by Kirk, Edwin;
On the other hand, it seems that we are just about to enter a golden age of new, targeted treatments for genetic conditions. For some, this might even mean that most elusive of goals in medicine — a cure.
7
Dysmorphology Club
I don’t want to belong to any club that would accept me as one of its members.
GROUCHO MARX
The face is the mirror of the mind, and eyes without speaking confess the secrets of the heart.
ST JEROME
When I first met her, 20 years ago, Dianne was a chubby, cheerful infant. She had been giving her parents and her doctors a good deal of concern, ever since she was born prematurely, a full ten weeks before her due date. Born weighing 2.2 kilograms, she was much heavier than you might expect — nearly a kilogram above average for such a premature baby. It’s no bad thing to be bigger than expected, when you’re born prematurely. But a whole kilogram over the odds was noteworthy, and her doctors took note. They also saw that she was unusually hairy for a newborn. More worryingly, she had a loud heart murmur. After a while, her heart began to fail, because it had not managed to adapt to life outside the womb.
You often hear the heart referred to as a pump. Actually, it is two pumps. One (the right side of the heart) collects blood from the body and sends it to the lungs to be scrubbed of carbon dioxide and enriched with oxygen. The second, larger pump (the left side of the heart) collects that revitalised blood from the lungs and sends it back to the body. Before a baby is born, however, things are different. The fetus gets its oxygen from the placenta, which also passes nutrients from the mother to the fetus, and cleans its blood — it’s like lungs, liver, and kidneys rolled into one. The placenta doesn’t get nearly the credit it deserves — calling it ‘afterbirth’ seems disrespectful, when you consider the remarkable and essential job it has been doing before birth.
While the placenta is doing its job, the lungs are breathing liquid, not air, so spending a lot of energy to pump the whole of the baby’s blood through the lungs would be wasteful. Instead, there are two bypasses, so that most of the blood that has been charged up with oxygen and nutrients by the placenta can skip the lungs and go straight to the body, where it is most needed. One of these bypasses is inside the heart: a channel, called the foramen ovale, from the right atrium (the blood-collecting chamber) to the left. The other bypass is outside the heart, a short artery that links the aorta — the arterial freeway that emerges from the heart and carries blood to the body — to the pulmonary artery — the equivalent artery carrying blood to the lungs. This is the ductus arteriosus, and it’s an important piece of plumbing.
Until birth, that is. At a baby’s first breath, things shift inside her heart. The pressure on the left side of the heart goes up, slamming shut a flap of tissue that covers the foramen ovale. And the ductus arteriosus spasms shut. In most people, the foramen ovale soon seals closed, and the ductus does, too, eventually withering away to become a humble strip of gristle linking the two great arteries.
But if it doesn’t … there might be trouble. Blood pumped to the aorta whooshes back through the ductus to the lungs, meaning that the heart has to pump it all over again. If the ductus is wide open — as it was in Dianne — the extra work can just be too much for the heart to cope with. Sometimes, medications can persuade a reluctant ductus to close. In Dianne’s case, this didn’t work, so that, at just two weeks of age, her tiny chest had to be opened by a surgeon, who closed the duct.
For a while, things seemed to go well, but by nine months it seemed that Dianne was struggling to breathe; tests showed that the right side of her heart was having to work much harder than it usually should. On top of that, she was not meeting her milestones — she was late to sit, late to stand, and, in time, late to walk.
Dianne’s doctors thought she probably had a syndrome — but which one? It was my job to figure it out, and I hadn’t a clue.
*
To most people, if the word ‘syndrome’ means anything at all, it conjures up thoughts of Down syndrome, Tourette syndrome, or even Stockholm syndrome. The villain in The Incredibles named himself Syndrome. Applied to your child, it has a frightening sound. But to a doctor, ‘syndrome’ just means a collection of features that are seen together, and there are literally thousands of different syndromes, most of which are very rare. Some are mild,1 some are severe, and many of them are variable: sometimes mild, sometimes severe, sometimes in-between. Even within the same family, we see great variability — one person may have almost no features of a syndrome while another has a lethal condition, both caused by exactly the same change in the same gene.
[1 Your idea of what constitutes a ‘mild’ condition may be quite different from mine. The distinction may seem arbitrary, but, as we will see in chapter 11, it can be quite important.]
One of the main ways we diagnose genetic syndromes — until recently, almost the only way — was simply to look at our patients, trying to recognise distinctive patterns. This is a skill called dysmorphology — a terrible word, because its literal meaning is the study of bad shapes. Not something you want applied to yourself, and still less to your child. It might be better named ‘pattern-ology’ or perhaps ‘protypology’, if we wanted to stick with Greek roots.
The dysmorphologist — one who studies dysmorphology — looks for recognisable patterns, in the shape of a person’s face and in their other features. The characteristics of hair, skin, nails, and teeth, the patterns of lines on palms and soles, and even fingerprints can all contribute to making a syndromal diagnosis, as can neurological and developmental problems, behaviour, and even patterns of sleep. Although professional dysmorphologists are almost all clinical geneticists by training, there is a real sense in which everyone who can see is a dysmorphologist, including you. If you have seen one or two people with Down syndrome, you are likely to recognise the condition in others, without needing a blood test to prove it. Even when you distinguish friends and family from acquaintances, you are employing the essential skills required of a dysmorphologist. But a clinical geneticist makes it her business to study rare facial patterns, particularly those that go along with other features such as intellectual disability. Sometimes, you see someone in clinic for the first time, and it’s like running into an old friend on the street, or like that shock of recognition when you see a celebrity in the supermarket.
The spot diagnosis in genetics comes from that shock of recognition. We typically book patients in to see us for an hour, and often that is barely enough to learn all that we need to about our patient. We may need to consider a complex family history, learn the medical history of the person we are seeing, conduct a physical examination, and discuss our findings and planned investigations. So how do you handle the consultation if you’ve made a diagnosis the moment the patient walks into the room? Carefully! You can’t say, ‘Hi, it’s nice to meet you. Your child has Noonan syndrome,’ because it’s not likely to go down well. As dysmorphologists go, I’m nothing special, but I’ve made the occasional spot diagnosis. It’s surprisingly awkward conducting the usual preliminaries, when you already know exactly where the consultation is heading.
Even approached with care, people may not be that happy that you’ve diagnosed a syndrome in their child, or in themselves. Sometimes it’s easy to understand why. A paediatrician once asked me to see a baby who had had low levels of sugar in her blood soon after birth. The problem had improved with treatment and now she was well. But the paediatrician considered the possibility that there might be an underlying problem with the way her body handled energy, and asked me to see her to think about whether any extra tests were needed.
There were some delays in making an appointment, so that Helena was nearly a year old when I first met her. I noticed she was very tall for her age, with a big head. She looked like her parents … but she also had a broad forehead, widely spaced eyes, and a small jaw with a distinctive crease above her chi
n. In short, she looked exactly like other people with a condition called Weaver syndrome. I arranged a genetic test that confirmed the diagnosis.
Children with Weaver syndrome, as well as being large for their age and having a recognisable ‘look’, tend to be slow at walking and clumsy as children. It’s common for them to have some degree of intellectual disability, but not inevitable — some affected people have normal intellect, and really just blend in to the normal population as they grow up. There’s a long list of other health problems that have been seen in people with the diagnosis, including low blood sugar in the newborn period. Most worryingly among these issues, perhaps, is that people with Weaver syndrome seem to have a higher than usual risk of some types of childhood cancer.
Imagine your young daughter has had low blood sugar a few times in the first week of life, but now she seems fine. Your paediatrician sends you to a geneticist just to be on the safe side; you consider cancelling the appointment because you don’t expect to learn anything important … and the geneticist tells you this news. How would you feel about it? You could argue (and I would) that, on the whole, it’s better to know. Perhaps the child has a heart condition that hadn’t been diagnosed before, but now will be picked up, because we screen newly diagnosed children with Weaver syndrome for heart problems (Helena did turn out to have a minor heart condition, but fortunately not of a type that needed any treatment). Similarly, if you know that your child is at risk of problems with development and learning, you can monitor her progress, and step in early with therapy if needed. And just maybe, being alert to the chance that your child might develop cancer will let you identify symptoms sooner than you might have done, and so get earlier treatment. But it seems that the increase in cancer risk is quite small, so there’s a good chance this part of the news isn’t relevant at all.
There are some pretty clear downsides to knowing the diagnosis. You are far more likely to experience the harm of worrying that your child might get cancer than to experience any benefit from the information. Knowing she may have problems with learning is also likely to be worrying, and it’s still possible that her development will be fine. What about stigma? How will others view your child, knowing she has a syndrome? How will it affect your relationship with her? Will you change your behaviour to become over-protective, perhaps? What will you tell your parents, your other relatives, your friends, your child’s school?
None of this is straightforward. There are times when I sit with a family, knowing I am about to send all of this worry, uncertainty, and ambiguity into their lives, and I wonder if I’m doing the right thing. Might it not be better to leave these happy, loving parents at peace for a while longer? Isn’t it better to wait until there’s a problem before making a diagnosis?
Mostly, of course, it’s not like that. People come to us looking for answers, and they rightly expect us to do our utmost to provide those answers — accepting the possibility of bad news as part of that. There is some comfort in knowing that, often, there are direct benefits to the child and family from having information, such as the possibility of finding out about an unrecognised health problem associated with the syndrome and treating it. And then there are those conditions that have a high chance of happening again in future children. Knowing this is helpful, because it gives couples choices they would not otherwise have (more on this later, particularly in chapter 11).
Even the best dysmorphologist can’t expect to make a spot diagnosis for every one of the many, many different syndromes, so we have tools to help us. The earliest of these, naturally, were books. The most famous of the dysmorphology books is Smith’s Recognizable Patterns of Human Malformation. First published in 1970, the book is a handbook of common and not-so-common syndromes. Grouped by major features, each syndrome has a page of description and a few photographs of people with the characteristic features of that condition. Gorlin’s Syndromes of the Head and Neck, a massive tome with similar content to Smith but with more comprehensive scope, dates back to 1964. The list of editors and authors of the latest edition of Gorlin is a who’s who of modern dysmorphology — names like Raoul Hennekam, the eminent Dutch dysmorphologist; Di Donnai, doyen of British dysmorphologists; the two great Canadian Judiths, Hall and Allanson; and Americans including Bob Gorlin himself, M. Michael Cohen, and others.
As a trainee and in my early days as a geneticist, I would often turn to Gorlin in particular. Fresh from seeing a patient in clinic, sure that I had seen his face somewhere before, I’d hunt for syndromes that might match. I’m not a maker of New Year’s resolutions, but the closest I’ve come is the occasional decision that I really should devote some time each day to reading Gorlin’s entry on a different syndrome,2 trying to memorise the details so I’ll know the condition when next I see it. If I had ever been able to sustain the effort for more than a few days, I’d doubtless be a better dysmorphologist than I am.
[2 One of these days I’ll read Proust’s Remembrance of Things Past, too. Definitely.]
When people started formally describing and naming syndromes, they did not think of themselves as dysmorphologists. None of them were clinical geneticists, because ours is a new specialty, and people have been describing syndromes for a long time. Identifying a ‘new’ syndrome is really an act of discovery, of something that has always been there in the population. As Ecclesiastes says, there is nothing new under the sun. It’s true that, before modern medicine, babies born with many of the more severe syndromes would not have survived past infancy, so some of the patterns we are recognising now have only recently emerged; they were always there in potential, but not in reality. But the record of human observation of syndromes goes back many centuries. Two ancient Egyptian gods, Bes and Ptah, had forms of dwarfism — perhaps they had achondroplasia, like the actors David Rappaport and Peter Dinklage. The forms of these gods were undoubtedly based on familiarity with real people affected by (mostly genetic) causes of short stature.
Later art contained ever clearer depictions of specific conditions, as painting techniques improved. There have been attempts to see the features of Down syndrome in the faces of various angels and infant Christs from the 15th and 16th centuries; most of these seem to me to be a bit of a stretch. But in the 17th century, the great Spanish painter Diego Velázquez produced at least ten paintings of people with short stature. Some, such as the Portrait of Sebastián de Morra (who undoubtedly had achondroplasia), are clear enough depictions that a diagnosis can be made with confidence, across the centuries.
More recently, the American painter Ivan Le Lorraine Albright’s 1929 painting Among Those Left unmistakably shows a man who has a condition called Noonan syndrome — 34 years before the cardiologist Jacqueline Noonan’s first systematic description of the condition.
People with Noonan syndrome tend to be shorter than average. Many are born with heart problems, particularly a narrowing of the main valve between the right-hand side of the heart and the pulmonary artery (the artery we met a few pages ago, carrying blood to the lungs to be oxygenated). Some struggle at school, but not all — I know of a doctor with Noonan syndrome. There can be other health problems. But it’s the look that really defines Noonan syndrome: drooping eyelids; eyes that slant a little downwards from nose to ears; ears that may be set low and tilted backwards; a broad, even ‘webbed’, neck. Written down like this, it seems like people with the condition would stand out in a crowd, but most are just normal-looking people who happen to resemble one another. As children grow into adulthood, the features tend to become less distinctive, so that, when I make the diagnosis of Noonan syndrome in a child, I’m not always certain whether one of the parents is also affected.
Some of the things that are different about people with Noonan syndrome are so subtle that you’d never see them if you didn’t know to look. Their fingerprints, in particular. There are three main types of human fingerprint: whorls, arches, and loops.3 Magnified, fingerprints look like a series of parallel ridges in th
e skin of the finger (or of the toe, but for some reason toeprints never seem to attract much interest). These ridges can form various patterns on the pads at the ends of fingers and thumbs. In an arch, some of the lines come in from one side, form a peak that points towards the end of the finger, and then cross to the other side. In a loop, some of the lines come in from the side (usually the side away from the thumb), come in to or across the middle, and then go back the way they came. In a whorl, some ridges loop back to themselves, forming an oval — although there are some variations, like the double whorl, which looks more like an S.
[3 Not strictly relevant to human genetics, but I can’t let this section pass by without mentioning that koalas have fingerprints that are indistinguishable from human prints. So if the burglars got in through a high window, and the only thing that was taken seems to have been the gum leaves from your vase of Australian natives … the police fingerprint database might not be much help in tracking down the culprit.]
Take a look at your own fingerprints — you probably have loops and whorls, and you may have an arch or two as well. If they aren’t easy to see and you don’t have a magnifying glass handy, you could photograph them with your phone and zoom in on the picture (good lighting helps with this). While you’re at it, have a look at the lines on your palms, and the creases on the palm side of your fingers. The study of these lines and creases is called dermatoglyphics,4 and, particularly when I started in genetics, we used to spend quite a lot of time peering at fingers, counting loops, whorls, and arches as part of the effort to reach a diagnosis.
[4 From Greek words meaning ‘skin’ (dermato-) and ‘carved’ (-gluphikos). It’s the study of the carving on your skin — rather poetic.]