Mutants

by Armand Marie Leroi

  CHAPTER VI: THE WAR WITH THE CRANES

  169 From the walls of the Prado. For the iconography of dwarfing see Tietze-Conrat (1957) and Emery (1996). Tanner (1981) pp.120–1 discusses Geoffroy and Buffon on dwarfs.

  170 Were all the court dwarfs unhappy. See Boruwlaski’s memoirs (1792) and Heron (1986) for a modern account of his life.

  175 At the base of our brains. See Laycock and Wise (1996) for the regulation of growth by the hypothalamus-pituitary pathway. Primary growth-hormone deficiency (262400) is caused by recessive mutations in the growth-hormone gene (139250). There is an enormous literature on this group of syndromes; see López-Bermejo et al. (2000) for a brief review.

  176 Joseph Boruwlaski has all the signatures. The Ecuadorean dwarfs have Laron- or growth-hormone resistance syndrome (262500) caused by recessive mutations in the growth-hormone receptor gene (600946); see Rosenfeld et al. (1994) and Rosenbloom and Guevara-Aguirre (1998).

  177 In 1782 Joseph Boruwlaski met. Frankcom and Musgrave (1976) write about Patrick Cotter; Bondeson (1997) about Charles Byrne; Thompson (1930, 1996) tells of both men as well as other famous eighteenth-century giants.

  179 Charles Byrne had a pituitary tumor. See Keith (1911) for original diagnosis.

  179 An old photograph shows a triptych of skeletons. See Schnitzer (1888) (Emin Pasha’s given name) for an account of how he obtained the skeletons. See Schweinfurth (1878) for an account of meeting Akadimoo. The Homeric quote is from The Iliad (1950 trans. E.V. Rieu, Penguin Books, Harmondsworth, UK). Tyson (1699, 1966); Schweinfurth (1878); de Quatrefages (1895); Cavalli-Sforza (1986) all give accounts of Greek and Roman writings on pygmies, but the authoritative work on pygmies in antiquity is Dasen (1993). See Addison (1721) for his verses on pygmies.

  182 Addison’s poem. See Tyson (1699,1966) for his dissection of a ‘pygmie’; de Quatrefages (1895) says that the word ‘Aka’ can be found inscribed on the frescos of a fifth-century Egyptian tomb beneath a depiction of a dancing pygmy; Cavalli-Sforza (1986) repeats the story. This would be remarkable if true, but sadly Véronique Dasen assures me it is not.

  183 The French anthropologist Armand de Quatrefages. See Schebesta (1952) and Weber (1995–99) for the history of the negritos; Diamond (1991) discusses theories about pygmy smallness. For the most recent study on the genetic relationships of Andaman Island negritos see Thangaraj et al. (2003).

  185 The diagnosis of achondroplasia. The Attic vase is just one of many examples of Greek pygmy iconography given by Dasen (1993). Gates (1961) asserted thatpygmies have achondroplasia.

  185 That pygmy proportions. The genetics of pygmy smallness are obscure, but the evidence seems to exclude a single locus with substantial dominance. See Shea and Bailey (1986), Shea and Gomez (1988) and Shea (1989) for an analysis of pygmy proportions.

  187 The geographers, entranced by their acquisition. The history of Chair-Allah and Thibaut is given in de Quatrefages (1895) and Schweinfurth (1878); their growth curve is given in Cavalli-Sforza (1986) p.366.

  188 A newborn infant grows. See Tanner (1990) p.12 for the pubertal growth spurt and Tanner (1981) pp.104–5 for the history of its study; see Bogin (1999) for pubertal spurts in other primates.

  189 The pubertal spurt is driven. There is some disagreement as to whether pygmies show low IGF-1 serum titres or whether they have a less effective IGF-1 receptor relative to taller people. In any event, what we know about short stature in pygmies is based on endocrinological studies (Merimee et al. 1981; 1987; Geffner et al. 1995). The following note also bears on the interpretation of these data.

  189 The proof of this is the mini-mouse. The account of the relationship between IGF and GH given here differs from the ‘somatomedin hypothesis’ given in most textbooks. Recent experiments have suggested that: (1) IGF-I’S primary role is as a paracrine (short-range) growth factor rather than an exocrine hormone; (2) that liver IGF-1 is responsible for most serum IGF, and that it contributes little to post-natal growth; (3) that IGF-1’s effects on growth are therefore to a considerable degree – though not entirely – inde pendent of GH’s. See Le Roith et al. (2001) for a review of these matters, and Lupu et al. (2001) for an account of the GHR; IGF-1 double knockout mouse.

  190 Schweinfurth’s discovery set off a global hunt. See Haliburton (1891; 1894)for ‘pygmies’ in Spain, the Atlas Mountains and Switzerland. See Johanson and Edgar (1996) for the stature of fossil hominids and Bogin (1999a) p.3 for the ‘Maya in Disneyland’.

  192 It is even possible that the most recent. Exploration accounts can be found in Kingdon-Ward (1924; 1937) and many other books by the same author. I first learned about the Burmese ‘pygmies’ from Prof. Harry Saing, who saw them while travelling in Kachin State in 1964. The Burmese government reports are given in Mya tu et al. (1962, 1966).

  194 It is not a pretty word. For a general review of iodine deficiency diseases and cretinism see Delange and Hetzel (2000). Several reports from western China show a form of myxedmatous cretinism that has many of the features seen in the Taron. Various co-factors have been suggested for the extreme form of cretinism seen in the Congo such as selenium deficiency or a fondness for eating goitrogenic plants.

  195 Cretinism is a global scourge. See Merke (1993) for Napoleon’s investigations into Swiss cretins and the iconography of cretinism in Aosta Cathedral. See Delange and Hetzel (2000) for the discovery of the thyroid and Laycock and Wise (1996) pp.203–40 for how it works. The hormone called here ‘thyroxine’ is, more formally, two hormones, tri and tetraiodothyronine or T3 and T4. Williams et al. (1998) discusses the cellular role of thyroxines on the growth plate. Among the many genes with known mutations causing a deficiency of thyroxine production or function are: thyroid peroxidase, an enzyme that is involved in thyroid hormone production (188450) (Abramowicz et al. 1992); thyroglobulin (606765), or the thyroid hormone receptor (190160) (Refetoff et al. 1996); as well as several other genes involved in the synthesis, transport or storage of thyroid hormone (de Vijlder et al. 1999; Vassart 2000). Mutations in all these genes tend to cause cretinism with goitre.

  197 There is also a class of mutations more vicious by far. Among the genes with known mutations that affect the pituitary’s stimuation of the thyroid are those that encode: thyroid stimulating-hormone (TSH) itself (188540) (Hayashizaki et al. 1989) and those that cause combined pituitary hormone deficiency (CPHD) due to mutations in transcription factor genes such as PROP-1 (601538) and PIT-1 (173110) required for the specification of somatotroph, thyrotroph and lactotroph cells (Tatsumi et al. 1992; Voss and Rosenfeld 1992; Sornson et al. 1996; Wu et al. 1998). These mutations cause cretinism without goitre and with or without dwarfism.

  199 Nearly fifteen hundred years ago. For Aristotle on the effects of castration see his Historia animalium in Complete works volume 1 pp.981–2. For a more recent view of the same subject see Wilson and Roehrborn (1999).

  203 We think of the estrogens. For estrogen-receptor deficiency (133430) in men see Smith et al. (1994). The enzyme that converts testosterone to estrogen is aromatase cytochrome P450 (107910) For loss-of-function mutations that cause continued growth in men see Sharpe (1998); Lee and Witchel (1997); for gain-of-function mutations that cause excess in women see Stratakis et al. (1998).

  203 Growth hormone and IGF are extremely powerful. One of the several cancer-predisposition syndromes caused by mutations in PTEN (601728) is Cowden syndrome (158350). For the evidence that Proteus syndrome (176920) is also caused – at least sometimes – by PTEN loss-of-function mutations see Zhou et al. (2000, 2001). The Ovid quote is from Metamorphoses (trans. A.D. Melville. 1986. Penguin Books, Harmondsworth, UK). Seward (1992) re-examines Joseph Merrick’s skeleton in detail and upholds the traditional diagnosis of neurofibromatosis type 1 (162200). Tibbies and Cohen (1986), Cohen (1988) and Cohen (1993), however, argue for Proteus syndrome.

  206 The intimate relationship between growth and cancer. For the relationship between IGF titres and dog body-size see Eigenmann et al. (1984, 1988); Eigenma
nn (1987). The association between osteosarcoma and size in dogs was detected by Tjalma (1966), in children by Fraumeni (1967). The latter result has been confirmed by three out of four studies since. See Leroi et al. (2003) for a general discussion on the causes of pediatric cancers. Jenkins (1998) reviews increased propensity of acromegalics to a variety of cancers. The causal role of IGF is reviewed by Holly et al. (1999). In his classic book on ageing, Comfort (1964) first noted that big dogs do not live as long as small dogs. See also Patronek et al. (1997) and Miller and Austad (1999). The best data on ageing rate, from the Swedish pet health insurance scheme, is given in Egenvall et al. (2000).

  208 I am fascinated by these findings. Krzisnik et al. (1999) discuss the dwarfs of Krk who are homozygous for recessive mutations in PROP-I. Samaras and Elrick (1999) and Samaras et al. (1999) give a partisan account of the evidence for a negative association between human height and longevity. See Waaler (1984) and Power and Matthews (1997) for the general positive association between health and longevity. There is, however, some evidence from the Finnish studies of a U-shaped mortality distribution in women, possibly associated with skeleto-muscular problems in the tallest women (Läärä and Rantakallio 1996; Silventoinen et al. 1999).

  208 These results seem to tell us. The first dwarf mice which were shown to be long-lived were Snell dwarfs (dw) which are deficient in a number of their pituitary gland lineages because of a mutation in PIT-I, a pituitary specific transcription factor. Ames dwarf (dj)has the same phenotype, but has a mutation in another transcription factor, PROP-I. Both these mice are long-lived, but since they lack both somatotrophs and thyrotrophs, they fail to produce both growth hormone and thyroid-stimulating hormone, making it impossible to distinguish the effects of lacking either (Brown-Borg et al. 1996; Bartke et al. 2001 a; b). However, the Little mouse (lit) is also long-lived (Flurkey et al. 2001). Since this dwarf mouse has a mutation in its growth-hormone releasing-hormone receptor (GHRHR), it is very likely that it is growth-hormone deficiency, or its sequelae, that cause the longevity of these strains.

  209 To be poor is to be both short and at higher risk. See Mansholt (1987) on Dutch growth; Mackenbach (1991) on the socio-economic causes of height differences in Holland and Didde (2002) for height-related activism in the Netherlands. Also see Cavelaars et al. (2000) for a fascinating comparision of the secular increase in all European countries which shows that although all countries show a secular increase in height, they are all getting taller at more or less the same rate. There is much evidence that milk consumption is responsible for a good deal of environmental variation in height, for example, in the Japanese; Takahashi (1984); Bogin (1999a) p.268.

  210 The poverty and short stature of the north’s people. See Rosenbaum et al. (1985) and Mascie-Taylor and Boldsen (1985) for regional differences in height in England and Townsend et al. (1992) for the authoritative survey of health inequalities in Britain. Tanner (1981) p.147 discusses Chadwick and his surveys of height.

  211 It is precisely the antiquity of the positive association. There is a huge literature on the attractions of height. Some of it reviewed by Bogin (1999a) pp.326–7. See Sandberg et al. (1994), Guyda (1998) and Root (1998) on growth-hormone therapy for short children.

  CHAPTER VII: THE DESIRE AND PURSUIT OF THE WHOLE

  217 In February 1868, a Parisian. For the journal and other relevant papers see Barbin (1980). Confusingly, Herculine Adélaïde (Alexina) refers to herself as ‘Camille’.

  221 Is Alexina a woman? Chesnet (1860) Annales d’hygiène et de médecine légale 2e série, XIV: 206 quoted in pp.124–8 of Barbin (1980). See Goujon (1869) for her autopsy. See Dreger (1998) for a social history of hermaphrodites.

  223 Anatomists, however, have other tastes. Laqueur (1990) claims that Vesalius’ and Galen’s homologies are confirmed by modern, or rather nine-teeth-century, embryology, but this is not so. Thiery and Houtzager (1997) p.51 describe the background of Vesalius’ analysis of the vagina and note that Vesalius so loved his homology between the uterus and scrotum that he depicted the former with a dividing cleft comparable to the raphe of the scrotum where there is none.

  225 It was another Paduan anatomist. Laqueur (1989) delves deeply into the history of the identity of male and female genitalia. O’Connell et al. (1998) redescribe the vestibular bulbs as the clitoris; Williamson and Nowak (1998) add further details about the discovery; Kobelt (1844) gives an earlier view.

  228 By day 28. Descriptions and timing of embryological events are from McLachlan (1994). I have omitted a description of the internal genitalia (fallopian tubes, uterus and upper vagina, epididymus, vasa deferentia and seminal vesicles), all of which have other embryological origins and are controlled by other hormones.

  230 To develop as a female is to travel. For an account of the discovery of the Y see Mittwoch (1973); XX[n]Y males are also often mentally retarded and sterile. The condition is known as Kleinfelter syndrome and occurs a frequency of 1 in 1000 male births (Conner and Ferguson-Smith 1993).

  231 The search for the source of the Y’s power. The papers that describd SRY (480000) in humans and mice are Sinclair et al. (1990); Gubbay et al. (1990); McLaren (1990) gives a contemporary commentary.

  233 Perhaps SRY activates a few critical genes. For an update of the genes known to be regulated by SRY in the gonad see Graves (1998). For Alexandre Jost’s experiments see Jost (1946–47). The results described are true for rabbits castrated before day 22 post coitem.

  234 Or at least it needs its Leydig cells. The testosterone synthesis pathway can be upset at many points. Luteinising hormone is needed for proper Leydig cell growth. Mutations in the luteinising hormone receptor gene (152790) cause Leydig cell hypoplasia and so pseudohermaphroditism (Kremer 1995 and Laue et al. 1996). Then various mutations can disrupt the testosterone biosynthetic pathway (Besser and Thorner, 1994). Some of these cause a group of syndromes known as the congenital adrenal hyperplasias (CAH) (e.g. 201910) since they affect not only testosterone synthesis but the synthesis of other steroids by the adrenal gland as well and have, accordingly, widespread physiological effects. Good examples of testoterone synthesis mutations are those in the 17-? hydroxysteroid dehydrogenase gene (605573) (Russell et al. 1994; Geissler et al. 1994).

  235 Such girls are, it is often said, exceptionally feminine. Androgen insensitivity syndrome (300068) caused by mutations in the testosterone receptor gene (313700). For the height of testosterone receptor-null people see Quigley et al. (1992). For the identical twin flight attendants see Marshall and Harder (1958); for the French model see Netter et al. (1958).

  236 Alexina/Abel and Marie/Germain were both isolated cases. Montaigne, the humanist, attributed Marie/Germain’s sex change to sublimated sexual desire; Pare, the (evidently Vesalian) surgeon, thought that the exertion of the chase had caused Marie’s genitals to fall out. Montaigne (1580; 1958) p.38; Paré (1573; 1982) p.31. For the Dominican Republic guevedoche see Imperato-McGinley et al. (1974); for the Papua New Guinea kwolu-aatmwol see Imperato-McGinley et al. (1991). The mutated gene in all these cases has either been shown, or else is presumed to be, 5-?-reductase (264600; 607306).

  238 When I said that the route to femininity. For infant female pseudohermaphroditism caused by deficiency in aromatase (107910) see Shozu et al. (1991); for the adult aromatase deficiency see Conte et al. (1994) and Morishima et al.(1995). For aromatase excess (shortness, gynecomastia in boys, large breasts in girls) due to dominant gain-of-function mutations, see Stratakis et al. (1998).

  240 Spotted hyenas are unsympathetic creatures. See Neaves et al. (1980); Glickman et al. (1992); Licht et al. (1992); Holekamp et al. (1996) and Frank (1997) for spotted hyena endocrinology, genitalia and social structure. Moles (Talpa) also have a kind of female pseudohermaphroditism – although they actually have ovotestes, so could be said to be true hermaphrodites.

  242 In The symposium. Plato, The symposium pp.59–65 (trans. W. Hamilton. 1951. Penguin Books, Harmondsworth, UK). For sexual relations of the gue
vedoche and kwolu-aatmwol see Imperato-McGinley et al. (1991) and Herdt (1994).

  CHAPTER VIII: A FRAGILE BUBBLE

  247 Our species has, since 1758. Bendyshe (1865) gives a summary and English translation of Linnaeus’ anthropological works; Pearson et al. (1913) and Broberg (1983) discuss Homo troglodytes. Lindroth (1983) discusses Linnaeus’ intellectual roots in medieval thought.

  251 His French rival Buffon. For an account of Geneviève see Buffon (1777)Addition à Particle qui a pour titre, Variétés dans l’espèce humaine, Supplement à l’histoire naturelle volume 4 pp.371–454.

  253 We are a polychrome species. For a general review of pigmentation genetics see Sturm et al. (1998). The most common form of albinism is oculocutaneous albinism type 1 or OCA1 (203100), which is due to recessive mutations in the tyrosinase gene (606933). Albinism with grey eyes is oculocutaneous albinism type 2 or OCA2 (203200), due to recessive mutations in the P gene (Durham-Pierre et al. 1994; Stevens et al. 1997).

  254 In 1871, en route to his encounter with the Aka. See Schweinfurth (1878) volume 2 pp.100–1 for his account of albinos in Africa, and Woolf and Dukepoo (1969) for albinos among the Hopi.

  255 Those children would have fascinated Buffon. For the history of Marie Sabina see Buffon (1777) p.557. Pearson et al. (1913) and Dobson (1958). For some of the other eighteenth-century piebalds see Blanchard (1907). For Lisbey’s history see Pearson (1913). Pearson’s insistence on this rather forced account of the inheritance of piebaldism stems, again, from his opposition to the Mendelian theory of inheritance.

  261 Molecular devices are required. Piebald trait, white forelock and bilateral hypopigmentation of the limbs and trunk (172800) is caused by dominant mutations in c-Kit (164920) which encodes a receptor tyrosine kinase. c-Kit’s ligand is steel (Sl) in mouse, but no human disorder has been identified with mutations in this gene. c-Kit and its ligand are thought to help in guiding the migration of the presumptive melanocytes. The other piebald syndromes often only cause white forelock but are associated with deafness or megacolon. These are Waardenburg’s syndromes types I through IV (193500, 193510, 602229), caused by dominant mutations in Pax3, Sox10 and MITF (Tassabehji et al. 1992; Watanabe et al. 1998). These genes are transcription factors needed for specification of melanocyte lineages (Goding 2000). All these syndromes manifest variably, all are caused by dominant mutations; homozygotes are probably lethal.