Table Of ContentMULTIPLE
CONGENITAL
ANO MALIES
MULTIPLE
CONGENITAL
ANO MALIES
A DIAGNOSTIC
COMPENDIUM
Robin M. Winter
Consultant Clinical Geneticist,
Kennedy Galton Centre and Dysmorphology
Research Group,
Northwick Park Hospital,
Harrow, UK
Michael Baraitser
Consultant Clinical Geneticist,
The Hospitals for Siek Children,
Great Ormond Street, London, UK
Springer-Science+B usiness Media, B. V.
ISBN 978-0-442-31316-6 ISBN 978-1-4899-3109-2 (eBook)
DOI 10.1007/978-1-4899-3109-2
Firstedition 1991
© 1991 R. Winter and M. Baraitser
Originally published by Chapman and Hall Medical in 1991.
Softcoverreprint ofthe hardcover1st edition 1991
Typeset in 10/llpt Palatino by
Megaron, Cardiff
All rights reserved. No part of this publication may be reproduced or
transmitted, in any form or by any means, electronic, mechanical,
photocopying, recording or otherwise, or stored in any retrieval
system of any nature, without the written permission of the copyright
holder and the publisher, application for which shall be made to the
publisher.
British Ubrary Cataloguing in Publication Data
Winter, Robin M.
Multiple congenital anomalies.
1. Children. Congenital abnormalities
I. Title. D. Baraitser, Michael
618.920043
Ubrary of Congress Cataloging-in-Publication Data
available
Contents
Preface vü
How to use this book xili
Part One: A catalogue of multiple congenital anomaly
syndromes 1
Part Two: Diagnostic index 673
Part Three: Appendices 1399
Appendix A: Features used in the Diagnostic index 1401
Appendix B: Features not used in the Diagnostic index 1411
Appendix C: List of syndromes, with synonyms 1412
Preface
This book is an off-shoot of the computerized The size of the problem, can be assessed
London Dysmorphology Database which is from the following. Of 50 children bom, 1
now widely used by many geneticists and will have an easily detectable major malfor
dysmorphologists. Both the database and this mation. Many of these will have a single
book have arisen out of a need to cope with malformation, but in the region of 8 in 1000
the ever increasing nurober of multiple will have multiple abnormalities. This group
congenital anomaly syndromes, especially will include 50% with chromosomal disorders
details about their features and where infor recognizable by performing a karyotype, the
mation can be found in the Iiterature. Indeed rest needing tobe diagnosed by other means.
there are more than 2000 non-chromosomal It is to the diagnosis of this latter group that
multiple malformation syndromes to which this book is dedicated.
access is essential.
If computerized databases have solved
THE DIAGNOSIS OF DYSMORPHIC
some of the problems, why is there a need
SYNDROMES
for this book? There are many physicians
who do not have a desk computer or do not
History
feel at ease in using one. In addition
geneticists are doing more satellite clinics and Before identifying the specific dysmorphic
in some circumstances it would be more features, at least a three generation family
convenient to carry a book than a computer. history needs to be taken. It is necessary to
For the time being, at least, a book is likely to ask specifically whether there are other
be eheaper than a computer and our own members in the family who might have the
experience is that unless the computer is on same condition or anything similar, the
your desk, you do not use it. Finally books causes of death in first degree relatives and
'go wrong' less frequently than computers details about stillbirths or neonatal deaths.
and this book will not throw-up error Enquiries about consanguinity are imperative.
messages! This should be followed by a full pregnancy
The importance of the information in this history, especially enquiry about matemal
book is abundantly clear to those who need a illness such as diabetes or SLE and any
diagnosis for purposes of genetic counselling, substances taken early in pregnancy. It is
an assessment of the prognosis and an important to know whether there had been
answer to the basic question asked by nearly oligo- or polyhydramnios or whether fetal
all parents 'what is wrong with my child?' movements had decreased or ceased at some
It is not an uncommon situation that stage. Details about possible matemal uterine
parents, despite not wanting further children malformations should also be sought. In
and quite accepting their child's malforma order to assess developmental delay,
tions, still seek a name for the condition in evidence of fetal distress needs to be
order to communicate with friends and documented. Information should be obtained
family, to look at the Iiterature themselves about pre-natal diagnostic tests with the
and, where appropriate, to meet other results. For instance, it is important to know
families who have a child with the same when a microcephalic syndrome is under con
problem. Evidence for this is the growing sideration, whether this had been detected
nurober of lay organizations dedicated to during pregnancy and at what stage.
single syndromes.
Basic investigations are necessary all undiagnosed multiple malformation
syndromeso However clinicians must adopt a
Chromosome analysis flexible attitude to chromosomal investiga
A chromosome analysis is essential. The tions, repeating tests in selected cases
diagnostic process stops if an abnormalilty is perhaps after a couple of years, but not over
found, but the dysmorphologist might not be burdening their laboratorieso
satisfied with a normal resulto lt is almost In summary most dysmorphologists have
certain that. a number of malformation learnt that the difficult task of syndrome
syndromes are caused by small deletions recognition begins after one is sure that,
which, using present techniques, are missedo given the limitations of chromosome analysis,
Most clinicians have had the experience of the karyotype performed recently at a
being suspicious that an infant had the Wolf reputable laboratory does not show any
Hirschhorn syndrome (4p-), only to be faced abnormality There remains in every clini
0
with a normal karyotypeo When the labora cian' s mind a feeling that conditions such as
tory has been asked to recheck the tip of the Rubinstein-Taybi, or Cornelia de Lange
short arm of chromosome 4, the deletion is syndromes will eventually be shown to be
then foundo Another example is that of a caused by small chromosomal deletions and
child with an undiagnosed multiple malfor all clues in the form of patients who have
mation syndrome and perhaps a sib with visible chromosome rearrangements and
similar problems who died soon after birtho some obvious features of a recognizable
Chromosome analysis on the affected living syndrome, should be recordedo
child has been normal, but when, because of
clinical suspicion, the parental chromosomes Biochemical tests
are looked at, a balanced rearrangement is In dysmorphic children biochemical diagnoses
found in one parent and only then an may have tobe consideredo Storage disorders
unbalanced translocation is detected in the are well known to cause dysmorphic features,
childo If the clinician can in some way direct but disorders of amino acid and organic acid
attention to a specific area of the genome metabolism should also be consideredo The
then this increases the likelihood of finding reason for this is that the clinician faced with
small deletionso This is true in the Miller a floppy infant with minor dysmorphic
Dieker syndrome which was originally features, say a high-arched palate and
thought to be an autosomal recessive single perhaps a small jaw, could be looking at
gene detect, but is now known to be the secondary phenomena caused by severe
result of rearrangements involving the short hypotonia in utero, and the primary cause
arm of chromosome 17 Other examples are could be a metabolic conditiono lf intractible
0
Prader-Willi syndrome and Angelman seizures are in addition a part of the clinical
syndromeo Both have, in roughly a half of all picture then conditions such as non-ketotic
cases, a deletion in the long arm of hyperglycinemia will need to be considered
chromosome 15, and asking the laboratory to and can only be diagnosed by the appropriate
look especially carefully at this area is part of biochemical testso
good clinical practice What constitutes a reasonable battery of
0
Another clinical problern is that some recog biochemical tests depends on the clinical
nizable dysmorphic syndromes have their picture and the medical setting under which
origin in mosaic chromosome aneuploidieso the clinician is operatingo For instance
The best known example is the Pallister Zellweger syndrome or infantile Refsum
Killian syndrome where the diagnosis can disease could easily be overlooked when
only be confirmed by looking for the 12p presented as a floppy infant with a broad
tetrasomy in skin fibroblastso There must forehead or an enlarged liver, unless the
undoubtedly be other examples but it is not aware clinician performs the correct tests to
practical at present to look for mosaicism in look for abnormalities of peroxisosomal
function. This book expects the user to exer the wrong emphasis in interpretation of a
cise that degree of caution, but it will at the CA T scan. There is in essence no easy way to
same time prompt the clinician to think about practice syndrome identification in isolation
these conditions. The evaluation of a dysmor and it is best, but not always possible, to
phic child becomes even more complicated as have units where additional expertise is at
the diagnostic tests become more invasive. hand.
For instance, patients with mitochondrial
cytopathies are often dysmorphic, but can Clinical photographs
only be diagnosed by muscle biopsy looking These are essential for clinical documentation,
for ragged-red fibres or looking at respiratory publication of important cases and consulta
chain enzymes. Clearly these are not routine tion with professional colleagues. Over the
investigations, but this group of conditions past 10 years an informal syndrome iden
might need to be excluded before diagnosing tification meeting has taken place, 4 times
other non-mitochondrial conditions with every year, at the Hospital For Siek Children,
similar clinical features. London, in conjunction with the Institute of
Child Health, where clinical geneticists from
Diagnostic imaging throughout the UK meet to show each other
These are not routine tests, and yet there are pictures of rare syndromes that they have
a number of dysmorphic syndromes which diagnosed, and ask help in the diagnosis of
cannot be diagnosed without a CT brain scan. others. It is not unusual for the grouping of
For instance, an agenesis of the corpus unknowns to occur thereby delineating new
callosum is a good diagnostic handle and is syndromes. It has become clear that photo
an essential part of the acrocallosal syndrome. graphy is an important diagnostic procedure.
Whether or not to do a brain-scan and Parents are often informed of these meetings
whether it should be CT or magnetic and are aware that pictures of their children
resonance must remain in the sphere of are being shown to a select professional
clinical judgement, but one of these group, and know the benefit of other
specialized procedures must be considered in opinions being canvassed in this way.
any very floppy or very microcephalic infant
or child. If one of the main techniques in
The diagnostic procedure
dysmorphology is the gathering together of
all of the dysmorphic features and sorting There are several ways of making a clinical
through them, dividing what one finds into diagnosis.
good and poor handles, then it is often
necessary, when perplexed, to slowly Gestalt recognition
increase the number of investigations to There are some syndromes which are
include, where indicated, tests such as visual instantly recognizable and do not need a
evoked responses, brain-stem evoked res detailed analysis of the dysmorphic features.
ponses or various types of brain imaging. For instance Williams syndrome is mostly an
immediate recognition diagnosis, i.e. a
A link with other disciplines Gestalt recognition syndrome. The individual
Many of the diagnostic handles (features) facial features are not all that specific nor
might be outside the competence of particularly unique, but the visual picture is
individual dysmorphologists to evaluate. For distinct and the diagnosis might be instan
instance, the diagnosis of Aicardi syndrome taneously made. All Gestalt diagnoses must
does, to a large extent, depend on the be checked; for example, in the case of
recognition of punched-out areas in the retina Williams syndrome, serum calcium levels and
and this might need an ophthalmological the cardiovascular system would need to be
opinion. Likewise it has been our experience investigated and as many other positive
that diagnoses have been missed because of diagnostic criteria need to be evaluated before
being confident about the diagnosis. Features manifestation or even an indication of somatic
against the diagnosis must also be con mosaicism. lt is also important to evaluate
sidered. Again, in the case of William' s carefully the parental reports of familial traits
syndrome, retardation is seldom severe, as they might tend, given the emotive circum
except if the seizure disorder is intractable, so stances of genetic counselling, to gloss over
that a child with the facial Gestalt of Williams important findings by dismissing some
syndrome, but with a development which is features as being common in the family or,
far behind what one would expect, needs to alternatively, tend to want to blame 'the other
be reconsidered before being certain about side of the family', for every feature found.
the diagnosis.
'Gaad handles' and 'paar handles'
Dysmarphic features The concept of 'good' and 'poor' handles is
If immediate recognition fails, the next step is centrat to dysmorphology and to the optimal
to identify and define the specific dysmorphic usage of this book. Features of 'good'
features. These features might be obvious, or handles are as follows.
need to be looked for carefully. An accurate
assessment of these features is essential in 1. They are easily recognizable as being
order to use this book in an optimal way. abnormal and do not merge with normal
Where possible dysmorphic features must variation. Anal atresia is a good handle
be quantified, for example, has the child got whereas over-riding toes is a poor handle.
hypertelorism (eyes which are truly too 2. The severity of the malformation might
widely spaced) or telecanthus (eyes which turn a poor handle into a good one. Mild
appear to be too widely spaced because of the hypertelorism might not be a good handle
laterally displaced inner canthat margins)? whereas an interpupillary distance well
Are the ears low-set, or are they posteriorly above the normal centiles must be
rotated giving the impression of being considered as an important feature of the
low-set? condition under consideration and should
The clinician should ask whether the dys not be ignored.
morphic feature is important in that particular 3. A 'good handle' is not common to many
patient. For instance a patient is mentally syndromes. Pre-axial polydactyly is a good
handicapped and has syndactyly involving handle as it does not occur in a large
toes 2 and 3. This might, or might not, have number of syndromes. For the same
relevance to the diagnosis under considera reason 'mental retardation' is not a good
tion. The evaluation of its significance will handle as there are at least 600 different
change if the parents reveal that it is known syndromes in which this occurs. Having
within the family that many members with said that, mental retardation is such an
perfectly normal intelligence have this same important feature that it may be essential
feature. The problern is a little more to the diagnosis of a specific condition.
complicated if the child has instead broad 4. Good handles can change with age. For
thumbs and big toes. Here the condition of example prominence of the lips is an
Rubinstein-Taybi must be considered, but important handle in the Coffin-Lowry
there are undoubtedly families in which big syndrome. This feature might not be
thumbs and toes are inherited as a harmless present during the first 6 months of life
trait and clinicians must satisfy themselves and it might be necessary to follow up
that the facial features and other parameters patients to assess the evolving phenotype.
of Rubinstein-Taybi syndrome are present Noonan syndrome is a further condition
before making that diagnosis. The other where the clinical appearance and
problern which must always be considered is characteristic features change significantly
whether a dysmorphic feature in a parent with age.
occurring in isolation is a heterozygote 5. Dysmorphic features may be primary or
secondary phenomena. lt is important to important that the techniques used in genetic
take account of the possibility that a counselling clinics are applied in dealing with
feature you might choose as a good dys patients, both in those cases in which a
morphic handle might not be a primary diagnosis has been made as well as those
phenomenon. For instance a high arched many situations in which no diagnosis has
palate might be a consequence of general been possible. lt is perhaps in this latter
ized longstanding hypotonia and not be situation that most skill is needed. To put our
per se an important handle. Or likewise a own experience into perspective, about a half
dolichocephalic skull shape can be the con of the patients we see at our tertiary referral
sequence of prematurity. Handles should genetic counselling clinics leave without a
be thought about and judged before using diagnosis. lt is at least comforting for both
them as 'main features'. lt should be patient and doctor to know that by using a
noted that secondary features could also database or a book such as this a reasonably
be important. Joint contractures occur as a thorough search of the Iiterature has been
consequence of fetal akinesia secondary to made, and important for the doctor, that this
neuromuscular abnormalities in the Pena has been achieved in a short time.
Shokier syndrome but they are important What is clear is that syndrome identification
clinical features and cannot be ignored. by using purely clinical criteria is likely to be
a necessary, but essentially preliminary step
· which anticipates newer methods of making
Conclusions definitive diagnoses, by cytogenetic,
biochemical or molecular techniques.
Labels (d iagnoses) tend to stick, and it is
