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Also, some laboratories have changed recentlyto testing any baby with a diaphragmatic herniafor Pallister Killian.

How many are there?One question many families in the study askedme was ‘How many are there?’ I can now saythat when I did the study in 2009, there were36 people alive in Great Britain with PallisterKillian. That gives you a population frequency of0.6 cases per million or, put another way, oneperson with PKS for every 1.63 million of theBritish population. In 2005–2009, the birthprevalence in Britain was 5.2 children withPallister Killian per million live births, or onenewborn baby with PKS per 192,000 livedeliveries – and that is still an underestimate.

For whatever reason, PKS has turned out to bemore common in males: from my totalnumbers 39 were male and 16 female – whichat a probability value of p=0 .005 is statisticallysignificant. An important bit for families is thatthere has never been a reported recurrence ofPallister Killian within a family, and that includesterminations. So the risk to any couple with achild with PKS of having more children withPKS should be no greater than the populationrisk. For reassurance, though, any family inBritain would be offered prenatal testing. For patients’ siblings having children, there is noreason to think the risk would be any higherthan the general population. But if a child withPallister Killian – obviously one with the milderpicture – has children, the risk is somewherebetween zero and 50%. One’s feeling is that itis closer to zero because an embryo whoinherited the isochromosome and hadtetrasomy 12p in all cells of the body wouldpresumably not survive, but that is a‘presumably.’ If it came to it, we would offer

prenatal testing for reassurance until we knowmore.

So far we have not been able to explain howor when the isochromosome develops,whether it is in an egg or a sperm or whetherit happens just after fertilisation once the babyis a few cells.

When do people die?The second big question during the study waswhen do people die and what do they die of?Using British data we were able to identifyeight who had died. One was a baby born at21 weeks who died of prematurity on the firstday of life; two children died at 4, one at 10,one adult at 20 and two at 38. One was anunexpected death in epilepsy; one died ofaspiration, which is very common in childrenwith something like Pallister Killian where themuscles are very weak. The other four died ofsome form of respiratory infection but formost, we only know what was on the deathcertificates. Sometimes ‘pneumonia’ can be away of explaining a natural death that youcannot completely explain; sometimes it is achild with a very severe picture whose parentsmight choose not to go for intensive care; orthese may be children who had overwhelminginfections; we cannot tell.

DevelopmentLooking at development, in the medicalliterature there are just four people with eithera mild or moderate learning disability; the resthave a severe or profound picture and so arenot expected to walk or talk. If you meet someof the people with Pallister Killian who arehere, you will realise that is definitely not true: itis very variable.

Of the 12 school-age children I saw, three werein mainstream schooling. Quite a lot do havesignificant delay and in some it is severe orprofound. Walking is something that peopleoften ask about: we class walking before 18months as normal. Of my group, one walked at

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Unique hosted an international study weekend for families with a child withPallister Killian syndrome in Oxford, United Kingdom in October 2010. The meeting brought together families from Romania, Italy, the Netherlands,the USA and the Channel Islands as well as the United Kingdom.Unique’s Pallister Killian weekend was the fifth and last in a series ofdisorder-specific weekends, supported financially by Jeans for Genes and theGrocers’ Charity.

Pallister Killiansyndrome

Natural history ofPallister Killian syndrome

Dr Moira Blyth,consultant in clinicalgenetics for theYorkshire GeneticsService, told a familyaudience for the firsttime about herrecent survey ofpeople with PallisterKillian syndrome.

In 1977 a Dr Pallister reported in the medicalliterature an adult with a learning disability and no obvious diagnosis. Four years later, a Dr Teschler-Nicola and a Dr Killian described a child, again with an unidentified learningdisability. We now know that both have whatwe now call Pallister Killian syndrome. In theearly literature it has different names:Killian/Pallister mosaic syndrome, TeschlerNicola Killian syndrome, but longer term wehave stuck with Pallister Killian.

Pallister Killian is mosaic tetrasomy 12p. If you look at a normal cell you have 46chromosomes. A child with Pallister Killian has some normal cells and some with a littlestructure called an isochromosome thatconsists of the short arm of chromosome 12[12p] repeated either side of the centromere.In some of their cells, the child has four copiesof 12p.

For my survey, I looked first at every publishedreport of someone born alive with PallisterKillian: only 102 in the entire medical literature.Of these, 25 died within the first month of life.Beyond the age of 10, only 16 people haveever been reported. So answering the question‘What happens with the older kids?’ is veryhard.

I looked for everyone I could contact in Britain with Pallister Killian and got 22 families.The oldest patient I saw was 31 and mostwere pre-school. There was a relative lack ofgirls. There’s no reason why there should bemore boys but there does seem to be.

I looked then at babies diagnosed in pregnancywho were either miscarriages or the familyterminated the pregnancy. Before 1990, therewere only five live born babies and fiveterminations, while in 2005–2009 there were20 terminations and 19 live births. I do notbelieve for a minute that Pallister Killian isgetting that much more common: I am surethat we are getting a lot better at detecting it.

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16 months and the oldest one at 8 years.Nearly a third were walking by their thirdbirthday and about half by their fourthbirthday; three children of 10 or 11 were notwalking.

In terms of development, we looked at grossmotor skills [walking, running, jumping etc]; finemotor skills [hand movement]; language; andpersonal and social skills [feeding yourself, usinga knife and fork; dressing]. I saw one four-month-old who was entirely normal, somechildren who were very significantly delayedand others who were functioning at almosttheir actual age. One noticeable thing is thatnormally children’s developmental level wasbroadly the same in all the areas we looked at.So we didn’t see children whose gross motorskills were really good and whose fine motorskills or language was really bad. That said, theoldest patient I saw was happily walking aroundthe room but did not say a word – but she hadnot developed the skills like running, jumping orhopping that you expect two or three yearolds to start developing.

In the ones over 5, again we have got somewho have done really well but another groupwho are really not doing anything much.

Answering a question from a parent, Dr Blythexplained that the language assessmentmeasured speech ability rather than ability tocommunicate, so it would underestimate theabilities of someone who communicates, forexample, by signing.

SeizuresLooking at the features of the syndrome, a lotof children have seizures [fits]. These startedeither between 6 months and three years oldor between 8 and 11. No-one started fittingbetween 3 and 8, but that may simply be dueto small numbers or to when it was diagnosed.Some children have absence seizures, wherethey do not seem to be there for a minute,and then progress to other forms of seizure. A lot of parents said the children havemyoclonic seizures and I thought that might be a clue that Pallister Killian is having somedifferent effect from other chromosomaldisorders. We had three babies already fitting

before their first birthday and five before theirsecond. By their fourth birthday there are 11,more than half, and by 13, only one child is nothaving seizures. Looking in the medicalliterature there are reports of babies fittingwithin the first month of life and also of peoplewho had their first seizures as adults so youhave a massive spectrum.

Answering questions, Dr Blyth repeated thatsome people only had their first seizure as adults and said she came across no-onewho completely stopped having seizures. That said, she admitted that, unlessantiepileptic medication was withdrawn whenseizures were believed to be controlled, it wasnot possible to be certain that seizures wouldcontinue without it, but that epilepsy generallylasts.

‘Common’ featuresLooking at other common features, nothinghappens in 100% of people and lots of‘common’ features do not happen even in 50%,which may be a reason it is difficult to diagnosePallister Killian in children without thecharacteristic facial picture. Starting inpregnancy, polyhydramnios [extra fluid roundabout the baby] was fairly frequent [17%] inmy group, although mothers who had it mildlylate in pregnancy may never have been told.

Now, looking at birth weights, the medicalliterature and summaries of PKS tell you thatbabies with Pallister Killian are supposed to big– but they aren’t. Most of the birth weights inmy group were within the normal ranges –only 13% of mine were at the top of the birthweight scale and none were off it. It is only inthe group as a whole that you see any increasein comparison to the general population.

Floppy babies [hypotonia] were very common[77%], from parental recall. When I examinedthe children, in half [52%] the muscle tone wasstill not as good as you would expect. Morethan a quarter [27%] of parents really felt theirnewborn baby had difficulties feeding. Theyneeded additional help or multiple goes atdifferent types of teat before they startedfeeding, though only a couple needed artificialfeeding. Feeding was still an issue, but less of

one, in 41%, so overall two thirds of parentssaid they had some difficulties with feeding.Most of this is because babies are floppier thannormal, so the tone in the mouth and throatand the ability to use the tongue is reduced.They do tend to outgrow this with age.

In this group there were not many birthdefects [congenital malformations]. Cleft palateoccurred in two babies [9%], one a ‘proper’cleft palate, right across the roof of the mouth,the other a submucous cleft palate where theskin has grown over the roof of the mouth butthe bone above is not sealed togethercorrectly. Split uvula [bifid uvula] is reportedfairly commonly, although I did not look intothroats unless the patient could cooperate.

Congenital dislocation of the hips, where theball of the femur [thigh bone] is not correctlypositioned in the hip joint, is fairly common[14%]. Based on children where a report froma chest X-ray was still available, a quarter onlyhave 11 pairs of ribs instead of the normal 12,compared with about 5% of the generalpopulation.

Umbilical hernias [around the belly button]were found in about a quarter [23%],compared with 2–5% in the general population.Inguinal hernias [in the groin] are morecommon in boys and two boys I saw had them.That works out as 9% of the Pallister Killiangroup and about 14% of boys with PallisterKillian, significantly higher than the general riskof under 1%.

A lot of parents [55%] said their child definitelyhad a delay in the closure of the fontanelle [thesoft spot on top of the head] and this figuremay actually be higher. A very similar number[57%] had delay in the teeth coming in.Medically, the two go together as they are dueto a delay in the bone age.

Often a good clue to a mosaic disorder is thatpeople have patches of paler skin, darker skinor both, and sometimes stripes. Some of thesechildren have wavy stripes on the top of thechest and abdomen and down the back andlinear streaks on the limbs. You might find thatwith a cohort of those with the conditionrather than those in whom the diagnosis hasbeen made the number would be lower, but Ifound this in 64%.

Additional nipples are very common accordingto the literature but most parents say they

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know nothing about them. The human bodyhas a nipple line that runs from under the armthrough the normal nipple down onto theabdomen. Extra nipples tend to be very subtle, but 41% of my group had at least one.They are often very small and quite a lot ofparents thought it was a birthmark.

The percentage of children with some hearingimpairment seems surprising. In the medicalliterature, a little group have them, a fewsignificantly. Of my group 32% had hearing aidsand 77% had some hearing impairment. Doremember of course that glue ear is commonin the general population and three of thesePKS children had glue ear with grommets.

Nystagmus [the eyes wobble backwards andforwards], was seen in 14%. Another 14% hadhypoplasia [poor growth] of the optic nervewhich takes the vision from the eyes to thebrain and this is likely to affect their ability tosee or to process what they see.

Scoliosis [27%] is a bend in the spine and ismuch more common in children who arehypotonic [floppy]. Without the muscle tone tohold the back straight and well aligned, scoliosiscan develop over time, although whenprofessionals are aware of it and children aregiven wheelchairs with appropriate support, itis less significant. I could still straighten thechild’s back in quite a few children I saw, so thiswas a position they chose rather than anymalformation of the back.

Nobody in my group had what we could callreally significant or severe infections, but 55% ofparents said they believed their child had moreinfections or more severe ones than children ofa similar age. Again, this is likely to be due inpart to hypotonia, so not having good musclecontrol in the lungs, not coughing up secretionswith a cold, making these children more proneto getting chest infections. There may also bean increase in ear infections. As they get olderand bigger and stronger, this does tail off.

One parent told me early on that their childdoes not sweat, so I added the question formost families and got 41% saying either theirchild does not sweat or they have markedlydecreased sweating. I have no idea why thishappens but it is clearly a feature of PallisterKillian and is giving some people significantproblems.

Another oddity was spells of hyperventilation[breathing very fast] which I noticed in a childin an early interview. I found four [23%] whodid this and of those, two also had spells ofbreath holding. There are various bits of thenervous system that control breathing andsome genetic conditions like Rett andAngelman syndromes where children are proneto hyperventilation but they are notchromosomal ones. I do not know whychildren with Pallister Killian would be moreprone to it.

In terms of behaviour, a quarter of the group[27%] said that their child had some autisticfeatures – either the children desperately

needed routine, or instead of playing with toyswould put them into tidy lines. However, thesechildren did not have full-blown autism, which ismassively different from that.

We also have about a third [36%] saying thattheir child has some self-injurous behaviours,from banging heads on walls or floors, biting athands or fingers or whacking themselves on thehead. You do get this sort of behaviour inchildren with developmental delay and perhapssometimes it is just because they feelsomething when they do it.

And I am sure a lot of you are thinking aboutsleeping problems. Half of the families I saw[50%] said they either have problems gettingthe child to sleep, waking up repeatedly in thenight or deciding that four o’ clock in themorning is a nice time to get up.

Now just taking the group detected antenatallywho underwent termination of pregnancy, 36%had diaphragmatic hernias. In some cases, thefetus had a diaphragmatic hernia, theyterminated the pregnancy and then had genetic

testing. In others, the genetic testing was doneduring pregnancy and then the termination wascarried out. That is 36% compared to 0% in thegroup I saw and in the medical literaturediaphragmatic hernia is reported in around60% in the first month of life. So I think thisreally shows us that with improvements inantenatal care and testing, people are havingthe diagnosis made earlier and children withthese malformations are not being born.

We also have a 9% rate for heartmalformations, significant defects that arepotentially fatal. This again supports what is saidin the older medical literature.

One feature that is supposed to be common isextra fingers or toes but we only found it in4%, although the way the data are collectedmeans this may be an under-representation.

Diagnosing PKSFinally, we looked at where the diagnosis wasmade. Most children here will have had a skinbiopsy to confirm the diagnosis and 82% of my

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QuestionsQ When our daughter was born 20 years ago, I had amniocentesis [amnio] but was told then

that Pallister Killian could not be picked up. Has there been progress?A There are lots of amniocenteses coming through confirming Pallister Killian.

Q My Pallister Killian son is my older son, and I wanted prenatal testing for my younger son. I wanted CVS but was advised against it and to go to amniocentesis.

A First, the miscarriage risk for CVS is 1–2% and for amniocentesis more like 0.5%. Second, amniosthese days seem to be picking up all the Pallister Killian babies whereas out of a very smallnumber of CVSs, we know of 30% giving normal results and the baby turning out to havePallister Killian.

Q Why would an amnio be more correct than the CVS?A Partly because an amnio is analysing fetal skin shed into the water around the baby whereas

a CVS is a biopsy of the placenta. It may also be partly to do with the way the cells divide. We know that cells with the isochromosome do not divide as well when you provoke them asnormal cells do. For CVSs you have to push the cells to divide, whereas in an amnio you have topush them less. Theoretically, you could have a false negative on an amnio because there arefalse negatives on skin biopsies – but we didn’t see this happen.

Q Are these percentages on CVS very different for other chromosomal abnormalities?A Yes, because this is a mosaic disorder and not present in all cells. In other conditions there may

be mosaicism in the placenta but not in the baby. In Pallister Killian, there may be mosaicism inthe baby with a normal placenta, or there may be normal and abnormal parts of the placenta,so if you take the biopsy from the normal part you will not pick up any abnormal cells.

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group had a skin biopsy. In some instances thediagnosis had already been made on a mouthbrush sample and the skin biopsy was forconfirmation, in other cases the skin biopsymade the original diagnosis. I repeated themouth brush sample on all the children I couldand got a positive result in 75%. This meansthat 25% would not have been picked up if youonly used this test for diagnosis.

We also tried array CGH testing, which gives amuch more detailed picture of thechromosomes and is becoming the first-linetest in quite a lot of genetic centres for anychild with learning difficulties. I wanted to seewhether an array CGH test diagnoses PallisterKillian or not. The answer was that only 17% ofmy group were positive so a negative result onarray CGH does not in any way mean the childdoes not have Pallister Killian.

Finally, how accurate is antenatal testing?Amniocentesis at 16–18 weeks seems to havea good pick-up. But my data showed that outof 13 women who had chorionic villus sampling[CVS] in early pregnancy, four were givennormal results but the child had Pallister Killian.

Treatment options forepilepsy – medication andindication for theketogenic diet

Dr Christin Eltze,consultant paediatricneurologist at GreatOrmond StreetHospital, talked tofamilies aboutmedication andother treatments.

I want to talk about the principles ofantiepileptic drug [AED] treatment and whatcan be done if AEDs are not working. Normalbrain function is quite complex and is carriedout by nerve cells in the mantle of the brain,the cortex. In simple terms nerve cellscommunicate with each other using electricalimpulses and work in networks to establishcomplex functions like language production andunderstanding, vision and motor function.During an epileptic seizure there is a suddenburst of abnormal electrical activity which leadsto a transient brain dysfunction. You can seepatients’ behaviour change or patientsthemselves may feel something. What you seedepends very much where in the brain thisdysfunction occurs.

We divide seizure types into two maincategories. In focal seizures, earlier called partialor complex partial seizures, the abnormalelectrical activity mainly starts within one side(hemisphere) of the brain. In generalisedseizures, the abnormal activity starts on bothsides of the brain.

One epileptic seizure does not constituteepilepsy. In epilepsy, seizures are recurrent.Many conditions and disorders manifest withepilepsy and chromosomal abnormalities areonly one of these. There are also events,medically termed paroxysmal events, whichoccur intermittently but are unrelated toepilepsy, such as fainting. Sleep-related eventslike night terrors must also be distinguishedfrom epilepsy. Description of the events fromwitnesses such as parents helps us decide if anattack is epileptic or non-epileptic andadditional information from home videos isparticularly useful. The EEG recording that wemake between attacks can help, but a normalrecording does not rule out epilepsy. An attackduring a video recording with EEG (video-EEG)can confirm that the event is a manifestation ofepileptiform activity.

Currently we do not know what causesepileptic seizures in Pallister Killian but certainseizure types are more common. The literaturegives very little information on seizure typesbut I noticed five reports of patients whopresented with late-onset epileptic spasms (17 months to 9 years of age). In most,epileptic spasms were difficult to control withantiepileptic medication. In young childrenepileptic spasms often manifest with a brief(1–2 seconds) sudden flexion of the neck and trunk with sidewards movements of thearms, often recurring repeatedly over a periodof time (cluster of spasms). Epileptic spasmscan be subtle and might be overlooked. A myoclonic seizure is a sudden jerk-likemovement, usually briefer than a spasm, that

QuestionsQ How do you describe an absence

seizure?A In absence seizures, you see a specific

feature on the EEG[electroencephalogram] and a very brief‘switching off ’, stopping, staring, eyelidflickering or lip smacking. They often lastless than half a minute and canoccasionally be quite frequent.

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may involve the limbs (one side of the body orboth, often involving arms), neck or trunk.Some episodes described by parents as ‘jerks’turn out on video-EEG to be epileptic spasms.

Treatment and side effectsThe first aim is to improve seizure control:overall a quarter of children have epilepsy thatis resistant to AEDs. Drug resistance is moreprevalent when there is a known cause such asan underlying brain abnormality, an abnormalneurological examination or if the seizuresstarted very early in life.

QuestionsQ What are the consequences of spasms

that are not picked up early?A The impact on cognitive outcome of a

delay in treating epileptic spasms withonset in very early childhood is subject toresearch and is debated amongpaediatric neurologists. Some data inchildren with early-onset epileptic spasms(particularly with no underlying cause),suggest that the cognitive outcomes areless favourable when treatment isdelayed. But the underlying causeprobably plays a big role and at themoment we have too little data toconfirm that early treatment will improvecognitive outcome in all cases,independent of the underlying cause. Ourcurrent practice in paediatric neurology isto treat epileptic spasms in very youngchildren early (under the age of 2 years),promptly (as soon as these arerecognised) and rigorously.

Q What kind of test can I request? Mydaughter is 12 and sometimes gets thesejerks.

A No single test unfortunately makes thediagnosis. Your doctor, paediatrician orpaediatric neurologist can decide, basedon a home video and clinical information,what further investigations are needed. If they are really frequent, an EEG orvideo-EEG would be helpful.

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Some children have seizures that continue afterfive minutes and evolve into status epilepticus;others experience periods of very frequentseizures that interfere with their consciousnessand functioning. An emergency régime forthese kinds of seizures is important: we usebenzodiazepines: buccal midazolam or rectaldiazepam.

If AEDs failThere are at least 10 AEDs available and youcan work your way through them. But otheroptions to explore include the ketogenic diet.This is a high-fat, carbohydrate-restricted dietwhich aims to simulate the biochemical changesof starvation in the body. During starvation, thebody breaks down fatty acids in the liver andbuilds up ketones which are used as a sourceof energy by the brain and muscles.Paediatricians in the 1920s noted that whenchildren with epilepsy were unwell and unableto eat, they appeared to have fewer seizures.Physicians then devised fat-rich, low-carbohydrate diets that forced the body toproduce ketones: some patients with epilepsybecame seizure-free and others showedmarked improvement. The classical ketogenicdiet was developed.

In our normal diet, a little over half the energycomes from carbohydrate and 20–25% fromfat. In the classical ketogenic diet we increasethe fat to 90%, reducing the combinedcarbohydrate and protein proportion to 10%.This means that a child has to follow a verystrict diet with a calculated meal plan. Theother form is the medium chain triglyceride[MCT] diet, derived from the observation thatMCTs make the body produce more ketones.On the MCT diet, 40–60% of daily calories aregiven as MCT oil or as Liquigen, a specialformula. This diet has 75% fat and patients areallowed 15–20% of calories from carbohydrateand protein. Matthew’s Friends[www.matthewsfriends.org] is one of thecharities which help parents, particularly withrecipes. The modified Atkins diet is a high fatdiet with restricted carbohydrate intake butunlimited protein allowance.

We consider the diet firstly with patients whohave drug-resistant epilepsy who have trialledseveral AEDs but still have seizures with asignificant impact on their quality of life, alsowith patients who tolerate AEDs very poorlyand in some rare metabolic disorders. Someconditions, generally ones that cause low bloodsugar or high lipids and some metabolicdisorders are worsened by the ketogenic diet.There is also no point in starting any child with massive feeding or significant swallowingproblems on the ketogenic diet withoutaddressing these first. The diet can beconsidered for children who are fed through a gastrostomy. There is a risk of vitamin andmineral deficiencies so all our patients are onsupplements and have regular blood tests. We also monitor weight and growth.

But does the ketogenic diet work? A systematicreview of studies [Pediatric Neurology 2006 Vol35 pp 1–5] reported that after six months,16% of 972 patients became seizure-free and33% had more than 50% seizure reduction. I don’t know how many patients had less than 50% seizure reduction. Forty to 50% ofchildren who remain on the ketogenic diet for6 months experience more than 50% seizurereduction.

Trials at Great Ormond Street Hospital [LancetNeurology 2008 Vol 7(6) pp 500–6; Epilepsia2009 Vol 50(5) pp 1109–17] show that boththe ketogenic and MCT diets appear to work.But side effects can be a problem, particularlyin the beginning, with vomiting, diarrhoea,constipation, hunger and compliance issues.Both diets have similar side effects althoughvomiting was a little more common on theclassical diet. Relatively few patients droppedout because of side effects. Side effects such asconstipation can usually be managed by adding

QuestionsQ Surely ketones are poisonous? Isn’t it

dangerous to induce them?A When I am unwell and do not eat for

two days, my body produces ketoneswhich provide energy but my body doesnot poison itself. They are a naturalresponse to starvation. Occasionally theketone level may become too high inwhich case a child may show symptoms.These usually improve if somecarbohydrate is given, usually as a smallamount of fruit juice, to reduce ketoneproduction. If a child on the ketogenic dietis unwell, the ketone level may becometoo high and worsen the condition of thechild. We instruct the parents/carers ofour children on the ketogenic diet how tomanage children when they are ill andespecially to recognise the signs whentheir children become unwell, when theyshould be brought to a doctor or hospitalfor assessment and treatment withoutdelay.

Choice of AED is guided by seizure andepilepsy type. For example, in cases withabsence seizures we would consider startingsodium valproate, ethosuximide or lamotrigineand would avoid use of carbamazepine orvigabatrin because these can make absencesworse. We also try to avoid carbamazepine andvigabatrin for myoclonic seizures because theycan make them worse. You have to go throughthis with your doctor.

Consideration of side effects is very important.Phenytoin and phenobarbitone were veryeffective drugs but their side effects are worsethan many of the newer antiepileptic drugs andwe use them now as third choice when otherAEDs fail or for short-term treatment inemergencies. To minimise side effects, we aimfor as few AEDs as possible, one or two ifpossible and only exceptionally three. Veryinfrequent seizures probably do not warranttaking an AED every day: discuss this with yourpaediatrician or paediatric neurologist. Anddiscuss treatment goals: if seizure freedom isnot achievable, drug treatment should betargeted at seizures with the greatest impacton the child’s quality of life.

Side effects commonly include sedation,tiredness, dizziness and unsteadiness,particularly when AEDs are initiated, so weusually start with a low dose, increasing itgradually. The biggest problem for patients withdifficult epilepsy is that some AEDs, forexample sodium valproate, may exacerbatebehaviour difficulties. Concentration problems,loss or increase of appetite and nausea andvomiting can be a problem with some AEDs.Allergic reactions, especially a skin rash, canoccur more frequently with carbamazepine,lamotrigine or phenytoin. Severe life-threateningreactions are rare but can affect skin, liver oreven the bone marrow. Long term AEDtreatment can be associated with hormonedisturbances and thyroid function may have tobe monitored. There is an impact on bonemineralisation because some AEDs interferewith vitamin D metabolism. And some AEDsmay cause increased phosphate leakagethrough the kidneys.

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fibre and using laxatives. We give our patientsinformation on what to do if they have otherside effects at the beginning such as low bloodsugar or excessive ketosis, which is monitoredby carers. A proportion of patients may alsopresent with kidney stones. The risk of thishappening can be minimised by alkalising theurine (using polycitrate supplements).Hyperlipidaemia is a long-term problem, butshould be balanced against the risk ofuncontrolled epilepsy. Weight and growth mustbe monitored. Other long-term side effectsinclude decreased bone density (because ofimpaired bone mineralisation on the ketogenicdiet) with risk of fractures. Cardiac problemshave been reported in very rare cases.

Before starting the diet, we assess patients in detail, looking for any contraindications. We then set goals, aiming for seizure reduction– only a small proportion of patients becomeseizure free – and reduction of antiepilepticmedication. There is little evidence that theketogenic diet directly improves cognitive ormotor function, though it may do so indirectlyby reducing seizure burden and reduction ofAEDs (reduction of AED side effects). Someteams start the diet in hospital, others like us as outpatients. After three months we usuallyestablish whether it has worked. Seizure diariescan be very helpful when comparing seizurecontrol before starting and while on the diet. If it works, we carry on, reviewing patients six-monthly, but after two years we usually tryto reduce the fat ratio to see if the epilepsyhas progressed and the ketogenic diet may no longer be necessary to control seizures.

Data show that patients drop out over time,either because the diet is not working or thereare difficulties with compliance. After two yearsonly 20% may still be on the diet. But there areobservational data suggesting that seizurecontrol remains improved 4 years after startingon the diet in a proportion of patients – evenafter coming of the diet.

You need a team for the ketogenic diet: aspecifically trained dietician, a paediatricneurologist or experienced paediatrician andperhaps a clinical nurse specialist to liaise withyour local paediatric team if problems occur.

Vagus nerve stimulation[VNS]VNS therapy, another non-pharmacologicaltreatment, is based on repeated electricalstimulation of the left vagus nerve by a pulsegenerator device. It can abort a seizure andmay increasingly prevent seizures. Otherbenefits can include positive effects on mood,alertness and behaviour.

An electrical generator device is implantedunder the skin on the chest or armpit; anelectrical lead goes under the skin up to theneck where it is then coiled around the vagusnerve. The device on the chest is programmedand the pulse sequence, frequency and thestrength can be changed or stopped with alittle swipeable magnet. It’s unclear how itworks but we know that the vagus nerve isconnected to many areas in the brain includingthe locus coeruleus and there may bemetabolic changes in the thalamus, brainstemor elsewhere in the brain that raise the seizurethreshold.

Studies have shown that one third of implantedpatients have at least 50% seizure reductionand in some newer studies including children ahalf do. In one trial, a third of patients hadsome response but less than 50% improvementand a third had no response. The optimumeffect took a few months to 1–2 years toshow.

The vagus nerve is responsible for the functionof the voice and the swallowing muscles so achild with severe swallowing problems is usuallynot suitable for VNS treatment. Side effectsinclude a hoarse voice, cough and throattickling but decrease over time. You can removea VNS device that is not working but the wirealong the vagus nerve is difficult to remove andusually stays in place, so children with a VNSdevice cannot go through a normal MRI scanbecause the wires can heat up and causedamage. There are special MRI scanners whichonly cover the head area and these would besuitable for such patients.

In conclusion, diagnosing epilepsy correctly isimportant and AEDs are usually the firstoption. We aim for the fewest AEDs with the

least side effects and you should set realisticgoals. Explore non-pharmacological treatmentsearly because they may take time toimplement. The ketogenic diet works for some but needs a dietician: physician team,significantly changes lifestyle and may be hardfor some families and children to follow.

Families’ QuestionsCE = Dr Christin EltzeEH = Emma HydeES = Dr Eugen StrehleMB = Dr Moira BlythNL = Nicola LatheyPE = Pattie Everitt

EpilepsyQ How specific is epilepsy in Pallister Killian? Our

local services have very little information.A In general we assess patients with PKS like any

other patient with epilepsy. We are collectingdata but PKS is rare. [CE]

Q What causes spasms after my son wakes up?A You should consult your paediatrician or

paediatric neurologist, because you cannotassume that you are seeing epileptic spasms.Reflux is a differential diagnosis and should beevaluated. [CE]

Q A lot of seizure activity is sleep-related,nocturnal or as they wake.

A We commonly see epileptic spasms afterwaking. We are not certain what makesseizures more frequent in sleep but the brainmay switch to a different state that we cansee on the EEG. [CE]

Q Are children having epileptic spasms consciousor unconscious?

A They are often very young, so we can onlyobserve them. From my observation, someappear to be aware. [CE]

Q During these episodes can they speak?A You saw the little girl on the video who was

playing, had the spasm and carried onimmediately afterwards. [CE]

Q The episodes are not particularly short, severalminutes maybe.

A Episodes like that don’t sound like seizures.Sometimes parents say that their child carrieson, is aware or cries between spasms. Whetherhe is aware in the two seconds of the spasm, Idon’t know. [CE]

Q Is it helpful to do an EEG during theseepisodes?

A Yes: video-EEG capturing these episodes wouldbe very helpful and diagnostic. I would gothrough the history in great detail and assuremyself that the episode has the characteristicsof an epileptic spasm before considering AEDs.Some people are confident to make thisdecision based on the clinical signs and historywhereas others want at least a baseline EEG.Most of my colleagues would like an EEG inwaking and sleep to develop a betterunderstanding. [CE]

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Q My daughter has episodes in the night. Wedon’t know if they are epilepsy or night terrors.

A Children can be admitted for overnight filmingand EEGs. I don’t think there’s any other wayto judge it. [MB]

Melatonin for sleepQ Do you use melatonin?A Melatonin is a natural hormone whose main

job is to induce sleep. Some children with brain-related conditions may release it but at thewrong times or use it incorrectly. In the UK it’sunlicensed, so is normally available throughconsultants. Melatonin can sometimes helpwith getting off to sleep, but very rarely helpswith night waking. It works in some children,but not all. [PE]

Q Our daughter’s been on melatonin for 9 yearsand we are wondering about taking her off itbecause she is very drowsy in the morning,though she is also on AEDs.

A There isn’t enough research into the long termeffects. Melatonin is often used short term toget a child into a sleep pattern. Children I haveseen have normally come off it because it’s nolonger effective. [PE]

Q Could it be addictive?A It doesn’t seem to be. Compared to other sleep

medications it has very few side effects. Somechildren become tolerant but that may bebecause they are getting older and bigger. [PE]

SupplementsQ My baby was very shut off from the world

until we gave her supplements of aminoacids,iron, vitamin B, folic acid and DHA [an omega-3 fatty acid]. Within a week, shewas more alert. When I stopped the vitamins,she regressed. When I gave them again, herattention improved. Her therapists and doctorwho didn’t know about the supplementsremarked on her progress. I don’t know if thisis due to her normal development or thesupplements.

A These are substances normally found in food;fish contains omega-3 fatty acids. The evidenceis not very strong but they have been shown tohelp – though not cure – autism and ADHD[attention deficit hyperactivity disorder]. For chromosome disorders, there is really noevidence but at the recommended dose theyshould do no harm. Many parents say they seechanges with food supplements but there isalso the placebo effect: simply giving a pill canhelp a child to improve. [ES]There is no evidence but if you feel it’s having asignificant impact, then presumably it’s doingno harm. I would be cautious with iron becauseyou can give too much. [MB]

Pain thresholdQ Our daughter won’t tell us when she is in pain

but she signs if she falls over and is bleeding.We suspect that she has a lot of pain anddoesn’t know how to manifest it. Did you comeacross this?

other families experienced this and how havethey dealt with it?

A Sometimes you need to chew and stimulatethe mouth: the Chewy Tube [available in theUK through www.eg-training.co.uk or fromKapitex at www.kapitex.com] might help oryou can get a vibrating teether fromMothercare. [NL]Our son’s teeth were slow to come throughand two are fused; he was born with a bulge inone of the gums. Try a child’s battery-operatedtoothbrush. [Families]

First stepsQ At what age were children able to walk? Why

do some not walk?A The range I found was 16 months to 8 years.

Some children are much more severely affectedthan others. [MB]Our physical therapist said that a child whostarts walking after 3 will have a modified gaitbut before 3 can have a normal walk. Ourdaughter walked at 7: never give up. We useda wheeled toy dog. [Families]

Q Is there any sign in early development to tellus whether our child will walk?

A No: it is individual. There are very severe oneswho at 3 make no effort to sit and are thesame at 13. The ones who were maybe sittingon their own at 18 months are more likely towalk later. [MB]

ConstipationQ Our son takes lactulose a few times a day but

can still go 2–3 days without doing his numbertwos [poos] and is then in excruciating pain.

A Anything oral like lactulose gives our sonstomach ache; we give him a Duphalacsuppository [prescribed by the GP] every otherday. Movicol. I use a natural remedy, onecapsule of Oxy-Powder every morning withbreakfast, recommended by a herbalist.Benefiber and Senokot. We inject warm waterthrough a syringe, hold the child for a couple ofminutes, then take him to the toilet. Warmwater with sugar to drink before breakfast. Nomedicines but we help with a stick. Sometimesthe reflex doesn’t work so we scoop. [Families]

A Not specifically in the Pallister Killian group. It’sfairly common in children with learningdifficulties: whether they don’t feel pain as wedo or whether they don’t express it, I can’t tellyou. [MB]There are signs for pain in a particular areaand a general sign for hurt. You could rôle playsomebody falling over and say ‘Ow! Ow’ or‘Hurt’ so she knows that should lead to gettinghelp. Using puppets or social stories mighthelp: look on the internet [‘Social stories’ atwww.autism.org.uk]. [NL]You are halfway there if she acknowledgespain when she sees blood. You could use fakeblood to show ‘Blood means pain and I needMummy’. [EH]Try plasters or magic bandages. One familymentioned delayed pain, 15–30 seconds afterthe event.. [Families]

Ear infections and ear waxQ Any advice for a child with narrow ear canals,

constant ear infections and ear wax?A Ear wax is normal; you shouldn’t try to remove

it. Most ear infections are caused by virusesand don’t need antibiotics. If a child has asevere infection, the wax often melts and you perhaps have discharge. These are theinstances when you need to give antibiotics. If you are worried about frequent earinfections, perhaps associated with glue ear,your child should see an ear, nose and throatspecialist. [ES]

GallstonesQ Gallstones: has my daughter’s diet affected this

and has anyone else had them?A It’s an isolated one from my point of view. [MB]

Different types of gallstones can occur in anychildren. To my knowledge, it’s not diet-related.In children, they are often not painful. [ES]

Cutting teethQ Our son has had two huge symmetrical lumps

on his lower jaw for a year, where the teethdon’t cut through. The dentists have never seenthis before. We don’t know if it is painful. Have

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w w w . r a r e c h r o m o . o r g

Professor Peter Hammond Nicola Lathey Emma Hyde Karen Sutherland Dr Eugen Strehle Pattie Everitt

This report is dedicated to the memory ofJosh Rayner and Edward McMahon.

any cancer. That said, you should assume thatvery pale skin patches are more likely to burnso if your child has any that will be sun-exposed, you should take more precautions.[MB]Before my son’s diagnosis, we took himcamping. I smothered him in sun cream and hegot ‘raspberry ripple’ on his legs. We protect theareas that burn very easily with factor 50 suncream as with any child but a little earlier inthe season. [Family]The darker skin has more melanocytes thatmake the tanning. Quite a few families saidtheir child didn’t seem to have any stripes untilthey took them to Majorca or wherever. [MB]

DribblingQ What treatments are there for dribbling?A As well as hyoscine patches, a medicine called

glycopyrrolate can be given by mouth. Somechildren have had Botox injections into thesalivary glands but this has to be done in aspecialist centre. [ES]Our son has had the salivary ducts at thebottom of the mouth tied off so saliva stillcomes from the top of the mouth but not thebottom. This worked for us. My son outgrewdribbling around 6–8 years. [Families]

PubertyQ When do we expect puberty, what should we

expect and how do we manage it?A In my small group, puberty occurred at normal

times. [MB]It is likely to be variable. In general inchromosome disorders puberty can be delayed,but can also start early. Periods can be difficultto manage in children with learning difficulties.Some paediatricians or paediatricendocrinologists recommend the contraceptivepill or an operation as a last resort. [ES]

Joint dislocationsQ How can joint dislocations be reduced?A Lots of Pallister Killian kids can dislocate their

hips and legs and sit in any position when theyare little without pain. The ones who areoperated are usually those who are walking or

expected to walk. The dislocated hip quiteoften doesn’t bother the child and has beenleft. These are children who are more severeand are not trying to weight bear, so there’slittle point in putting them through anoperation that’s not going to help them. [MB]My son is due to be operated because his righthip is 70% dislocated and his left hip 50%. He weight bears and his hips are now startingto put his back out of line. [Family]

This report includes the specific Pallister Killian and epilepsypresentations as well as families’ questions. The slides from the otherpresentations are also available on the members-only part of theUnique website. These include: Creating a 3D model of typical faces inPallister-Killian syndrome [Peter Hammond, Professor ofComputational Biology, Institute of Child Health, London]; PracticalStrategies for Developing Communication Skills [Nicola Lathey, speech

and language therapist]; Challenging Behaviour in Children with SpecialNeeds [Emma Hyde, Clinical Nurse Specialist]; What is ‘normal’development? [Karen Sutherland, clinical psychologist in training; TheChild with a Chromosomal Disorder from a Paediatric Perspective [DrEugen Strehle, paediatrician]; and Cerebra Sleep Service [Pattie Everitt,Sleep Counsellor]. Transcripts of the key presentations are availablefrom Prisca Middlemiss at Unique at prisca@rarechromo.org.

Managing children who don’tsweatQ How do you manage a child’s inability to sweat

and control their temperature?A A fan that sprays water on the face. [Family]

Cold feetQ My daughter always has cold feet though not

hands, a normal colour. She has no underlyingheart disease.

A Children with chromosomal disorders quitecommonly have cold feet and it doesn’tnecessarily mean there is underlying heartdisease. Always make sure her feet arewrapped up. [ES]

Life expectancyQ What is the life expectancy and is this

governed by the severity of the PKS?A The data isn’t available to give a very good

answer. I’m sure that how badly they areaffected will have a significant impact. But inmy group, the child who had the sudden deathin epilepsy was one of the milder ones. Theoldest surviving one in the medical literaturewas 45. [MB]

Different biopsiesQ To diagnose our son, they took skin and

muscle biopsies. The skin biopsy gave PKS. The muscle biopsy gave a mitochondrialdisorder. Because both disorders are rare, ‘they’ skip the metabolic diagnosis.

A Without seeing the metabolic report, this isguesswork, but a lot of metabolic abnormalitieson muscle biopsies are subtle. If you have askin biopsy that 100% confirmed PallisterKillian, the question on the muscle biopsyreport is: are those subtle abnormalities thatdon’t add up to anything specific or has thechild got two separate diagnoses? [MB]

SkinQ Do PKS children have an increased risk of skin

cancer?A There is no evidence anywhere that children

with Pallister Killian have an increased risk of