9599:8421 13/9/10 13:51 Page i 4qdeletions Unique, the worldwide rare chromosome disorder support group, hosted Array-CGH the first-ever international meeting for families with a child with a deletion Dr Strehle described array-CGH, a way of from the long arm of chromosome 4 in Coventry, UK in April 2010. testing DNA that shows extra or missing Families came from round the world to meet researchers, interested chromosomal material throughout the genome. doctors and therapists – and each other. This report contains the Using this technique, his colleague Dr Taosheng presentations that were specific to 4q-. Presentations from the day are also Huang was able to find a potential new gene available on Unique’s website. for cleft lip and palate. What is 4q- syndrome? reports of 70 per cent, which most likely relates to improved medical care. Other cWith this technique you can Dr Eugen Strehle, a systems - muscles, eyes, skin and hair and the determine to the individual gene where paediatrician in gastrointestinal tract – were involved to a lesser the breakpoint is.d Newcastle, UK with extent. Hearing was commonly affected, with an interest in 4q, sensorineural or conductive hearing Pinpointing the gene: explained that the impairment, making it important to test term ‘4q syndrome’ children’s hearing. One third of children had a a child with a 4q33 deletion was first used by Dr cleft lip or palate or a condition called Pierre Dr Strehle presented a child with a terminal Charles Ockey over Robin sequence characterised by a receding deletion from 4q33. She was born by caesarean 40 years ago in 1967. chin, a posteriorly placed tongue and also a section, with a birth weight of 2.9 kilograms cleft palate. There was central nervous system and Apgar scores of 8 and 9 meaning that she involvement in about 30 per cent. was in good condition at birth. She had an Twelve years later, Dr Phillip Townes applied the Dr Strehle suggested this programme of occipital encephalocele, which is like a tumour, term to a syndrome where the breakpoint is investigations: imaging of the brain; X-rays if the and this was successfully removed when she found in band 4q31 and the end of the child has any significant abnormality of the arms was two days old. A brain scan and MRI when chromosome is lost. Then in 2001, Dr Strehle or legs; an abdominal ultrasound scan; pH she was three months old showed she had a suggested that the term should be used to studies to test for gastro-oesophageal reflux; an neuronal migration defect, which means that cover all microscopically visible deletions of the electrocardiogram or echocardiogram because the grey matter of the brain is inserted into the long arm of chromosome 4 – that is, any of the common heart anomalies; an white matter. She also had an Arnold Chiari deletion that you can see under a light electroencephalogram (EEG) for seizures, which malformation, where the brain stem is pushed microscope. Broadly, there are two categories are relatively common; and hearing and vision through a hole in the skull and which can lead of 4q deletion: interstitial deletions with two tests. Children with 4q deletion syndrome to hydrocephalus – an increase in the fluid breaks and a part missing along the length of should be cared for by a multidisciplinary team within the brain. She was the first child with an the chromosome, and terminal deletions, including a paediatrician, geneticist, a surgeon encephalocele reported with a terminal where the end of the chromosome is lost. where needed, a dietician to support growth, a deletion of chromosome 4q. One other child speech and language therapist for any was reported but with a different interstitial Review of people with swallowing difficulties, a physiotherapist, deletion at 4q13q23 and unfortunately she 4q- syndrome occupational therapist, a psychologist because died when she was seven months old. There is Dr Strehle reviewed 100 patients with 4q there can be behavioural difficulties, and a a condition called Knobloch syndrome that is deletion syndrome and found an incidence of special needs teacher. characterised by eye abnormalities and an perhaps one in 100,000 with more recent occipital encephalocele, caused by a mutation COL18A1 data suggesting perhaps a higher of the gene incidence. The male to female ratio was roughly equal at 48:53. Some deletions occurred relatively frequently, for instance 4q12q21 interstitial deletions and 4q31 and 4q33 terminal deletions. The chromosomes of the parents were normal in about 86 per cent of cases. Among those affected, the most typical characteristics were: unusual facial features (craniofacial dysmorphism) in 99 per cent, developmental delay in 94 per cent and unusual fingers and/or toes (digital dysmorphism) in 88 per cent. Growth failure occurred in 60 per cent, skeletal and cardiac anomalies in about half. The mortality rate was almost one third, a reassuring finding compared with earlier
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on chromosome 21. It’s possible that other Among the adults was a 28-year-old woman genes on chromosome 4q are also involved in with an interstitial deletion of 4q25q27 who cOften parents become specialists in the development of encephaloceles and one was well and studying for a psychology degree. their child’s condition. It’s not uncommon way of finding out is to study patients like this A man of 47 with a terminal deletion from that parents will know more after a few little girl. 4q34 said he had aggressive behaviour and years than the people they meet.d The girl also had severe, complex heart disease went to a special school but was well. Another man with a similar deletion had a cleft palate but urgent surgery was successful. It is known Parents’ own knowledge of their child’s and hypermobile joints and was working as an from Dr Taosheng Huang’s work that when chromosome disorder was good. The medical accounting technician; another with a small some genes are present in only one copy advice given to parents was deemed to be terminal deletion from 4q35 also reported instead of the expected number of two cautious. (haploinsufficiency), abnormalities can occur. aggressive behaviour and dyspraxia. Some families felt abandoned by the geneticist When the HAND2 gene on 4q34.1 is missing, Of 32 returned questionnaires (a 58 per cent because they did not offer follow up cardiovascular malformations can occur. response rate), there were 16 interstitial and appointments; it may be more appropriate for 20 terminal deletions. The mean age of the What were the unusual facial features? She had a paediatrician to follow families up. a large fontanelle (soft spot on top of the children was 11 years, ranging from 10 months head), widely spaced eyes, overfolded ears, a to 47 years. The chromosome abnormality was Positive experiences small mouth and chin, overlapping fingers, inherited in 16 per cent. All children had some What were families’ positive experiences? They unusually placed toes and a sacral learning difficulty but in almost half it was mild; said that bringing up a child with 4q- had haemangioma, like a birthmark near the base of in one third it was moderate and it was severe enriched their lives and provided new her spine. in seven. Thirty-eight per cent had growth deficiency; 65 per cent had small hands and perspectives. Parents referred to their child as Normal chromosome tests showed a terminal feet. Two out of three children with a terminal ‘our gift’, ‘the best thing that ever happened’ deletion, not inherited from her parents, at deletion showed an anomaly of the fifth finger and ’a constant reminder of what is important’. 4q33. A CGH test showed a very large and finger nail in which the finger is small and Many children surpassed doctors’ predictions. deletion of 25.7 megabases with a breakpoint the nail is not well developed. More than two Some parents were impressed by the level of at 4q32.3. (Bases are the bonds between the thirds of children had feeding difficulties, mainly care and acquired detailed medical knowledge. two strands of DNA that look like the rungs of when young, needing nasogastric tube feeding, a ‘He made us laugh, worry and cry just like any a ladder; megabases are one million bases.). gastrostomy and sometimes a fundoplication to other child would.’ In follow-up she had growth deficiency and prevent reflux. feeding difficulties. Her developmental What were parents’ feelings at diagnosis? In conclusion milestones were delayed, walking by 2½, and at Parents said that it was the worst experience Of the 20–25,000 genes in the human genome, 5 saying single words and following a simple ever but didn’t change the way they loved their most display no obvious phenotype when one instruction. At 5 her unusual facial features child. Others said: ‘It knocked the wind out of copy of the gene is missing because of a were still visible and her short stature was very me’ and ‘The baby I brought home ‘died’ that chromosome deletion. That means that the striking. day’. More positively, one family said: ‘It gave our other copy present on the intact chromosome In the wider context, a lot of children with son’s disability a title’. 4 is enough to enable the child’s enzymes and abnormalities on any chromosome have Parents felt the diagnosis should be given by proteins to work properly. But alterations in the learning difficulties and much is not yet someone knowledgeable, in a personal, sincere dose of some genes can lead to disease or understood. Research in animals and humans and sympathetic manner. Some parents even death. In summary, 4q- has a fairly has shown that the nerve cells in the brain criticised the clinician giving the diagnosis for distinctive clinical and behavioural phenotype. (neurons) have fewer connexions. So having insufficient knowledge or time to Gene dosage effects may contribute to the something led to decreased networking research the disorder thoroughly. effects of 4q-. Early diagnosis and between the neurons and this may account for multidisciplinary management can improve life the learning difficulties. Some professionals were felt to be insensitive, giving an unnecessarily poor prognosis and expectancy. Summing up referring to older literature. As children grew older, parents became more positive and Genotype-Phenotype 4q syndrome is a valid disease entity. It is confident and searched for more information characterised by overlapping features in which Study themselves. They became more accepting, other factors may play a causative role. As for Dr Taosheng Huang starting to take each day at a time and not the encephalocele, the genes responsible for is an associate looking too much into the future. There was the development of the basement membrane professor with some criticism of doctors. Many health may reside on chromosome 4 and if abnormal tenure in paediatrics, professionals involved with the child were may lead to encephaloceles. developmental perceived to either not have the time or to biology and focus on one part of the child, leading to pathology at Unique survey fragmented care. Dr Strehle described a survey conducted University of through Unique. Using an 8-page questionnaire, California, Irvine, parents’ views at diagnosis and subsequently cMy personal opinion is that the first USA. were elicited. 55 questionnaires were sent out, two years of life are the most crucial. If as well as a short form to five adults, all congenital abnormalities are present but He is also the director for the Cardiovascular relatives identified after their child was surgery goes well and is a full correction, Genetics Clinic and the co-director for the diagnosed. These people went through life then as the child grows older and MitoMed Molecular Diagnostic laboratory. without knowing they had 4q- until their child stronger it’s less likely that something Clinically, he is interested in genetic syndromes was born. This suggests there is quite a large severe will happen. with congenital cardiac defects, metabolic number of undetected 4q deletions. d disease and genetic screening.
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He talked about his research in creating what is called a genotype:
Viewing chr4:150045706-191273063 phenotype correlation. within All deletions Window Size 41.23 Mb ‘A phenotype is something you can 4q (light green) Dark green are BAC see or measure, like a picture that you probes on the current array can see. For instance, you can do an version (WG) echocardiogram for congenital heart disease or you can measure IQ. A
genotype is your genetic make-up. In Deletions encompassing 4q33 the case of 4q-, if you are missing a gene, what kind of phenotype will you see? My final goal is to try to pinpoint the phenotype to particular genes and then see if we can intervene and help children with 4q- and come up with treatment. Maybe that’s a big goal but years in the US, I estimate that our that’s what we aim for. project then spelled out each word in the cases represent less than one-third of the ‘The human genome is very complicated with a whole volume. diagnoses. three-billion-character code within the 46 ‘The first version of the human genome project chromosomes. Chromosomes make a pair, half cost three billion dollars and took 13 years to Common break points from the mother and half from the father. Using finish. Now technology has advanced so much ‘We want to see if there are common previous technology, looking at chromosomes that I can do a genome in one week, and it deletions, common break points, if a lot of under a microscope, even with the best would cost 50,000 dollars. Being able to read people’s chromosomes break at the same spot technician and the highest resolution, you can what each chapter says is critical and is a critical (slide above, left). And we do see some probably see 2000 bands. Since there are 3 component of my research. hotspots where deletions are more common. If billion codes, each of these bands represents we then look in more detail (slide above, right), one to two million codes, so still a huge Array-CGH we can see that a lot of deletions are very number. So the previous technology was used ‘We are now using third generation array-CGH similar. That means that the structure of the for diagnosis but it is not good enough for the with a chip that is even smaller than a chromosome in that region is vulnerable to be questions I want to answer. matchbox and has increased the sensitivity of broken. the test 100–1000-fold compared with 4q- or 4q- syndrome? ‘But research is very limited. Now we have the karyotyping. In the past I could only see when a genome, we know how many genes and which ‘Some people say 4q-, some say 4q- syndrome. whole book or a chapter was missing. Now I ones have been deleted. Now we need to The clinical phenotype is very well known in can see the detail in the book down to each relate the deletions to what we see clinically. the 4q- group. For some genes on 4q, one paragraph. To use a cookbook analogy, once I We have compiled a long questionnaire for copy is not sufficient – haploinsufficiency. That’s know what a paragraph means, I can cook physicians and we have data from 20 patients. why you have disease, for example congenital macaroni cheese! What we have found so far is that if you lump heart disease. ‘We now realise that 4q-/4q- syndrome is way them together you find the clinical phenotype ‘My research relies on two advances in science more common than we thought. We missed a is very similar to what Dr Strehle published – one is the complete sequencing of human lot of people with tiny deletions when we only many years ago (slide below, left). genome in 2003, and then advances in array- looked under a microscope. In just one ‘How many genes are there in this region? CGH. People argue: should we say 4q- or 4q- laboratory in a two-year period in the US we Perhaps1000. Some deletions encompass a lot syndrome? 4q- syndrome means there is a have 150 patients. Since we have probably of genes; some deletions are very small. constellation, a recognisable pattern. In 4q-, it’s made the diagnosis of 4q- in around 500 Patients with very small deletions are very very diverse. Each child depends on the patients in the last two valuable for us to understand which genes deletion, they can be very different from each cause disease because they have only lost one other. However, many individuals with or two genes (slide below, right). terminal deletions do look very similar. Typically, they have a very thin upper lip and may have congenital heart disease and limb anomalies. But others look Results completely different. So we can argue:
Should we call it 4q- syndrome or 4q-? • Clinical features in our 20 patients are 75.00 Mb 100.00 Mb 125.00 Mb 150.00 Mb 175.00 Mb 4q12 4q13.1 4q13.3 4q22.1 4q24 4q25 4q26 As far as terminal deletions are compared with 101 patientsstudy in Strehle 4q28.1 4q28.3 review 4q32.1 4q32.3 2003 1 3 56 and Bantock’s 2 4 7 8 12 13 concerned, it’s appropriate to talk about 9 11 – Craniofacial(100%) 10 14 15 a 4q- syndrome. – 16 developmental (95%) 17 18 – digital(70%) 19 ‘How does the first human genome Start: 4q21.1 20 – End: 4q35.2 muscular(55%) Largest: 25.7MB (45 OMIM genes) project help us? The genome is like a book – skeletal(50%) Smallest: 160KB (3 OMIM genes) but with 23 volumes and two copies of – cardiac(50%) Clusters: #7-#10 (q25-q28.2), #13-#20 each volume. Before the human genome • Figure: Deleted region on 4q in each (q32.2-q35.2) project finished, you knew you could take patient one volume or one chapter out of the genome (a deletion), but you didn’t know what that chapter said. The human genome
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large head, frontal bossing, maxillary microcephaly, ear and hypoplasia, short saddle nose, bilateral nasal anomaly, and strabismus, finger postaxial polydactyly, clinodactyly of toes, unilateral multicystic anomaly, growth short stature, poor weight gain, speech dysplastic kidney deficiency, delay, learning difficulty, hyperactivity, developmental delay oppositional behaviors, cryptorchidism, and speech delay, SPARCL1, PKD2 seizures and severe ichthyosis. feeding difficulty, congenital cardiac vomiting and HHIP, SMAD1 defects, finger/toe autistic features, developmental delay and abnormal seizures/epilepsy anomaly and random speech delay, behavior teeth developmental delay and movements, problems, staring spells, a ARHGAP24, speech delay MAPK10 and epicanthal folds, relatively large tongue, a large GK2 micropenis and head, possible overgrowth and PTPN13 HAND2, PALLD small testes asthma TACR3 and CXXC4 75.00 Mb 100.00 Mb 125.00 Mb 150.00 Mb 175.00 Mb
4q12 4q13.1 4q13.3 4q22.1 4q24 4q25 4q26 4q28.1 4q28.3 4q32.1 4q32.3
1 3 567 12 13 2 4 8 14 GDEP, ANTXR2, 9 11 15 FGF5, BMP3, PRKG2, 10 16 HNRNPD, HNRPDL, 17 SCD5, SEC31A and PPP3CA, BANK1, 18 PLAC8 SLC39A8, NFKB1, MANBA, PCDH10 VEGFC UBE2D3, CISD2, NHEDC1, 19 NHEDC2 and CENPE neurological glabellar hemangioma 20 Short stature, brachydactyly, PDLIM3 and TLR3 hypotonia, hypotonia, developmental movement disability, delay, speech delay and PLK4, MFSD8, PGRMC2, abnormal teeth, developmental delay, feeding difficulty PHF17 and SCLT1 finger/toe absence of speech FRG1, FRG2 & 5DUX4 anomalies,Cleft and incontinence small/abnormal jaw, palate/lip, a large AFF1, KLHL8, HSD17B13, strabismus, vision tongue and NUDT9, SPARCL1, DSPP, anomalies, skeletal FSHD ????? COQ2, HPSE, HELQ, congenital cardiac DMP1, IBSP, MEPE, anomaly and MRPS18C, FAM175A, defects, upturned SPP1, PKD2, ABCG2, developmental delay and AGPAT9, NKX6-1 CDS1 nose, hypotonia, and PPM1K, HERC6, HERC5, speech delay gastroesophageal PIGY, HERC3, NAP1L5, reflux, small hands macrocephaly, hypoplastic GPRIN3, SNCA and supraorbital ridges, short MMRN1 palpebral fissures, low-set microcephaly, posteriorly rotated ears, other brain/CNS C4orf16, TIFA, short nose, short philtrum, PLK4, MFSD8, PGRMC2, PHF17, SCLT1 anomaly, growth ALPK1, NEUROG2, short neck, strabismus, deficiency or LARP7 and ANK2 lacrimal stenosis, growth failure, sagittal craniosynostosis, dolichocephaly, growth deficiency ventricular septal defects, developmental flat supraorbital ridges, prominent upturned nose and clubfeet, autistic features delay, speech philtrum, rhizomelia, hypertonia, small month and eosinophilic delay and feeding intermittent extension dystonia and enteropathy difficulty autistic features
Features and lost genes in 20 individuals with a 4q deletion.
‘Recently we have found some people who will have congenital heart disease. Also we instead of having lost one copy of a part of 4q, have a cleft palate gene. We are pretty have an extra copy (known as a duplication), specific as to where it is because we had 16.3 16.2 and yet the clinical phenotype can be very one patient with only three known genes 16.1 15.33 15.32 15.31 similar to people with a deletion. That is deleted, no learning difficulties so far but 15.2 15.1 14 p 13 strange. It means that not only not having with very complicated congenital heart 12 11 11 12 13.1 enough is the problem; sometimes too much is disease, a limb anomaly, unusual craniofacial q 13.2 q21.21- BMP3 - short statue/skeletal anomaly 13.3 q21.22 -SEC31A - craniofacial anomaly 21.21 21.1 21.23 21.22 q21.3 - MAPK10 - epilepsy not good either. features and a cleft palate and cleft lip. But 21.3 q22.1 - SPARCL1- neurological defect 22.1 22.2 q22.1 - DMP1/IBSP - growth deficiency 22.3 q22.1 - PKD2 - polycystic kidney disease type 2 there are only two or three genes in the 23 q22.1-q22.2 - GRID2 - neurological defect/ataxic gait ‘What can we do for all these patients? We can 24 25 q22.3 - PGDS - asthma 26 q25 - PITX2 - Axenfeld-Rieger syndrome deleted region. That means that those 27 tentatively assign genes to phenotypes, but only 28.1 q25 - NEUROG2 - neurological defect 28.2 q25-q26-ANK2 - cardiac arrhythmia genes are responsible for most phenotypes 28.3 q27 - FGF2 - CNS/limb defect maybe because the number of patients is still 31.1 31.21 31.23 31.22 in 4q-. So there must be a very critical 31.3 not big enough. We also search databases and 32.1 32.2 33 32.3 34.1 gene or genes in this region. 34.2 q34.1 - HAND2 - cardiac defect we look at animal models because we can do 34.3 36.1 q33-q35.1 - a hypothetical gene associated with clefts actual haploinsufficiency studies in animals, ‘Based on the database we think there 36.2 q35.2 - DUX4 - facioscapulohumeral muscular dystrophy taking out one copy of a gene and then two may also be other genes that can be and watching the effects. assigned to some of the phenotype such as eye anomalies or neurological defects. Genes and disease To pick out a few, BMP3 (in 4q21.21) is a ‘Taking congenital heart disease, we know gene that is associated with bone development. have some speculations. What are we trying HAND2 (in 4q34.1) is one gene expressed in A lot of kids we see with 4q- are very short, so to do? For example, if my hypothesis is right, the heart, but exclusively in the right side of the we thought that may be important. and BMP3 that we know is important for bone heart. So if this gene is deleted most likely you development, is causing the short stature so Patient care kids are small, we can intervene in this pathway. ‘So how will this research apply to patient care? Gene pathways are very complicated but many Treatment at the moment is totally c The purpose of research is to benefit our drugs are already used for other purposes in speculative.d children. This is an ongoing project but I do clinical trials for something like osteoporosis. If
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Questions has been on growth hormone for three cOne problem in the US is that 4q- is years and now that we’ve found out a rare disease. For research funding from Growth deficiency and growth hormone that she has 4q deletion we are the National Institutes of Health, the first treatment wondering whether it’s beneficial to thing they want to know is what the Q Growth deficiency is an obvious keep her on it. It seems to have helped impact will be. And because 4q- is rare, problem. In your professional opinions her but because she has been on it for the impact will be relatively small. But do growth hormones help or are they so long, we wonder how it can be good while it’s true that 4q- is a rare disease, irrelevant? for anybody to be on hormones for so some of the discoveries made by TH Growth hormone has been used in long. Now she seems to have stopped studying 4q- could be applied to more many genetic disorders like Russell growing again and if she shows no common conditions. So if I can identify a Silver syndrome where children are very more signs of growth they are probably going to take her off it. The growth cleft palate gene, cleft palate is quite tiny and Turner syndrome where they hormone also seems to have made her common. Congenital heart disease is are short. Some respond well, some don’t. I just started one of my patients stronger in that she can fight other even more common: about one per cent diseases a bit better. Whether that’s of babies are born with defects of the and so far they are doing very well from the growth point of view. But we because of or in spite of the growth heart. So hopefully in future we can go in need a lot of studies. We don’t know if hormone we don’t know. that direction and say my research is children with 4q- have a growth A show of hands revealed that out of using 4q- as the basis of the study but hormone deficiency. That would be very 13 families, eight children with 4q- the research can apply to other helpful to know. The good thing is that were short for their age and five areas.d generally growth hormones are pretty were not. One child was tall for her safe. age. Two children were taking growth we can assign BMP3 as responsible, maybe we ES The practice of treatment with growth hormone. can borrow a drug for this purpose. hormone varies from country to Parent 2 My daughter aged 9 will have been on ‘Recently we studied a patient who is very country. In the UK growth hormone growth hormone for two years in July. In short and wondered: Do we want to start treatment is not generally the first year we saw a big difference, growth hormone treatment? Some children recommended for chromosome then it tailed off but because it respond to treatment, some don’t. At least one disorders apart from Turner syndrome. increased her appetite, they are of my patients has been willing to try and so Parent Our daughter is 14, and was diagnosed keeping her on it. In two years she grew far is doing very well, fingers crossed. six months ago with 4q deletion. She 19 centimetres and put on four pounds ‘Again, the gene FGF2 (in 4q27) is associated (about 2 kilograms) in weight. with the central nervous system, limb Q Those on growth hormone, did it make development and heart problems. The pathway There are limitations to our work. c a difference to their strength and has is complicated but we already know many One is the sample size. If I could have that in turn helped their development? drugs that are already being used to intervene one third of the patients diagnosed in in this pathway so again we can maybe use the US in the past year I would have Parent Our daughter suffered from really bad drugs that have already been tested. great confidence in assigning the genes chest infections 15 to 20 times a year. ‘What is our future direction? If we can responsible for the clinical phenotype Growth hormone treatment cut it down noticeably fast to three or four times a pinpoint genes for some clinical signs, hopefully much better. So we definitely need year. we can find some treatment for patients. increased sample size. A lot of things Treatment at the moment is totally speculative that are currently speculation would then Parent 2 It was seasonal. As soon as the season because sample sizes are very small, but it is be more real. changes, she’d be coughing and chesty. feasible.’ d Now I forget to give her inhalers, she’s
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can help to promote learning in those flowing back into the food pipe and the cAs a clinical geneticist I want to tell children with a learning difficulty? child gets it into the mouth and into you we are still trying to understand why ES There are supplements like omega-3 the lungs and cannot cough well and 4q- happened. You should know that this fatty acids that may be helpful in cough it up, then that leads to is not anything you did right or wrong. autism as well. The yahoo group aspiration pneumonia and is serious. It Without families like you participating in website has other suggestions such as needs to be taken seriously and treated studies it’s impossible to get any coenzyme Q10. We are looking into this appropriately with medicine in the first instance. conclusions. So I really appreciate all the but more from a parental observational families participating in the study and experience at present. It‘s not based on Q How do you know if a child is the physicians with their detailed clinical hard evidence but there are positive aspirating? phenotype. Hopefully we can find opinions about some food supplements ES A pH study or a barium meal or from some parents. It can’t be proven treatment for at least some aspects of ultrasound scan can give the diagnosis. at this point that they are beneficial. the condition.d A speech and language therapist can Q Could they be harmful? do a videofluoroscopy to see if there is ES These are over-the-counter products aspiration or not. The last resort got so much stronger and healthy in treatment is a fundoplication operation herself. which anyone can buy. I don’t think there is any suggestion that they are and possibly a gastrostomy and that ES I’m not certain that it’s possible for can prevent aspiration but you would harmful. growth hormone to have an impact on want to try medicine first. other aspects of a child’s health – TH In my clinic, early intervention is the Q In this group, about 69 per cent have supporting growth is the main reason most effective way to help these reflux. In how many is it still a for giving growth hormone. children. They intervene early with speech and physical therapy, and for problem? Q Is it age-related? example physical therapy does seem to A show of hands showed reflux was Parent We thought that just growing makes improve muscle strength significantly. still a significant problem. you stronger and that was the effect. Speech therapy also makes significant Parent In my son it is a problem at 18, but he She coughs less. Apart from when she improvements. didn’t get it until he was 10. He has gets chest infections, she’s relatively Q Is your database US children only? had a gastrostomy since he was two or healthy. three. TH It’s international, with children from the TH Some children with 4q- have low UK and South America as well. ES One reason it improves naturally is muscle tone. For those children, because of the upright position and respiratory function may be affected. Diagnostic test also the valve mechanism improves Growth hormone also increases muscle Q When we got our diagnosis three years naturally in quite a number of children. strength – that’s one possibility. ago, how do we know what sort of test The angle between the food pipe and One of the two children on growth was done and how do we get a more the stomach changes and that hormone had a low growth hormone up-to-date one? improves reflux. level before treatment; the other TH If it was done three years ago, most TH In the US we often use a pH probe child did not. likely an older technique was still being because stomachs are very acidic and I TH Most endocrinologists test a child for used. You have to ask the doctor what can see the level of acidity. If it’s higher, growth hormone deficiency and that’s a kind of arrays they used. The latest third that‘s a risk for aspiration. In some definite indication for treatment. But generation uses oligoarray CGH. Getting cases thickening the formula by adding some people will put a child on growth a new array done may be done as a rice cereal can help. hormone when the level is not low. research resource or there may be an Neurons branching indication if it’s important to know the exact break point. If a big chunk has Parent In relation to the branching of the been deleted, it may not be necessary neurons, when does that show up and to repeat the test because 95 per cent how can it be tested for or seen? of genes are already known in that ES These are research studies. In children region. But if you have a small deletion you can do an MRI scan of the brain and the test shows greater precision which shows myelination, the myelin over the break points, it can maybe sheath around the nerve axons and make a lot of difference. that gives you some indication about maturation of the brain. At this point we Gastro oesophageal reflux can not infer from a brain scan how a Q What are the implications of reflux? child will perform in the future from an ES Gastro oesophageal reflux is common intellectual point of view. There’s an in children whether they have a interesting book by Moyra Smith about chromosomal deletion or not. It has to learning difficulties and various do with the fact that the sphincter (ring chromosome abnormalities, called of muscle) at the entry to the stomach Mental Retardation and Developmental is not working properly. That usually Delay published by Oxford University corrects itself in the first year of life but Press in 2005. it can lead to aspiration as one of the Q Are there any interventions or diet that most serious side effects. If food is
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