ACHONDROPLASIA. MARY ASHBERRY (d. 1856) WITH THE SKULL OF HER STILLBORN INFANT, USA.
We know this because 99 per cent of all cases of achondroplasia are caused by a mutation in which an amino acid (a glycine) at a particular location in the FGFR3 protein sequence (position 380) is replaced by another (an arginine). This mutation has the peculiar property of causing the FGFR3 molecule to become hyperactive. Nearly all of the mutations discussed in this book cause a deficiency in the quantity or efficacy of some protein, often by causing it to be completely absent. If the protein is a signalling molecule like FGF, the disorder that we see is due to an absence of some critical piece of information that the cells require. The achondroplasia mutation is, however, different in that it occasionally causes the receptor to transmit a signal into the interior of the cell even if no FGF is bound to it. The effect is like a switch that spontaneously flips on when it should be off, and that transmits a blast of unwanted information to the cells of the growing limb.
If an excess of FGF signalling causes limbs to be unusually short, then the usual role of FGFs must be to act as a brake on the growth of the infant limb. They do this by limiting the rate at which the cells of the growth plate divide. The bones of achondroplastic children have growth plates that are only a fraction of the size they should be. They contain far fewer dividing chondrocytes than those of normal children, and fewer yet that swell and form cartilage.
Achondroplasia is a relatively mild disorder. However, a surplus of FGF signalling can, in the extreme, have terrible consequences. Among the many skeletons in Amsterdam’s Museum Vrolik is one that belonged to a male infant stillborn sometime in the early 1800s. When you look at the skeleton, now labelled M715, you can see quite clearly that there is something the matter with it. The child’s vertebrae, ribs and pelvis are all truncated, bowed or flattened, and the skull is enormously enlarged. In his great 1849 teratological treatise, Willem Vrolik depicts the child’s forehead as a large tuberose object. The stunted limbs and the large head are both characteristic of ‘thanatophoric dysplasia’ – death-bringing dysplasia. As the name suggests, it is fatal at birth.
Thanatophoric dysplasia is also caused by activating mutations in the FGFR3 gene, but of a far more destructive variety than those responsible for achondroplasia. The havoc they wreak shows that FGFs control the growth not only of the limbs, but of some other parts of the skeleton as well, such as the skull. The mildly domed foreheads of many achondroplastic dwarfs remind us that their disorder is a weaker version of a lethal one. Should a foetus inherit two copies of the achondroplasia mutation (by virtue of having two achondroplastic parents), it too will die shortly after birth with all the symptoms of thanatophoric dysplasia.
FGF must be only one molecule among many that limit the growth of this or that part of the body. Every organ must have devices that tell it to stop growing, and many will be unique to particular organs. There is hardly a part of the body that is not stunted or overgrown in some genetic disorder or other. Some mutations cause children to be born with tongues that are too large for their mouths; others result in intestines that do not fit inside abdominal cavities. Even muscles have their own devices for regulating growth. Belgian blues, a breed of beef cattle, are remarkable for having about a third more muscle than normal cows; their flanks resemble the thighs of Olympic weightlifters. They lack a protein called myostatin (related, as it happens, to BMPs) that instructs muscles to stop their growth. Myostatin-defective mice have about two or three times the normal muscle mass, but this gain seems to be bought at the expense of growth elsewhere, since they also have smaller than normal internal organs. Myostatin-defective people surely also exist, but there seems to be no record of them. Perhaps extra muscles are not noticed or, if noticed, are not something worth worrying about.
RENEWAL
The pseudoachondroplasia gene encodes one part of the matrix that chondrocytes spin about themselves. But it is only a minor one. Indeed, mice in which the protein has been engineered out altogether seem to suffer no ill-effects at all. One has to wonder just what it’s doing there in the first place. Not so for the rest of the matrix. Most of the cartilage is made of collagen. Humans have about fifteen different types of collagens that make up about a quarter of the total protein in our bodies. Collagens are found in our connective tissue and skin. They are the stuff that holds our cells together. And they give bone much of its flexibility and strength.
Mutations that disable bone collagens cause a disorder called osteogenesis imperfecta. There are at least four forms of the disease, some of which are lethal in infancy. The most characteristic symptom of the disorder is the extreme fragility of its victim’s bones. For this reason it is often known as ‘glass bone disease’. The mutations have their devastating effects because of the hierarchical nature in which collagens are organised. Any given collagen protein is made up of three peptides – strings of amino acids – wrapped together in a triple helix. The triple helices are in turn grouped together in enormous fibrils that, woven together, make up the structure of connective tissue and cartilage. Each peptide is encoded by a different gene, but a single mutant gene can wreck any number of triple helices, and so any number of fibrils, and so any number of bones.
Osteogenesis imperfecta is the disorder that afflicted the French painter Achille Empéraire (1829–98), who was himself painted by Cezanne, and the French jazz pianist Michel Petrucciani (1962–99). These artistic associations have lent the disorder, at least in France, a spurious romance (the ‘glass-bone man’ in Jean-Pierre Feunet’s film Le fabuleux destin d’Amélie Poulain springs to mind). The reality is more mundane. Children with osteogenesis imperfecta often suffer minor bone fractures of which their parents are quite unaware. When, after a more severe fracture, the children finally wind up in hospital, radiographs reveal a long history of broken and healed bones. Suspicions of child abuse often follow. In the United States, afflicted children have been taken into care by over-zealous social workers; some parents have even been jailed.
OSTEOGENESIS IMPERFECTA TYPE II. STILLBORN INFANT, AMSTERDAM.
Even once our growth plates are sealed and growth has stopped, there is no rest for the skeleton. The interiors of most adult bones are fully replaced every three or four years, while their outer peripheries, being harder, turn over about once every decade. This cycle of destruction and renewal is the product of an engagement between osteoblasts and other cells that continually wear the skeleton away, taking minute bites from its fabric and reducing it to its constituent parts, rather in the manner of so many chisels. These are the osteoclasts: giant cells that attach to fragments of bone and dissolve them using protein-chewing enzymes and hydrochloric acid. Bones may be built by osteoblasts, but they are carved by osteoclasts, for it is these cells that hew the ducts, channels and cavities through which nerves and blood vessels thread, and bone marrow percolates.
There are many ways to upset the balance between growth and destruction that is found in every bone. An excess of bone may be due to an excess of osteoblasts, but it can also be caused by a want of osteoclasts. Osteopetrosis, literally bones-like-rock, is an osteoclast disorder, the opposite of the far more familiar osteoporosis that is the bane of post-menopausal women. Having bones-like-rock can be lethal. There is a particularly harsh variety of the disorder that affects children and usually kills them before they turn twenty. Often they die of infections because bone accretes in the cavities where marrow is manufactured, marrow being one of the main sources of immune-system cells. Somewhat paradoxically, the bones of people with osteopetrosis also tend to fracture rather easily, the probable consequence of an architecture that has gone awry. And when fractures do occur they are not easily repaired, for among the things that osteoclasts do is to smooth away the jagged edges of our bones should we break them.
Osteopetrosis, albeit of a fairly mild variety, is thought by some to be responsible for the shortness of Henri de Toulouse-Lautrec. This is just one of several retrospective diagnoses –
achondroplasia and osteogenesis imperfecta among them – that have been attempted of the French painter. None is particularly convincing, but then bone disorders are so many, and their symptoms so various and subtle, that they are easily mistaken for one another, particularly when all we know of the patient comes from biography, a handful of photographs, and a selection of self-portraits, mostly caricatures. Yet the search for ‘Lautrec’s disease’ goes on. Part of his fascination, particularly for French physicians, comes from the fact that he was a scion of one of France’s most noble houses, the Comtes de Toulouse-Lautrec, a dynasty of rambunctious southern noblemen who had, at one time or another, ruled much of Rouergue, Provence and the Languedoc, sacked Jerusalem, dabbled in heresy, been excommunicated by the Pope (on ten separate occasions) and, in the thirteenth century, felt the military wrath of the French Crown. But more than this, the impulse to diagnose Henri Toulouse-Lautrec comes from the belief that this gifted painter made his deformity part of his art.
There may be something to this. As one walks through the Musée d’Orsay in Paris or else the museum at Albi, not too far from Toulouse itself, which is dedicated to his work, what strikes you are the nostrils. In painting after painting – of the dancer La Goulue, the actress Yvette Guilbert, the socialite May Milton, or the many other anonymous Parisian demi-mondaines who inhabit Lautrec’s art – what we see are nostrils, gaping, dark and cavernous. It is hardly a flattering view, but perhaps it is one that would have come quite naturally to the artist, for he was rather short. By the time he was full grown, Lautrec was only 150 centimetres (four feet eleven inches) tall. Critics have also argued that Lautrec’s disorder had a more subtle effect on his art: a tendency after 1893 to truncate the limbs of his models so that only the heads and torsos remain in the frame, a device for excluding that part of his own anatomy that he would much rather forget: his legs.
Lautrec’s legs caused him much grief. He seems to have had a fairly healthy childhood, but by the time he was seven his mother had taken him to Lourdes, where she hoped to find a cure for some vaguely described limb problem. He was stiff and clumsy and prone to falls, and only went to school for one year, leaving when he proved too delicate for schoolyard roughhousing. By the age of ten he was complaining of constant severe pains in his legs and thighs, and at thirteen minor falls caused fractures in both femurs which, to judge from the length of time during which he supported himself with canes, took about six months to heal. He would use a cane nearly all his adult life; indeed, friends believed that he walked any distance only with reluctance and difficulty.
As he grew, Lautrec also underwent some unusual facial changes. A pretty infant, and a handsome boy, he later developed a pendulous lower lip, a tendency to drool, and a speech impediment rather like a growling lisp, and his teeth rotted while he was still in his teens – traits which his parents, who were notably good-looking, did not share. He was self-conscious about his looks, wore a beard all his adult life, and never smiled for a camera. Many critics have argued that it was a sort of physical self-loathing that caused him to seek and portray all that was most vicious and harsh in his milieu. But then, fin-de-siècle Paris could be a vicious and harsh place. One night at Maxim’s, when Lautrec had sketched some lightning caricatures of his neighbours, one of them called to him as he hobbled away. ‘Monsieur,’ he said, gesturing to a pencil stub left on the table, ‘you have forgotten your cane.’ On another occasion, looking at one of the many portraits he had done of her, Yvette Guilbert remarked, ‘Really, Lautrec, you are a genius at deformity.’ He replied, ‘Why, of course I am.’
PYCNODYSOSTOSIS (PUTATIVE). HENRI TOULOUSE-LAUTREC (1864–1901).
Lautrec is thought to have been afflicted by a variety of osteopetrosis called pycnodysostosis. It is caused by a deficiency in the enzyme that osteoclasts use to dissolve the protein matrix of bones. During adulthood the activity of this enzyme is partially repressed by hormones, and it is the declining levels of estrogen in post-menopausal women – and hence the unwarranted activity of the enzyme – that causes osteoporosis. Lautrec was diagnosed with pycnodysostosis in 1962 by two French physicians, Pierre Maroteaux and Maurice Lamy, but their claim has not gone unchallenged. Lautrec’s most recent biographer, Julia Frey, concedes that at least some of his symptoms are consistent with the disorder, but points out that others are not. Where pycnodysostosis patients typically have soft heads – rather in the manner of the boneless Cape Malays – there does not seem to be any evidence that Lautrec’s head was anything but solid.
Whatever his disorder, it seems that he shared it with several other members of his family. By the time Henri Marie Raymond, Comte de Toulouse-Lautrec-Montfa, was born in 1864 his family, though still rich, was quite inbred. The Napoleonic abolition of primogeniture had prompted an already much-reduced French nobility to keep what wealth remained in their families by the simple expedient of not marrying out of them. Henri’s parents were first cousins, as were his aunt and uncle: between them they produced sixteen children, of whom four including Henri were dwarfed, the other three far more severely than he. Indeed, it is likely that at least some surviving members of that noble house still carry the mutation, though it is not likely to be expressed if they have discontinued their consanguineous habits.
Lautrec himself had no doubts about the ultimate cause of his malady. One night, in one of his favourite haunts, Montmartre’s Irish and American Bar, two women were arguing about a pitiful dog whose legs shook from hip dysplasia. The dog’s owner conceded that the animal wasn’t handsome, but insisted nevertheless that it was pure-bred. ‘Are you kidding, that dog has a pedigree? Have you taken a look at his ugly fur and his twisted feet?’ laughed her friend. ‘He makes you feel sorry for him.’ ‘You obviously don’t know anything about it,’ said the dog’s owner, and turned to Henri who was sitting next to her. ‘Tell her, Monsieur, that my dog can perfectly well be ugly and still be pedigreed.’ Henri, getting down from his high barstool and standing up to his full four feet eleven inches, saluted her with a charcoal-stained hand and murmured, ‘You’re telling me.’
VI
THE WAR WITH THE CRANES
[ON GROWTH]
From the walls of the Prado, the Louvre and the National Gallery they stare balefully at us. As depicted by Velazquez, Argenti, Bronzino, Carracci, Van Dyck and another dozen now forgotten painters, the court dwarfs stand clad in rich and elaborate dress, miniature daggers at their sides, surrounded by the other possessions of rich and powerful men. In one painting, a princeling stands next to a dwarf, the better to display the boy’s youthful elegance. In another, a dwarf is placed next to a glossy, pedigreed hound. The man’s shoulders are level with the dog’s withers.
‘Towards the end of the seventeenth century,’ wrote Isidore Geoffroy Saint-Hilaire, ‘it was necessary to dream up amusements of a special sort for the leisure of princes and it was to dwarfs that fell the sad privilege of serving as the toys of the world’s grandees.’ But the court dwarfs were older than that. Most of the paintings that depict them date from a century earlier. Catherine de Medici (1519–89) had set the fashion. In the hope of breeding a race of miniature humans she had arranged a marriage between a pair of dwarfs. A few years later, the Electress of Brandenburg tried the same thing, but both couples proved childless. Peter the Great took the amusement to its extreme. In 1701 he staged a wedding between two dwarfs to which he invited not only his courtiers, but also the ambassadors of all the foreign powers posted to his capital. He also ordered all dwarfs within two hundred miles to attend. A dozen small men and women rode into the capital on the back of a single horse, trailed by a jeering mob. At court some of the dwarfs, perceiving that they were there to be ridiculed, refused to take part in the fun. Peter made them serve the others.
PYGMY DEPICTED WITH ACHONDROPLASIA. ATTIC RED-FIGURE RHYTON C.480 BC.
Were all the court dwarfs unhappy, degraded creatures stripped of all human dignity? Geoffroy, writing in 1832, thought so. So had Buffon fifty years earli
er. Joseph Boruwlaski, however, would not have agreed. For him, being small was a gift, an opportunity. It had lifted him out of obscurity. His Memoirs take up the tale:
I was born in the environs of Chaliez, the capital of Pokucia, in Polish Russia in November 1739. My parents were of middle size; they had six children, five sons and one daughter; and by one of those freaks of nature which it is impossible to account for, or perhaps to find another instance of in the annals of the human species, three of these children grew to above the middle stature, whilst the two others, like myself, reached only that of children in general at the age of four or five years.
The Boruwlaskis were poor. Joseph was only nine years old when his father died, leaving the family destitute. Eighteenth-century rural Poland was, however, a profoundly feudal society in which patronage counted for all; Boruwlaski’s mother had a patron, a young local noblewoman, the Staorina de Caorliz. Charmed by the young Joseph, she prevailed upon his mother to send the boy to live with her so that he could be educated. Boruwlaski thrived in his new home. By his early teens he was only 61 centimetres (two feet) tall, but he had acquired graces that would not have shamed the most noble of Polish youths. Things became a bit difficult for Boruwlaski when the Staorina got married and had a child, but even then he had an eye for a good thing. He became the protege of another, even wealthier, aristocratic woman, the Comtesse de Humiecka. It was the making of him. For the Comtesse was not one to linger in the obscurity of provincial Poland; she had a yen for travel and for society. Bundling Boruwlaski into a carriage, she set out to conquer the courts of Europe.
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