150 years of congenital adrenal hyperplasia: translation and commentary of De Crecchio's classic paper from 1865.

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ENDOCRINOLOGY

150 Years of Congenital Adrenal Hyperplasia: Translation and Commentary of De Crecchio’s Classic Paper from 1865 Luisa Delle Piane, Paolo F. Rinaudo, and Walter L. Miller Department of Gynecology (L.D.P.), Humanitas Clinical and Research Institute, 20089 Milan, Italy; the Departments of Obstetrics, Gynecology and Reproductive Sciences (P.F.R.), and Pediatrics (W.L.M.), and the Center for Reproductive Sciences (P.F.R. and W.L.M.), University of California, San Francisco, San Francisco, California 94143

In 1865, Luigi De Crecchio, a Neapolitan pathologist, published a detailed autopsy description of Giuseppe Marzo, who lived as a man, had nearly-normal appearing male external genitalia, female internal reproductive organs, and massively enlarged adrenals. This report is widely cited as the first report of non-salt-losing congenital adrenal hyperplasia (CAH), but a complete English translation has not been available. Via interlibrary loan, we obtained the original volume containing De Crecchio’s paper. The complete 39-page publication was translated by two reproductive endocrinologists (L.D.P. and P.F.R.) who are native speakers of Italian. A pediatric endocrinologist conversant with CAH (W.L.M.) summarizes and comments on De Crecchio’s observations. Anatomically, the external genitalia were characterized by labio-scrotal fusion and a 10-cm curved phallus with hypospadias. Internally, the ovaries, tubes, and uterus were hypoplastic but otherwise normal, except that the uterus inserted into a utricle. The adrenals were massively enlarged, but this observation was dismissed as unimportant. De Crecchio’s exposition of Marzo’s life shows many of the issues affecting patients today: family ill-ease regarding genital ambiguity at birth, social pressure following reversed sex assignment in childhood, adult embarassment about genital appearance, difficulties with a legal sex assignment on a birth certificate, and substantial efforts to exhibit maleness to self and associates. De Crecchio was an astute observer who provides insight into both nineteenth-century endocrinology and continuing twenty-first-century difficulties in the care of patients with disordered sex development. (Endocrinology 156: 1210 –1217, 2015)

he year 2015 marks the 150th-year anniversary of the publication of Luigi De Crecchio’s classic, Sopra un Caso di Apparenze Virili in una Donna (A Case Report of Masculine Appearance in a Woman) in Il Morgagni, an Italian pathology journal that is no longer published (1). The paper is generally regarded as the first detailed report of congenital adrenal hyperplasia (CAH), describing the autopsy and life of Giuseppe Marzo, who lived as a man but had internal female anatomy and enlarged adrenals, and died in an apparent Addisonian crisis at the age of 44 years. The paper was brought to the general attention of modern endocrinologists by the late Professor Alfred

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Bongiovanni, who translated a few key sentences in his classic review of The Adrenogenital Syndrome in 1963 (2). De Crecchio was a well-known pathologist whose passing was noted by the British Medical Journal in 1895: “PROFESSOR LUIGI DE CRECCHIO has lately died. He was Professor of Legal Medicine in the University of Naples, and for some years was a Senator of the Kingdom. He was born at Lanciano, in Abruzzo, in 1822, and was elected Professor of Legal Medicine in the University of Naples in 1858” (3). De Crecchio was born September 11, 1832 (not 1822), graduated from the Faculty of Medicine in Naples in 1856, was appointed to the faculty in Forensic

ISSN Print 0013-7227 ISSN Online 1945-7170 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received October 30, 2014. Accepted January 27, 2015. First Published Online January 30, 2015

Abbreviations: CAH, congenital adrenal hyperplasia; DSD, disorders of sexual development; U:L, upper:lower segment ratio.

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Medicine in 1861, and died December 3, 1894 in Naples. There is a small street in Naples (Vico Luigi De Crecchio) near the university named for him in honor of his service as a member of the Italian Chamber of Deputies. He established the Institute of Forensic Medicine in Naples, was dean of the School of Medicine, and authored the textbook, Lezione di Medicina Legale (Lessons of Legal Medicine). The manuscript under consideration was written when De Crecchio was a 32-year-old junior faculty member and is written in a long, flowery nineteenth-century style of circumlocution that is difficult for today’s reader. A photocopy of the Italian text is provided as Supplemental Material 1 and a complete translation is provided as Supplemental Material 2, with the pages numbered to match the original. Here we summarize the text, reproduce the figures, and offer comments in the context of mid-nineteenth-century understanding of adrenal function. However, we leave detailed analysis of the psychological aspects of De Crecchio’s case to others. De Crecchio’s first four paragraphs introduce his collaborators in the autopsy and suggest that the case has educational value. The third paragraph states that he wishes to show how it may be difficult or impossible to determine a person’s sex. The fourth paragraph states that the autopsy was performed in January 1865 at The Hospital of the Incurables (rather than at the University of Naples), and was principally performed by Doctors L. Di Lauro and G. Teserone under the supervision of Professor F. Teserone, a private teacher, and that he was mainly an observer. In a rather ghoulish footnote (top of page 152) it is noted that the body had been procured from a cemetery, and on page 163 De Crecchio notes the autopsy was performed 15 days after death. Pages 151–155 describe the external anatomy and measurements in detail, emphasizing the masculine appearance. The body is identified as that of Giuseppe Marzo, and said to appear about 40 –50 years old. The body is washed and shaved and the color of the skin is described as “the usual cadaveric,” and “not thin nor white,” but firm and “swarthy” or “tanned” (depending on the translator); much later we are told that Marzo had huge adrenals, so he must have produced abundant ACTH; this swarthy or tanned appearance may be the hyperpigmentation of ACTH excess. A photograph of the body is shown in Plate I, Fig. 1, but this illustration is not cited in the original text (Figure 1). The body’s length was 150 cm, which would be short for a mid-nineteenth-century Neapolitan man, with an upper segment (head to pubic symphasis) of 76 cm, so that the upper:lower segment ratio (U:L) would be 76:74, a ratio of 1.03. The usual adult male U:L is approximately 0.85, but short stature and high U:L ratios are commonly seen in people who are prematurely


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exposed to sex steroids. The hairline and general appearance are described as masculine, with prominent cheekbones, nose, and thyroid cartilage, angular features, and a prominent beard that seemed to be that of “a fully masculine man.” De Crecchio notes that the ratio of head height to total body height is 1:8, as is typical of men, rather than 1:7.5, as is typical of women. This head-tobody ratio is 1:4 in newborns (as seen in Renaissance art but not in Medieval art) and changes as a consequence of the change from fetal to adult circulation at birth, and as a consequence of the subsequent actions of GH and sex steroids. The musculature of the neck is said to be “as in weak men,” and the thyroid cartilage is described as being not so pronounced as in men, but larger than in women; this is consistent with the common observation that the Adam’s apple is typically much larger in men. The nipples and areolae were less developed than in most men. The hips were narrow, and the pubic hair was in a male pattern. Other aspects of the legs from the hips to the knees were described as being typically male, whereas the feet and hands were described as feminine. However, these observations seem to be qualitative impressions unsupported by comparative measurements, and a footnote on page 155 notes that other males in the Marzo family had small hands and feet. The external genitalia are described on pages 156 –157 and shown in Plate II, but those illustrations are not specifically cited in the text (Figure 2). De Crecchio first comments that the suprapubic fat pad was large, even for a woman. The penis is described as having inferior curvature and a stretched length of 10 cm (⫺1.56 SD for an adult male) (4), with a normal-seeming glans with first-degree hypospadias (ie, at the base of the glans) (Fig. 2 of Plate II). The labioscrotal folds were hypoplasic, without rugation or pigmentation, and “formed a collar” over the shaft (what today would be called a shawl scrotum). The tissue is described as similar to the labia minora adjacent to the clitoris. No gonads were palpable up to the inguinal rings, and a perineal raphe was not apparent. At the bottom of page 156 De Crecchio suggests that he suspected that this was a female, even before the abdomen was opened. The anus was described as broad and lacking stellate wrinkles; a prostate was palpable, and catheterization of the bladder was accomplished easily, yielding urine. The description of the internal anatomy begins at the top of page 158. The abdomen is entered and there is esoteric discussion of the cremasteric muscle and the presence of a muscle alternately described as the vagina constrictor muscle of females or the bulbo-cavernosus muscle in men (cited as Fig. 1 of Plate III) (Figure 3). The path and curvature of the urethra are male but short, due to the


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tatic urethra connecting to a prostatic utricle, and several other openings in the urethra. De Crecchio points out that despite the clearly masculine urinary tract, he found a vagina, uterus, ovaries, tubes, broad ligament, and utero-ovarian ligament. Insufflating air from the urethral orifice identified a connection to the vagina and uterus with the prostatic utricle acting as a valve (cited as Fig. 2 of Plate III) (Figure 3). The openings in the prostatic urethra that looked like male ejaculatory ducts were explored with probes, showing one communicated with the vagina and the other was a dead end. The other openings in the prostatic urethra similarly had dead ends, but De Crecchio was unsure of what they represented. The vagina was 6.5 cm long with an inner circumference of 4 cm. The vaginal wall was only 2 mm thick and the inner surface was smooth and atrophic; microscopic examination did not reveal a mucosal layer, which De Crecchio attributes to the long time (15 days) between Marzo’s death and the autopsy. There follow several paragraphs describing postmortem degradation of vesicular and tubular structures that could not be identified, but were considered to be related to seminal vesicles, despite the absence of testes. A 4-mm opening in the vagina near the cervix connected to a thin-walled, fluid-filled structure “the size of a peach stone”; De Crecchio speculates that this might be prostatic fluid, and that the orifices connecting to the vagina are Figure 1. De Crecchio’s Plate I (page 185) Fig. 1 is derived from an actual photograph of from the prostate. the body after the autopsy. The text indicates the body had been shaved for the autopsy and that the hair was reattached for the photograph to ensure an accurate likeness. Fig. 2 is a drawing of the The uterus was in the expected lolarynx: a and a⬘, left and right superior vocal cords, respectively; b and b⬘, left and right inferior vocal cation with respect to the rectum and cords, respectively; c and c⬘, left and right ventricles, respectively. bladder with normal broad ligaments on both sides, and measured hypospadias. The prostate is said to be in the normal lo- 4.5 cm from fundus to os and 4.5-cm maximal internal cation and of normal size at 3.5 cm, so that the typical male width. De Crecchio indicates the uterine dimensions are anatomy of prostatic, membranous, and spongiosal ure- larger than those in nulliparous women, but that the uterthra were identified. The prostatic anatomy is said to be ine walls were very thin (2 mm). Fibrous and muscular normal, although there was a 7-mm opening in the pros- components of the tunica media were identified, but a


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and to the uterus by utero-ovarian ligaments. The right ovary measured 25 ⫻ 11 ⫻ 12 mm and the left 20 ⫻ 8 ⫻ 9 mm, which De Crecchio says gave them a narrow, elongated shape similar to that found in newborns rather than in adults. Microscopic examination revealed normal-seeming tunica albugenia and stroma, but the potential presence of a Graafian follicle was debated among the team of examining pathologists (see Fig. 3 of Plate 3). The utero-ovarian and broad ligaments were normal but the posterior utero-sacral and round ligaments were not identified. Fetal testes and Wolffian duct remnants were not identified. De Crecchio comments (page 168) that the adrenals were huge: larger than the kidneys, but remarkably he said he did not believe further investigation was necessary. It is fascinating to imagine what microscopic examination might have revealed, as adrenal zonation had not yet been described in 1865. Although the brief attention to the adrenal strikes the contemporary reader as a major oversight, the capacity of the adrenal to influence a sexual phenotype was unknown in the nineteenth century. The adrenals were not described anatomically until Lancisi published the figures from Eustacchio’s Tabulae Anatomicae in 1714. A physiologic role for the adrenals was first proposed by Addison in 1855 and confirmed experimentally in 1856 when Brown-Sequard showed that adrenalectomy was lethal to dogs, but it seems that De Crecchio was unaware of these obFigure 2. De Crecchio’s Plate II (page 187) Fig. 1, perineum: 1, mons veneris; 2, and 2⬘; rudimentary labia minora; 3, juncture of the labia minora, “forming a kind of collar above the servations, and it was not until 1938 clitoris”; 4, rudimentary right labia majora; 5, clitoris (pulled to the left with a hook); 6, glans; 7, that Philip Hench proposed that the prepuce; 8, anus. Figure 2, inferior aspect of the phallus (elevated with a hook): 2, labia minora; adrenal produced a “bisexual hor3, juncture of the labia minora; 4 and 4⬘, labia majora; 5, clitoris; 6, glans; 7, frenulum (chordee); 8, urethral meatus; 9, perineum. mone” (cortisol, made by both sexes) (for historical review, see reference 5). mucosa could not be identified, possibly due to postmor- By 1949, the distinct physiologic classes of steroids secreted by tem changes. The Fallopian tubes were 9 cm long, patent each zone were fairly well understood (6). and in the normal location as in nulliparous women. There De Crecchio describes the larynx in detail in Plate 1, Fig. were two ovaries joined to the tubal fimbriae by ligaments 2, but that illustration is not cited in the text (see Figure 1).


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Figure 3. De Crecchio’s Plate III (un-numbered page facing page 188). Fig. 1, drawing of a longitudinal view of the pelvic contents, with the pelvic bone removed from the sacroiliac and pelvic joints: 1, right lateral face of the sacrum; 2, pubic bone; 3, urinary bladder; 4, bladder ’ugula’ (prominence); 5, urethra (opened); 6, vagina opening on the ’verumontanum’ (seminal colliculus); 7 and 7⬘, openings resembling ejaculatory ducts; 8, bulbous urethra; 9 and 9⬘, prostate; 10, vagina; 11, small retrovaginal pocket; 12, small pouch; 13, opening of No. 12 into the vagina; 14, uterus (opened); 15, cervix; 16, uterine os; 17, right broad ligament containing the right ovary and fallopian tube; 18 and 18⬘, rectum; 19, left fallopian tube and fimbriae; 20, left ovary; 21, ischio-cavernous muscle (cut); 22, bulbo-cavernous muscle (cut); 23, right corpus cavernosum (cut); 24, urethral meatus; 25, skin (retracted); 26, anal sphincter; 27, anus. Fig. 2, magnification of “those parts where the anomaly is most conspicuous.” The numbered structures are as in Fig. 1; the four structures indicated by ’x’ are asymmetric openings in the prostatic urethra; the dotted lines designated a and a⬘ indicate the vaginal course from the input to the outlet in the thickness of the prostate. Fig. 3, drawing of the 620⫻ microscopic appearance of a possible Graafian follicle recognized by Professors Barone and Schron, and drawn by Professor Vizioli.


The right superior vocal cord was 15 mm long and the left 18 mm, and the arch of the right inferior cord was 18 mm and the left 21 mm, so that on the smaller right side the ventricle was 5 mm deep and the left was 4 mm. This anatomy is described as being “feminine.” He concludes that Marzo’s voice was “rather weak but virile” and suggests that people who knew him in life confirmed this impression. On pages 169 –177 De Crecchio describes Marzo’s life; one should read the full translation to appreciate the detail, depth, and poignancy of the text. Any endocrinologist who deals with patients with disorders of sexual development (DSD) will recognize common, recurring themes that remain challenging today: family embarrassment about a child with DSD, teasing and bullying, the perpetual awkwardness of feeling one is different, the difficulty in dealing with people who make assumptions, overcompensating behaviors, and the power of the sex assignment on a birth certificate. We refer to Marzo as “he” because he conducted his life as a man. Marzo was born to Anna Piatta and Raffaele Marzo in June 1820; the midwife characterized him as female and he was baptized and registered with the female name Maria Giuseppa Margharita Marzo. At age 3 months his mother pointed out some anatomic differences to the father, but he continued to be dressed and regarded as a girl until age 4 years, when a surgeon was consulted who concluded he was a boy with undescended testes. De Crecchio comments that such errors in sex assignment are common, that the penis and clitoris are similar, and that boys with hypospadias (and undescended testes) are frequently labeled as girls, but he provides no guidance toward an effective differential diagnosis of sex. Marzo’s childhood metamor-


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phosis made a profound impression on his neighbors, so that he became the subject of mockery, and although De Crecchio says that Marzo’s childhood was otherwise cheerful and carefree, he became quiet, “concentrated and meditative” as a youth. By age 17 or 18 years Marzo’s father was still uncertain about his sex, but was reassured by his masculine voice and beard growth. The father reported that his bed linens were never stained with either sperm or menstrual blood, a fact confirmed by the de Giorgio family for whom Marzo worked for the last 18 years of his life. It is not surprising that Marzo regarded himself as male, given that 29 of 33 contemporary 46,XX patients with CAH who were raised as males retained a male gender identity (7). Marzo’s father and brother stated that his “sexual instinct” developed early, and that he first had sex with a woman before he was 18 years of age. Between ages 20 and 25 years he was described as being shy, but fell in love with “a certain B., who was a pretty waitress.” They planned marriage, but Marzo’s birth certificate indicated he was female. She angered Marzo by “flirting” with other men, and they apparently went their separate ways, but De Crecchio provides no additional details. Marzo is said to have contracted “the French sickness in the form of gonorrhea” twice. In 1786 the famed Scottish surgeon John Hunter published A Treatise on the Venereal Disease, stating that gonorrhea and syphilis were a single disorder (8); the distinction between the two was only first reported by Philippe Ricord in 1838 (9), hence the “French sickness,” as Italian physicians called it, could be seen in either form. De Crecchio spoke with a pharmacist who treated Marzo (probably by intraurethra administration of silver nitrate), who indicated his surprise that the urethral orifice was not in the usual location, that the penis was bent, and that Marzo hid his genitalia to the extent possible. Despite his relations with women, De Crecchio says that Marzo “did not trust his manhood” and compensated by boasting about his sexual encounters whenever possible. De Crecchio contrasts behaviors he considers to be feminine or masculine. He describes Marzo as being patient and affectionate as a boy, who “acted as a mother to his younger sisters” and walked “with such a grace that a woman would not have known better.” He was meticulous about cleanliness and punctilious in his service to his employers, the De Giorgio family. He was quiet, methodical, intelligent, and noted for keeping secrets and confidences; he zealously guarded the house’s honor and was disinterested in the private affairs of others. He was politically liberal and intolerant of religion, especially Roman Catholic ritual, which De Crecchio says is atypical of female behavior.


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Marzo was a heavy drinker from an early age; he went out of his way to be “one of the guys,” spending evenings at taverns buying drinks and boasting about encounters with women, although such encounters were never witnessed. He had recently stopped smoking, and his habits never interfered with the performance of his duties to the de Giorgio family. Nevertheless, he endeavored to hide his genitalia from childhood to the end, even from his doctor who wished to bleed him by applying leaches to his anus (page 175). The cause of Marzo’s death is unclear from both the history and the autopsy. De Crecchio’s summation on page 177 states: “He often suffered from convulsive vomiting. Last time this happened, the vomiting was associated with copious diarrhea. This, in a few days, reduced him to a state of such severe exhaustion and weakness, that Professor Buonomo could not save him. One evening he was talking with his sister, when she felt he had a sudden gasp. She called him, he did not reply. After a few minutes he died, probably of a syncope.” Thus it appears that he died of adrenal insufficiency in an Addisonian crisis. Genetic 46,XX patients with simple virilizing CAH only rarely have Prader 5 genitalia like Marzo; life would have been much different if Marzo had been born recently. Although the medical and psychological management of DSD (10) and CAH remain complex areas of evolving opinion (11, 12), DSD would probably have been identified at birth, and/or a newborn screening program would have led to a diagnosis of CAH. A feminizing genitoplasty could have been performed in the first year of life, the sex of rearing would have been female, and the gender identity would probably have been female, as it is in 92% of 46,XX patients with CAH raised as girls (7). Hormonal replacement therapy, while still imperfect, would probably have improved his statural growth, permitted fertility (if desired) and would have saved Marzo’s life. On page 177 De Crecchio begins his Considerations, a discussion and interpretation of his findings by discussing “hermaphroditism.” He recounts “the mythological wisdom of the ancients” that early humans were hermaphrodites, having both sets of sex organs and capable of self replication. This alludes to Aristophanes’ hilarious description of the status of early humanity and the origins of sex and Love in Plato’s Symposium (13). De Crecchio says that this, and “the myth in Genesis of Eve being born of Adam’s side” are “imaginary stories” that must be replaced by “well-established facts,” a modern conceptualization that remains alien to many. De Crecchio displays broad biological knowledge in saying that there is no evidence of true hermaphroditism in humans, in the sense that plants and some “lower” animals have both male and female sex organs and are capable of self fertilization and


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reproduction. Rather, he says there are human males that look like females and females that look like males, and even individuals posessed of both sex organs, but who are nevertheless incapable of self reproduction. De Crecchio states that a simple, all-encompassing classification of human hermaphroditism is not possible and would contain too many isolated examples to be useful, hence he lists only five categories: 1) males, 2) females, 3) males with female appearance (which he calls “masculine hermaphroditism” or “androgyny”), 4) females with male appearance (which he calls “feminine hermaphroditism” or “gynandry”), and 5) individuals with both types of sex organs (which he calls “mixed” or “neutral” hermaphroditism). Using this framework, he points out that Marzo had ovaries but not testes, and hence was a female who appeared male and thus had “feminine hermaphroditism” or “gynandry.” Modern endocrinologists have not shied away from the complexities of classifying the disorders of sexual development; until recently most endocrinologists classified CAH as a form of “female pseudohermaphroditism,” much as De Crecchio did. Today Marzo would have been said to have DSD, probably secondary to nonsalt-losing 21-hydroxylase deficiency. De Crecchio’s categories 3–5 are rather similar to the contemporary terms 46,XY DSD, 46,XX DSD, and ovotesticular DSD, respectively. De Crecchio is clearly awed by the profound discordance between Marzo’s external and internal anatomy, and is at a loss to explain Marzo’s phenotype, saying that the female internal genitalia and lack of testes should have corrected the incorrect sex assignment at puberty. He concludes, “it is clear that the ovaries have never worked.” Because De Crecchio did not know that the adrenals could produce the androgens that led to Marzo’s secondary male characteristics, he incorrectly concludes that these male characteristics were the result of puberty. Obviously, De Crecchio did not understand puberty, given that the role of gonadotropins was only established in the 1950s, and even today, some endocrinologists fail to distinguish “puberty” from “sexual precocity,” using oxymoronic terms such as “gonadotropin-independent puberty.” Thus, De Crecchio concludes that Marzo’s case contradicts the standard view that sexual hair represents testicular function, saying that Marzo’s sex determination could not have been established with standard rules. De Crecchio then returns to Marzo’s sexual behavior. First he discusses the wide anus without wrinkles, speculating that this might indicate repetitive anal intercourse, but, based on the lack of other findings, eventually concludes that this was unlikely. Second, he recounts that Marzo was attracted to and had relations with women, pointing out that he had a “clitoris similar to a penis” with


the anatomical components needed for an erection, so that copulation was possible. Based on Marzo’s internal anatomy, De Crecchio speculates that ejaculation of prostatic fluid was possible, but that he had to be infertile. Although the overall appearance is important, De Crecchio says that determining someone’s sex should be based on the “genital organs.” He congratulates himself for having predicted, based on the external anatomy, that Marzo’s internal sexual organs would be female, in contrast with his supervisor, Professor Tesserone. But he also says that had he known of Marzo’s life and behavior at the time of the autopsy, he would not have drawn this conclusion. He concludes that Marzo would have been judged either as a man with cryptorchidism or that he had indeterminate sex; he speculates that, at least in the first scenario, Marzo could have married (had it not been for the female sex assignment on the birth certificate). Working in a department of “Legal Medicine,” De Crecchio speculates that if Marzo had been accused of rape, his anatomy would not have excluded the possibility. He also speculates that if he had been sued for child support, the court would certainly have considered him to be able to father children, even though the autopsy showed this was impossible, and hence would have been a miscarriage of justice. De Crecchio concludes by exhorting forensic doctors against making speculations when sufficient facts are not in evidence— advice that remains appropriate today.

Acknowledgments W.L.M. thanks Professor Stephen M. Rosenthal for helpful discussions about the psychological aspects of DSD. Address all correspondence and requests for reprints to: Paolo F. Rinaudo, MD, PhD, Associate Professor, Department of Obstetrics, Gynecology and Reproductive Sciences, 1452B-HSW, University of California, San Francisco, San Francisco, CA, 94143-0916. E-mail: [email protected]. Walter L. Miller, MD, Distinguished Professor of Pediatrics, Emeritus, Department of Pediatrics, 1401-HSE, University of California, San Francisco, San Francisco, CA, 94143. E-mail: [email protected]. Dr Delle Piane’s new affiliation is Gynecology and Obstetrics, Physiopathology of Reproduction and IVF Unit, Department of Surgical Sciences, University of Torino, Sant’Anna Hospital, via Ventimiglia 3, 10126 Torino, Italy. This work was not supported by any funding source. Disclosure Summary: The authors have nothing to disclose.

References 1. De Crecchio L. Sopra un caso di apparenze virili in una donna. Il Morgagni. 1865;7:151–189.


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2. Bongiovanni AM, Root AW. The adrenogenital syndrome. New Engl J Med. 1963;268:1283–1289; 1342–1351; 1391–1399 (in three parts). 3. Anonymous Obituary. BMJ. 1895;5:54. 4. Herbenick D, Reece M, Schick V, Sanders SA. Erect penile length and circumference dimensions of 1,661 sexually active men in the United States. J Sex Med. 2014;11:93–101. 5. Miller WL. A brief history of adrenal research: Steroidogenesis— The soul of the adrenal. Mol Cell Endocrinol. 2013;371:5–14. 6. Jacobsen AW, Koepf GF, Talbot NB, Wilkins L. Panel discussion: The adrenal gland in health and disease. Pediatrics. 1949;3:515– 548. 7. Dessens AB, Slijper FM, Drop SL. Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia. Arch Sex Behav. 2005;34:389 –397. 8. Wright DJM. John Hunter and venereal disease. Ann Roy College Surg Engl. 1981;63:198 –202. 9. Anonymous Editorial. Philippe Ricord (1800 –1889), syphilographer. JAMA. 1970;211:115–116. 10. Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics. 2006;118:e488 – e500.


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11. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95: 4133– 4160. 12. Houk CP, Lee PA. Approach to assigning gender in 46,XX congenital adrenal hyperplasia with male external genitalia: Replacing dogmatism with pragmatism. J Clin Endocrinol Metab. 2010;95:4501– 4508. 13. Plato. Symposium, 189c–193d. Translated by Michael Joyce, in: The Collected dialogues of Plato, Hamilton E, Cairns C, eds. New York, Pantheon Books, 1961. [See especially 189e–191d, where Aristophanes describes primordial hermaphrodites as being globular, with four arms, four legs, and both types of genitalia. Their great strength threatened Olympus so Zeus sliced them in two, thus halving their strength, creating two sexes and doubling his number of worshipers (and their offerings). Apollo closed the wound, leaving only the umbilicus as a scar to remind mankind of its origins. The two halves then yearned desperately to return one another, so Zeus rearranged their genitalia, permitting them to reunite, face to face, and males and females have been reuniting ever since; thus Aristophanes claimed that the origin of Love was biological.]


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