UK Dysmorphology Meeting
Future dates:
VENUE:
Kennedy Lecture Theatre, ICH, Guilford St, London
Meetings start at 10.00am.
For more details, contact:
Chris Thalasselis, Unit Administrator, Clinical & Molecular Genetics
1st Floor, Institute of Child Health
30 Guilford Street, London, WC1N 1EH
Tel: 020 7905 2608 Fax: 020 7905 2832
c.thalasselis@ich.ucl.ac.uk
Reports from previous meetings
These reports have all been included on this page to make searching easier.
Dysmorphology Audit
Have you ever wondered how effective we are at making diagnoses? Here
is at least part of the answer...
Report on UK Dysmorphology Club
Meeting, Liverpool, 11/03/2008
We all enjoyed
a day out in Liverpool for the March Dysmorphology meeting which was organised
by Alan Fryer and colleagues in the Education Centre at Royal Liverpool
Children’s Hospital. The meeting was held to tie in with the Spring Meeting of
the CGS/Dutch Medical Genetics Society in Liverpool on the 12th and
13th and this encouraged a good attendance with participants from 34
centres, most of whom presented cases. Anticipating a good attendance, the
number of cases was limited to three per centre and we managed to finish shortly
after 5pm. Our day was punctuated by an extremely good lunch and there were many
compliments to the Education Centre staff and the organisers.
The set piece
after lunch was on Costello syndrome, and was a double act from Bronwyn Kerr and
Peter Hammond. Bronwyn reviewed the clinical features of Costello syndrome
and gave us the benefit of her experience of screening a cohort of Costello
patients for mutations within HRAS and associated genes in the MAPK pathway.
Almost all patients with Costello syndrome have been shown to have HRAS
mutations, with G12 and G13 positions involved most commonly. Some genotype/phenotype
differences are now emerging e.g. G13C is a milder mutation. It was particularly
interesting to seethe clinical phenotypes of some of the milder patients and to
have the differences between CFC syndrome and Costello syndrome pointed
out. Many of us were not aware of the very severe CFC phenotype where
neurological features and intractable epilepsy are features. Peter demonstrated
the findings of 3D photographs of a group of 20 patients with HRAS mutations,
and compared the facial phenotypes as detected by the camera and computer in
Noonan, CFC and Costello syndromes. The main differences were the more prominent
forehead and more depressed nasal bridge in Costello syndrome. Profile views
were particularly informative, but I guess this was something which didn’t
surprise us too much since there is always a shout of “Have you got a profile?”
when we are deciding on such diagnoses as Kabuki syndrome or 3M. We discussed
the role of imaging and the question as to whether at some stage in the future
we would possibly be asking “Have you done the profile?” instead of “Have you
done an array?”
So on to the
cases; The first session took a little while to warm up but we were once again
treated to some well presented and very instructive cases. The dysmorphology
club is a popular place to present patients with rare complications of “known”
syndromes, usually proving that we all have a lot to learn about even the
commoner conditions we come across. We were shown a patient with
Rubinstein-Taybi syndrome with syringomyelia and it was pointed out that
spinal dysraphism with a tethered cord has been reported previously in several
patients with RTS. We also saw a child with proven Gorlin syndrome who
presented with an ocular malformation. The presence of a large head led to the
diagnosis. Squint, micropthalmia, cataract, coloboma and orbital cysts have all
been described in this condition previously. Another rarer manifestation of a
common condition was the finding of pontocerebellar hypoplasia in a patient with
CHARGE syndrome. In fact, brain malformations, particularly
arhinencephaly but also holoprosencephaly, ACC and intracranial calcification
are not that uncommon in this condition, and are seen much more frequently in
patients with membranous choanal atresia.
So what
syndromes were new to us? We heard about a family with the rare autosomal
recessive syndrome of Thiamine responsive megaloblastic anaemia. The main
features of this disorder are sensorineural hearing loss, diabetes mellitus,
optic atrophy and megaloblastic anaemia. Cone dystrophy may also develop. It is
thus a mitochondrial “look-alike”. The condition is particularly prevalent in
populations from Kashmir or Punjab and it is caused by mutations in SLC19A2 , a
reduced folate carrier protein. The anaemia responds dramatically to thiamine
supplementation so early diagnosis is very beneficial. We also learned about
Simosa syndrome, a distinctive condition affecting the face and ears. The
ears have a very unusual shape. They are large with hypoplastic lobes and a tube
or duct of tissue extends from the lobe to the external auditory meatus. You
probably wouldn’t miss this if you saw it. We also mentioned Nablas mask-like
syndrome, a condition with a strikingly unusual expressionless face with
tight, glistening skin and almost absent eyebrows. Intelligence is usually
entirely normal. There were some phenotypes which were clearly distinct entities
but which we couldn’t put a name to, including a family where absent cruciate
ligaments and shoulder dimples were inherited in a dominant fashion.
We have
learned from previous dysmorphology meetings and brought further cases of
emerging syndromes. We saw two patients with classical features of
Pitt-Hopkins syndrome due to TCF4 mutations. It was pointed out that the
presentation can be quite Rett-like ( though without a period of early normal
development) and self-harm was a prominent feature in one patient. Perhaps the
most distinctive feature with this phenotype is the very prominent lips.
Hyperventilation is also common but only begins in mid childhood and is not seen
in every patient. Another phenotype we are becoming more familiar with is that
of carbimazole embryopathy. The main features include choanal atresia,
scalp defects, athelia, and unusual patterning of the hair and eyebrows. Many
individuals with this pattern have normal intellect but developmental delay has
been seen as a feature. The use of carbimazole in pregnancy has been extensively
reviewed. The risks to the fetus are thought to be low, and possibly related to
differences in the way in which mothers metabolise the drug. Since untreated
maternal thyrotoxicosis can also cause problems to a fetus and to the mother it
has been concluded that treatment with carbimazole during pregnancy is probably
the safer option.
With the use
of arrays becoming much more common, it was not unusual to be shown some
interesting microdeletion phenotypes. One particularly interesting one is the
5q23.2-q23.3 deletion which involves the FBN2 locus, causing
haploinsufficiency for this gene and for lamin B1. We saw an interesting family
with this deletion presenting with some features of Beal syndrome, but a
common presentation of this same deletion is with Pierre-Robin syndrome and some
patients have had severe micrognathia and a cleft palate. The family presented
also had unusual ears with a deficient upper pole. We saw a patient with a
17q21 duplication, the reciprocal abnormality to the 17q21 microdeletion.
This patient had truncal obesity, tapering fingers and prominent incisors and
struck me as somewhat of a Cohen syndrome look-alike. In another interesting
family an X-linked condition was clearly segregating where severe learning
disability was associated with some unusual behaviours including hand movements
which were slightly Rett-like. Numerous investigations of X-linked genes over
the years had failed to bear fruit. Recently, however, a high density X
chromosome array and the Affymetrix SNP array had both revealed a small deletion
of the X chromosome removing both the monoamine oxidase A and B genes.
This may tie in with a family reported in 1993 by Brunner et al where a
mutation within the MOA gene was segregating with behavioural features in a
family. The Norrie disease gene also lies within this region and it’s
possible that some of the patients with Norrie disease who have had severe
developmental problems have had mutations extending to MOA and/or B.
It’s always
interesting to have a few thought-provoking cases where we can ponder on the
mechanisms which might be involved and we had several; Once again, we were
challenged to think about the cause of the malformations in a patient with a
cleft lip and amputation defects. Are amniotic bands too simple as an
explanation? Why should you get a primary malformation such as a cleft lip which
is present early on in fetal life with amniotic bands? What causes
“Disorganisation”? If parts of the body get amputated by strands of amnion can
they reattach? How broad is the spectrum of p63 mutations? Another family was
presented where a mother had had two pregnancies where there had been a cystic
placenta ( placental mesenchymal dysplasia). One of these had resulted in the
birth of an infant with Beckwith-Wiedeman syndrome, the other had not continued
to term. Another sibling had a different presentation, but interestingly, both
siblings had abnormal 11p methylation. Are there any similar families out there
who might help understand this sequence of events?
Finally, a
couple of quick dysmo tips which came up; If you are considering Feingold
syndrome, then be aware that all the patients in whom mutations have been
found have had some limb involvement, even if minor. This usually takes the form
of clinodactyly of the 2nd and 5th fingers and minor thumb
hypoplasia. The classical toe syndactyly is not always present. For those
thinking about screening patients for mutations in the Ellis Van Creveld
gene, it may be useful to look at the nails first, since all those with
mutations have the typical nail dysplasia.
And let’s end
with a question which we never really got the answer to – What is the cause of
lagophthalmos? Answers on a postcard please….
All are
welcome at the next dysmorphology meeting back at the Institute of Child Health
in London on June 11th.
Jill Clayton-Smith March 2008
Report
From Dysmorphology Meeting 05/12/2007
Dr Jill Clayton-Smith, Manchester
27 centres participated in the December Dysmorphology meeting at the Institute
of Child Health and we were pleased to welcome visitors from several overseas
centres including Kiel, Ljubliana , Luebeck , Oslo, Bergen and even Trondheim!
With so many centres to present it was a tight schedule and time allotted as
usual after lunch for the “set piece” which on this occasion was by Katherine
Lachlan from Southampton. Katherine discussed PTEN related syndromes and though
we have had several presentations on Cowden and Banayan Riley Ruvalcalba
syndrome at genetic meetings over the past couple of years, this presentation,
with fantastic photographs, particularly of the skin lesions, contained a lot
new information for us. It demonstrated well the overlap between the various
eponymous syndromes associated with PTEN mutations a spectrum of conditions
which is still expanding and now also includes such entities as patients with
VATER/hydrocephalus and hemimegalencephaly. The demonstration of the oral
lesions seen with PTEN mutations was particularly interesting, and now we all
know to look for a cobblestone appearance of the mucosa, overgrowth of the gums
between the teeth and of course the characteristic tongue with fissures and
papillomata. Another interesting feature which was demonstrated were the little
localised patches of freckles on the skin and some patients get acanthosis.
There is still a lot of dispute as to what screening should be carried out for
predisposition to malignancy in the PTEN disorders. Risks are increased for
thyroid, breast , endometrial and colon cancer but these are still not extremely
high.
But what about the cases which were presented? As usual there were some very
good ones; A child who had been born with severe nasal hypoplasia following a
pregnancy complicated by hyperemesis was presented. This child had
periventricular nodular heterotopia. Several other people had seen similar cases
and there have certainly been some reports of the nasal hypoplasia phenotype
with hyperemesis over the last couple of years. Vitamin K deficiency is one
possible cause of this. Some affected infants have also had brachytelephalangy.
It was suggested that this topic should be reviewed for the literature.
A possible case of Nicolaides Baraitser syndrome was presented. This is a
relatively rare condition but we were reminded of the most characteristic
features which include sparse scalp hair, knobbly joints, visible veins on the
skin, thickened, flared nasal alae, long philtrum, full lower lip and cupid’s
bow to the upper lip. This condition shows some overlap with Coffin Siris
syndrome. Watch out for a report on it in the literature soon.
Mowat-Wilson syndrome was a popular condition this time; One particularly
interesting patient with MWS had been diagnosed to have a mitochondrial disorder
and there was debate as to whether she should be treated for this with Coenzyme
Q as it was thought that the abnormal ratios of the mitochondrial complexes were
probably secondary to her underlying diagnosis. We were reminded of the
presentation from one of our colleagues in Paris at a previous BSHG meeting
demonstrating that several children investigated for “mitochondrial disorders”
were thought to have these as secondary phenomena as they also had other proven
syndromic diagnoses e.g Cockayne syndrome. Another instructive case was one
which improved our knowledge of the differential diagnosis of intracranial
calcification . This was a child who presented with a spastic paraparesis ,
vasculitis and basal ganglia calcification. Subsequently a diagnosis of SLE was
made but later endochondromas of the radius and ulna developed. All of these
features form a distinct entity with the lengthy title of
spondylochrodrodysplasia with spasticity, cerebral calcifications and immune
dysregulation, as reported by Renella et al in Am J Med Genet in 2006. We should
add this rare entity to Aicardi-Goutière and Coats Plus as causes of vasculitis
and cerebral calcification.
Now for some known, but rare syndromes; A case of Heimler syndrome was
presented. This is an autosomal recessive disorder where the main features are
sensorineural hearing loss and enamel hypoplasia. The nails show unusual
transverse lines or grooves called Beau’s lines and there is often leuconychia.
IQ is normal. SAMS syndrome comprises the rare finding of scapulohumeral
synostosis with absent external auditory meati , small mandible, conductive
hearing loss and short stature. The patient presented with this condition looked
extremely similar the the one on the London database. The condition is thought
to be autosomal recessive.
Interesting chromosomal cases included a child with Pierre-Robin syndrome who
had a 5q22-23 deletion. There have been previous published cases, some with
coloboma and Arnold Chiari malformation but the Pierre-Robin syndrome is a good
marker for this particular deletion and it should be considered in a child with
PRS who does less well than expected. We also saw a child with mosaic hexasomy
12p which is a very unusual finding. Interestingly, the child was quite mildly
delayed but one remarkable physical feature was clinodactyly of the thumb with
an underlying delta phalanx. Hypopigmentation of the skin following Blaschko’s
lines gave away the presence of mosaicism which was only detectable on skin. A
patient with a 1p36 deletion with cardiomyopathy was presented. We were reminded
that this is a relatively common feature, occurring in up to 1 in 4 patients. I
was particularly interested by a presentation right near the end of the day of a
patient with a 16p11.2-p12.2 microdeletion. This is another of the newly
emerging recurrent microdeletion syndromes and I thought the facies , with very
short palpebral fissures looked quite similar to the Fetal Alcohol Face. Ballif
et al. describe several patients with this microdeletion in Nature Genetics
2007.
There are some syndromes which crop up in discussion at the dysmorphology
meeting repeatedly and about which there is always debate. One of these is Teebi
hypertelorism syndrome. There is no doubt that there are some convincing cases
of this, but those reported in the literature and subsequently added to the
dysmorphology database clearly don’t all have this condition and it seems to be
a “ragbag” of entities with patients having hypertelorism of varying degrees.
Teebi originally described a large dominant family with this condition, but
other convincing dominant cases have been few and far between. There is
considerable overlap with Aarskog syndrome and craniofrontonasal dysplasia but
males and females seem equally affected. Again, it would be useful for someone
to review this particular syndrome. The HMC syndrome ( hypertelorism, microtia,
clefting) is similarly contentious . A patient with this condition was
presented, but again it’s not well defined and our knowledge of it is scanty.
Now, what syndromes come into your mind when we see patients with absent nails?
There are actually 80 listed on the database, and most of us would think of
Coffin-Siris Syndrome and DOOR syndrome ( deafness, onychonychia, onycholysis,
retardation ) first, but we saw two good examples of other “absent nail”
syndromes. The first patient had Zimmerman Laband syndrome , with gum
hypertrophy and cataracts being additional features. A further patient had
Gorlin-Chaudhry- Moss syndrome, where there is a striking facial appearance due
to small, deep-set eyes which are down-slanting. The nails of the 4th and 5th
dingers are predominantly affected here, as in Coffin-Siris syndrome.
And for cases which surprised us; a 17 year old Nigerian boy with Williams
syndrome was presented. He had been fully investigated previously for sagittal
craniosynostosis. It was a very difficult diagnosis to make from the face but
the sloping shoulders gave some people the clue. We were also a little surprised
to learn of the diagnosis in a 9 year old girl who had presented with short
stature, microcephaly , mild learning disability and minor facial dysmorphism
but with no striking dysmorphic features or malformations. After developing a
few axillary freckles mitomycin C studies were carried out, confirmimng a
diagnosis of Fanconi anaemia.
I could go on; the number of instructive cases was lengthy; but all good things
come to an end and we actually managed to finish on time due to efficient
chairing of the final sessions. We look forward to seeing everyone again on
March the 11th at Alder Hey Hospital in Liverpool for a special dysmorphology
session the day before the CGS Spring Meeting in the European City of Culture!
Report
From Dysmorphology Meeting 06/06/2007
Dr Jill Clayton-Smith, Manchester
70 cases were presented from 24 centres at June’s Dysmorphology meeting, and
we welcomed visitors from Amsterdam, Leiden, Luebeck, Barcelona. Lille and
Ghent. Restricting the number of cases to no more than four per centre has given
us more time for discussion and it was especially good to see some excellent
presentations from some of the trainees.
There was a superb “set piece” presented by Bart Loeys from Ghent and
entitled “Connective tissue disorders: a selected miscellany”. On this occasion
Bart didn’t focus specifically on the Loeys-Dietz syndrome, but we were treated
to an excellent presentation on several other connective tissue disorders. The
first part of his talk gave new insights into the pathogenesis and treatment of
Marfan syndrome, mentioning specifically the studies which have used the drug Losartan in the Marfan animal model to prevent and reverse aortic dilatation. In
both Marfan syndrome and Loeys-Dietz syndrome there is enhanced TGFβ signalling
and Losartan reduces the available amount of TGFβ. This is encouraging news, and
as Bart said, it means that there is real potenetial for treating disorders
which are due to mutations in structural proteins. The second part of the talk
was on arterial tortuosity syndrome. The main features of this condition, which
is due to mutations in the GLUT10 gene are cutis laxa with a prematurely aged
appearance, severe diaphragmatic hernia and cyanosis. Joint laxity and
keratoconus are seen but the hallmark of the condition is severe arterial
tortuosity. There are often aberrant origins of the large vessels ( be sure to
image those arising from the aortic arch) and stenoses are common, especially in
the aorta. One message was that this disorder can be milder than one might think
from the literature, with some patients surviving well into adulthood. Finally,
there was a discussion of the phenotypes associated with fibulin 4 and fibulin 5
mutations. FBLN5 mutations cause autosomal recessive cutis laxa with or without
emphysema. FBLN4 mutations are more likely to have vascular involvement. Overall
, we all felt vastly better informed about these vascular phenotypes after
Bart’s presentation, and in a better position to decide on which genes to target
first for testing.
So what themes emerged at this meeting? One of them was definitely MECP2
duplication syndrome. Two X-linked families were described with very similar
phenotypes. The main features were severe developmental delay, recurrent chest
infections, seizures and extreme constipation. Hypotonia and dystonia with
Rett-like stereotypies were described in some boys and there might even be a
face to this duplication as several of the boys had a fragile look with thin
skin, deep set eyes and a rather pinched nose. The head size is often small but
can lie within the normal range (it might be relevant that the L1CAM gene at
Xq28 can sometimes be included in the duplicated region).
At previous meetings we had discussed Pierpont syndrome, the condition where
you get a fat pad on the instep of the foot. We learned a bit more about the
phenotype; There are often prominent pads, too on the fingers and toes and this
condition is progressive. Seizures are a feature and increase in frequency with
time. The behaviour gets more and more aggressive. There is a face to this
condition, the eyes are deep set, the upper lip thin and the philtrum smooth.
As always, some syndromes which were new to many of us (though not new to the
London Dysmorphology Database!) A patient with Pfeiffer-Singer-Zschiesche
syndrome was presented. The main features of this condition are sagittal
craniosynostosis, congenital heart disease, cleft palate and low set,
posteriorly rotated ears. Like the patient previously reported in the literature
the patient presented had Fallot’s tetralogy. A chromosome abnormality has been
identified in one patient with this condition. Von Voss Cherstvoy syndrome is
one of the syndromic causes of encrphalocele. It’s better known as DK
phocomelia. Radial aplasia and thrombocytopaenia are associated features and the
features overlap with “Hydrocephaly with features of VATER”. The inheritance is
uncertain, and one patient with a chromosome abnormality has been reported in
the literature. A family with the dominant condition of Weyers acrofacial
dysostosis was presented. The main characteristics of this condition are
post-axial polydactyly, dystrophic nails and dental abnormalities with mild
short stature. This condition is associated with heterozygous mutations in the
EVC gene.
There is always a chance to learn more about conditions which you think you
know all about already; We had a discussion about a patient with a severe
presentation of CFC syndrome. Seizures, optic atrophy, hair loss , acanthosis
nigricans and premature puberty were present in addition to severe learning
disability and some café au lait patches. Others had witnessed CFC presenting in
a similar way, but many of us wouldn’t have considered CFC with a presentation
this severe. We saw some relatively mildly affected patients with Rubinstein Taybi syndrome, one was mutation positive but had completely normal thumbs.
Cutis aplasia was also present in this case. A dominant RTS family was
described, the child having a more classical presentation and the father being
quite mildly affected. We learned a new fact ( well I did, anyway) about SHORT
syndrome. This short stature syndrome is characterised by lipodystophy,
characteristic facies and anterior chamber defects. The patient presented had
the additional features of neonatal hypercalciuria and subsequently
nephrocalcinosis and renal calculi. Nephrocalcinosis appears to be a real
feature of SHORT syndrome since this complication has been reported in other
patients. We saw a patient with classical features of Miller syndrome, one of
the acrofacial dysostosis syndromes distinguishable by the fact that there are
associated post-axial limb defects, and the patient presented had hypoplasia of
both ulnae and radii and oligodactyly. A cleft palate was also present ,
reminding us that Miller syndrome is one of the syndromic causes of clefting.
Marshall-Smith syndrome is one of the rarer overgrowth syndromes and has a poor
prognosis. One of the hallmarks of the condition which was demonstrated to us
was the presence of bullet-shaped phalanges on X-ray. We were reminded that
congenital glaucoma can be a feature of this condition.
As usual, some chromosomal conditions featured. A child with a microdeletion of
2q23.2 was presented and this microdeletion appears to be another recurrent one.
We can expect to hear about it more frequently now that the use of aCGH has
increased. This patient had brachycephaly, synophrys , a poor sleep pattern and
unusual behaviour with a tendency to chew wood. Seizures may also be a feature
of this chromosome disorder. A child with a 15q terminal deletion was presented.
This phenotype is a Russell-Silver look-alike with pre and postnatal growth
retardation. Fifth finger clinodactyly , cardiac defects and learning disability
are associated features. The short stature is attributed to the fact that the
IGF1 receptor gene lies within the deleted region. Another child with a
Russell-Silver-like phenotype was shown to be mosaic for a mutation within the
COL1A1 gene, and this same mechanism has been reported in other children
previously labelled as having “severe” RSS.
As usual, there were some puzzling cases with interesting discussion about
underlying mechanisms. A surviving monochorionic twin ( originally from a
triplet pregnancy) with large areas of aplasia cutis congenita involving the
abdomen and flanks was presented. Scans had shown that there was deficiency, too
,of the abdominal musculature. Several people had seen similar occurrences, and
this presentation is known to be more common in a surviving MZ twin. The lesions
are often very symmetrical, and although the areas appear raw at birth, they do
heal over with time. Sometimes there are concomitant bowel atresias. Several
causative hypotheses have been proposed, including placental infarction, but
this might be too simple an explanation.
Once again, we enjoyed the day. We even made a diagnosis in the afternoon!
Not only do we improve our dysmorphology skills but networking with colleagues
is also an important part of this meeting. We will be back again for more next
time.
Report
From Dysmorphology Meeting 06/12/2006
Dr Jill Clayton-Smith, Manchester
There were concerns that the dysmorphology meeting in December might not be
so well attended because of its proximity to both the Manchester Birth Defects
Conference and Christmas, but these were easily dispelled as cases from 21
centres throughout the UK and Europe were presented. With each centre presenting
up to 4 cases ( we noted that you slipped in five, Liverpool!) we had plenty of
interesting cases for discussion. We also had the opportunity to see some very
interesting patients who had been seen by some of our colleagues on a visit to
India. One of these had Kenny-Caffey syndrome presenting with
papilloedema , unusual teeth and short stature (rule out a 22q11 deletion if
you’re suspecting this diagnosis) and the second had idiopathic multicentric
osteolysis involving the carpal and tarsal bones which had the
characteristic “sucked candy” appearance. In this particular case there were no
renal problems and so fitted best with the Hemingway or Thieffry-Kohler type.
The set piece on this occasion was by Daniela Pilz who presented a very
comprehensive overview of Polymicrogyria. Beginning with an embryological
perspective, Daniela went on to cover the clinical and genetic aspects of PMG,
pointing out that it was a relatively common feature amongst the MRI scans she
and her colleagues are sent to review. It was present in 187/610 scans and has a
male to female ratio of 2:1. A useful classification of PMG was given and the
known genes discussed ( GPR56, SPRX2, PAX6, MTTL1) Three chromosomal regions
specifically associated with PMG are 22q11, 1p36 and 6q26. PMG can also be seen
after congenital infection where it’s associated with white matter abnormalities
and calcification. There are also a number of syndromic associations including
Adams Oliver, Aicardi, Goldberg Schprintzen, Joubert,
Kabuki , Fetal Alcohol Syndrome and others. Reference was made to
a paper by Jansen and Anderman in the J Med Genet in 2005 for further
information. The presentation overall was a veritable tour de force and
we are very grateful to Daniela for enlightening us on this topic.
Moving on to some of the themes of the meeting, we mentioned UPD 14 on
several occasions. This phenotype has considerable overlap with that of
Prader-Willi Syndrome because of its presentation with hypotonia and
obesity. Learning disability may be a feature and precocious puberty is a good
pointer towards the diagnosis. At the recent Manchester Birth Defects Conference
Gabriella Gillessen-Kaesbach described the success the Essen group has had with
the use of a PCR based methylation analysis of the imprinted MEG3 locus on
chromosome 14 for the diagnosis of UPD 14. This analysis has the advantage of
not needing parental DNA samples. Other conditions in the differential diagnosis
of UPD14 include 1p36 deletion and Borjesson-Forsmann-Lehman
syndrome. Smith Lemli Opitz syndrome was mentioned a couple of times and
it’s clear that you can always learn something new about a relatively “old”
syndrome. Did you know for example, that pyloric stenosis is associated with
this condition and that photosensitivity is a feature. This latter finding
prompted investigation in an older patient who presented with a depressive
psychosis, eczema and a photosensitive rash. She had two healthy children. She
was short with central obesity and borderline learning disability and a degree
of 2/3 syndactyly. The diagnosis of SLO was confirmed.
Now for “new” syndromes…new to us that is. A patient with Camera syndrome
was presented. This is an obesity syndrome and the patient also had a bilateral
cleft lip and palate and learning disability. The patient reported previously in
the literature had hemivertebrae and camptodactyly and the point was made that
this phenotype overlaps that seen with diploid/triploid mosaicism, the latter
being an important differential diagnosis. Two patients with Gerodermia
osteodysplasticum, both from consanguineous Asian families, were presented.
This recessive syndrome is an important differential diagnosis of cutis laxa. It
may be associated with osteoporosis, leading to pathological fractures,
particularly of the vertebrae as patients get older. There is a characteristic
facies with prominent eyes which have blue sclerae and infants usually have some
contractures at birth. The patients shown had a very characteristic posture of
the hands with “wrist drop” similar to the one shown on the dysmorphology
database. Intellect is entirely normal in this condition. Sneddon syndrome
is a condition where cutis marmorata and other vascular malformations (
described as livedo reticularis in the old literature) may be associated with
seizures, hypertension and cerebrovascular accidents. Vascular malformations of
the brain and a moya moya appearance on angiography may be present. The patient
described with this condition was heterozygous for Factor V Leiden deficiency
but the relevance of this finding was not certain. Now that many of the genes
involved in vascular malformations have been identified, there is scope to
investigate Sneddon syndrome patients further. One of the main messages here was
to be wary of the patient with cutis marmorata who presents with raised blood
pressure. Lopez- Gomez-Hernandez syndrome is an unusual craniosynostosis
syndrome associated with a tall head shape and brachcephaly. Cerebellar
abnormalities may be present and the patient presented had temporal alopecia,
corneal insensitivity and learning disability. Some patients have also had
growth hormone deficiency.
Interesting chromosomal conditions always crop up at the Dysmorphology Club
meeting and on this occasion we were shown a patient who had presented with poor
feeding, moderate learning disability and a disturbed sleep pattern. Subsequent
investigation showed a duplication (not a deletion) of the Smith Magenis
Syndrome region on 17p11.2. This particular phenotype has come to be known as
the Potocki syndrome, but sleep disturbance seems to be a new feature
here. There was a fascinating family with Langer-Gideon syndrome due to
an 8p23.3 deletion. A striking feature in this family was a “bobble” of skin in
the midline inferior to the lower lip. A skin bobble of this type had been noted
independently in other patients and appears to be a specific feature of the
condition.
Several useful diagnostic tips were mentioned during the course of the
meeting. When discussing holoprosencephaly we were reminded to look
carefully at the frenulum of the upper lip to see if it is absent or very thick
as this may represent a microform of HPE. Chylothorax can be a manifestation of
chromosomal mosaicism and patent ductus arteriosus is a frequent heart defect in
Malpuech syndrome ( clefting, unusual eyebrows and sacral appendage ). A
patient with multiple anomalies including non-compaction of the myocardium was
described. When you see this finding the conditions to consider are Barth
syndrome, 1p36 deletion, mitochondrial abnormalities and
Melnick Needles syndrome.
A very instructive case concerned a family with two brothers who had learning
disability and cerebellar hypoplasia. One of them had an inverted nipple and one
a supernumerary nipple and both had abnormal fat distribution and nystagmus.
Surprisingly, isoelectric focussing of serum transferring was normal but
analysis of the phosphomannomutase enzyme directly showed low levels consistent
with carbohydrate deficient glycoprotein syndrome Type 1. The lesson here
is to persist with further investigation if the clinical signs are right for
CDGS. Analysis of antithrombin III levels can also be used for diagnosis. This
case has sent some of us scurrying back to reinvestigate some of our cerebellar
hypoplasia patients.
As some of us have got older it’s been possible to follow the progress of
patients over a number of years and look at the evolution of their phenotypes. A
27 year old patient with Nicolaides-Baraitser syndrome, first reported in
1993, was described. This condition is rather Coffin-Siris like with the main
features of sparse scalp hair, microcephaly, coarse facial features and rather
knobbly interphalangeal joints with short 4th and 5th metacarpals. This patient
had severe learning difficulty and epilepsy and had gradually lost all her scalp
hair. She had very unusual broad thumbs and tiny feet. She had developed a
scoliosis and flexian contractures of her large joints. A similar patient with
almost identical features was subsequently presented, confirming that this is a
distinct phenotype. The cause of this condition remains unknown, perhaps
microarrays will help us here! We were also given an update on a family with
Robinow syndrome who were first published in the literature by Bain in 1986.
This family have subsequently proven to be ROR2 negative!
Once again, this was a very informative meeting and an excellent opportunity
for trainees to be exposed to dysmorphology. We look forward to more instructive
and interesting cases next time.
Report
From Dysmorphology Meeting 07/06/2006
Dr Jill Clayton-Smith, Manchester
The meeting was held on a
beautiful day in June, and what a cracker it was! We all came away feeling that
there were a lot of patients we should get back to as the cases presented were some of the most
instructive we have had for some time. There were participants from 22 centres,
three of them from overseas (not counting Dublin and Belfast!) and although the
number of cases presented was perhaps a little fewer than usual, they were
universally well worked-up and there was some excellent discussion.
It’s interesting that, without any prior planning, there are always a
few conditions which feature several times during the meeting in presentations
from different centres. This time, the Loeys-Dietz Syndrome featured
prominently. Some people were especially knowledgeable in this area as they had
recently heard Dr Loeys speak on this topic. The condition is caused by mutations in the TGFβreceptors
1 and 2 and the phenotype can be confused with Marfan syndrome because there is
often arachnodactyly , pectus deformity , joint hypermobility and a Marfanoid
habitus. The skin may be thin with prominent vascular markings. Good
discriminating features for LDS are that there is often a cleft palate and that
eye examination is usually normal. The sclerae may be blue and the facies are
unusual with hypertelorism and prominent eyes. There is often early dilatation
of the aorta and sometimes of other large vessels. One of the patients presented
had a very large PDA, the size of which was remarked upon by the cardiac
surgeons as being unusual. This same patient had ricket-like changes on X-ray
and developmental delay.
In the same pathway as TGFβR2
is the GLUT10 gene, mutations of
which cause Arterial Tortuosity Syndrome. This is an autosomal recessive
condition and a patient from a consanguineous Turkish family was presented. This
child’s initial presentation had been with inguinal hernias, cutis laxa and an
aortic coarctation where the aorta had been examined histologically and found to
have elastic fibre disarray. The facial skin was particularly loose.
To complete the differential diagnosis of arterial problems, a family with
probable EDS Type IV was presented. The reason for referral in the
proband had been “elastosis perforans serpiginosa” a skin condition arising
due to the thin nature of the skin which allowed herniation of subcutaneous
tissues. This lady had the typical tight facial skin with pinched nose and
prominent eyes and easily visible subcutaneous vessels. There was easy bruising
and a family history of death in childbirth and death from aortic
dissection/aneurysm. One interesting tip when considering this diagnosis is to
look at the ear lobes as these are usually deficient so that affected women
complain that it’s not easy to get their ears pierced! There was some
discussion about testing for EDSIV; Peter Byers’s lab in the USA will do this
on cultured fibroblasts for $770 and have an excellent turn-around time of
around 6-8 weeks.
Moving on to the next theme, for those people who have
been sceptical in the past about the diagnosis of KBG syndrome, this
meeting was perhaps a turning point. First of all we learned that those little
notches in the incisors are called mammelons and that if there are four or more
of them then it’s probably not normal. Not everyone with KBG has extra
mammelons, but they do have big central incisors and an upper lip shaped like a
Hunter’s bow, along with short stature, brachycephaly and dysmorphic facies
with a rather triangular shape, striking eyebrows and protruding ears. We were
reminded that the patient with KBG shown at the last meeting had behaviour
problems. KBG is a topic which needs a review if ever there was one and
hopefully these three cases can be brought together as a report.
Well, we thought we knew all there was to know about LEOPARD syndrome
but we were wrong! You don’t always have to have loads of spots and they
aren’t always there early on. We were shown one patient, aged 7 years who was
small with a mild pulmonary valve stenosis and rather Noonan-like facies. She
had no hearing loss and just a single café au lait patch but no lentigines.
This patient had had PTPN11 screening a few years ago with a normal result but
this was repeated because now more exons are screened. A typical LEOPARD
mutation was identified. This patient also had a choristoma of the cornea which
has been reported in another LEOPARD patient. A second patient with a LEOPARD
mutation was presented. This patient had a large head , severe learning
difficulties and a cardiomyopathy and had had a breast papilloma in infancy.
There were some CAL spots but very few freckles. One might have suspected a
mutation in the HRAS pathway here, but probably not a typical PTPN11 LEOPARD
mutation. So this just goes to show that LEOPARD syndrome isn’t always a
“spot” diagnosis.
Now to mention just some of the rarer syndromes which were presented;
There was a patient with very classical Black Locks, Albinism, Deafness
Syndrome, a name which
describes succinctly the main clinical features. This child was interesting,
however, in also having congenital cataracts. The condition is an autosomal
recessive one, caused by homozygous mutations of the endothelin receptor B (ENDRB)
gene.
We saw two patients with a Fraser-like Syndrome
where there were colobomata of the upper eyelids rather than cryptophthalmos and
downward extension of the hair-line laterally to the upper eyelids. These
patients , like true Fraser patients, had broad nasal tips with midline grooves.
No mutation had been found in any of the Fraser syndrome genes so far but the
facial phenotypes in this and true Fraser syndrome are strikingly similar. There
are no limb abnormalities in the Fraser-like syndrome.
A patient who was referred because of
hemihyperplasia had one leg larger than the other but in fact it was just the
girth that was increased rather than the length, and it was cleverly pointed out
that this was much more likely to be lymphoedema, especially as MRI showed no
increase in muscle bulk and there was associated swelling of the scrotum and
penis. A diagnosis of Mucke Syndrome was suggested. This
type of congenital lymphoedema often causes associated hypertrophy of the
prepuce.
A final rare
syndrome which got a mention was Pitt-Hopkins syndrome , a condition
associated with coarse facies, wide mouth and overbreathing. The
hyperventilation classically comes on around the age of 7 or 8 and can be
dramatic, causing intense cyanosis. Affected individuals often develop a clubbed
appearance of the fingers. MRI findings including agenesis of the corpus
callosum and cerebellar abnormalities. The
cause is not known. Attention was drawn to the excellent article by Peippo et
al. on this condition which was published in the last edition of the “pink
journal”.
There were several chromosome abnormalities which
featured during the meeting. One of these was the 6p25 deletion syndrome.
This contiguous gene syndrome is associated with anterior segment dysgenesis/Peter’s
anomaly, sensorineural hearing loss and cardiac defects. There are
characteristic facial features such as hypertelorism and a short nose. In
addition affected patients may have MRI abnormalities including Dandy Walker
malformation and it was pointed out that some of the patients who have been
diagnosed with 3C syndrome have subsequently been identified to have 6p25
deletions. The deletions are usually submicroscopic and include the Forkhead
gene FOXC1.
A newly recognised 17q21.31 microdeletion
syndrome was presented. The most distinctive features of this condition are a
silvery colour of the hair in infancy and a rather bulbous nose. Hypotonia and
seizures are also prominent and speech development is poor. This phenotype is
somewhat reminiscent of Angelman syndrome as affected individuals have a very
amiable phenotype.
A further chromosome anomaly mentioned was the 22q11
duplication. The phenotype here is very variable, and the duplications are
often familial, with a parent being more mildly affected e.g. with mild learning
disability or dyslexia. The duplications are often identified by chance when
22q11 FISH is carried out to detect VCFS. However, they can be missed on
metaphase FISH and are more easily detected on interphase FISH. Associated
dysmorphic features include preauricular pits, cleft palate /bifid uvula and
fifth finger clinodactyly. In one patient, previous CGH studies had failed to
detect the duplication as the 1Mb array used did not have good coverage of the
22q11 region. A further family was described where polygyria was a feature and
behaviour problems were a prominent feature.
A further learning point came from the demonstration of
a patient who looked phenotypically like she had a 1p36 deletion, but in
whom subtelomeric FISH had been negative with the Vysis 1p36 probe. In view of
the classical 1p36 appearance the diagnosis was pursued and this child was
identified to have a smaller 1p36 deletion than normal which was detected on
FISH using the SKI oncogene probe. It is estimated that 10% of cases will be
missed if only the standard FISH probes are used.
We saw a Trisomy 13 baby who presented with a
scalp defect and an upswept frontal hairline. The features thus overlapped with Johanson-Blizzard
syndrome – a point which has been made previously. There was also a
fascinating Trisomy 8 mosaic patient who had overgrowth with
hemihypertrophy and immune deficiency associated with a blood dyscrasia. We were
reminded that Trisomy 8 patients have a high risk of developing myeloid
leukaemia, and that patellar abnormalities are common in Trisomy 8 mosaicism.
Many other chromosome abnormalities were mentioned at the meeting and the list
above is not comprehensive.
So what other tips did we learn? Rubinstein-Taybi
patients may have pits at the back of their ears and the talon cusps on their
teeth are a useful aid to diagnosis. Cystic ear lobes are a feature of the Winter-Tsukuhara
syndrome which is a lissencephaly syndrome. We also learned a lot from the
set piece on Smith-Magenis Syndrome which was very well presented by
Alison Male. The behavioural features of this condition are particularly
interesting, but not all patients have the classical self-injurious behaviour we
all associated with the condition, especially not the very young ones. 39% have
cardiac defects, 15% renal tract anomalies and many have palatal or vocal cord
abnormalities. The sleep disturbance is a classical feature and there has been
some success in treating it with a combination of beta blockers and melatonin.
Poor sleep pattern is a strong predictor of poor behaviour. We saw a 3D
representation of the SMS face compared to normal which made it much easier to
recognise which parts of the face were actually dysmorphic, and I for one have a
much better idea of what I’m looking for now.
Well, we saw and heard all this and more, and will all be busy re-FISHING
our 1p36 suspects, re-doing PTPN11 analysis on everyone who had an incomplete
screen first time round and looking for new microdeletion phenotypes. I’m sure
this will keep us busy until the next meeting in December! Thank-you to everyone
who came and participated to make this a great meeting.
Report from Dysmorphology Meeting, 7/12/2005
Dr Jill Clayton-Smith, Manchester
The meeting was held as usual at the Institute of Child
Health in London and, maybe because of the Christmas shopping opportunities,
it had a truly European attendance list with participants from the UK,
the Netherlands, Italy, Norway, France, Germany, Denmark, Portugal and even
Ireland! The format of the meeting was as usual, with presentation of a maximum
of four cases from each centre. With 74 cases to get through in addition to the
set piece the schedule was tight, especially as there were quite a lot of
unknown cases.
We were treated to an excellent “set piece” by
Elizabeth Sweeney who presented an overview of nail patella syndrome (NPS)
documenting her findings from a study of 123 patients with NPS.
The main take home messages were the need for regular ophthalmological and renal
screening, MRI scanning of joints prior to surgery, and the multi-system
involvement in this very variable condition." This was an excellent example of how useful large clinical studies are
and we all benefited from listening to someone with personal experience of a
large number of patients. Carrying out a study of this type which combines both clinical and molecular studies provides both
excellent training for an SpR, enabling them to become an international expert in their own area and adds significantly to the clinical
information available on rare syndromes.
It was clear that we have arrived at the “day of the
array” with reports of several patients where small chromosomal imbalances
have been detected on CGH arrays; Several of these were small duplications
(dup12q42, in a patient where previous investigations had been along the lines
of Angelman/Rett , dup 16p13.3 in a child with cystic kidneys and a VSD and
short thumbs and dup19p13.3 in a child with precocious puberty at the age of 1
year. We were reminded that other phenotypes associated with precocious puberty
are 1p36 deletion, maternal UPD for chromosome 14, dup 11p15 and triploidy. A
further CGH imbalance was a deletion of 22(q11.23-q12.2) in a child with choanal
atresia, ASD and opthalmological abnormalities (Peter’s anomaly,
microphthalmia and cataracts). Sadly, this child went on to develop some
pigmented skin lesions and the complications of NF2.als. Some other chromosomal phenotypes were described where the diagnosis had
been made without the help of arrays. A child with an 18q23-qter
deletion had a conductive deafness due to bilateral atresia of the external
auditory canals. This particular finding, a good marker for 18q deletion is seen
in 60% of patients with this deletion but does not occur with breakpoints which
are more distal than 18q23. Another frequent malformation with this deletion is
an abnormality of the male genitalia seen in 80%. Another chromosomal phenotype
which was discussed was the 1q deletion.
These patients characteristically have midline problems including agenesis of
the corpus callosum. The patient presented was very similar to those reported
previously by De Vries et al., with one striking similarity being oedema of the
dorsum of the feet. There were some puzzling chromosomal findings, however, e.g.
a patient with Peter’s anomaly and an X;Y translocation with a breakpoint at
Xp22.3 had a large deletion which encompassed the microphthalmia/linear skin defects region and
the OFD1 gene, yet had no skin defects and no manifestations of OFD1.
A rare syndrome diagnosis which came up several times
during the course of the day was the Bohring-Opitz
syndrome (appears to be the same as Oberkleid-Danks). The main features of this
condition are a prominent metopic suture, a glabellar haemangioma, exopthalmos,
hypertelorism and a hirsute forehead. The facies are coarse and a good marker
seems to be the very thick alveolar margins ( similar to those seen in patients
with cholesterol biosynthetic disorders). Cleft lip and palate and intracranial
abnormalities have occurred in some and there are multiple joint contractures,
most characteristic in the hands. These babies are usually growth retarded and
affected siblings have been reported. We also revisited the oto-facio-cervical
syndrome, mentioned at a couple of previous meetings. The main phenotypic
abnormalities in this condition are conductive hearing loss, preauricular pits,
cervical fistulae, sloping shoulders and an elongated face with a narrow nose.
Previous discussions have centred on the relationship of this condition to BOR
syndrome and an update of a previously presented case added further
information; Cases of OFC syndrome have been associated with both EYA 1
deletions and duplications and with renal agenesis. EYA mutations have been
identified in BOR syndrome patients who have sloping shoulders. This is further
suggestive evidence that BOR syndrome and OFC syndrome are one and the same
condition.
We learned a few lessons which will help us with the
practical aspects of genetic counselling. We were reminded , for example, that
in a previous meeting a diagnosis of Oto-palatal-digital
syndrome type 2 had been suggested in a patient with radioulnar synostosis,
small thumbs and absent big toes. This patient does not have a mutation in the
filamin A gene, however, and the phenotype has also been seen in females. The
possibility of an autosomal recessive form of OPD2 must therefore be considered.
We rarely see Warfarin
embryopathy now but a baby with typical features of flat nasal bridge, and
brachydactly, particularly of the distal phalanges was presented where an astute
SpR had noted the history of exposure to Warfarin in the maternal antenatal
notes. The big clue in this condition is the stippled epiphyses. Another patient
with an unusual presentation of a relatively common condition was a baby with CFC
syndrome who presented with a malrotation and this has been noted previously
and is listed as a feature of CFC on the dysmorphology database. We also heard
of a young patient with LEOPARD syndrome
who, when examined at two years had no lentigines but these appeared later on. A
mutation was subsequently identified in the PTPN II gene, but interestingly, not
in the typical LEOPARD region. We were assured that St George’s searches for
mutations throughout the PTPN gene,
anyway in LEOPARD syndrome patients.
And now for the even rarer conditions: a pair of very
interesting siblings with progressive thoraco-lumbar kyphoscoliosisand nystagmus
with impaired horizontal gaze undoubtedly have the autosomal recessive condition
reported by Riley in 1979 and known as “horizontal gaze palsy;kyphoscoliosis” believe it or not. These
siblings had a mutation in the gene involved, ROBO3 which is involved in axonal
migration and failure of decussation of the coticospinal tracts. A baby who had presented with severe Pierre-Robin syndrome and deviated
index fingers had a supernumerary epiphysis of the proximal phalanges of the
index finger was considered to have Catel-Manzke
syndrome. Interestingly, this
baby had dislocated patellae which have been noted in previous patients and
thin, arched eyebrows. Congenital
heart disease was not present, although it’s been seen frequently in other
patients and a 22q11 deletion is in the differential diagnosis. Van den Ende-Gupta syndrome was suggested as a possible diagnosis in
a child with a very slender thorax and long, thin fingers with camptodactyly.
Patients with this condition often have blepharophimosis so it’s in the
differential diagnosis of Marden-Walker syndrome and is also presumed to be
autosomal recessive.
The dysmorphology meeting isn’t all about syndrome
recognition and there was some good discussion about mechanisms, too. The
question of mosaicism cropped up several times when we were shown photographs of
patients with features such as asymmetry and pigmentary anomalies in the lines
of Blaschko. It’s common knowledge that even though chromosomal mosaicism is
suspected in such patients, it can be very difficult to prove on skin biopsy,
especially a single skin biopsy. We were reminded that Celia Moss in Birmingham
suggests that it is better to look for karyotypic abnormalities in keratinocytes
rather than fibroblasts because keratinocytes are of epidermal origin and genes
involved in pigmentary disturbance are more likely to be expressed in epidermal
cells rather than dermal fibroblasts. If one was really convinced about
mosaicism and wished to pursue this, therefore, keratinocytes would be the best
bet but at the present time these usually have to be done in Birmingham.
Leading on from this, we had a great debate over the
genetic mechanism which might be involved in the presentation of a patient who
presented with hyperkeratosis following Blaschko’s lines. A skin biopsy showed
evidence of autosomal recessive ichthyosis Type II and a single mutation of the
transglutaminase 1 gene was identified in DNA from this patient. The question
was as to whether an autosomal recessive condition could exist in a mosaic form
and manifest with skin findings in Blaschko’s lines? Answers on a postcard
please………
There are clearly some fascinating cases out there. We were
shown a mother and child with unusual focal skin defects in the preauricular
region, who both had pre-axial polydactyly, sensori-neural hearing loss and
anterior placement of the anus. The mother also had learning difficulties. The
skin defects were very distinctive and looked just like healed skin biopsy
sites. Patients with similar pre-auricular dermal dysplasia have been presented
at dysmorphology meetings elsewhere and if anyone else has seen this it would be
useful to bring them along next time. Also, as usual, we’d like to encourage
you to write up your interesting patients for Clinical Dysmorphology. Some of
you have been busy and we had a good response to our pleas last time. For single
distinctive cases, or to report a new finding in a previously described syndrome
we have a new short report format which is incredibly simple to use. The journal
is also about to go electronic which should speed things up.
Report from Dysmorphology Club Meeting, 8/6/2005
Institute of Child Health, London
Dr Jill Clayton-Smith
Those who weren’t able to attend the June meeting really missed a good one! There was a plethora of interesting cases, many useful comments from the audience and an excellent set piece. The meeting was well attended with cases presented from 22 centres, all sticking to the new rule of no more than four cases per centre to allow time for discussion. Most people agree that this have actually improved the quality of the meeting, as now people tend to present only their most distinctive cases and leave behind the not so distinctive ones that they might perhaps have been tempted to bring before “because I promised the parents I would show them”. Rotating the centres is definitely a good idea, too, especially since a
recent survey proved what we had always suspected, that there were fewer diagnoses made during the last session of the day. Lastly, we seemed to have far more audience participation this time with some really useful comments and stimulating discussion.
And now on to summarise the meeting itself; There was an excellent set piece on
“Conditions with vascular abnormalities” by Jonathan Berg from Dundee. He gave a very clear and comprehensive overview of the subject, beginning with an explanation of the important distinction between a haemangioma (proliferative lesion of endothelial cells which later involutes) and a vascular malformation (an abnormal collection of blood vessels which is hamartomatous in nature). He went on to discuss the classification of haemangiomas and hereditary vascular dysplasias and included an excellent description of his “pet” subject,
hereditary haemorrhagic telangiectasia. This included very useful information about screening and management of HHT, along with information on
genotype/phenotype correlation (HHT associated with mutations in Endoglin is, on the whole, more severe than that with
ALK1 mutations). Other conditions including cerebral cavernous malformation and familial glomangioma were also described with some excellent photographs.
So many good cases were presented that this time it’s difficult to single out the ones which were most noteworthy. Syndromes which appeared to crop up more than once included the
oto-facio-cervical syndrome, a condition which, it has been argued is allelic with
BOR syndrome. However, although an EYA1 deletion has been identified in one patient with oto-facio-cervical syndrome, others would argue that the condition is distinct from BOR. The main clinical features of oto-facio-cervical syndrome are a narrow elongated face, conductive hearing loss, preauricular pits and lateral cervical fistulae. Distinctive signs which were pointed out in the cases we discussed were the sloping shoulders with downward slanting of the clavicles on X-ray and obvious winging of the scapulae. Like BOR, this syndrome follows autosomal dominant inheritance and is associated with renal agenesis. No EYA abnormality had been found on testing one of the cases presented.
This was also a day for Dubowitz syndrome, a short stature syndrome which is probably overdiagnosed and includes the
fetal alcohol syndrome as a differential diagnosis. Low birth weight, microcephaly, full cheeks and troublesome eczema are the main hallmarks and it was pointed out that a useful feature to look for here is that the profile of the nose has a “ski-jump” shape.
Maternal UPD of chromosome 14 was mentioned twice, once as a confirmed diagnosis and once as a suggestion. The clues here were truncal obesity. macrocephaly and early puberty and the phenotype bears some resemblance to
Prader-Willi syndrome.
We learn a lot about natural history of syndromes when very young or very old patients with known phenotypes are shown. This time we were shown a baby with
Hajdu Cheney syndrome (characteristic face with prominent eyes and long philtrum and distinctive skeletal abnormalities including Wormian bones, abnormal vertebral bodies which ultimately acquire a biconcave or fishbone shape , dislocated elbows and long fibulae). The classical acro-osteoloysis which is a hallmark of this condition develops later in childhood and in the child shown there were small distal phalanges and the erosion was just beginning. Interestingly this child, like several reported in the literature had needed surgery for malroatation of the bowel. The older patient which we will all remember was one with premature aging, found to be due to a mutation in the LMNA gene, the mutation involved a deletion of 35 amino acids as opposed to the typical dletion of 50 amino acids and this presumably accounted for the milder presentation. At 16 years this patient had clear evidence of a lipodystrophy, and the features which had been noticed from around the age of four years were her sparse hair, prominent eyes and increased skin pigmentation.
Presentation of some patients led to very interesting discussion. A boy with a hypoplastic corpus callosum, hypertelorism, congenital heart defect, talipes and constipation had been found to have periventricular nodular heterotopia and was originally diagnosed to have cerebro-fronto-facial syndrome. It transpires that this boy has an interesting FLMNA mutation, with a family history suggestive of X-linked inheritance. The overlap of the features seen in this child with those seen in FG syndrome was commented upon. Another X-linked syndrome we discussed was the OFCD (oculo-facio-cardio-dental) syndrome. This has recently been shown to be due to mutations in the BCOR gene, also associated with X-linked anophthalmia. In OFCD the main features are cataracts, congenital heart disease, a characteristic face with a narrow nose and notched alae and radiculomegaly, the teeth characteristically having huge long roots. Cleft palate may be a feature and a patient was presented with very suggestive facies, a cleft and congenital heart disease. Discussion followed as to whether the chracteristic long dental roots were seen in every patient, and there has apparently been a patient who had only one long root, so perhaps the phenotypic spectrum is broader than initially suspected. It will be interesting to hear the results of the BCOR mutation analysis here.
We usually see some interesting chromosomal conditions at the dysmorphology meeting and this meeting was no exception; Right at the beginning there was a patient with coarse facies, epicanthic folds, supernumerary nipples and hypoplastic bile ducts. Tetrasomy 12 had been suspected but the clinical features perhaps weren’t quite severe enough. It was interesting, then, to hear that this child actually had trisomy of part of 12p. Others had seen similar cases, and the suggestion is that there there appears to be a dosage effect of the extra cxopies of 12p, with the trisomy patients looking similar, but not as severe as those with tetrasomy. The trisomy had been picked up on blood rather than just in skin, however. A second patient with a chromosomal abnormality had joint contractures and a webbed neck along with learning difficulties as the main features. He had a duplication of 6q25 and this same presentation which one might describe as arthrogryposis had been seen in other patients. A patient with a 1p36 deletion had features which overlapped significantly with those of Cohen syndrome and when thinking of one of these diagnoses, the other needs to be considered. A rare complication of 1p36 deletion is cardiomyopathy. The patient shown had an interesting family history with a sibling having died of a neuroblastoma previously. As most 1p36 deletions encompass a locus for neuroblastoma , parental studies have been initiated. We discussed whether 1p36 deletion patients need to be screened for neuroblastoma. At the present time there doesn’t seem to be enough evidence to suggest this needs to be done. Moving on to other patients, a child with pyloric stenosis, perimembranous VSD and easy bruising was found to have an 11q deletion (Jacobsen syndrome). An interesting observation in this patient is that the MRI scan had shown multiple lesions of the white matter in the parietal lobes and in fact a metabolic disease had been suspected because of this. In the last few meetings we have always had a patient or two with a 9q34 deletion and we’re all gradually getting better at recognising this phenotype (If you think it’s Down syndrome and it isn’t then it’s a 9q34 deletion; the synophrys which is often present is also reminiscent of De Lange syndrome). Now the story has moved on, because a single gene which appears to be responsible for the recognisable phenotype has been identified within the region. The 9q34 patient presented this time had originally had a normal 9q34 telomeric analysis but has subsequently been shown to have a deletion of the critical region encompassing this gene. I think a few of us will now be going back to our suggestive patients once again.
And now some very rare entities: Not many of us had heard of Temple -Baraitser Syndrome, where seizures and developmental delay are associated with absent nails on the thumbs and great toes. It’s a DOOR look-alike, without the biochemical abnormality found in DOOR syndrome. We were shown a patient who looked just like those previously reported and who had a chromosome abnormality with monosomy of 8q and trisomy of distal 15q. We saw a convincing example of Oberklaid-Danks syndrome, an autosomal recessive disorder (also referred to in the literature as Bohring-Opitz syndrome) where the main features are trigonocephaly with a characteristic haemangioma over the forehead, high (Byzantine) or cleft palate, exophthalmos and unusual contractures of the hands and feet. This child had developed a cardiomyopathy, a hitherto unreported feature in this condition. Finally, we were shown the striking X-rays of a baby with intrauterine onset of Caffey disease. This is thought to be separate from the milder, dominant form of infantile cortical hyperostosis.
One patient which really brought home the usefulness of post mortem examination was a baby who presented with a “cystic hygroma” prenatally and who, after birth appeared to have total body involvement of all of the tissues with a ? infiltrative process. The answer came from the post mortem which revealed diffuse neurofibroma and a mutation in the NF1 gene has now been confirmed.
There were many other interesting and instructive cases too numerous to mention. Presenters were encouraged to consider preparation of short reports for the literature. To facilitate this the Clinical Dysmorphology Journal will be aiming to publish more brief reports, and a template for the format of these was shown and will be circulated to those on the UK Dysmorphology Club list soon. These will still be subject to peer review, but will be fast-tracked. New and distinctive phenotypes, interesting findings in patients with known syndromes and cases showing the natural history of rare disorders would be particularly welcome. They can be sent in electronically as long as a written consent for publication of photographs is sent on, too. We’ve all got some patients we’ve been meaning to write up and we look forward to being overwhelmed with cases soon!
We went home much better informed, but some of us realised that we musn’t be too confident in our diagnostic skills….. after all, most of us would have missed the diagnosis of 22q11 deletion in that patient with moderate learning difficulties, myopia, conductive hearing loss, obesity and delayed puberty!!
Report from Dysmorphology Club Meeting, 9/3/2005
Institute of Child Health, London
Dr Jill Clayton-Smith
The March Dysmorphology
meeting was held as has become the
custom the day before the Clinical Genetics Spring Meeting in London. There were
cases from twenty-three centres, but for the first time the number of cases
shown from each centre was limited to a maximum of four. This made a big
difference to the meeting, as we had a longer time to present and discuss each
case. The initial feedback from attendees was very positive and the chairpersons
certainly felt under less pressure to hurry everyone up. The decision has
therefore been made to stick to four cases per centre from now on.
In addition to the above change, Michael
Baraitser pointed out that this particular dysmorphology meeting was a somewhat
historic occasion as due to the new system of rotating the order of presenting
centres, Liverpool started off the
meeting and presented their cases first! Finally,
people had been encouraged to use a few words
of text on their slides to remind people of the main presenting features, and
this also seemed to be helpful.
Katrina Prescott from the department of Clinical Genetics
at the Churchill Hospital, Oxford presented the “set piece” on the 22q11
deletion syndrome. Along with a clinical review she summarised the molecular
genetic findings of the condition. The 22q11 region, in common with other
regions where deletions occur frequently, contains
a series of low copy repeats and 87% of patients have a 3Mb deletion of this
region. A further 7% have a 1.5Mb deletion and 2% have a deletion between 1.5
and 3Mb. 4% of deletions are
atypical, but there is no clear shortest region of overlap and it is still not
clear whether the 22q11 deletion syndrome is a contiguous gene deletion syndrome
or a single gene disorder. In the mouse model, the TBX1 gene within the deleted
region certainly appears to be important, and TBX1 mutations have now been
reported in humans and appear to be a rare cause of non-deletion DiGeorge
syndrome.
It’s interesting how, by chance, we always seem to have
certain themes emerging in the dysmorphology meetings and this one was no
exception. There were , for example, two patients with confirmed or possible
GLI3 mutations and both were instructional. The first had the classical hand and
foot abnormalities with polydactyly and syndactyly of the fingers and toes but
had a much less classical facial appearance because he had a prominent metopic
suture and a sagittal synostosis so he lacked the familiar broad forehead we are
used to seeing in Greig syndrome. He
had a confirmed GLI3 mutation and in
fact trigonocephaly is listed as a feature of Greig syndrome on the London
Dysmorphology Database. The second time Greig syndrome cropped up in the
discussion concerned a child with craniosynostosis and polydactyly where the
diagnosis of Carpenter syndrome had been suggested. We were reminded that
several patients who have been thought to have Carpenter syndrome have in fact
turned out to have GLI3 mutations and have Greig syndrome instead.
There were two good cases of Adams-Oliver syndrome, the
combination of scalp defects and terminal transverse defects. The manifestations
can be very variable in severity – you might have to search for the scalp
defects and be very suspicious if you are told that a small bald area on the
scalp is due to a fetal scalp electrode! The limb defects may also be variable
in severity and both presenters commented on the fact that that the limb defects
may often resemble amniotic band disruption because of the presence of
constriction rings. This is important to remember as the recurrence risks for
the two conditions are so different. One of the children presented had a
similarly affected parent.
The Mowat-Wilson syndrome featured once more at this
meeting. There were two definite cases and a third where there was some debate;
the truth will out once the ZFHX1B analysis has been undertaken! Overall it was
decided that the infant photographs of the condition are perhaps not that
remarkable but that the facies become more recognisable at a few months of age
because of the deep set eyes, mild hypertelorism and characteristic mouth with a
deficient vermilion border at the lateral parts of the upper lips. The ear lobes
are also classically upturned. Interestingly, one patient had presented with
nuchal oedema in utero. Could this be a reason for the upturned earlobes? As the
children got older the facies tend to become coarser, the shortening of the
philtrum is more marked and the lips more prominent.
As usual, skeletal
dysplasias featured at this meeting. Two very similar patients who were cousins
from a consanguineous Pakistani
family were shown. Both were of low
birth weight and had striking arachnodactyly, adducted thumbs, rocker bottom
feet and flexion contractures. Looking at them, one might have wondered about
Beal’s syndrome or neonatal Marfan. Both started to have seizures at a week of
age and MRI imaging had been performed in one child and showed pachygyria,
“open” Sylvian fissures, reduced white matter volume and cysts in the
caudate head. A diagnosis of Bowen-Conradi syndrome was suggested and indeed,
both patients looked remarkably similar to those on the LMD. The other
“skeletal” syndrome discussed was osteodysplastic primordial dwarfism. This
diagnosis was suspected in two separate patients. Both were extremely small with
low birth weights and the facies showed a relatively large nose and micrognathia.
It was pointed out that the skeletal features of the condition which include
narrow interpedicular distance, long clavicles and a small and narrow pelvis are
not always apparent at a very young age and X-rays carried out over the age of
three years are more informative.
Now for the rarer diagnoses, some of which were very
clever! One that didn’t even feature on the database (although Michael
Baraitser says it’s in the new version) was that of congenital
dyserythropoetic anaemia. The patient in question had presented with
jaundice requiring an exchange transfusion at birth and had gone on to have
learning difficulties. At the age of 20 she was investigated for anaemia and
noted to have dysmorphic features including growth retardation, ptosis and
abnormal tarsal bones. The facies bore some resemblance to Saethre-Chotzen
syndrome. These features are documented in the medical literature as being
associated with congenital dyserythropoetic anaemia, as is Madelung deformity.
A further rare diagnosis was that of Birt-Hogg-Dube syndrome, which is a rare autosomal dominant
cancer-predisposing syndrome . The main features are dome shaped skin papules
called fibrofolliculomas which appear on the face, neck, chest back and arms in
adult life. There is a predisposition to thyroid and renal cancer, including
Wilms tumour and to intestinal polyposis. The patient reported had also had a
history of recurrent pneumothoraces and had some cystic lesions in her lungs.
There were some very distinctive “unknowns” shown at
this meeting. Particularly noteworthy was a patient with imperforate anus,
multiple gut stenoses and an ASD
and VSD who had congenital microcephaly and on brain imaging had polymicrogyria,
hypoplastic corpus callosum and hypoplastic optic nerves and chiasm. This
patient also had marked facial asymmetry.
A second “unknown” patient was a man with anterior
segment cleavage syndrome, giving a strikingly unusual appearance to the irides.
In addition he had preaxial polydactyly and very unusual abnormalities of the
fingernails, which grew increasingly poorly the further away they were from the
radial side. There was Y-shaped syndactyly and polydactyly in the feet. A
mutation in some type of patterning defect was proposed.
Patients like this would make extremely interesting case
reports and a plea was made from the editors of Clinical Dysmorphology to
encourage more people to write up their distinctive patients. At the present
time, only a small proportion of the papers submitted to this journal are from
UK authors, so please get writing!
Finally, don’t think that you always have to have a
patient with a rare condition to present at the dysmorphology meeting; One might
think, for instance that showing patients with Trisomy 21 and achondroplasia
would be too simple for an audience of dysmorphologists. However, they are
clearly more difficult to diagnose when they are present in the same patient as
was the case on this occasion. Many thanks for sharing this and all the other
interesting patients with everyone and we look forward to another successful
meeting in June.
Report from Dysmorphology Club Meeting, 8/12/2004
Institute of Child Health, London
Dr Jill Clayton-Smith
The December meeting , often a quiet one, was particularly
well attended this year with cases
presented from twenty four centres and
visitors from Norway, Germany and the Netherlands. We began with a discussion
about the format of the meeting and Dian Donnai outlined some proposed changes
now that our group has grown from a small gathering into a much larger meeting.
From now on , each centre will be able to present four cases to ensure that all
centres get a chance to present and there is enough time for discussion. For
additional cases there may be some spare slots at the end of the day. The order
in which the centres will present will rotate, with the five first centres on
the list at one meeting moving to the end for the next and the other centres
moving up accordingly. Although it’s always been a tradition that GOS have
presented first, and we’ve been grateful to them for starting off the meeting
promptly and with good cases, it
was decided that overall it is fairer if they, too take their turn in the list
like everyone else. We will continue to have a chairperson to move things along
and two facilitators to comment and work the database. It was suggested that the
key features for each patient be highlighted in the abstract, enabling the
facilitators to search the database on these more efficiently. As usual a
mixture of both knowns and unknowns is encouraged, and comments from members of
the audience are warmly welcomed. Finally, if all the members of one centre can
get together beforehand and put these into a single PowerPoint presentation it
helps to move things along more quickly.
So now on to the highlights of the meeting. The set piece this time was by Sanjay Sisodiya from the Institute of
Neurology and was entitled “The Eye As Window to the Brain.” He told us
about a study which involved the investigation of families with epilepsy, where
MRI scans were used to identify structural abnormalities so that specific brain
phenotypes could be delineated. Specific genes which might be candidates for
human epilepsy were selected and brain phenotypes associated with these studied.
In individuals with PAX 6 mutations common findings are absence of the anterior
commissure in the presence of a corpus callosum, absent olfactory bulbs, absent
pineal gland and polymicrogyria. The corpus callosum may be small in cross
section. The scans shown demonstrated these beautifully and now that we know
where and what the anterior commissure is I’m sure we’ll be attempting to
look for it! The findings suggested that PAX6 is a candidate gene for human
polymicrogyria and explained why some individuals with PAX6 mutations have
impaired olfaction. Interestingly, they may also have a specific hearing deficit
, detected by a dichotomous hearing test which delivers simultaneous but different
stimuli to both ears. The deficit is due to impaired interhemispheric transfer
of information. Further genes with brain phenotypes which Sanjay talked about were SOX2 which is associated with abnormal hippocampi and RIM1 which is
associated with polymicrogyria and late onset cone-rod dystrophy. The
supposition is that these genes may be candidates for epilepsy in humans. The
presentation was very clear and informative, and covered an area about which
most of had had little prior knowledge – an ideal choice for a set piece.
As usual there were a large number of interesting cases
presented; Following on from the last meeting we saw several more patients with
9q34 deletions including the one
reported in the literature several years ago by Oliver Quarrell. We seem to be
getting our eye in for the face, here. The key thing to remember is that if you
see a patient who looks like they have Down syndrome, but there is no trisomy
21, then seriously consider a 9q34 deletion which is usually only detectable on
telomeric FISH. There is often a “dished-out” mid face, synophrys,
downturned mouth with everted lower lip and tendency to tongue protrusion and
prominent nuchal oedema. One 9q34 patient presented had a complex congenital
heart defect and a further one had epilepsy and a corneal opacity with cataract.
As regards more unusual findings in known syndromes, we
were shown a Kabuki patient with macrocephaly and subependymal cysts in the
frontal horns of the lateral ventricles. A further Kabuki patient with
colobomatous microphthalmia was presented.
De Lange syndrome cropped up a couple of times, and the presentation of
mild CDLS as non-cleft velopharyngeal incompetence is a useful one to remember.
There was discussion later on about the adult CDLS phenotype. With age truncal
obesity develops, and oesophageal reflux is a common complication. Two cases of
Feingold syndrome were presented; This is the combination of microcephaly and
oesophageal or duodenal atresia with syndactyly of the toes, usually 4/5 but can
be 2/3. There may be mild learning difficulties but many individuals with this
condition do extremely well despite the microcephaly.
A likely dominant family with Feingold syndrome was presented. The index
case had short stature which may also be a feature.
Several rarer syndromes were brought to our attention.
Pierpont syndrome is the association of plantar lipomatosis with characteristic
facial features and developmental delay. The fat pads seen on the medial aspects
of the feet in this condition are striking and there are often prominent fetal
pads on the digits. The mode of inheritance is unknown. A very astute diagnosis
of branchio-oculo-facial syndrome had been made in a patient who had presented
with a unilateral cleft lip and palate, heart defect, pneumothoraces, renal cyst
and premature greying of the hair. This latter feature is a good sign for BOF
syndrome, along with the prominent philtral pillars which can look like a
repaired cleft and unusual upturned ear lobes. Some of these patients have had
raw areas which look like grazes behind the ears and running down the border of
the sternomastoids, but these aren’t always present. Keep an eye out, those of
you who do cleft clinics, as BOF is probably underdiagnosed.
On the skeletal front, a child who had originally been
suggested to have achondroplasia re-presented at 13 years with short limbs,
learning difficulties and optic atrophy. Review of his X-rays by the European
Skeletal Dysplasia Network revealed him to have the rare autosomal recessive
metaphyseal acroscyphodysplasia where you get very distinctive v-shaped
metaphyses. The ESDN network is proving very useful in situation like this and
their website is very user-friendly and replies quick.
Dysmorphology club meetings always provide a good
opportunity to see patients who have been followed up and learn about the
evolution of phenotypes. We saw a
boy of ten years old who was seen initially at 18 months because of hearing loss and short stature and no cause was
identified at that time. He went on to develop multiple lentigines over the
face, trunk and limbs and now has classical features of LEOPARD syndrome. A
study to look at he long term outlook of LEOPARD syndrome is currently being
planned at St George’s. We also
saw a couple of patients of varying ages with Costello syndrome, with evolution
of the phenotype during infancy. The coarse facies, uplifted earlobes, deep
palmar creases, distended abdomen and thick lips are the prominent features here
in a baby who is often born following a history complicated by polyhydramnios
and who has severe feeding difficulties.
And finally, an interesting genetic mechanism; A twin
presented with macroglossia and an umbilical hernia and went on to have mild
learning difficulties. The co-twin, who had a significantly lighter birth weight
was normal. The affected child has been shown to have loss of methylation of the
KVLDR1 gene on 11p, so this is probably relevant to the question of whether
methylation abnormalities in the early embryo may “drive” MZ twinning in
Beckwith syndrome.
So once again there was plenty to learn and lots of food
for thought. We will meet again on Wednesday the 9th March, the day
before the CGS meeting in London. As I write this, we have just heard the news
that Dian Donnai received a CBE in the New Year’s Honours List, in recognition
of the work she has done for our specialty. We as dysmorphologists have
certainly benefited greatly from her expertise over the years and continue to do
so and we offer her our warmest congratulations.
Report from Dysmorphology Meeting, 8/9/2004
Institute of Child Health, London
Dr Jill Clayton-Smith
There was a large attendance at this meeting with
75 cases presented from 19 centres. The new format of having a chairperson and
two “commentators” who work the database and make instructive comments seems
to be working well and encourages participation from many different centres.
Setting a limit of 4-5 cases per centre seems to be working, too, on the whole
and meant that the number of cases could be discussed sufficiently within the
time allowed. The plan is to rotate the order in which centres show their cases
so that some centres don’t always end up showing their cases during the
“graveyard shift” after tea when the audience has run out of ideas.
The set piece at the meeting was on “Dysmorphology in Rett
Syndrome” and was extremely well presented by Hayley Archer from Cardiff who
has been carrying out research into Rett syndrome. After reviewing the clinical
features of the condition and updating us on the molecular situation she went on
to talk about a study carried out in Cardiff where photographs of girls with
Rett Syndrome at different ages were reviewed by a team of Cardiff
dysmorphologists who scored the
photographs independently of each other for various features. This made for
interesting results ! The consensus of opinion, however, was that there probably
isn’t a typical Rett Syndrome face. There was some concurrence, however, with
previous studies which showed that individuals with Rett syndrome often had a
broad face with full cheeks and an everted lower lip. The other feature
consistently mentioned in the literature is the presence of a short fourth
metacarpal. Hayley is still interested in looking at Rett syndrome patients who
are clinically typical but don’t have MECP2 deletions for her project and is
contactable at the Institute of Medical genetics in Cardiff.
There were several instructive cases presented during the
coarse of the meeting. These started with the very first case, a patient with
exomphalos, a coarse face with periorbital fullness, low set ears with thickened
helices and small, deep set nails. This baby had been exposed to cocaine in
utero and although he/she looked remarkably similar to others on the
dysmorphology database it perhaps wasn’t what first sprung into most
people’s minds when thinking of the fetal cocaine phenotype.
Barely a meeting goes by without mentioning useful clues in
the diagnosis of microdeletion syndromes and this was no exception. One patient
worthy of note was a child in whom Down syndrome had been suspected at birth
because of brachycephaly, nuchal thickening, Down-syndrome-like facial features
and small, rounded ears. There was also a tendency to tongue protrusion. This
child has been found to have a deletion of 9q34 on telomeric FISH. Comparison
was made to other reported patients with the same chromosome abnormality, a
useful exercise which enabled us all to “get our eye in” for this phenotype,
which is undoubtedly a recognisable microdeletion syndrome. Other pointers to
look for are the presence of a rather dished-out face with protruberant mandible
and synophrys. Remember, if you think it’s Down syndrome and it isn’t, look
for a 9q34 deletion.
A further patient presented with an Angelman-like picture of
absent speech , behaviour problems and seizures. This patient was found to have
a terminal 22q13 deletion on subtelomeric FISH. Some children with this finding
are overgrown but the phenotype varies
with the size of the deletion.
As always , there seemed to be a few recurrent themes emerging
as the day went on, and continuing on the Angelman theme, we were shown two
patients with imprinting defects as evidenced by abnormal methylation.
One had presented with a Prader-Willi like phenotype and macrocephaly, a
not uncommon presentation with this type of Angelman syndrome. The other was
more Angelman-like. Neither had an imprinting centre mutation. Many Angelman
patients with this type of imprinting defect are mosaics, hence the variability
in presentation, with a milder phenotype being possible. Mosaicism
can sometimes be identified by looking for a weak maternal band on
routine methylation analysis.
The next theme concerned the differential diagnosis of Marfan
syndrome. Two patients who had presented with a very convincing Marfanoid
habitus and normal development had
subsequently been shown to have Larsen syndrome with a filamin B mutation and
Trisomy 8 mosaicism, the clue in the latter patient being the deep creases in
his feet. This should remind us to look at the bottom of the feet, too, in our
Marfan patients in future! Another condition which got more than one mention was
Meier Gorlin syndrome, where the main features are microtia, micrognathia,
absent patellae and short stature. The rather prematurely aged appearance of
some patients with this condition was remarked upon.
Single cases of especial interest were the patient with
harlequin ichthyosis , where prenatal detection had been achieved by noting
particularly the position of the limbs. We were shown the evolving phenotype,
from the very impressive 3D fetal scans, through to photographs of the child
after birth and the evolution of the skin condition. The usefulness of showing
progression of a phenotype with age was also apparent in the presentation of a
child with Schwartz-Jampel syndrome, where one could note the subtle changes ,
particularly around the mouth, as time progressed. A useful management tip was
that carbamazepine may be helpful
in this condition.
Syndromes that were new to us (or to most of us!) included
Heimler Syndrome, a pattern of sensori-neural deafness, enamel hypoplasia and
abnormal nails and Iso-Kikuchi Syndrome where there is hypoplasia of the index
finger nail transmitted as an autosomal dominant. Now who will forget that one?
Finally, there were some very distinctive patients where not
even a database search could help with diagnostic suggestions. The family where two brothers with IUGR, narrow choanae, cleft palate, dermatitis
and agammaglobulinaemia springs to mind. Presenters of such cases were
encouraged to write them up as case reports (the “pink” journal would be
happy to receive them!).
The IT worked
well thanks to the staff at ICH and now that most people bring digital images
the cases follow one another almost seamlessly with little time wasted. Once
again, all seemed to find the day useful. More volunteers are needed to present
set pieces so come on SpRs, this is your chance to shine!
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