ESSENTIAL READINGS - Chromosomal

abnormalities and early development in Down

syndrom
Learning Objectives

The genetic mechanisms that lead to the developmental anomalies encountered in Down
Syndrome and subsequent cancer and premature aging in postnatal life

Content

The human chromosome complement was established as recently as 1956 as 23 pairs, i.e. 46
chromosomes. This is called the diploid number of chromosomes. Down syndrome was the first
disorder in which a chromosome abnormality was discovered by Lejeune and colleagues in
1958. They established that the majority (95%) of Down syndrome subjects had an additional 21
chromosome. More sophisticated cytogenetic techniques reveal that a variety of different
chromosomal mechanisms result in Down syndrome although these all share the common
abnormality of triplication of chromosome 21 genes.
Cytogenetic Mechanisms Responsible for Down Syndrome

Trisomy 21 95 %
Translocation 2.5%
Mosaicism 2.5%
Other <1%
What are the Mechanisms which Produce Trisomy 21
During meiosis (the formation of germ cells), the chromosome complement is halved to 23. This
is called the haploid number. There are 2 steps, Meiosis I in which the diploid number is halved
to 23, and Meiosis II in which the chromosomes are replicated similar to a mitotic step. Non-
disjunction, i.e. the non-segregation of paired sister chromosomes to 2 daughter cells, results in
a germ cell with 24 chromosomes and a corresponding germ cell with 22 chromosomes.
Molecular Cytogenetic and DNA polymorphism studies demonstrate that the error occurs in
maternal meiosis I in 75% and meiosis II in 25% of patients. When the error occurs in paternal
meiosis the ratios are reversed meiosis I (25%) and II (75%). Epidemiologic studies show that an
increased incidence of trisomy 21 Down syndrome is strongly connected with the maternal age
>37 years. Errors occur in meiosis in women at all ages. At 40 years, the incidence of Down
syndrome is approximately 1:100 compared with an incidence of 1:1000 in women 29 years.

Translocation
Physical fusion of two chromosomes (or part of chromosomes) is known as translocation. This
anomaly may be stably inherited. Fusion between chromosomes which have their centromere at
one end (acrocentrics) i.e. chromosomes 13, 14, 15, 21 and 22 are known as Robertsonian
translocations. A Robertsonian translocation which does not affect the absolute number (dosage)
of chromosome 21 causes no phenotypic effects. Balanced translocations may be stably
inherited. However balanced translocations result in abnormal pairing at meiosis and in gametes
with an unbalanced composition (excess or insufficiency). Unbalanced Robertsonian
translocation is responsible for 2-3% of Down syndrome, in which half those affected are
inherited. Recurrence risks vary. The 21;21 translocation when present in a parent results in
100% Down syndrome offspring (the monosomic conceptus is previable lethal).
Mosaicism
About 2.5% of patients have a mixture of body cells, normal cells with 46 chromosomes and
Down syndrome cells with 47 chromosomes. There is a wide variation in intellectual disability (if
any) and phenotypic effects. Some individuals with Down syndrome mosaicism commence life as
full trisomic embryos but one 21 is lost by anaphase lag in early embryogenesis. This is
sometimes known as trisomic rescue.
Other
Patients have been described with partial trisomy (duplication) for a region of the long arm of
chromosome 21. The region of chromosome 21, 21q 22.13-22.2 is responsible for most of the
phenotype. Partial trisomy may be undetectable by standard methods of chromosomal
(cytogenetic) analysis such as G banding and Fluorescence in situ hybridisation (FISH)
employing probes for a region of chromosome 21. Tiny duplications may be detected by
interphase FISH and Comparative Genomic Hybridisation Array technology (CGH array) (Ronan
et al 2007).
ESSENTIAL READINGS - Features of Down syndrome
Learning Objectives

The major features seen in newborns with Down Syndrome

Content

Down syndrome is diagnosed where there is effectively trisomy for chromosome 21 (see learning
topic on Chromosomal abnormalities and early development in Down syndrome).
The features which Dr Langdon Down identified in 1866 as 'mongoloid' are present in many but not all
patients with Down syndrome. The dysmorphic, i.e. abnormal craniofacial features, are modified by
familial and ethnic facial features. Down syndrome may be found in children and adults in every ethnic
group throughout the world. The dysmorphic features which are identified with Down syndrome may
be found in a large number of other syndromes. Thus the presence of the features singly or in
combination is never diagnostic, but a suspicion of Down syndrome should always be confirmed by
chromosomal study.
Features which are commonly seen in the Newborn with Down syndrome:

Hypotonia
Excessive skin folds at the back of the neck
Maxillary (malar) underdevelopment (hypoplasia)
In curving of the little finger (clinodactyly)
Hypoplasia of the middle phalanx of the 5th finger - recognised by a short middle segment or a
single interphalangeal crease.
Wide gap between the first or second toes (sandal gap)

Features which may be seen in normal newborns

Epicanthic folds (prominent skin folds at the inner canthi of the eyes) which are usually seen in babies
of African and Asian descent and not uncommonly in European infants.
Single transverse palmar crease

Down syndrome Normal

Bilateral 45% 1%

Unilateral 4%

Major malformations in the Newborn with Down syndrome

Congenital Heart Anomalies (40%)

Atrio-ventricular canal (13%)
Ventricular septal defects (13%)
 Tetralogy of Fallot (7%)
Atrial septal defects (10%)
Gastrointestinal Anomalies (10-18%)
Duodenal atresia
Hirschsprung disease
Undescended testes (21%)

Features commonly seen in childhood

Delayed psychomotor development

Intellectual disability
Prominence of the tongue (due to a small mouth)
Persistent epicanthic folds
Flattening of the back of the head (brachycephaly)
Short stature
Brushfield spots (speckling around the rim of the iris) except in subjects with brown irides
Joint hypermobility

Preventive health maintenance in childhood

Leukoerythroblastic anaemia
Acute Leukaemia
Hypothyroidism
Atlanto-Occipital Instability

Preventive health maintenance in adults

Leukoerythroblastic anaemia
Acute Leukaemia
Hypothyroidism
Atlanto-Occipital Instability

Specific terminologic notes

By international convention the term 'mongolism' had been abandoned

Syndromes are named without the possessive ie Down syndrome, Edwards syndrome etc.
'Simian' means 'pertaining to a monkey'. It is an inappropriate (obsolete) term for 'single
transverse palmar crease' or 'bridged transverse palmar crease' which should be distinguished
from the Sydney line which is a proximal complete transverse palmar crease in the presence of a
partial distal palmar crease.
ESSENTIAL READINGS - Cyanosis: causes and
consequences
Learning Objectives

The meaning and significance of cyanosis, together with the pathophysiological mechanisms that
result in cyanosis

Content

Cyanosis refers to an abnormal dusky blue discolouration of the skin and/or mucous membranes due
to a higher than normal concentration of deoxygenated or unsaturated haemoglobin
(deoxyhaemoglobin) in the tissue capillaries. Haemoglobin changes colour from red to blue as it
unloads oxygen from the capillaries into the tissues. Normally, the high proportion of saturated
haemoglobin in the capillaries of visible tissues imparts the usual pink colour while the veins draining
these tissues appear blue. Cyanosis arises through two basic mechanisms; either 1) the arterial blood
entering these capillaries is less saturated than normal or 2) the circulation may be slowed so that
more extraction of oxygen per gram of haemoglobin occurs, hence increasing the concentration of
deoxyhaemoglobin in the capillaries. Both mechanisms may operate together.
Cyanosis is classified as peripheral or central. When extremities appear blue but the warm buccal
mucosa and conjunctivae appear pink it is usually due to slowing of the circulation causing peripheral
cyanosis and this is most often associated with cold induced vasoconstriction. More important
pathological causes of peripheral cyanosis are reduced circulation due to atheromatous or traumatic
narrowing of arteries (eg diabetic vasculopathy) or abnormal arterial spasm (eg Raynaud's
phenomenon). Central cyanosis affecting the warm mucous membranes is more important because
this usually implies mechanism 1) above and this means that the systemic arterial blood perfusing the
whole body is deficient in oxygen. It is essential to appreciate that, by the time cyanosis is detectable,
the oxygen deficiency (hypoxaemia) in the arterial blood is very severe and potentially life threatening,
particularly if it is acute. Arterial hypoxaemia arises when venous blood from the tissues, finally mixing
in the right side of the heart (mixed venous blood), is not normally oxygenated by passage through
the lungs to the left side of the heart and thence the systemic arteries. Direct shunting of blood from
the right to the left side of the heart, bypassing the lungs (as in this case), or perfusion of abnormal
shunt vessels in the lungs which have no contact with alveolar gas are the "shunt" causes of
cyanosis. The more common cause, however, is an imbalance or mismatch between ventilation and
blood flow among the gas exchanging units of the lung (ventilation-perfusion inequality) which occurs
to some degree in most diseases affecting the lungs.
The detection of central cyanosis means that in systemic arterial blood the partial pressure of oxygen
(PaO in mmHg), the percentage saturation of haemoglobin (SaO in % oxyhaemoglobin / total
2 2

haemoglobin), and the content of oxygen (CaO in ml/dL of blood) are lower than normal. Useful
2

normal values to remember for a young adult breathing air at sea level are PaO 97 mmHg, SaO 97%
2 2

and CaO 20.4 ml/dL, the latter given a normal (total) haemoglobin concentration of 150 gm/L. There
2

is a complex sigmoid relation between PaO as the independent variable and SaO or CaO as the
2 2 2

dependent variable known as the oxyhaemoglobin dissociation curve. The most important features of
this curve are that PaO must fall to 60 mmHg before SaO falls below 90% but, thereafter, SaO falls
2 2 2

quite steeply such that a PaO of 40 mmHg corresponds with an SaO of 75%. Central cyanosis
2 2

cannot usually be detected until there is a concentration of 50 gm/L of deoxyhaemoglobin in the

arterial blood. It can be seen, from the above relations, that a patient with a normal total haemoglobin
concentration of 150 gm/L would need the SaO to fall to 67% (PaO 35 mmHg) before cyanosis could
2 2

be detected and this is a very dangerous level of hypoxaemia below the normal mixed venous PO of 2

40 mmHg. Cyanosis may be detected at a less extreme degree of hypoxaemia when the patient has a
high haemoglobin. Detection of cyanosis in the mildly anaemic subject corresponds with a
desperately low PaO .2

The importance of early detection of hypoxaemia lies in the fact that the body has very small stores of
oxygen and most tissues are critically reliant on a continuous adequate arterial content especially the
brain and the heart. The oxygen partial pressure (PO ) in the capillary is the immediately critical
2

factor, as oxygen moves along a pressure gradient to the mitochondria in the cells where the
prevailing partial pressure of oxygen is probably less than 2 mmHg. However, the oxyhaemoglobin
saturation and oxygen content of the arterial blood entering the capillaries are crucial in maintaining
an adequate driving pressure as the oxygen is consumed. For example, the anaemic patient with
normal lungs may have a normal PaO and SaO but the low CaO means that the PO (and
2 2 2 2

saturation) fall much more rapidly as oxygen is taken up from the capillaries. The precise relation
between oxygen content and pressure in determining oxygen delivery is incompletely understood.
The important principle is that the causes of hypoxaemia should be rapidly identified and corrected,
particularly when it is acute. Compensatory mechanisms play an important role in minimising the
deleterious effects of chronic hypoxaemia. The patient in this case is likely to develop these
mechanisms including a high cardiac output and a high total haemoglobin concentration, but these
compensations bring other complications.
ESSENTIAL READINGS - Overview of congenital heart
disease
Learning Objectives

The physiology of cardiac shunts and vascular resistance, the incidence and range of congenital heart
disease and congestive cardiac failure in infants

Content

Congenital Heart Disease is one of the most common forms of serious congenital abnormality. Its
range, however, is wide and many patients may have minor abnormalities not likely to produce either
overt or occult damage to the patient.
Congenital heart lesions are quite unlike the pathology seen in the adult.
The wide range of congenital heart abnormalities can be divided into broad subcategories of
acyanotic and cyanotic heart disease. Alternate approaches may consider physiology of left to right
shunts, and obstructive lesions. These may occur independently or in combination (such as in this
case).
The problems of differentiating congenital cardiac pathology from the normal heart arises often in
young children and babies since a cardiac murmur, commonly seen arising from the normal heart of a
child, may raise suspicions when its character is unusual.
Early and appropriate management can be life saving or avoid the long term damaging sequelae of
unrecognised abnormality. This management will usually be delivered by a paediatric cardiologist and
paediatric cardiac surgeon, but initial recognition will depend on the primary care physician in many
cases.
Heart and Great Vessel Anatomy
An understanding of normal cardiac anatomy will prepare the student to appreciate the variety of
structural lesions possible, without needing to be familiar with each one. Each area of the heart (alone
or in combination) may be affected by maldevelopment.
Physiology of cardiac shunts and vascular resistance
These lesions will often have associated septal defects allowing blood to cross between the
pulmonary and systemic circulations. This movement of blood, or 'shunt', will be dictated by a number
of factors including the size of the defect and the 'downstream' resistance to flow. In many important
lesions resistance may be either at a structural level or at the level of vascular resistance (especially
in the pulmonary circulation). The issue of PVR is particularly important to understanding the clinical
presentation and course of young infants with ventricular septal defect and other types of 'left to right
shunt' lesions.
Incidence and range of congenital heart disease and congestive cardiac failure in infants
Once these concepts are recognised the incidence and range of congenital heart abnormalities can
be better appreciated, and the causes of congestive heart failure in babies, and its time of
presentation, be understood.
ESSENTIAL READINGS - The foetal circulation
Normadiah M.Kassim

Learning Objectives

The major anatomical and physiological features of foetal circulation and its differences to the adult
circulation

Content

The adult circulation contains two separate pumps in series. The right ventricle pumps blood through
the lungs where it is oxygenated. The left ventricle pumps blood through the body where oxygen is
consumed. In the foetus the circulation differs markedly from the adult since the placenta replaces the
lungs as the source of oxygen while the fetal lungs have no gas exchange function. Furthermore at
birth, after tying and cutting the umbilical cord and the expansion of the lungs with the first breath, the
fetal circulation changes rapidly to one approximating to the adult.
The main features of the fetal circulation are as follows.

Two large umbilical arteries leave the iliac artery and carry about 50% of the cardiac output to the
placenta.
A single umbilical vein carries oxygenated blood back from the placenta and joins the inferior
vena cava, bypassing the liver.
Of the blood returning to the right atrium about half crosses through the foramen ovale, which
connects the R and L atria, and enters the left atrium.
Of the blood pumped out of the right ventricle into the pulmonary artery, about half, instead of
entering the lungs, passes through the ductus arteriosus which connects the pulmonary artery
and the aorta, and enters the systemic circulation.

These differences between fetal and adult circulation occur both because of the anatomical
connections present in the foetus but also because the uninflated fetal lung has a very high resistance
to blood flow and the fetal systemic circulation has a low resistance because of the placenta.
Consequently the pressures on the right side of the heart are higher than on the left (in contrast to the
adult) and blood flows from R to L atrium through the foramen ovale and from the pulmonary artery to
the aorta through the ductus arteriosus.
At birth three main changes occur. The cord is tied and systemic peripheral resistance doubles
increasing pressure in the L heart and aorta. At the first respiratory inflation the resistance to
pulmonary blood flow falls dramatically, pressure in the R heart drops and flow through the foramen
ovale and ductus arteriosus falls or reverses. In the next day or so the ductus arteriosus, which
contains smooth muscle in its wall, normally constricts and is no longer patent. The foramen ovale
acts as a valve so that once L atrial pressure is greater than R it normally prevents flow.
An understanding of these pressure changes is essential to understanding the direction of abnormal
flow if any of the normal fetal connections remain patent or other abnormal anatomical connections
are present in the heart. If right to left shunts occur in the adult then deoxygenated venous blood
becomes mixed with arterialised blood and cyanosis is possible.
ESSENTIAL READINGS - Long term management of
childhood cardiac disease
Learning Objectives

At the end of the Medical Program (on graduation), students should be able to apply

To describe the approach and know the general outcomes and long term management of childhood
congenital cardiac diseases

Content

Generally there are three categories of possible congenital childhood cardiac diseases:-
congenital structural defects, conduction abnormalities and myocardium abnormalities. These defects
are usually - but not always - diagnosed early in life.
The course of congenital heart disease is influenced largely by its severity (impact on normal
cardiovascular physiology) and the medication and surgical procedures used to treat when
necessary.
Differentiation of the consequences of these management strategies is important.
The general outcome for unoperated patients with significant left to right shunts and right to left
shunts, should be differentiated from the lesser range of problems for patients with minor,
haemodynamically unimportant lesions.
When surgery is required issues such as surgical myocardial scar, the fate of the cardiac 'prosthetics',
myocardial or valve dysfunction, incompletely corrected lesions and rhythm abnormalities may arise in
later followup.
An approach to primary care management of these patients may need to take this into account.

Consequences of unoperated congenital heart disease include

: cyanosis
polycythemia
volume overload
congestive cardiac failure
pulmonary hypertension
paradoxical embolus, stroke, brain abscess,
ventricular dysfunction
arrhythmias
infective endocarditis (and its prophylaxis)
failure to thrive

Consequences of surgical management of congenital heart disease, normally it is good but there
are situations with
.Practical advice for patients and families after surgical management of congenital heart disease
should include
Social, emotional and financial impactof CHD on patient and families in very complex lesion
including application for health and life insurance Successful treatment requires highly specialized
care. Severe congenital heart disease requires extensive financial resources both in and out of
the hospital often resulting in enormous emotional and financial strain on young families
School and physical activities
Adolescent issues
Future pregnancies in these children who will sooner or later become adult individuals

o residual lesions,
o rhythm abnormalities
o myocardial dysfunction
o possibility of reoperation

o Advice on physical activities

o Management of future pregnancies for girls
o Prevention of endocarditis
o Advice on insurance application (health, life and medical coverage)
ESSENTIAL READINGS - Prenatal Diagnosis and Down
Syndrome
Learning Objectives

The foetal diagnosis and screening for chromosomal anomalies, with particular reference to Down
Syndrome

Content

The population frequency of Down Syndrome is approximately one in six hundred and sixty in NSW.
During the 1950s several epidemiologic studies of Down syndrome showed a strong correlation in
incidence of Down syndrome and maternal age. The incidence of Down syndrome rising from one in
four hundred and seventy four at maternal age 20-24 to one in twenty eight at maternal age 45 (See
fact sheets 15 and 27 at http://www.genetics.com.au/factsheet/default.htm).
This observation became the cornerstone of interventions requested by couples to reduce the risk of
having a baby with Down syndrome.
Fetal Diagnosis of Chromosome Anomalies
Fetal diagnosis of chromosome aneuploidy, specifically Down syndrome became feasible in the early
1970s when it became technically feasible to karyotype dividing fetal cells from amniotic fluid. Other
technical advances permitted highly accurate diagnosis from analyses of chorionic villus cells. Initially
fetal diagnosis was offered where the risk of Down syndrome approximated the risk of the procedure
(procedure related pregnancy loss of 1 %).
Fetal Screening for Chromosome Anomalies
Fetal screening which at best provides a risk estimate is based on combinations of:

Maternal serum parameters of fetal well-being (e.g. Alpha Fetoprotein, Unconjugated Estriol,
Human Chorionic Gonadotrophin, Inhibin A)
Fetal measurement (e.g. nuchal fold translucency, femoral length, length of nasal spine).

Considerations to be taken into account in counselling families and also evaluating the public health
efficacy of screening interventions include:

the sensitivity, specificity, risks and negative consequences associated with the various screening
methods (e.g. Triple test, Nuchal Fold Translucency) that are available for prenatal prediction of
Down syndrome;
the need for and benefits of genetic counselling and informed consent to screening or diagnostic
testing;
the dilemmas encountered by prospective parents faced with the possibility of the birth and
subsequent parenting and care of a child with Down syndrome; and how factors such as the
prospective mothers age, whether the prospective parents already have children and whether
they already have a child with Down syndrome affect the dilemmas;
the legal and ethical issues associated with decisions about the abortion of a fetus with Down
syndrome.