by Kirk, Edwin;
This was because of the observation that there are some differences in patterns in certain syndromes. People with Noonan syndrome, and some other conditions, have a higher proportion of whorls than the population in general. People with Down syndrome commonly have a single transverse palmar crease: instead of two prominent lines running across the palm at an angle, from just below the index finger, they are likely to have a single line running more horizontally across the hand. Don’t be worried if you have a single transverse palmar crease — about 1–2 per cent of people have this on one or both hands, just as a normal variation. Likewise, don’t read too much into it if you have a lot of whorls, or none. The link with various syndromes is real enough, but there’s so much normal variation that, taken in isolation, the information is pretty meaningless. This hasn’t stopped people trying to find meaning, mind you — there have been all sorts of attempts to link dermatoglyphics to intelligence, personality traits, risk of cancer, and so on. Even today, there are still companies that will happily take your money,5 analyse your fingerprints, and issue you with a report, telling you about your strengths and weaknesses and advising on career choices. Since horoscopes are now available for free online, this may not the best way to spend your money.
[5 Crossing their palms with silver is no longer required. A credit card will do fine.]
As well as the extra whorls, people with Noonan syndrome usually have fetal fingertip pads — little bumps in the middle of their fingertips. These, too, can be a normal variation. Like the whorls, though, in people with Noonan syndrome they are a clue to something that happened during early development, in the first months after conception. Fingerprints develop from about the tenth week of pregnancy, and by about the 18th week they are complete. Ultrasound scans have shown that a developing fetus with Noonan syndrome typically has an excess of fluid under the skin around this time, because the system for draining it away doesn’t seem to work as well as it should. This leaves permanent marks — the fingertips are a little swollen while the fingerprint ridges are forming, which makes whorls more likely, and a little extra skin grows there and stays as fetal pads. More obviously, fluid can collect at the back of the neck, expanding the skin and leaving the ‘webbed’ look seen in some people with Noonan syndrome.
So, there can be some real clues written on the hands about events during early development. Nowadays, the most useful of these is probably an absence of creases. If we see that a child with a neurological condition has absent or faint creases at the joints of the fingers, it tells us that those joints weren’t moving much at the time the creases should have formed. This means there was less movement than there should have been, from very early on — making it less likely that, for example, something happened around the time of birth that caused the neurological problems.
Speaking of absences — almost everyone has fingerprints, but there are some unfortunate souls who do not. Sometimes, this can go along with other health problems, but there have been a handful of families described with ‘isolated adermatoglyphia’. These are people who are otherwise completely healthy, but do not have fingerprints or the usual creases on their palms. You may think this is a harmless state of affairs, and indeed for much of human history it has been. Better than harmless, even, for the occasional criminal with adermatoglyphia who may have been active (and undetected) in the years since the first forensic use of fingerprints in the 1890s. However, it turns out that adermatoglyphia is increasingly a problem when people try to cross borders. More and more countries require a fingerprint on entry. Can you imagine trying to explain to a US immigration officer why you don’t have any fingerprints? Affected families call the condition ‘immigration delay disease’, for good reason.
Adermatoglyphia is a good example of a descriptive syndrome name. The name describes the condition, in this case concisely and completely: the prefix a- means that something is absent, and in this case it’s the dermatoglyphics. It would sound a bit cryptic if you heard it without knowing what dermatoglyphics are, but, now that you do, the word is perfectly straightforward to understand. There are plenty of other syndromes with more or less descriptive names along the same lines. Fibrodysplasia ossificans progressiva means:
fibrodysplasia — an abnormality of fibrous tissue (ligaments and tendons)
ossificans — turning to bone
progressiva — progressively.
If you have fibrodysplasia ossificans progressiva, your fibrous tissue progressively turns to bone — gradually immobilising you. It is an unfortunate and disabling condition.6
[6 There are some potential treatments for FOP undergoing trials. Fingers crossed that one or more will work.]
It’s no longer compulsory for medical students to know Latin and Greek, and there are plenty of more straightforwardly descriptive syndrome names. Doctors love an acronym, and geneticists are no exception. VACTERL, for instance, is the association of abnormalities of the Vertebrae (bones that make up the spine), Anal abnormalites, Cardiac (heart) anomalies, Tracheo-oEsophageal fistula (an abnormal connection between windpipe and gullet; the condition was named by an American, for whom the structure is spelled Esophagus), Renal (kidney) abnormalities, and Limb abnormalities.
Sometimes, the urge to make up a clever acronym can lead to unfortunate outcomes. SHORT syndrome includes short stature as one of its features, but it must be a considerable nuisance for the parents of an affected child to explain that SHORT syndrome is a real thing and doesn’t just mean the kid is small. CHILD syndrome must also be irksome to families. PHACE syndrome does indeed affect the face, and it seems a bit harsh that the syndrome’s name draws extra attention to it in this way. SeSAME, CRASH, and RIDDLE syndromes are all a bit problematic, especially the latter (increased Radiosensitivity, mild ImmunoDeficiency, Dysmorphic features, and LEarning difficulties). Nobody wants to hear that their child, despite having a diagnosis, is still a riddle. ANOTHER syndrome7 would just be a nuisance to explain. CHIME and TARP maybe aren’t so bad. But probably it’s best, if you’re creating an acronym for a new syndrome, to aim for something without an existing meaning: CADASIL, CODAS, GAPO, MASA, MEDNIK, and MELAS all seem pretty safe.
[7 I am not making this up.]
It’s not just the names of syndromes that can be problematic. Take the single transverse palmar crease — a single line across the width of the palm, mentioned above. The old name for this, and one that some people still use, is ‘simian crease’. Simian, in this context, means monkey or ape-like. Monkeys and the other apes (besides us, that is) don’t all have the same pattern on their hands, but some do indeed have a single crease. That doesn’t mean it’s okay to describe a child by comparing her with a monkey.
Some syndromes wind up with a plethora of names. The champion in this regard is probably velocardiofacial syndrome (VCFS — a harmless enough acronym). People with VCFS may have cleft palate (‘velo’ refers to the palate), heart abnormalities (‘cardio’), and a distinctive facial appearance, which is often very subtle, and certainly not abnormal. Other past and present names for VCFS include:
22q11.2 deletion syndrome — for the tiny chunk of chromosome 22 that is missing in most people with VCFS
22q11.2 microdeletion syndrome — because … it’s a tiny chunk of chromosome
monosomy 22q11.2 — another way of saying that there’s a tiny chunk of chromosome 22 missing
CATCH22 … never mind why, but suffice it to say that this is another prime example of how not to construct a medical acronym. This was graciously acknowledged by the originator of the term, Professor Sir John Burn, the great British geneticist, when he formally withdrew the name from use in 1999, just six years after its introduction. As he noted, in Joseph Heller’s book, the titular Catch-22 describes a no-win situation8 — again, not something you want applied to yourself or your child.
CATCH phenotype — a short-lived attempt to retrieve the CATCH part of the CATCH22 acronym, in th
e face of criticism by patient groups.
conotruncal anomaly face syndrome (CAFS) — ‘conotruncal’ refers to a particular group of heart malformations seen in babies with the condition; ‘face’ because of the characteristic facial appearance.
DiGeorge syndrome
Sedláčková syndrome
Shprintzen syndrome
Strong syndrome
Takao syndrome.
[8 You’ve probably read Catch-22. But just in case: the catch was that, for the World War II pilots in the book, if you’re crazy, you don’t have to fly missions. But asking to be grounded was proof of rational thinking … so you couldn’t be crazy. In the words of the book, ‘Orr would be crazy to fly more missions and sane if he didn’t, but if he were sane he had to fly them. If he flew them he was crazy and didn’t have to, but if he didn’t want to he was sane and had to.’]
There’s a good reason why the condition has so many different names. It’s relatively common, but it can show itself in different ways, and so was described independently by various different people. Later, we realised that each of these apparently different conditions was just another version of the same thing. Even now, there’s an argument that it may be worth keeping some of the different names. Angelo DiGeorge, an American paediatric endocrinologist, described children affected by a particularly severe form of the condition, with a life-threatening immune deficiency. Most people with VCFS don’t have problems with their immune systems. You might be able to measure some differences in their white blood cells, but they don’t have more infections than anyone else. So, maybe if we see a child with a deletion of the right part of chromosome 22 who also has a severe immunodeficiency, we should still speak of DiGeorge syndrome.
Otherwise, though, it’s generally best if a genetic syndrome has a single name. This has a number of advantages — it makes it easier for patient groups to find one another, it unifies the medical literature, and it prevents confusion.
Of the various names of people listed above, DiGeorge and Shprintzen are the two best known among geneticists. For a while in the 1990s, Shprintzen syndrome looked like it might wind up settling down and becoming the name of the condition. In 1978, Dr Robert Shprintzen — a speech pathologist — and colleagues published a description of 12 children with the condition that they named VCFS. Three years later, the group published another paper describing 39 individuals and correctly identifying the inheritance pattern of the condition. Over the following years, Shprintzen made contribution after contribution to our understanding of VCFS, to the point that others in the field started referring to it as Shprintzen syndrome. But as far as I can tell, Shprintzen himself never used the name, always using his original term — velocardiofacial syndrome.
Had the name stuck, it may have been something of an injustice, through no fault of Robert Shprintzen. In 1955, Eva Sedláčková had pre-empted Shprintzen by more than two decades, publishing a description of 26 patients with — as it later emerged — the same condition. Her paper was written in Czech, so it was hardly surprising that Shprintzen and colleagues had no knowledge of it. At the time, Prague was an important European centre for the treatment of cleft palate, and the term Sedláčková syndrome found its way into textbooks in German and French over the coming years, but it wasn’t until the 1990s that the link with VCFS was firmly established, and Sedláčková’s achievement came to the notice of the English-speaking world (or at least, that part of the English-speaking world with an interest in velocardiofacial syndrome).
Getting a syndrome named after yourself can be a bit of a lottery. Quite often, things work out fine — someone is the first to describe a particular syndrome, the next person to publish a paper about the condition acknowledges this by attaching the original describer’s name to the condition, and all is well. However, there have been plenty of instances where things are not so straightforward — possibly we should all be doing our best to pronounce Dr Sedláčková’s name every time we refer to VCFS, for instance. It’s also not always obvious in retrospect why a particular name or combination of names is used — sometimes just the first author of an original paper, sometimes more than one author, and so on. There are some charming eccentricities. Why, for example, does Cornelia de Lange syndrome — the only instance of this that I know — include the first name of Dr de Lange, instead of just her surname as is usual?
Sometimes, two or more doctors have their names joined together in the naming of a syndrome. Occasionally, this happens because someone has been particularly prolific, and the use of an additional name avoids confusion. There’s a Shprintzen-Goldberg syndrome, which could not have been named just Shprintzen syndrome because the name was already taken. Confusingly, there’s also a Goldberg-Shprintzen syndrome; same Goldberg, same Shprintzen, completely different conditions. Perhaps the champion of multiple genetic syndrome names is John Opitz. His name is attached to Opitz G/BBB syndrome (also known as Opitz G, Opitz BBB, and Opitz-Frias), Opitz C syndrome (also known as Opitz trigonocephaly syndrome), Opitz-Kaveggia syndrome, Bohring-Opitz syndrome, and Smith-Lemli-Opitz syndrome. The G, BBB, and C come from the practice Opitz had in the 1960s and 70s of naming newly described syndromes after the first initials of the patients he was describing (a typical paper was entitled ‘The C Syndrome of Multiple Congenital Anomalies’). This never really caught on among others in the field, and wouldn’t have been useful much past 26 syndromes in any case.
Shprintzen’s modesty regarding the term Shprintzen syndrome is not unusual, by the way. There were (in retrospect) some reports of Noonan syndrome well before Jacqueline Noonan’s first full description of the condition, and it seems it took a long time for her to become comfortable with her name being used in this way — it was nearly ten years before she would write a paper in which she referred to Noonan syndrome. In a special issue of a journal published in 1968, four of five papers about the condition had a running title ‘Noonan syndrome’; the odd one out was written by none other than Dr Noonan.
This modesty is not just something from a bygone age. In 1998, my friends David Mowat and Meredith Wilson, with colleagues, described a syndrome that others soon dubbed Mowat-Wilson syndrome.9 Although David and Meredith eventually published papers that use the name, I don’t think I’ve ever heard either of them utter the words ‘Mowat-Wilson syndrome’. The closest they come is to use the acronym ‘MWS’.
[9 I once made the diagnosis of Mowat-Wilson syndrome in a child I saw in a shopping mall. I was going down a moving ramp; she was coming up the other side, in a wheelchair. She had absolutely typical facial features. There was no doubt in my mind about the diagnosis. For a few seconds, as we approached each other, I wondered — should I speak to the family? It would feel rude and intrusive, but what if they didn’t know their child’s diagnosis? I couldn’t decide, and my indecision became a decision. The family went past me, and out into the car park, and the opportunity was lost. I will never know if I did the wrong thing.]
Of course, wherever there’s a trend, there’s someone who will buck it. You have to admire the chutzpah of Drs Bettex and Graf, who decided to cut out the middle-man in entitling their 1998 paper ‘Oro-palatal Dysplasia Bettex-Graf — a New Syndrome’. Sadly for them, the term seems not to have caught on, or perhaps the condition is just too rare for others to have seen it and considered adopting the name.
There have been occasions when the naming of syndromes has generated controversy. Sometimes, this relates to disagreements about precedence, or just national pride. Is it Silver-Russell syndrome or Russell-Silver? Silver was American, Russell British … guess where the term Silver-Russell is more common? More seriously, we no longer refer to Hallervorden-Spatz disease — now we call it pantothenate kinase–associated neurodegeneration (PKAN for short).
This is not because of any dispute about priority. In a 1922 paper, Julius Hallervorden and Hugo Spatz described five sisters affected by a condition that had never been reported
before; the paper contained considerable clinical and pathological detail. Hallervorden was a pioneering neuroscientist, described by a former student as having ‘a quiet, reserved nature’ and being ‘wholly devoted to science and to neuropathology, and at the same time, warm, friendly and an inspiring teacher’. Others described him as ‘good-natured, personally modest and possessing a dry humour’. During his career, Hallervorden published 120 papers and received many honours for his contributions to medical science. So — Hallervorden was an all-round nice guy, an eminent scientist, and had clear priority in describing what proved to be an important neurological condition. The perfect person to honour with an eponym, surely?
Except … except for the source of some of his scientific material. The work that led to the first description of PKAN was conducted in Munich, at an institute led by Hugo Spatz. In the late 1930s and 1940s, Hallervorden was working in Berlin. At the time, the Nazi doctrine of ‘racial hygiene’ was being enacted, in the form of the systematic murder of children who were regarded as mentally defective, or were physically disabled by malformations; and in the form of the T4 program, in which more than 70,000 people taken from psychiatric hospitals were gassed to death. Hallervorden evidently saw all this as a wonderful opportunity to obtain material for study. In 1942, he wrote, ‘I have been able to dissect 500 brains from feeble-minded individuals’. Hallervorden was fully aware of the source of the brains he studied. He is quoted as saying, ‘I heard that they were going to do that, and so I went up to them and told them, “Look here now boys, if you are going to kill all those people, at least take the brains out so that the material could be utilized”’. When asked how many he could examine, he replied, ‘I told them an unlimited number — the more the better’. There’s more to the story than this, and worse — but you get the picture. PKAN it is.
Among eponymous genetic syndromes, the most famous is Down syndrome.10 John Langdon Down was a British doctor who became chief physician of the Earlswood Asylum in the early 1860s. Down seems to have done a fine job, transforming a brutal and filthy institution into one in which the inmates were treated with kindness and humanity. Down took the opportunity to study his charges, and in 1866 published his famous paper ‘Observations on an Ethnic Classification of Idiots’. Just a few pages long, it was to stamp Down’s name in medical history. While we would not be comfortable with much of Down’s language today, the paper makes fascinating reading and is well worth seeking out. Down starts by pointing out the difficulty of classifying ‘congenital mental lesions’, as he calls them — a problem we are still wrestling with more than 150 years later. He criticises existing systems of classification and then canvasses some possible causes one might need to consider, especially environmental influences, addressing the question of whether the problem arose before or after birth. ‘Has the nurse dosed the child with opium? Has the little one met with any accident?’, and so on.