Medical Monday

It's difficult for me to get into something, to research something, if it's not on my mind all the time. So I think it's best if I start off with the Medical Monday posts by discussing something that's of interest to me at this point. And as you can imagine, looking into genes gone wrong is what occupies my research time at the moment.

The geneticist believes that Boeboe has a few random genes that got damaged, and different things that went wrong. Either before birth, and/or after birth, I don't know. I haven't researched this option much yet, but from what I did read, I believe that a number of genes next to each other got damaged during conception. What's the chance that, for example, a gene on chromosome 1, a gene on chromosome nr 4, another on nr 11 and another on nr 18, for some inexplicable reason, got damaged. Maybe she inherited them? That would explain it. When I look at the bigger family picure on our side, there is intellectual dissabilities, psychiatric disorders, Spina Bifida occulta, neonatal death, miscarriages, vision problems, heart defects and disease, etc.

So maybe, like the geneticist suggests, Boeboe was just really unlucky, and got all the bad genes from her family. Maybe, she got the bad/damaged gene that caused our family's psychiatric problems, and she just got it worse than anyone else. Maybe she got the bad gene that causes the Spina Bifida Occulta, and she was the really, really unlucky one where it went even futher, and caused a Tethered Cord. Maybe instead of vision problems, her bad gene caused the lack of tears. Maybe she got the gene that caused the learning problems. And so forth.

I does sound plausible, doesn't it? Another option though, like I said, is what if something went wrong with conception. When one copy of every one of the 23 chromosomes from the father merges with one copy of the 23 chromosomes from the mother. The chromosomes break up, rejoins, etc., and this process is very vulnerable to errors. It's quite easy for the one chromosome to rejoin the wrong one. Or to switch wrong-way around. Or to switch places with another piece. Or for a small piece to go missing, or duplicate itself when reattaching. Some of these mistakes causes absolutely no problem. While others would cause a miscarriage. Either before the mom even knew she was pregnant, or a bit later on. Sometimes, the baby lives through pregnancy, and is born. Sometimes at birth, it is clear that something went wrong in the formation. Maybe there's dysmorphic features (eyes that look "different" from the typical child's eyes, or the ears is a little crooked or the baby's head shape is somewhat misshapen). Maybe there's some major birth defects, like a Spina Bifida, a heart defect or a missing thumb or missing limb. Sometimes, there's just one or 2 things that happened to the baby, and it is assumed that at some point during development, those first crucial 12 weeks in pregnancy, something interrupted a process and the defect happened. Like with Spina Bifida.

When a baby have more than 2 birth defects though, and especially when it goes hand in hand with dysmorphic facial features, the doctors start to think that it's not just one process that was interrupted during pregnancy. They start to wonder if there wasn't something wrong with more than one gene that caused the organ or body defect. In this case, they do a chromosomal analysis or such test, to see if they can find the problem on the chromosome that went wrong.

With some of these babies, it's really obvious from the start. Like most babies with Down Syndrome. Or, if not at birth, within a few weeks or months it would become obvious. When the baby doesn't smile by 6 weeks, have head control within a few months, doesn't want to sit by 6 or 7 months, etc. Most babies are diagnosed within a year. Unfortunately, for others, it may take a lot longer. The fault on the chromosome might be so small, that it didn't cause many obvious features. And only with time, would it become clear that there's too many things that went wrong. Leading to genetic tests.

Chromosomal analysis is still in its infant shoes, unfortunately. It's not a very precise field. There's alot of variables influencing this. Family history, chance, environmental influences, hormonal influences, etc. And the tests aren't very good. For example, if you take 100 children that has chromosome problems, only 7% of them (accordingly to our geneticist) will be picked up by chromosomal analysis (looking at the chromosomes with the best microscopes possible). The next best test, a microarray, has a better view of the chromosomes and would see smaller errors than what the chromosomal analysis can. But, it would still only cover about 15% of those 100 children. So 85% of children that has a chromosome problem, will not be diagnosed with today's technology. Hopefully in 10 or 20 years, that figure would look better. Currently, we just have to accept that's as good as it gets. So even if I'm right, and Boeboe has a range of genes on one chromosome that went wrong, she might never get a diagnosis. Or not yet, for the next decade or two.

The reason why I believe Boeboe has a chromosome problem, is because there's just TOO much wrong, with her. Why would one child inherrit EVERY bad gene from both sides of the family, and still have a number of other things that wents wrong as well, like a Tethered Cord, feeding difficulties, developmental delays, speech problems, etc. etc. etc. It's just so many variables that all had to go awry in her, that it feels inprobable to me. Not unlikely, just less likely than one process going wrong with conception. Looking back, I believe that she would've been diagnosed with global development delay because of her delays in speech, social, maturity and some in gross and fine motor development. Global developmental delay doesn't just happen. It usually have a cause in a number of genes.

I believe that when her 46 chromosomes joined up, one of them lost a little piece, or gained another little piece by copying the wrong thing. A tiny piece. Giving rise to all her peculiarities, because that deletion or copied material is in every cell of her body. It's in her heart, her liver, her spleen, her spine, her brain, her feet and her hands. Every cell. Most of the time, it wouldn't matter, because there's still 1 completely normal chromosome inherited from either the mother or father. Sometimes though, you need 2 and only 2 of that chromosome. Too much, or too little, hinders some tiny developments and causes something to go wrong. Like in her tear ducts or tear nerves or where ever that problem arrises from. It just isn't NORMAL for a child NOT to cry tears. It just isn't normal. And extremely rare. In fact, it's so rare, that I daresay that of ALL her diagnoses, this must be THE rarest of them all. Even the occult tethered cord, without Spina Bifida Occulta, that was attached to the dura - that happens in about 1 in a million or so. Maybe even less. Not crying tears is rarer than that. It's so rare, that I struggle to find medical information on it. (Sounds like the perfect Medical Monday subject for another time!)

It's also not NORMAL for a child to develop a tethered cord. Something interrupted the process of closing the neural tube perfectly, like in most human beings. It's also not NORMAL for a child to have language barriers in the brain. It's also not NORMAL for a child to have long fingers with underdeveloped and lax knuckles/joints. It's also not NORMAL for a child to have psychosis from practically birth, and bipolar at age 10. It's not normal for a child to have a placenta completely fail at 37 weeks, turning black, causing even the gynae to exclaim in surprise. It's not normal for a child to struggle to breath and maintain temperature after birth at 37 weeks. Etc. I can go on and on, you get the picture. Too many abnormal things in Boeboe. Too many things went wrong in one child.

So, I've started to study chromosome disorders. The rarechromo.org website (also called Unique) is absolutely amazing, and has written guides on all the different things that can go awry (or most of them). And I've been reading many, many hours. From everything I've read, Boeboe perfectly matches a chromosome disorder. The way she developed, the delays, the way those delays presented, everything matches perfectly. Just 2 things throws a stick into the wheel. One is that she has an average IQ. By far the most chromosomal disorders comes with a low IQ of 70 and under. Because of the effect a mistake on the chromosome will have on the brain. The second thing is that Boeboe is what I'd call a very mild case, compared to what chromosome disorders does to kids. She didn't get Spina Bifida, she got an occult tethered cord. She didn't get eyes that never even developed, or a severe squint, she got a mild squint that corrected itself and tears that's absent. She didn't get eye lids that's visibly deformed at birth, she got eye lids that's a bit hooded. She didn't get a missing kidney or a malfunctioning one. No, she just got one that's a bit misshapen. A curiosity, that's all. She didn't get severe delays, no, all her delays are mild (except arguably the emotional delay). She has the lightest case of dropfoot possible. She has a very mild in-toe. She did admittedly have one of the worst neurogenic bladders, with pressures about 4 or 5 times what was normal, but that was due to the tethered cord. Overall, she's just a very mild case of not being normal. Hard enough to live with, but in medical terms - just mild.

That's why I say, I think she has a microdeletion or -duplication on one of her chromosomes. A very, very small piece. That caused all of these defects and delays in Boeboe. It might be so small, that no current test available will be able to pick it up. The effect of it though, on our family, isn't so small. We struggle. Life hasn't been easy, and probably will never be easy with Boeboe in our lives. We worry about her and her future. And we have cried many tears because of the difficulties she faces every day in her life.

From what I've read, I believe that there's 3 possibilities that matches the picture of Boeboe. I haven't researched all chromosomes or problems just yet. Not by a long shot. So there's most likely others. So this is just a discussion about possibilities. I don't believe, yet, that Boeboe must have one of these. They've just piqued my interest, for various reasons. The first, is 16p duplication. The second is 17p duplications. And the last is 22q11.2 duplication. This last one is interesting, since it is the exact same region that they've tested Boeboe for, as having a deletion. Thus, I doubt if they would've missed a duplication on there while searching for a deletion.

It'll take too long to go into all 3, so maybe for a start, let me just go into 16p for a bit. Here's the list of symptoms, signs and comments from parents whose children was diagnosed with a 16p11.2 duplication. Remember, this duplication could be really small, or a little bigger. Also, some could be on the 11th band, while others would be on the 13th band, for example. I'm just looking at the 11.2 duplication at this point in time, because it will be easier and shorter, else I'll be typing away until the end of the week. Maybe at a later stage I can go into the other possibilities of 16p duplication. I'm just going to bulletpoint some things for easy reading. Most of these information was taken from the www.rarechromo.org site.

• Some parents, brothers and sisters of children with a 16p11.2 microduplication have the same microduplication but do not have any obvious unusual features or delayed development. Some people with a 16p11.2 microduplication seem completely unaffected by it. Others have some problems with their development, speech, behaviour, learning or health that may be caused by the extra genetic material (This is a very rare thing with a chromosome problem, which is what caught my attention first. So the fact that Boeboe's not as bad off as some other children, will fit in perfectly with this duplication.)
• The signs in others with the duplication are so subtle that you would hardly notice. Some children with a 16p11.2 microduplication also develop normally. The effect on development, health and behaviour of some genetic disorders ranges from being barely perceptible to being obvious and severe. There is a lot of variation even between different members of the same family who have the same microduplication.
• It’s estimated that for every 10,000 people in the general population, three have a 16p11.2 microduplication. It’s slightly more common among people who have a language or psychiatric disorder, being found in four per 10,000 people. If these estimates are correct, 16p11.2 microduplications are not really rare. (Like I said, Boeboe was already a 1 in a million child to have a certain condition, so to be one of 3 or 4 in 10 000 to have something, is very much possible.)

So looking at these first points - it's not a rare occurence, and it could cause no symtpoms, few symptoms or a whole list of severe symptoms. Exactly what would fit with Boeboe. She's not the severest case by a long shot. But to me, it's obvious that there is something.

So here's the most common features (a child can have none, one or all of these, in various degrees of severity, from very mild to severe):

• Delay in starting to speak and in language development (Boeboe has this)
• Possibly very minor unusual facial or physical features (Boeboe has this)
• Some delay in learning to sit, move and walk (Boeboe had this)
• Some need for support with learning (Boeboe has this)
• Increased likelihood of difficult behaviour (Boeboe has this)
• Increased susceptibility to autism or an autism spectrum disorder (Boeboe has autistic traits)
• Increased susceptibility to mental health problems (Boeboe has this)
• In a few, a birth defect that might cause health problems (Boeboe has a couple of these)
• Possible tendency to underweight (Boeboe has this - she's the smallest in her class)
• Possible vulnerability to seizures

So as you can see, Boeboe has just about every possible symptom for 16p11.2 duplication. The only one she never had, was seizures. She had an EEG, and as far as I know, it was clean.

 

So here's a few notes about children with 16p11.2. As usual, I'm putting my opinion on Boeboe in italics and brackets.

Parents may notice that their baby isn’t babbling or their toddler isn’t saying words. (Boeboe never babbled as a baby, rarely made any sounds and was very late and slow developing speech.)

 

Your child with a 16p11.2 microduplication will most likely look much like other members of your family. They may well have one or two unusual facial features but these won’t necessarily be the same in others with a 16p11.2 microduplication. There isn’t a typical 16p11.2 microduplication ‘look’ and overall, your child is unlikely to stand out facially from other people. Some people but certainly not all have a slightly small head. (Boeboe has a very small head (3rd percentile), and a number of non-specific dysmorphic features. Thus, there's some dysmorphisms, but it doesn't point to a specific syndrome, like a baby with Down Syndrome would have.)

Delay in reaching baby milestones is apparently common although not among Unique members who generally sat, crawled and walked close to the expected age. (Boeboe was late with smiling and other milestones, and a tiny bit late with sitting and crawling. She walked around 14-15 months, which is at the upper side of normal, I believe.)

Some babies, although not all, have a low muscle tone and feel floppy to hold; this hypotonia is one of the causes of their slow progress in reaching their mobility milestones. (Boeboe was diagnosed with low muscle tone in her upper body, and this was addressed by therapy before primary school. She was definitely much more "floppy" as a baby than her brother, but I thought it was due to her much lower birth weight.)

Some also have unusually bendy [lax] joints which may need support as they learn to move and walk.
(Boeboe has lax joints in her hands and fingers. I'll take pics of this at some point. It might be one of the reasons why her hand writing is so atrocious, and why she struggled with some of her fine motor control.)

Typically, intellectual ability ranges from normal to a mild delay and where an IQ has been measured it has fallen within the 50-110 range, with 100 representing the average for the general population.
However, this probably underestimates the range of ability, since IQ testing would be more likely for people with developmental delays than for people with the microduplication and no delays.
(Boeboe falls into this typical ability.)

Depending on local schools, some children start their education in a mainstream setting, usually working within a small group and moving to a more supportive learning environment to complete their education.
(Boeboe is in mainstream, with ALOT of hard work,  an individual plan, extra teacher support, extra classes and time and planning conscessions in exams. We also request alot of extra help from the teachers, and all of this has surprised everyone with how much it has helped Boeboe. Her teacher today said we should not write highschool off just yet!! I was so happy to hear that. Though, it's the psychiatrist's opinion that Boeboe's anxieties might be too overwhelming in a formal highschool setting. We'll have to see.)

Various studies have found mood or behaviour difficulties in a minority of young people with a 16p11.2 microduplication. Most commonly children are overactive with a short attention span [ADHD/ attention deficit hyperactivity disorder] but other types of behaviour difficulty have been found. ADHD has been identified in 2/7 Unique children.
(Boeboe does not have ADHD, but she definitely have behaviour difficulties.)

One boy of 15 had an anxiety disorder that responded well to medication and in one study 4/10 youngsters had outbursts of aggression.
(Boeboe has outbursts of aggression/anger, and is treated currently for general and separation anxiety disorders.)

The typical 16p11.2 microduplication is found more often among children and adults diagnosed with autism or a disorder on the autistic spectrum such as Asperger syndrome than among the general population. Yet only a minority of people with the microduplication has autism or autistic features. Autistic traits have been observed in around half of Unique members, all male.
(Boeboe has been diagnosed as having autistic traits.)

The typical 16p11.2 microduplication is found more often among children and adults diagnosed with mental health problems than among the general population. Yet only a minority of people with the microduplication has a mental health problem. Anxiety, depression, bipolar disorder and particularly schizophrenia have been found.
(Boeboe has anxiety, bipolar disorder and psychosis.)

Some babies with a 16p11.2 microduplication are born completely healthy. Others have a birth defect which can be quite minor or more serious. Here's list of some birth defects that was found.

• Two babies were born with a diaphragmatic hernia. (Obviously Boeboe hasn't had this.)
• Two babies were also born with a cleft palate [an opening in the roof of the mouth, usually closed surgically], and one of these babies had a cleft lip as well. (Boeboe doesn't have this.)
• On investigation, five/28 people with the microduplication have some anomaly of the brain structure that shows on magnetic resonance imaging [MRI]. (Boeboe's brain MRI was normal.)
• In four babies the kidneys and drainage system for urine were affected. One baby has a ‘horseshoe kidney’, where the bottom points of the two usually separate kidneys are joined, creating a U [horseshoe] shape. Another baby has a double set of tubes leading from the kidneys. Two babies had kidney reflux, where urine flows back from the bladder towards the kidneys. (Boeboe has a misshapen kidney, as well as a narrowed urether that had to be dilated surgically.)
• Two babies were born with unusually-shaped chests. In one it was hollowed [pectus excavatum] and another baby was born with a ‘pigeon chest’ [pectus carinatum]. (Boeboe, and her brother, has a very mild hollow that I believe might be pectus excavatum.)
• In three babies the spine was affected, but in quite different ways. One baby had spinal cord cysts [syringomelia]; another had a ‘tethered cord’, where the bottom end of the spinal cord that is usually free within the spinal column gets attached to one of the surrounding structures. If necessary the cord can be surgically released so that it can hang freely. Another had a curved spine [scoliosis]. (As you know, Boeboe had a tethered cord, surgically released.)
• One baby boy was born with hypospadias. (Obviously Boeboe didn't have this.)
• In one baby the heart was affected. (As far as we know, her heart is normal.)
• One baby had malrotation of the intestines.

Preliminary data suggests that people with the 16p11.2 microduplication have a tendency to be underweight. (Boeboe weighs about 24kg now, at age 10. I believe that's less than the 5th percentile for her age. Since birth, we struggled with her weight. As a tiny baby, it was blamed on her not taking in enough nutrients via the breastmilk (pead "accused" me of not producing enough milk). When she was a toddler, her appetite was small, limitted and she had a texture issue and gagged on some foods. So her weight was blamed on this. As she grew older and still didn't pick up weight, even when she started to eat more and better and a bigger variety, the drs said "oh, but look at you, she must have your genes". Certainly this can be very true. I'm underweight myself, and has always been since I was a toddler (I was a fat baby). So ya, no one ever wanted to look futher into Boeboe's lack of gaining weight. Even when they were worried about her failing to thrive as a baby.)

Most children with a 16p11.2 microduplication have never had a seizure or a seizurelike episode. All the same, a minority - up to around 15% - have. This has led to the suggestion that there is an association between the microduplication and a vulnerability to seizures, although seizure types and severity vary widely. Typically, they start under 12 months of age, are easily controlled with anti-epileptic medication and tend to resolve or decrease in severity during childhood. (Boeboe has not had any seizures. Her eldest brother has. It started around 3-4 years, I believe, was very easily controlled with anti-epileptic medication, and it resolved around age 11-12.)

OK, so I've typed a way too long first Medical Monday post. Hopefully some of them will be shorter in the future. This has helped me though, ordering some of my thoughts and believes. I just received an email from the geneticist, wanting to know when we can come and see her. I was hoping my research would be finished before we go. I guess I'll have to step it up, if I want to have a better idea of what I believe Boeboe might have.