads and preceded by exchange of chromosome segments
is also known as ‘reduction division’ because it between homologous chromosomes called crossing
results in four haploid daughter cells, each contain- over. In males the onset of meiosis and spermato-
ing just one member (homologue) of each chromo- genesis is at puberty. In females, replication of the
some pair, all genetically different. Meiosis involves chromosomes and crossing over begins during fetal
two divisions (meiosis I and II). The reduction in life but the oocytes remain suspended before the
chromosome number occurs during meiosis I and is first cell division until just before ovulation.

Meiosis

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 Genetics

Translocations • Webbed or short neck

• Low hairline
• Reciprocal – exchange of genetic material
• Shield chest with widely spaced nipples
between non-homologous chromosomes
• Cubitus valgus (wide carrying angle)
• Robertsonian – fusion of two acrocentric
• Cardiovascular abnormalities (particularly aortic
chromosomes at their centromeres, e.g. (14;21)
coarctation in 10–15%)
• Unbalanced – if chromosomal material has
• Renal anomalies (e.g. horseshoe kidney,
been lost or gained overall
duplicated ureters, renal aplasia) in a third
• Balanced – if no chromosomal material has
• Non-pitting lymphoedema in a third
been lost or gained overall
Carriers of balanced translocations are usually phe- Triple X syndrome (karyotype 47,XXX)
notypically normal but are at increased risk for
having offspring with a chromosomal imbalance. This affects 1 in 1000 live-born girls. These patients
There is also commonly an increased risk of mis- show little phenotypic abnormality but tend to be of
carriage and of reduced fertility. tall stature. Although intelligence is typically re-
duced compared with siblings it usually falls within
Carriers of a robertsonian translocation involving normal or low–normal limits. However, mild devel-
chromosome 21 are at increased risk of having opmental and behavioural difficulties are more
offspring with translocation Down syndrome. For common. Fertility is normal but the incidence of
female and male (14;21) translocation carriers the early menopause is increased.
observed offspring risks for Down syndrome are
approximately 15% and 5%, respectively. This may Klinefelter syndrome (karyotype 47,XXY)
be due to a selective disadvantage to spermatozoa
carrying an extra chromosome. Remember, translo- This affects 1 in 600 live-born boys. Phenotypic
cation carriers can also have offspring with normal abnormalities are rare prepubertally other than a
chromosomes or offspring who are balanced trans- tendency to tall stature. At puberty, spontaneous
location carriers like themselves. expression of secondary sexual characteristics is
variable but poor growth of facial and body hair is
common. The testes are small and associated with
azoospermia, testosterone production is around
1.1 Common sex chromosome 50% of normal and gonadotrophins are raised.
aneuploidies Gynaecomastia occurs in 30% and there is an in-
Turner syndrome (karyotype 45,X) creased risk of male breast cancer. Female distribu-
tion of fat and hair and a high-pitched voice may
This affects 1 in 2500 live-born girls but it is a occur but are not typical. Intelligence is generally
frequent finding among early miscarriages. Patients reduced compared with siblings but usually falls
are usually of normal intelligence. They have within normal or low–normal limits. Mild develop-
streak ovaries that result in failure of menstruation, mental and behavioural problems are more com-
low oestrogen with high gonadotrophins and infer- mon.
tility. Normal secondary sexual characteristics may
develop spontaneously or can be induced with
47,XYY males
oestrogens. If puberty is achieved, the uterus is
usually normal and pregnancy is possible with the This affects 1 in 1000 live-born boys. These males
use of donated ova. Short stature throughout child- are phenotypically normal but tend to be tall. In-
hood with failure of the pubertal growth spurt is telligence is usually within normal limits but there is
typical. Final height can be increased by early an increased incidence of behavioural abnormal-
treatment with growth hormone. Other features ities. Previous studies suggesting an increase in
may include: criminality have been disproved.

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Essential Revision Notes in Paediatrics for MRCPCH

1.2 Common autosomal chromosome common. Survival beyond early infancy is rare but
aneuploidies associated with profound learning disability.
Down syndrome (trisomy 21)
Patau syndrome (trisomy 13)
Down syndrome affects 1 in 700 live births overall
and is usually secondary to meiotic non-disjunction Affected infants usually have multiple malforma-
during oogenesis, which is more common with in- tions including holoprosencephaly and other central
creasing maternal age. Around 5% of patients have nervous system abnormalities, scalp defects, micro-
an underlying robertsonian translocation, most com- phthalmia, mid-line cleft lip and cleft palate, post-
monly between chromosomes 14 and 21. Around axial polydactyly, rockerbottom feet, renal anoma-
3% have detectable mosaicism (a mixture of trisomy lies and congenital heart disease. Survival beyond
21 and karyotypically normal cells) usually resulting early infancy is rare and associated with profound
in a milder phenotype. learning disability.

Phenotypic features include:

1.3 CGH microarray
• Brachycephaly
• Upslanting palpebral fissures, epicanthic folds, CGH (comparative genomic hybridization) micro-
Brushfield spots on the iris array is a method of more detailed chromosome
• Protruding tongue analysis than that provided by karyotyping. Patient
• Single palmar crease, fifth finger clinodactyly, genomic DNA and control genomic DNA are differ-
wide sandal gap between first and second toes entially labelled with different fluorescent probes
• Hypotonia and moderate learning disability and then hybridized together. The ratio of fluores-
cent intensity between patient and control DNA is
The following are more common in patients with then compared which detects areas of copy number
Down syndrome: difference. This can detect microdeletions and
• Cardiovascular malformations in 40%, microduplications as well as anomalies that would
particularly atrioventricular septal defects have been visible on karyotype. The sensitivity of
• Gastrointestinal abnormalities in 6%, the test, and thus the size of the imbalances de-
particularly duodenal atresia and Hirschsprung tected, are determined by the distances between
disease and number of the fluorescent probes. High-
• Haematological abnormalities, particularly resolution arrays can detect imbalances as small as
acute lymphoblastic, acute myeloid and 200 base-pairs, but those in current diagnostic use
transient leukaemias typically detect anomalies above 100 kilobases (kb).
• Hypothyroidism Arrays are not able to detect balanced rearrange-
• Cataracts in 3% ments, so the karyotype is still appropriate in cases
• Alzheimer disease in the majority by 40 years of such as recurrent miscarriage. Many small anoma-
age lies detected are inherited from a normal parent,
and thus are probably not significant in the patho-
genesis of developmental problems.
Edward syndrome (trisomy 18)
This typically causes intrauterine growth retardation,
1.4 MLPA
a characteristic facies, prominent occiput, overlap-
ping fingers (second and fifth overlap third and MLPA (multiplex ligation-dependent probe amplifi-
fourth), rockerbottom feet (vertical talus) and short cation) is a multiplex PCR (polymerase chain reac-
dorsiflexed great toes. Malformations, particularly tion) method able to detect abnormal copy numbers
congenital heart disease, diaphragmatic hernias, of multiple genomic DNA sequences. This can be
renal abnormalities and dislocated hips, are more used at a gene level, detecting exon deletions or

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 Genetics

duplications, or at a chromosomal microdeletion hypoplasia with T-lymphocyte deficiency,

level. Typically kits are generated with a set of congenital cardiac malformations, particularly
probes such as all the telomeres, or the common interrupted aortic arch and truncus arteriosus,
microdeletion syndromes. cleft palate, learning disability) also previously
called by many names including DiGeorge
syndrome. There appears to be an increased
1.5 Qf-PCR
incidence of psychiatric disorders, particularly
Qf-PCR (quantitative fluorescence polymerase chain within the schizophrenic spectrum
reaction) is a technique allowing fast assessment of • Williams syndrome (supravalvular aortic
copy numbers of whole chromosomes on small stenosis, hypercalcaemia, stellate irides,
samples. Small sections of DNA from the sample characteristic facial appearance, learning
are amplified, labelled with fluorescent tags and the disability) due to microdeletions involving the
amounts measured by electrophoresis. This is most elastin gene on chromosome 7
commonly used for identification of aneuploidy on • 16p11.2 microdeletion syndrome (autism,
prenatal samples. Typically only chromosomes 13, seizures, learning disability) no real diagnostic
18 and 21, and perhaps the sex chromosomes, are phenotypic features meant that this was not
tested because no other whole chromosome aneu- previously identified, but with the widespread
ploidy is survivable to term. Results are available in use of CGH microarray it is now apparent that
24–48 hours. this is the most common microdeletion
syndrome, found in 1 in every 100 on the
autistic spectrum. Frequently also found in a
1.6 FISH testing
normal parent, giving a high recurrence risk.
FISH (fluorescent in situ hybridization) is a tech-
nique used to assess the copy number of specific
DNA sequences in the genome. Fluorescently 1.8 Genetic counselling in
labelled probes are designed that are complemen- chromosomal disorders
tary to the DNA sequences being assessed, and they
are allowed to hybridize to the chromosome spread. As a general rule the following apply.
The number of copies can then be visualized as
fluorescent spots using confocal microscopes. FISH For parents of a child with trisomy 21
can be performed much more rapidly than formal
karyotyping. However, the use of MLPA, Qf-PCR Recurrence risks will be around 1% above the
and CGH microarray has largely superseded this maternal age-related risks for which there are tables.
process, except in testing other members of a family At age 36 years the background risk for Down
for a known chromosomal anomaly. syndrome is 0.5%. Parents with a robertsonian
translocation involving chromosome 21 have a
much higher recurrence risk.
1.7 Microdeletion syndromes
These are caused by chromosomal deletions that
For parents of a child with any other trisomy
are too small to see on standard microscopy but
involve two or more adjacent (contiguous) genes. Recurrence risks in future pregnancies for that spe-
They can be detected using specific FISH testing, cific trisomy will be ,1%. However, couples are
MLPA or CGH microarray. generally counselled that there is a 1% risk for any
chromosome abnormality in future offspring, which
Examples of microdeletion syndromes:
takes into account the small risks that one parent
• 22q11 microdeletion (parathyroid gland may be mosaic or may have an increased risk of
hypoplasia with hypocalcaemia, thymus chromosome mis-segregation at meiosis.

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Essential Revision Notes in Paediatrics for MRCPCH

For parents of a child with a microdeletion Marfan syndrome

Parental chromosomes should be checked. If they Myotonic dystrophy
are normal, recurrence risks will be ,1%. If one Neurofibromatosis types 1 and 2
parent carries the microdeletion then recurrence Noonan syndrome
risks will be 50%. Porphyrias (except congenital erythropoietic
which is AR)
For parents of a child with any other Tuberous sclerosis
chromosome abnormality Von Willebrand disease

Parental chromosomes should be checked. If they Conditions pre-fixed ‘hereditary’ or ‘familial’ are usually
autosomal dominant.
are normal then recurrence risks are usually small
(,1%). If one parent carries a predisposing trans-
location then recurrence risks will be higher,
depending on the nature of the translocation. 2.2 Autosomal recessive [AR]
conditions
Prenatal karyotyping is available for any couple
who have had a previous child with a chromosome These result from mutations in both copies of an
abnormality. autosomal gene. Where both parents are carriers
(with only one mutation and a normal copy), each
of their offspring has a 1 in 4 (25%) risk of being
affected and a 2 in 4 (50%) chance of being a
2. MENDELIAN INHERITANCE carrier. Carriers are usually indistinguishable from
normal other than by DNA analysis.
2.1 Autosomal dominant (AD)
conditions
Examples of autosomal recessive
These result from mutation of one copy of a pair of conditions
genes carried on an autosome. All offspring of an
affected person have a 50% chance of inheriting Alkaptonuria
the mutation. Within a family the severity may vary Ataxia telangiectasia
(variable expression) and known mutation carriers â-Thalassaemia
may appear clinically normal (reduced penetrance). Congenital adrenal hyperplasias
Some conditions, such as achondroplasia and Crigler–Najjar syndrome (severe form)
neurofibromatosis type 1, frequently start anew Cystic fibrosis
through new mutations arising in the egg or (more Dubin–Johnson syndrome
commonly) sperm. Fanconi anaemia
Galactosaemia
Examples of autosomal dominant Glucose-6-phosphatase deficiency (von Gierke
conditions disease)a
Glycogen storage diseases
Achondroplasia Homocystinuria
Alagille syndrome Haemochromatosis
Ehlers–Danlos syndrome (most) Mucopolysaccharidoses (all except Hunter
Facioscapulohumeral muscular dystrophy syndrome)
Familial adenomatous polyposis Oculocutaneous albinism
Familial hypercholesterolaemia Phenylketonuria
Gilbert syndrome Rotor (usually)
Huntington disease Sickle cell anaemia

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 Genetics

Spinal muscular atrophies • White people – cystic fibrosis

Wilson disease • African/African–Caribbean people – sickle cell
Xeroderma pigmentosa anaemia
• Mediterranean/Asian people – thalassaemia
a
Do not confuse with glucose-6-phosphate • Jewish people – Tay–Sachs disease and
dehydrogenase deficiency (favism) which is X-linked
multiple other recessive disorders
recessive.
Most metabolic disorders are autosomal recessive – Although consanguinity is regarded as taboo in
remember the exceptions. many societies, around 20% of all marriages are
consanguineous (second cousin or closer). There
Risk calculations for AR disorders are sound financial and societal reasons for consan-
guineous marriages in societies where these rela-
Remember: tionships are common, and the majority of offspring
• People who have no family history of an are healthy. Geneticists would never advise against
autosomal recessive disorder have the consanguineous marriage (or indicate that a child’s
background population carrier risk recessive disorder is the fault of the marriage), but
• The parents of a child with an autosomal families affected with recessive disorders have been
recessive disorder are assumed to be carriers known to employ carrier testing to assist in marriage
• Where both parents are known to be carriers for planning.
an autosomal recessive disorder, any of their
children who are known to be unaffected are
left with a two-thirds carrier risk (because if the
possibility that they are affected is discounted,
only three possibilities remain).
2.3 X-linked recessive (XLR)
conditions
Autosomal recessive inheritance and
consanguinity These result from a mutation in a gene carried on
the X chromosome and affect males because they
It is believed that everybody carries a few deleter-
have just one gene copy. Females are usually un-
ious autosomal recessive genes. First cousins share
affected but may have mild manifestations as a
on average one-eighth of their genes because they
result of lyonization. New mutations are common
share one set of grandparents. As a result, they are
in many XLR disorders which means that the mother
more likely to be carrying the same autosomal
of an affected boy, with no preceding family history,
recessive disorders. For consanguineous couples in
is not necessarily a carrier. XLR inheritance is char-
a family with a known AR disorder, specific risks
acterized by the following:
should be calculated and appropriate testing should
be arranged. For first-cousin parents who have no • No male-to-male transmission – an affected
known family history of any autosomal recessive father passes his Y chromosome to all his sons
disorder, their offspring have around a 3% increased • All daughters of an affected male are carriers –
risk above the general background risk of any an affected father passes his X chromosome to
genetic abnormality of 2% (i.e. a 5% overall risk). all his daughters
Screening should be offered for any autosomal • Sons of a female carrier have a 50% chance of
recessive disorder that is available and known to be being affected and daughters have a 50%
common in their ancestral ethnic group, e.g.: chance of being carriers

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Essential Revision Notes in Paediatrics for MRCPCH

males. New mutations are common. For the reasons

Examples of X-linked recessive outlined above:
conditions
• There is no male-to-male transmission
Alport syndrome (usually XLR; some AR forms) • All daughters of an affected male would be
Becker muscular dystrophy affected
Duchenne muscular dystrophy • All offspring of an affected female have a 50%
Fabry disease chance of being affected
Fragile X syndrome
Glucose-6-phosphate dehydrogenase Examples of X-linked dominant
deficiency (favism) conditions include:
Haemophilias A and B (Christmas disease)
Hunter syndrome (MPS II) Goltz syndrome
Lesch–Nyhan disease Incontinentia pigmenti
Ocular albinism Rett syndrome
Red–green colour blindness Hypophosphataemic (vitamin D-resistant)
Testicular feminization syndrome rickets
Wiskott–Aldrich syndrome

2.5 Constructing a pedigree diagram

(family tree)
2.4 X-linked dominant (XLD)
The basic symbols in common usage are shown in
conditions
the figure below. Occasionally symbols may be half
These are caused by a mutation in one copy of a shaded or quarter shaded. This generally means that
gene on the X chromosome but both male and the individual manifests a specified phenotypic fea-
female mutation carriers are affected. As a result of ture denoted in an accompanying explanatory key,
lyonization, females are usually more mildly af- e.g. lens dislocation in a family with Marfan syn-
fected and these disorders are frequently lethal in drome.

Basic symbols used in pedigree diagrams

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 Genetics

3. MOLECULAR GENETICS derived from peripheral blood lymphocytes, a tu-

mour biopsy or a biological fluid from a patient
3.1 DNA (deoxyribonucleic acid) with an infection.
DNA is a double-stranded molecule composed of In order to perform PCR, the sequence flanking the
purine (adenine + guanine) and pyrimidine (cyto- target DNA must usually be known so that specific
sine and thymine) bases linked by a backbone of complementary oligonucleotide sequences, known
covalently bonded deoxyribose sugar phosphate as primers, can be designed. The two unique pri-
residues. The two anti-parallel strands are held mers are then mixed together with the DNA tem-
together by hydrogen bonds which can be disrupted plate, deoxyribonucleotides (dATP, dCTP, dGTP,
by heating and reform on cooling: dTTP) and a thermostable DNA polymerase (Taq
polymerase, derived from an organism that inhabits
• Adenine (A) pairs with thymine (T) by two
thermal springs):
hydrogen bonds
• Guanine (G) pairs with cytosine (C) by three • In the initial stage of the reaction the DNA
hydrogen bonds template is heated (typically for about 30
seconds) to make it single stranded. As the
reaction cools the primers will anneal to the
3.2 RNA (ribonucleic acid)
template if the appropriate sequence is present.
DNA is transcribed in the nucleus into messenger • The reaction is then heated to 728C (for about a
RNA (mRNA) which is translated by ribosomes in minute) during which time the Taq DNA
the cytoplasm into a polypeptide chain. RNA differs polymerase synthesises new DNA between the
from DNA in that: two primer sequences, doubling the copy
number of the target sequence.
• It is single-stranded
• The reaction is heated again and the cycle is
• Thymine is replaced by uracil (U)
repeated. After 30 or so cycles (each typically
• The sugar backbone is ribose
lasting a few minutes) the target sequence will
have been amplified exponentially.
3.3 Polymerase chain reaction (PCR)
The crucial feature of PCR is that to detect a given
This is a widely used method for generating large sequence of DNA it only needs to be present in one
amounts of the DNA of interest from very small copy (i.e. one molecule of DNA): this makes it
samples. PCR can be adapted for use with RNA extremely powerful.
provided that the RNA is first converted to DNA.
PCR is a method by which a small amount of target
Clinical applications of PCR
DNA (the template) is selectively amplified to pro-
duce enough to perform an analysis. This might be • Mutation detection
the detection of a particular DNA sequence such as • Single cell PCR of in vitro fertilized embryo to
that belonging to a pathogenic microorganism or an diagnose genetic disease before implantation
oncogene, or the detection of differences in genes • Detection of viral and bacterial sequences in
such as mutations causing inherited disease. There- tissue (herpes simplex virus in CSF, hepatitis C,
fore the template DNA might consist of DNA HIV in peripheral blood, meningococcal strains)

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Essential Revision Notes in Paediatrics for MRCPCH

Polymerase chain reaction

3.4 Reverse transcription PCT 3.5 Next generation sequencing

(rt-PCR)
DNA sequencing is used to identify point mutations,
This is a modification of conventional PCR used to or small deletions/duplications, in a specific gene.
amplify messenger RNA (mRNA) sequence in order Typically a small number of individuals’ DNA is
to look at the expression of particular genes within tested for mutations in one gene. This is expensive
a tissue. mRNA is single stranded, unstable and not in terms of time and substrates. Next generation
a substrate for Taq DNA polymerase. For that reason sequencing allows multiple parallel analyses to be
it must be converted to complementary DNA performed at the same time. This can be used to test
(cDNA) using reverse transcriptase, a retroviral en- a single individual’s DNA for mutations in multiple
zyme, which results in a double-stranded DNA genes, or to test large numbers of individuals at the
copy of the original RNA sequence. PCR can then same time. Chips are being developed for specific
be performed in the normal way. related conditions caused by multiple genes, such

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 Genetics

as aortic dissection, Noonan syndrome, cardiomyo- the affected range, there are two other expansion
pathies and cardiac arrhythmias. These will allow sizes. Premutation sizes are smaller than the lowest
rapid genetic diagnosis of individuals with a clinical copy number to cause disease and are not asso-
diagnosis. Next generation technology is also the ciated with a risk of the condition, but have a high
basis of exome sequencing. risk of increasing into the disease range during
gametogenesis, generating an affected child. This
risk can be gender dependent in some conditions.
3.6 Exome sequencing
Intermediate alleles are smaller than the premuta-
Whole genome sequencing is expensive and time- tion range, but larger than normal. They have a risk
consuming. The exome consists of only the coding of increasing into the premutation range during
sequences in the genome, i.e. the parts of the gametogenesis.
genome that are translated into protein. This only
represents around 5% of the total genome, but is
4.1 Fragile X syndrome
estimated to contain 85% of all disease-causing
mutations. Exome sequencing is a method of ana- This causes learning disability, macro-orchidism,
lysing the entire exome for mutations. This is pri- autism and seizures, and was historically associated
marily a research tool used to identify unknown with a cytogenetically visible constriction (‘fragile
genes responsible for mendelian disorders, but has site’) on the X chromosome. The inheritance is X
also been used to identify functional variation asso- linked but complex. Among controls there are
ciated with more common conditions such as between 6 and 45 stably inherited trinucleotide
Alzheimer disease. repeats in the FMR1 gene. The intermediate allele
size is 50–58 repeats, and people with between 58
and 230 repeats are premutation carriers but are
unaffected. Only female gametogenesis carries a
4. TRINUCLEOTIDE REPEAT
risk of expansion into the disease-causing range
DISORDERS
(230 to .1000 repeats) known as a full mutation
These conditions are associated with genes contain- which is methylated, effectively inactivating the
ing stretches of repeating units of three nucleotides gene. All males and around 50% of females with
and include: the full mutation are affected, though females are
typically less severely affected. The premutation
• Fragile X syndrome – X-linked
does not expand to a full mutation when passed on
• Myotonic dystrophy – AD
by a male. Male premutation carriers are known as
• Huntington disease – AD
normal transmitting males and will pass the premu-
• Friedreich ataxia – AR
tation to all their daughters (remember that they
• Spinocerebellar ataxias – AD
pass their Y chromosome to all their sons). Although
In normal individuals the number of repeats varies premutation carrier status is not associated with
slightly but remains below a defined threshold. learning disability, female carriers have a high risk
Affected patients have an increased number of (around 50%) of premature ovarian failure or early
repeats, called an expansion, above the disease- menopause. There is also a condition called fragile
causing threshold. The expansions may be unstable X-associated tremor and ataxia syndrome (FXTAS),
and enlarge further in successive generations caus- which predominantly affects male premutation car-
ing increased disease severity (‘anticipation’) and riers over the age of 50. Parkinsonism and cognitive
earlier onset, e.g. myotonic dystrophy, particularly decline are also features. The lifetime male risk of
congenital myotonic dystrophy after transmission by developing FXTAS is 30–40% though 75% of men
an affected mother. Between the normal range and older than 80 show signs.

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Essential Revision Notes in Paediatrics for MRCPCH

5. MITOCHONDRIAL DISORDERS 6. GENOMIC IMPRINTING

Mitochondria are exclusively maternally inherited, For most genes both copies are expressed but for
deriving from those present in the cytoplasm of the some genes, either the maternally or paternally
ovum. They contain copies of their own circular derived copy is preferentially used, a phenomenon
16.5-kilobase chromosome carrying genes for sev- known as genomic imprinting. The unused copy is
eral respiratory chain enzyme subunits and transfer frequently methylated, which inactivates the gene.
RNAs. Mitochondrial genes differ from nuclear These genes tend to aggregate together in imprinted
genes in having no introns and using some different regions on chromosomes. Abnormalities of inheri-
amino acid codons. Within a tissue or even a cell tance or methylation of imprinted genes can there-
there may be a mixed population of normal and fore cause disease even in the presence of two
abnormal mitochondria known as heteroplasmy. apparently normal copies. The best examples are
Different proportions of abnormal mitochondria the Prader–Willi and Angelman syndromes, both
may be required to cause disease in different tis- caused by cytogenetic deletions of the same region
sues, known as a threshold effect. Disorders caused of chromosome 15q, uniparental disomy of
by mitochondrial gene mutations include: chromosome 15 (where both copies of chromosome
15 are derived from one parent with no copy of
• MELAS (mitochondrial encephalopathy, lactic
chromosome 15 from the other parent), or abnorm-
acidosis, stroke-like episodes)
alities of methylation, which labels both chromo-
• MERRF (myoclonic epilepsy, ragged red fibres)
somes as deriving from one parent. The disease
• Mitochondrially inherited diabetes mellitus and
condition is caused by the absence of one parent’s
deafness (typically caused by the same mutation
copy of genes in the region, rather than by exces-
as seen in MELAS but at lower levels)
sive numbers of copies of the other.
• Leber hereditary optic neuropathy (note that
other factors also contribute)

Prader-Willi syndrome Angelman syndrome

Clinical
Neonatal hypotonia and poor feeding Unprovoked laughter/clapping
Moderate learning disability Microcephaly, severe learning disability
Hyperphagia + obesity in later childhood Ataxia, broad-based gait
Small genitalia Seizures, characteristic EEG
Genetics
70% deletion on paternal chromosome 15 80% deletion on maternal chromosome 15
30% maternal uniparental disomy 15 2–3% paternal uniparental disomy 15
(i.e. no paternal contribution) (i.e. no maternal contribution);
remainder due to subtle mutations

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 Genetics

Other imprinting disorders ial cancer syndrome. Predictive testing is not usual-
ly offered without a formal process of genetic
Silver–Russell syndrome
counselling over more than one consultation with
Prenatal onset growth retardation, relative macro-
time built in for reflection. Where there are inter-
cephaly, triangular facies, asymmetry, fifth finger
vening relatives whose genetic status may be indir-
clinodactyly and frequently normal IQ. Around 35%
ectly revealed, there are additional issues that must
are caused by abnormal methylation of genes on
be taken into consideration. Written consent for
chromosome 11p15, whereas 10% are associated
predictive testing is required by most laboratories.
with maternal uniparental disomy of chromosome
Nationally agreed guidance is that predictive testing
7. The cause in the remainder is not yet known.
in children for disorders that have no implications
in childhood should not be undertaken until the
Beckwith–Wiedemann syndrome
child is old enough to make an informed choice.
Prenatal-onset macrosomia, facial naevus flammeus,
macroglossia, ear lobe creases, pits on the ear helix,
Carrier tests
hemihypertrophy, nephromegaly, exomphalos (om-
phalocele) and neonatal hypoglycaemia. There is an These are usually undertaken in autosomal recessive
increased risk of Wilms tumour, adrenocortical and or X-linked recessive disorders where the result has
hepatic tumours in childhood. Similar to Silver– no direct implications for the health of the indivi-
Russell syndrome, the condition results from dual, but is helpful in determining the risks to their
abnormalities of inheritance or methylation of offspring. Carrier status may be generated as a by-
chromosome 11p15 which contains several product of diagnostic or prenatal testing. National
imprinted genes, including the IGF-2 (insulin-like guidance is that specific testing for carrier status
growth factor 2) gene. The results in BWS tend to should be avoided in children until they are old
be directly opposite to those in Silver–Russell enough to make an informed choice.
syndrome.
Genetics in children
Diagnostic tests are obviously necessary and useful,
7. GENETIC TESTING as are predictive tests for disorders that may manifest
in childhood, and have a screening programme or
Genetic tests can be thought of as diagnostic, pre- treatment, such as the multiple endocrine neoplasias
dictive or for carrier status. Informed verbal, and (MEN1, MEN2) and familial adenomatous polyposis.
increasingly written, consent (or assent) should be Predictive testing for adult onset disorders such as
obtained before genetic testing. BRCA-1/-2 or Huntington disease are not appropriate
in children, because they are unable to give informed
Diagnostic tests consent, and a diagnosis can never be removed once
These are chromosomal investigations such as karyo- it has been made. Many adults opt not to have
type and CGH microarray, or mutation analysis of predictive tests for untreatable disorders such as Hun-
specific genes. The latter is frequently used where the tington disease, and an at-risk child should be al-
diagnosis is already suspected on clinical grounds lowed to make the same decision. Equally, carrier
but genetic testing is useful for confirmation, or for status for AR or X-linked disorders will impact only on
counselling or predictive testing in the wider family. a child’s reproductive decisions, not childhood
health, and thus is only tested when the child is able
to participate in the process and give proper informed
Predictive tests
consent. Parents do occasionally request such testing,
When an individual is clinically normal but is at and a clinical geneticist would meet them in clinic to
risk for developing a familial disorder, such as discuss their reasons for testing and the reasons for a
Huntington disease, myotonic dystrophy or a famil- reluctance to offer it.

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Essential Revision Notes in Paediatrics for MRCPCH

8. IMPORTANT GENETIC TOPICS

This section includes short notes on conditions that
form popular examination topics.

8.1 Ambiguous genitalia

Normal development of the reproductive
tract and external genitalia
A simplified outline is shown below.

Outline of the normal development of the reproductive tract and external genitalia

The 6-week embryo has undifferentiated gonads, In the absence of a Y chromosome the gonads
müllerian ducts (capable of developing into the become ovaries which secrete neither testosterone
uterus, fallopian tubes and upper vagina), wolffian nor MIF and, in the absence of testosterone, the
ducts (capable of forming the epididymis, vas defe- wolffian ducts regress and the external genitalia
rens and seminal vesicles) and undifferentiated ex- feminize. In the absence of MIF, the müllerian ducts
ternal genitalia. persist and differentiate.
In the presence of a Y chromosome the gonads The causes of ambiguous genitalia divide broadly
become testes that produce testosterone and müller- into those resulting in undermasculinization of a
ian inhibiting factor (MIF). Testosterone causes the male fetus, those causing masculinization of a
wolffian ducts to persist and differentiate and, after female fetus, and those resulting from mosaicism for
conversion to dihydrotestosterone (by 5Æ-reductase), a cell line containing a Y chromosome and another
masculinization of the external genitalia. MIF that does not. They are summarized in the diagram
causes the müllerian ducts to regress. opposite.

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 Genetics

Chromosomes

abnormal 46, XY 46,XX

UNDERMASCULINIZED MASCULINIZED
MALE FEMALE

• e.g. 45, X/46,XY mosaic par tial testicular failure external androgens
par tial androgen insensitivity e.g. OCP
5 α-reductase deficiency endogenous androgens
rare forms of congenital e.g. common forms of
adrenal hyperplasia congenital adrenal
e.g. 3β-hydroxylase hyperplasia
17α-hydroxylase - 21-hydroxylase
rare syndromes -11β-hydroxylase
e.g. Smith-Lemli-Opitz (AR)

NB. Complete testicular failure and complete androgen insensitivity (5testicular feminization
syndrome) cause apparently normal female external genitalia.

Ambiguous genitalia – outline of causes

8.2 Cystic ¢brosis much smaller proportion in many other ethnic

groups. Therefore, negative molecular testing cannot
This results from mutations in the CFTR (cystic
exclude a diagnosis of cystic fibrosis.
fibrosis transmembrane regulator) gene. The ˜F508
mutation (deletion of three nucleotides coding for a
phenylalanine residue at amino acid position 508)
8.3 Duchenne and Becker muscular
accounts for 75% of mutations in white people.
dystrophies
Most laboratories now screen for 32 common muta-
tions including ˜F508. Such testing identifies 90% These result from different mutations within the
of cystic fibrosis mutations in white people, but a dystrophin gene on chromosome Xp21.

Important distinguishing features of Duchenne and Becker muscular dystrophies

Duchenne muscular dystrophy Becker muscular dystrophy

Immunofluorescent Undetectable Reduced/abnormal
dystrophin on muscle
biopsy
Wheelchair dependence 95% at ,12 years 5% at ,12 years
Learning disability 20% Rare

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Essential Revision Notes in Paediatrics for MRCPCH

In around a third of boys with Duchenne muscular In practical terms, most families will have an identi-
dystrophy, the condition has arisen as a new muta- fiable mutation, and thus carrier identification will
tion, whereas a further third are the result of a new be relatively easy. In the absence of a mutation, e.g.
mutation in the mother. Mutation analysis in the the affected individual has died with no DNA
affected boy can often identify mothers who are stored, or no mutation is identified (a small propor-
carriers, but a normal result does not exclude germ- tion), then the above risks can be modified using
line mosaicism, where mutated cells are present in linkage to the X chromosome and Bayes theorem to
the ovaries but not the blood. A woman proven to take into account the number of unaffected males
be a carrier has a 25% (1 in 4) recurrence risk, but in the family, and the creatine kinase (CK) levels in
a woman without the mutation in her blood still has the at-risk females. Carrier females can have ele-
up to a 20% recurrence risk, and prenatal diagnosis vated CK levels, although a normal result does not
is offered in all circumstances. exclude carrier status because they follow a normal
distribution. A woman known to be at high risk, but
Given the high new mutation rate, both in the
with no identifiable mutation, may only be able to
affected child and in the mother, calculation of risks
opt to terminate male pregnancies if she wishes to
to other family members can be challenging. The
avoid having an affected child.
risk that the mother of an isolated case is a carrier is
two in three. The maternal grandmother’s risk is one
in three, due to the chance of a new mutation in
8.4 Neuro¢bromatosis
the mother. Thus, the sister of the isolated affected
boy has a one in three risk of being a carrier, but There are two forms of neurofibromatosis (NF) that
the maternal aunt has a one in six risk, and so on. are clinically and genetically distinct:

NF1 NF2
Major features >6 Café-au-lait patches Bilateral acoustic neuromas
Axillary/inguinal freckling (vestibular schwannomas)
Lisch nodules on the iris Other cranial and spinal tumours
Peripheral neurofibromas
Minor features Macrocephaly Café-au-lait patches (usually ,6)
Short stature Peripheral schwannomas
Peripheral neurofibromas
Complications Plexiform neuromas Deafness/tinnitus/vertigo
Optic glioma (2%) Lens opacities/cataracts
Other cranial and spinal Spinal cord and nerve compressions
tumours Malignant change/sarcomas
Pseudarthrosis (especially
tibial)
Renal artery stenosis
Phaeochromocytoma
Learning difficulties
Scoliosis
Spinal cord and nerve
compressions
Malignant change/sarcomas
Gene Chromosome 17 Chromosome 22
Protein Neurofibromin Schwannomin

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 Genetics

8.5 Tuberous sclerosis laxity or hyperextensibility, and this alone in a tall

individual is not sufficient to suspect the diagnosis
There are at least two separate genes that cause
of Marfan.
tuberous sclerosis (TS), on chromosomes 9 (TSC1;
hamartin) and 16 (TSC2; tuberin).
Clinical features of Marfan syndrome

Clinical features of tuberous sclerosis Musculoskeletal

Skin/nails • Tall stature with disproportionately long

limbs (dolichostenomelia)
• Ash-leaf macules • Characteristic facial appearance
• Shagreen patches (especially over the • Arachnodactyly
lumbosacral area) • Pectus carinatum or excavatum
• Adenoma sebaceum (facial area) • Scoliosis
• Subungual/periungual fibromas • High, narrow arched palate with dental
overcrowding
Eyes • Pes planus
• Retinal hamartomas
Heart
Heart • Aortic root dilatation and dissection
• Cardiac rhabdomyomas, detectable • Mitral valve prolapse
antenatally, usually regressing during
childhood Eyes
• Lens dislocation (typically up)
Kidneys • Myopia
• Angiomyolipomas
• Renal cysts Skin
• Striae
Neurological
• Seizures Lungs
• Learning disability • Spontaneous pneumothorax
• Apical bullae
Neuroimaging
• Intracranial calcification (periventricular)
• Subependymal nodules 8.7 Homocystinuria
• Neuronal migration defects
(see also Chapter 16)
This is most commonly the result of cystathione-â-
synthase deficiency and causes a Marfan syndrome-
8.6 Marfan syndrome
like body habitus, lens dislocation (usually down),
This results from mutations in the fibrillin 1 (FBN1) learning disability, thrombotic tendency and osteo-
gene on chromosome 15. Intelligence is usually porosis. Treatment includes a low methionine diet
normal. New diagnostic criteria do not include joint  pyridoxine.

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Essential Revision Notes in Paediatrics for MRCPCH

8.8 Noonan syndrome chromosome 4. There is a high new mutation rate.

Important complications are hydrocephalus, brain-
This is an autosomal dominant condition. Around
stem or cervical cord compression resulting from a
50% of individuals with Noonan syndrome have
small foramen magnum, spinal canal stenosis,
mutations in the PTPN11 (protein-tyrosine phospha-
kyphosis and sleep apnoea. Intelligence is usually
tase, non-receptor-type 11) gene on chromosome 12.
normal.
A further 10–15% are caused by SOS1 (son of seven-
less homologue 1 (Drosophila), on chromosome 2)
and RAF1 (v-raf-1 murine leukaemia viral oncogene 8.10 Alagille syndrome
homologue 1 on chromosome 3) causes another 5–
A variable autosomal dominant disorder resulting
10%. Multiple other genes on the RAS-MAPK path-
from deletions of or mutations in the JAG1 (jagged)
way have also been implicated in small proportions
gene on chromosome 20. Major features of the
of cases. The karyotype is usually normal.
syndrome include:

Clinical features of Noonan syndrome • Cardiac – peripheral pulmonary artery stenosis

 complex malformations
Cardiac • Eye – posterior embryotoxon, abnormalities of
the anterior chamber
• Pulmonary valve stenosis • Vertebral – butterfly vertebrae, hemivertebrae,
• Hypertrophic cardiomyopathy rib anomalies
• Septal defects (atrial and ventricular septal • Hepatic – cholestatic jaundice, paucity of
defects) intrahepatic bile ducts
• Branch pulmonary artery stenosis

Musculoskeletal 8.11 CHARGE syndrome

• Webbed or short neck A malformation syndrome including:
• Pectus excavatum or carinatum • Colobomas
• Wide-spaced nipples • Heart malformations
• Wide carrying angle (cubitus valgus) • Atresia of the choanae
• Short stature in 80% • Retardation of growth and development
(learning disability)
Other features • Genital hypoplasia (in males)
• Ptosis • Ear abnormalities (abnormalities of the ear
• Low-set and/or posteriorly rotated ears pinna, deafness)
• Small genitalia and undescended testes in • Cleft lip/palate and renal abnormalities are also
boys common
• Coagulation defects in 30% (partial factor The majority of patients with CHARGE syndrome
XI:C, XIIC and VIIIC deficiencies, von have new mutations or deletions of the CHD7
Willebrand disease, thrombocytopenia) (chromodomain helicase DNA-binding protein 7)
• Mild learning disability in 30% gene on chromosome 8.

8.12 VATER (VACTERL) association

8.9 Achondroplasia
A sporadic malformation syndrome including:
A short-limb skeletal dysplasia resulting from speci-
fic autosomal dominant mutations in the FGFR3 • Vertebral abnormalities
(fibroblast growth factor receptor 3) gene on • Anal atresia  fistula

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 Genetics

• Cardiac malformations of a wide variety of malformations, particularly

• Tracheo-oesophageal fistula cardiac (transposition of the great arteries, aortic
• Renal anomalies, radial ray defects coarctation, septal defects, cardiomyopathy), verte-
• Limb anomalies, especially radial ray defects bral (sacral abnormalities, hemivertebrae), renal
(agenesis, duplex collecting systems), intestinal
The cause is not yet known.
(imperforate anus, other atresias) and limb abnorm-
alities (short femurs, radial ray abnormalities).
8.13 Goldenhar syndrome
Maternal myasthenia gravis
Also known as oculo-auriculovertebral spectrum, or
first and second and branchial arch syndrome. It is This is associated with fetal arthrogryposis.
mainly sporadic and the cause is unknown. Major
features include: Maternal phenylketonuria
• Craniofacial – asymmetry, hemifacial Although the fetus is unlikely to be affected by
microsomia, micrognathia phenylketonuria (PKU: which is autosomal reces-
• Ears – malformed pinnas, deafness, preauricular sive), if an affected mother has relaxed her low
tags phenylalanine diet, the fetus is at risk of micro-
• Eyes – epibulbar (scleral) dermoid cysts, cephaly, cardiac defects and learning disability
microphthalmia secondary to exposure to the raised maternal
• Oral – macrostomia, cleft lip/palate phenylalanine levels.
• Vertebral – hemivertebrae
• Cardiac – cardiac malformations Maternal systemic lupus erythematosus
• Renal – renal malformations
Maternal systemic lupus erythematosus (SLE) with
anti-Ro and anti-La antibodies is associated with an
8.14 Pierre Robin sequence increased risk of fetal bradycardia and congenital
heart block for which pacing may be required. A
An association of micrognathia and cleft palate
self-limiting neonatal cutaneous lupus may also
which may occur alone, but a proportion will have
occur.
22q11 deletions or Stickler syndrome.

9.2 Infectious agents

8.15 Potter sequence
The following agents are associated with increased
Oligohydramnios as a result of renal abnormalities,
fetal loss in the first trimester; hepatosplenomegaly,
urinary tract obstruction or amniotic fluid leakage
jaundice and thrombocytopenia in the neonate; and
may lead to secondary fetal compression with joint
abnormalities particularly those affecting the central
contractures (arthrogryposis), pulmonary hypoplasia
nervous system, vision and hearing.
and squashed facies known as the Potter sequence.
Fetal cytomegalovirus
Infection may be associated with microcephaly,
9. FETAL TERATOGENS intracranial calcification, chorioretinopathy, deaf-
ness and learning disability.
9.1 Maternal illness
Maternal diabetes Fetal toxoplasmosis
Maternal diabetes is associated with fetal macro- Infection with Toxoplasma species, a protozoan,
somia, neonatal hypoglycaemia and increased risk may be associated with microcephaly, hydrocepha-

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Essential Revision Notes in Paediatrics for MRCPCH

lus, intracranial calcification, chorioretinopathy and Fetal retinoic acid

learning disability.
Exposure to retinoic acid (which is used in the
treatment of acne) is associated with structural brain
Fetal rubella abnormalities, neuronal migration defects, microtia
and complex cardiac malformations.
Infection with rubella virus is most often associated
with deafness particularly in the first and early Fetal valproate syndrome
second trimesters, but cardiac abnormalities (persis-
tent ductus arteriosus, peripheral pulmonary steno- Fetuses exposed to valproate have an increased risk
sis, septal defects), microcephaly, chorioretinopathy, of cleft lip and palate, neural tube defects, cardiac
cataract and learning disability are also associated. defects, radial ray defects, learning disability and
facial anomalies (frontal narrowing including meto-
pic craniosynostosis, thin eyebrows, infraorbital skin
Congenital syphilis, herpes and varicella grooves, long philtrum, thin upper lip). These effects
See Chapter 15, Section 11.1. appear to be dose dependent.

Fetal warfarin syndrome

9.3 Other teratogens Fetuses exposed to warfarin typically have nasal
hypoplasia, stippled epiphyses and are at risk of
Fetal alcohol syndrome
learning disability and brain, eye, cardiac and skele-
Pre- and postnatal growth retardation, neonatal irrit- tal malformations.
ability, microcephaly, learning disability, hyperactiv-
ity in childhood, cardiac defects (particularly
ventricular and atrial septal defects), small nails on
fifth fingers and toes, facial anomalies (short palpeb- 10. PRENATAL TESTING
ral fissures, ptosis, smooth philtrum, thin upper lip)
and a variety of less common, often midline, mal- • Chorionic villous sampling or biopsy (CVS or
formations. It is likely that the effects on any one CVB) – a small piece of placenta is taken either
fetus are determined by the degree, timing and transabdominally or transvaginally. CVS testing
duration of exposure as well as the susceptibility of can be safely performed from 11 weeks’
the fetus which is probably genetically determined. gestation
• Amniocentesis – amniotic fluid is taken,
containing cells derived from the surfaces of the
Illicit drugs in pregnancy fetus and amniotic membranes. Amniocentesis
is usually performed from 15 weeks’ gestation
Opiate drugs in pregnancy have a high risk of
• Cordocentesis – a method of obtaining fetal
dependency in the newborn, intrauterine growth
blood that can be performed from 18 weeks’
retardation and still birth, but do not appear to be
gestation
associated with significant risk of structural anoma-
lies. There are behavioural issues during childhood. Chromosome and DNA testing can be performed
Fetal cocaine has a higher risk of defects, apparently on any of the above types of sample, and biochem-
associated with vascular disruption, such as limb ical analyses can often also be performed if neces-
reduction defects and porencephaly. Survivors of sary. Each method carries a small risk of
this do not appear to have long-term intellectual miscarriage. As a result, most couples opt for pre-
deficit once their home circumstance has been natal testing only if they wish to terminate an
taken into account, though there is evidence of affected pregnancy. Although chromosome analysis
some attention and behavioural problems. can be performed on any pregnancy, DNA analysis

296
 Genetics

can be used only in families where known muta- viable pregnancy rate to IVF (25%). It is available in
tions have already been identified, and the family is the UK for a limited, although increasing, number
at significant risk. of conditions and virtually all inherited chromosome
anomalies. For funding purposes it is frequently
It is possible to identify the sex of an unborn fetus
regarded as fertility treatment, so families can find it
by prenatal testing and, in the case of X-linked
hard to get NHS treatment. Overseas centres have a
conditions where no specific mutation has been
wider range of conditions, but it is very expensive.
identified, this is often the only available prenatal
test. However, it is illegal in the UK to terminate a
pregnancy on the basis of gender alone unless the
child is at risk of a genetic condition due to its 13. GENETIC COUNSELLING
gender.
This is the process of assisting families or individuals
affected by genetic disease to understand the cause
of their condition, the risk of recurrence and the
11. NON-INVASIVE PRENATAL options available to them. It is entirely non-directive
TESTING and the aim is to deliver all available information to
Cell-free fetal DNA can be detected in the mother’s allow the family to make the appropriate decisions.
circulating blood from 4 weeks’ gestation. The vast Some families will opt for prenatal diagnosis and
majority of the cell-free DNA is maternal, however, termination, although this will not be acceptable for
so testing is currently limited to the identification or others. Equally, with predictive testing, not everyone
exclusion of genetic material not present in the at significant risk of a condition chooses to have
mother, such as Y chromosome, or rhesus D in testing to clarify this risk further. Genetic counsel-
RhD-negative women. In those at risk of an X-linked ling will be offered to all, with no obligation to
disorder in sons, this process will remove the neces- pursue testing.
sity for invasive testing in 50% of pregnancies.
Currently it is not possible to test for trisomy 21 or
other chromosomal anomalies by this method.
14. FURTHER READING
Firth HV, Hurst JA. Oxford Desk Reference –
12. PREIMPLANTATION GENETIC Clinical Genetics. Oxford University Press, 2005.
DIAGNOSIS Harper PS. Practical Genetic Counselling, 7th edn.
London: Hodder Education, 2010.
This technique is an in vitro fertilization (IVF)-based
process. At the 8- to 16-cell stage a single cell is Jones KL. Smith’s Recognizable Patterns of Human
removed from each embryo for testing. Only em- Malformation, 6th edn. Philadelphia: Elsevier
bryos predicted to be unaffected are reimplanted Saunders, 2005.
into the mother. Preimplantation genetic testing Kingston HM. ABC of Clinical Genetics, 3rd edn.
(PGD) is technically difficult and has a similar Oxford: Wiley-Blackwell, 2002

297