Sex Determination Secondary article

Joe Leigh Simpson, Baylor College of Medicine, Houston, Texas, USA Article Contents

. Reproductive Embryology Sex determination is the process by which genes direct male and female embryos to . Sex Determination in Males: Genes and Chromosomes become distinguishable from each other. Influencing Testicular Differentiation . Sex Determination in Females: Genes and Chromosomes Influencing Ovarian Differentiation Reproductive Embryology . True Hermaphroditism: An Autosomal Disorder of Gonadal Differentiation Primordial germ cells originate in the endoderm of the yolk . Selected Disorders of External Genital Development in sac and migrate to the genital ridge to form the indifferent 46,XX: Female Pseudohermaphroditism gonad. Initially, 46,XY and 46,XX gonads are indistin- . Selected Disorders of External Genital Development in 46,XY: Male Pseudohermaphroditism guishable. Indifferent gonads develop into testes if the . (Seminiferous Tubule embryo, or more specifically the gonadal stroma, is 46,XY. Dysgenesis) This process begins about 43 days after conception. Testes become morphologically identifiable 7–8 weeks after conception (9–10 weeks’ gestational or menstrual weeks).

Testicular differentiation tosterone is then converted by 5a-reductase to dihydro- testosterone (DHT), and it is this hormone that is Sertoli cells are the first cells to become recognizable in responsible for external genitalia virilization. These actions testicular differentiation, organizing the surrounding cells can be mimicked by the administration of testosterone to into tubules. Leydig cells and Sertoli cells exert their female or castrated male embryos. function in dissociation from testicular morphogenesis; Fetal Sertoli cells produce the nonandrogenic glycopro- thus, these cells direct gonadal development, rather than tein antimu¨ llerian hormone (AMH), also called mu¨ llerian the converse. These two cell types secrete different inhibitory substance (MIS); AMH diffuses locally to cause hormones, which in aggregate direct the embryo to develop regression of mu¨ llerian derivatives (uterus and fallopian into a male (Figure 1). tubes). This hormone may have functions related to Fetal Leydig cells produce testosterone, a hormone that gonadal development as well, given that when AMH is stabilizes wolffian ducts and permits differentiation of the chronically expressed in XX transgenic mice oocytes fail to vasa deferentia, epididymides and seminal vesicles. Tes- persist. Tubule-like structures develop in gonads, and mu¨ llerian differentiation is abnormal.

Indifferent gonad Ovarian differentiation In the absence of a Y chromosome, the indifferent gonad Product(s) of Y develops into an ovary. Transformation into fetal ovaries testicular determinant begins at 50–55 days of embryonic development. Germ cells are initially present in 45,X embryos (Jirasek, 1976), Embryonal testis but undergo atresia at a rate more rapid than that occurring in normal 46,XX embryos.

Testosterone Müllerian inhibitory factor Wolffian stabilization Müllerian inhibition Persistence of Regresssion of uterus, seminal vesicles fallopian tubes and Ductal and genital differentiation 5α-Reductase Vasa deferentia upper vagina Epididymides Ductal and external genital development occurs indepen- dently of gonadal differentiation. In the absence of Dihydrotestosterone Penis testosterone and AMH, external genitalia develop in Genital virilization Scrotum female fashion. Mu¨ llerian ducts form the uterus and Labioscrotal fusion fallopian tubes; wolffian ducts regress. These changes Figure 1 Embryonic differentiation in the normal male. Modified from occur in normal XX mammalian embryos and XY Simpson JL (ed.) (1976) Disorders of Sexual Differentiation. New York: mammals that were castrated (embryonically) before Academic Press. testicular differentiation.

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Sex Determination in Males: Genes and DAZLA (Deleted in AZoospermia-Like Autosomal Chromosomes Influencing Testicular homologue), located on human chromosome 3. Differentiation and testicular development Sex chromosomes (X and Y) as well as the In addition to genes on the Y chromosome, various clinical contain loci that must remain intact for normal testicular disorders indicate that testicular differentiation also development. requires loci on X. The importance of genes on the X chromosome has long been evidenced by an X-linked Y chromosome recessive form of XY (Simpson et al., 1971; German et al., 1978). Of more recent interest is the In mammals a single Y can direct male sex differentiation, demonstration of a region on the X short arm (Xp) that irrespective of normal X chromosomes (e.g. 47,XXY or suppresses testicular development when duplicated in 48,XXXY). Thus, sex determination in mammals differs 46,XY individuals. This Dose-Sensitive Sex reversal fundamentally from that in Drosophila, a species in which (DSS) phenomenon involves a region that contains the the ratio of the X chromosomes to autosomes determines locus for adrenal hypoplasia (AHC). Its murine homo- sex. The major testicular determinants (testis-determining logue is Ahch. We shall allude later to the role this gene has factor) in humans were localized to the Y short arm (Yp) in been purported to play in primary ovarian differentiation. the 1960s. Since the early 1990s it has become clear that sex- determining region Y (SRY) is the testicular determinant (Sinclair et al., 1990). Autosomes and testicular development SRY was identified as result of mapping that took Several different autosomal regions are pivotal for advantage of the syndrome of phenotypic males who are testicular differentiation. Based somewhat on circumstan- 46,XX and phenotypic females who are 46,XY. Pheno- tial reasons, it has been postulated that several genes (Sf-1, typic males with a 46,XX complement usually (80%) arise WT-1) are necessary for the indifferent gonad to differ- following interchange of not only the obligatory pseu- entiate into the testes. That is, they act upstream of SRY. doautosomal regions of Xp and Yp, but also the Other genes are presumed to act downstream, i.e. after contiguous nonpseudoautosomal region that contains SRY exerts its action. Among the latter is the locus the testis determinants. In these cases SRY is mapped to responsible for camptomelia dysplasia and XY gonadal the smallest translocated region compatible with male dysgenesis (sex reversal), located on 17q24.3!q25.1. This differentiation. Some sporadic XY females also show point region encompasses SOX-9, which, like SRY, is a DNA- mutations within SRY. SRY is composed of two open binding protein. Other autosomal regions that preclude reading frames consisting of 99 and 273 amino acids, testicular development when deleted include 9p and 10q. respectively. The pivotal sequence involves a high-mobility Further evidence of autosomal control over testicular group (HMG) box that shares features in common with development is the existence of testicular differentiation in other DNA-binding sequences. SRY is expressed before 46,XX true hermaphrodites, almost all of whom lack SRY. testicular differentiation is manifested and transgenic XX The responsible loci must therefore be autosomal. mice with SRY show testicular differentiation (Koopman Furthermore, in mice the Mus pociavinus Y is not always et al., 1991). capable of directing testicular differentiation. When placed on a predominately C57 autosomal background murine, Y chromosome and spermatogenesis true hermaphrodites result. Thus, murine autosomes play a role in preserving testicular development. The number of Deletions of Y long arm (Yq) may be associated with autosomal genes exerting actions both downstream and azoospermia. About 10–15% of azoospermic men have upstream from SRY is uncertain. The review of Ottolenghi deletions in DAZ (Deleted in AZoospermia), and about 5– et al. (1998) constitutes a good synthesis. 10% of oligospermic men have deletions. Several loci exist, but their exact number and interrelationship are uncertain. One popular model assumes three loci: AZFa, the rarest and whose phenotype is associated with absence of spermatogenesis and stem cell; AZFb, whose phenotype shows maturational arrest and corresponds to a locus called RNA-Binding Motif (RBM); and AZFc, associated with both azoospermia and oligospermia and considered to contain the locus DAZ. Autosomal genes are also important for spermatogenesis. One well-known locus is

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Sex Determination in Females: Genes X and Chromosomes Influencing Ovarian The chromosomal abnormality most frequently associated with ovarian dysgenesis is absence of one X (monosomy Differentiation X), also referred to as . In most 45,X adults with gonadal dysgenesis, the normal gonad is DAX 1 and the potential existence of a primary replaced by a white fibrous streak, located in the position ovarian determinant ordinarily occupied by the ovary. That germ cells are usually absent in 45,X adults despite being present in 45,X In the absence of a Y chromosome, the indifferent gonad embryos is the basis for the belief that the pathogenesis of develops into an ovary. Given that germ cells exist in 45,X germ cell failure is increased atresia, not failure of initial human fetuses (Jirasek, 1976) and 39,X mice, the germ cell formation. Oestrogen levels are low; gonado- pathogenesis of germ cell failure must involve increased tropins (follicle-stimulating hormone, FSH, and luteiniz- germ cell attrition, not failure of formation. If two intact X ing hormone, LH) are increased. Short stature and various chromosomes are not present, 45,X ovarian follicles somatic anomalies may occur – skeletal, cardiac, renal and usually degenerate by birth. The second X chromosome auditory. Verbal IQ is greater than performance IQ, but is therefore accepted as responsible for ovarian main- overt mental retardation is uncommon. tenance, as opposed to primary ovarian differentiation. That 45,X adults lack germ cells as adults is not so It is unclear whether primary ovarian differentiation predictable as one might expect. Relatively normal ovarian requires a specific gene, or rather occurs constitutively as development occurs in many other monosomy X mammals the default pathway in the absence of SRY and the other (e.g. mice). The likely explanation is that in humans not all testicular determinants. Some have focused on the Xp loci on the normal heterochromatic (inactive) X are region that, when duplicated, directs 46,XY embryos into inactivated. Indeed, about 15–20% of the human X-linked females. Could the region play a primary role in ovarian genes escape X-inactivation. Loci on Xp are far more likely differentiation in 46,XX individuals? The relevant region in to escape X-inactivation than those of Xq (perhaps 20– humans contains AHC (adrenal hypoplasia congenita) or 30% versus 1–2%). Genes that escape X-inactivation DAX 1 (dosage-sensitive sex reversal/adrenal hypoplasia appear to be clustered, and it is in these regions that key critical region X). Its mouse homologue is Ahch. Ahch is ovarian maintenance determinants are likely to occur. In upregulated in the XX mouse ovary, and transgenic XY addition, X-inactivation never exists in oocytes, X- mice overexpressing Ahch develop as females, at least in reactivation of germ cells occurring before entry in meiotic the presence of a relatively weak Sry. However, if XX mice oogenesis. lose Ahch (knockout) ovarian development is not impaired Clinically, 45,X women should be counselled to antici- and ovulation and fertility are normal (Yu et al., 1998). pate primary amenorrhoea and sterility. With hormone Furthermore, XY mice mutant for Ahch show testicular therapy uterine size becomes normal, and 45,X women can germ cell defects. Thus, Ahch is clearly not a primary carry pregnancies in their own uterus after receipt of donor ovarian differentiation in mice, and presumably neither is embryos or donor oocytes. The latter could be fertilized in human DAX 1. There remains no evidence that primary vitro with their husband’s sperm (assisted reproduction ovarian differentiation is other than passive (constitutive). technology) and resulting embryos transferred to the hormonally synchronized 45,X patient. Success rates per cycle are 20–40%. X-ovarian maintenance genes Irrespective of whether a primary ovarian-determining gene exists, regions of the X chromosome are important for Genes on the X short arm ovarian maintenance. The location and role of these Deletions of the short arm [46,X,del(Xp)] show variable ovarian maintenance determinants traditionally have been phenotype, depending upon the amount of Xp persisting. deduced by phenotypic–karyotypic correlations of indivi- Approximately half of 46,X,del(Xp)(p11) individuals show duals with absence of the X short arm, the X long arm, or primary amenorrhoea and gonadal dysgenesis (Simpson, the entire X (monosomy X). Each arm of the X has several 1998; Figure 2). The others menstruate and show breast distinct regions of differential importance for ovarian development, or show premature ovarian failure. Mole- maintenance. Pinpointing the location molecularly has cular analysis has somewhat refined the key region, but still proceeded more slowly than delineation of the Y. only to proximal–mid Xp. No candidate gene has been Considering phenotype as a function of region of the X proposed. Women with more distal deletions [del(X)(p21.1 deleted is genetically and clinically informative. to p22.1.22)] menstruate more often, but some are infertile or have secondary amenorrhoea. This distal locus [Xpter!p21] thus plays a less important role in ovarian maintenance than loci on Xp11 (Simpson, 1998).

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22.3 unknown, but several general hypotheses seem reasonable. 22.2 One possibility is a disturbance of meiosis, a mechanism 22.1 that can also be invoked to explain occurrence of germ cell 21 breakdown in both monosomy X and balanced chromo- 11.4 11.3 somal translocations. In plants and lower mammals, 11.2 meiosis is under genetic control, and it is likely that this 11.1 11 Primary amenorrhoea is true in humans as well. Other pathogenic possibilities 12 Secondary amenorrhoea include interference with germ cell migration, abnormal 13 oligomenorrhoea connective tissue, failure of DNA repair mechanisms, Fertility or regular menses disturbance of cell cycle check points, heat-shock proteins 21 (the chaperone proteins that accompany steroid recep- 22 tors), and receptor defects. Many autosomal 23 genes in mice and Drosophila deleteriously affect germ cell 24 development or gametogenesis, and are thus attractive 25 candidate genes for human XX gonadal dysgenesis. Often 26 the phenotype of these murine ‘knockout’ models is 27 28 restricted to germ cell abnormalities in the ovary or testes, genes being predicted to act in ways disparate from germ Figure 2 The X chromosome showing ovarian function as a function of cells deficiency or errors of gametogenesis. terminal . In familial cases involving Xq deletions, each Several distinct forms of XX gonadal dysgenesis exist. individual is counted. From Lobo RA (ed.) (1998) Perimenopause, Serono These genes include various pleiotropic genes that cause Symposium USA, Norwell, MA. New York: Springer-Verlag. ovarian failure and various somatic anomalies, galacto- saemia, 17a-hydroxylase deficiency, aromatase deficiency Genes on the X long arm and FSH or LH receptor defects. Almost all terminal deletions originating at Xq13 are associated with primary amenorrhoea, lack of breast development, and ovarian failure (Figure 2). Xq13 is thus a key region for germ cell (ovarian) maintenance. Loci True Hermaphroditism: An Autosomal could lie in proximal Xq21, but not more distal given that Disorder of Gonadal Differentiation del(X)(q21!q24) individuals menstruate far more often. In more distal Xq deletions (Xq25–28), the usual True hermaphrodites have both ovarian and testicular phenotype is not complete ovarian failure, but premature tissue. They may have a separate ovary and a separate ovarian failure (i.e. menopause under age 40 years) testis, or, more often, one or more ovotestes. Most true (Simpson, 1998). Distal Xq thus seems less important for hermaphrodites (60%) have a 46,XX chromosomal ovarian maintenance than proximal Xq, but the former complement; others have 46,XX/46,XY, 46/XY, 46,XX/ still plays a role in ovarian maintenance. 47,XXY, or rarer complements. Phenotype may reflect One candidate gene has been proposed: Diaphanous, the , but it is generally preferable merely to general- human homologue of the Drosophila melanogaster gene ize about the phenotype of all true hermaphrodites. diaphanous. In Drosophila this gene causes sterility in both If no medical intervention were to occur (in modern males and females. Human DIA maps to Xq21, and in one societies a rarity), two-thirds of true hermaphrodites Xq21; autosomal translocation characterized by sterility, would be raised as males. By contrast, external genitalia DIA was perturbed (Bione et al., 1998). However, in other are usually ambiguous or predominantly female. Breast Xq21; autosomal translocations conferring sterility, DIA is development usually occurs at , despite the not perturbed; nor is Xq21 the pivotal region. More distal predominantly male external genitalia. Gonadal tissue Xq deletions [del(X) (q25)] are far more likely to be may be located in the ovarian, inguinal or labioscrotal associated with premature ovarian failure (POF), or to regions. A testis or an ovotestis is more likely to be present show no abnormalities at all. on the right than on the left. Spermatozoa are rarely present; however, apparently normal oocytes are often Ovarian maintenance genes on autosomes observed, even in ovotestes. A few 46,XX true hermaph- Ovarian failure histologically similar to that occurring in rodites have even become pregnant, usually but not always individuals with an abnormal sex chromosomal comple- after removal of testicular tissue. A uterus is usually ment may be present in 46,XX individuals. Mosaicism has present, although sometimes bicornuate or unicornuate. been excluded in affected individuals, although mosaicism Absence of a uterine horn usually indicates ipsilateral testis restricted to the embryo can never be excluded. or ovotestis. The mechanism underlying failure of germ cell persis- tence in most forms of 46,XX gonadal dysgenesis is

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Acetate

Cholesterol A C D Pregnenolone 17α-OH Pregnenolone Dehydroepiandrosterone B B B C D E 17α-OH Progesterone Androstenedione Testosterone F F E Oestradiol 11-Deoxycorticosterone 11-Deoxycortisol Oestrone G G Corticosterone Cortisol

Aldosterone

Figure 3 Important adrenal and gonadal biosynthetic pathways. Letters designate enzymes required for the appropriate conversions. A, 20a- hydroxylase, 22a-hydroxylase and 20,22-desmolase; B, 3b-ol-dehydrogenase; C, 17a-hydroxylase; D, 17,20-desmolase; E, 17-ketosteroid reductase; F, 21-hydroxylase; and G, 11-hydroxylase. From Simpson JL (1976) Disorders of Sexual Differentiation: Etiology and Clinical Delineation. New York: Academic Press.

46,XX/46,XY and 46,XY true expected in 46,XX individuals. In male pseudohermaph- hermaphroditism roditism external genital development is at odds with that expected in 46,XY individuals. 46,XX/46,XY true hermaphrodites are usually chimaeras. The most common cause of female pseudohermaphro- In a single individual there are two or more cell lines, each ditism is congenital adrenal hyperplasia, resulting from derived from different zygotes. 46,XY cases may be deficiencies of the various enzymes required for steroid unrecognized chimaeras. However, chimaerism is an biosynthesis (Figure 3): 21-hydroxylase, 11b-hydroxylase, unlikely explanation for 46,XX true hermaphrodites. and 3b-ol-dehydrogenase. In each disorder inheritance is Explanations for the presence of testes in individuals who autosomal recessive. These first two genes are mitochon- ostensibly lack a Y include: (1) translocation of SRY from drial P-450 enzymes, located on chromosomes 6 and 8, the paternal Y to the paternal X during meiosis; (2) respectively. 3b-ol-Dehydrogenase is a microsomal en- translocation of SRY from the paternal Y to a paternal zyme coded by a gene on . In 21-hydroxylase ; (3) undetected mosaicism or chimaerism; and deficiency molecular pathogenesis includes gene conver- (4) autosomal sex-reversal genes. sion involving a contiguous pseudogene, point mutations and deletions. In the other two enzyme deficiencies point 46,XX true hermaphroditism mutations predominate and, as in 21-hydroxylase defi- ciency, no single nucleotide is consistently involved. 46,XX true hermaphrodites almost never show SRY or The common pathogenesis involves decreased produc- DNA sequences from their father’s Y. Genes seem more tion of adrenal cortisol, a glucocorticoid that regulates likely explanations, given existence of sibships showing XX secretion of adrenocorticotrophic hormone (ACTH) true hermaphroditism, or occurrence of both 46,XX males through negative feedback inhibition. If cortisol produc- and 46,XX true hermaphrodites. In these kindreds 46,XX tion is decreased, ACTH secretion increases. Elevated males usually show genital ambiguity, unlike the typical ACTH levels lead to increased quantities of steroid 46,XX male (Simpson, 2000). precursors, from which can be synthesized. Because the fetal begins to function during the third month of embryogenesis, excessive production of adrenal androgens will virilize the external genitalia. Selected Disorders of External Genital Mu¨ llerian and gonadal development are normal because Development in 46,XX: Female neither is dependent. Pseudohermaphroditism

In some disorders of sexual development, gonadal devel- opment is normal but abnormalities exist in external or internal genital development. In female pseudohermaph- roditism external genital development is at odds with that

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Selected Disorders of External Genital of a phallus that resembles a clitoris more than a penis, a perineal urethral orifice, and usually a separate, blindly Development in 46,XY: Male ending, perineal orifice that resembles a vagina (pseudo- Pseudohermaphroditism vagina). This disorder results from deficiency of the enzyme 5a- There are a number of different forms of male pseudo- reductase, which is necessary to convert testosterone to hermaphroditism (Simpson, 2000). In male pseudoher- dihydrotestosterone (DHT). That intracellular 5a-reduc- maphroditism testes are present as expected for 46,XY tase deficiency results in this phenotype is consistent with individuals. However, external genitalia fail to develop as virilization of the external genitalia during embryogenesis expected in males. requiring dihydrotestosterone; wolffian differentiation requires only testosterone. Two 5a-reductase (SRD5) genes exist. The Type I gene is Defects in testosterone biosynthesis located on (SRD5A1), the Type II gene Male pseudohermaphroditism (genital ambiguity) due to (SRD5A2) on chromosome 2p23. Expressed in gonads, deficiencies in testosterone biosynthesis may result from Type II mutations produce male pseudohermaphroditism. deficiencies of 17a-hydroxylase, 17,20-desmolase, 3b-ol- dehydrogenase or 17-ketosteroid reductase (Figure 3). A LH receptor defect () mutation may also involve StAR, the protein responsible for transporting cholesterol to the nucleus in order that it In complete absence of Leydig cells 46,XY individuals can be converted to pregnenolone. Deficiencies of 21- or show female external genitalia, no uterus and 11b-hydroxylase, the most common causes of female bilateral testes devoid of Leydig cells. The molecular basis pseudohermaphroditism, do not cause male pseudoher- is a mutation in the LH receptor gene, located on maphroditism. chromosome 2.

Androgen insensitivity In complete androgen insensitivity (complete testicular Klinefelter Syndrome (Seminiferous feminization) 46,XY individuals show bilateral testes, Tubule Dysgenesis) female external genitalia, a blindly ending vagina and no mu¨ llerian derivatives. These findings are entirely predict- Males with at least one Y chromosome and at least two X able given the pathogenesis: receptors that are unable to chromosomes have seminiferous tubule dysgenesis. Usual- respond to testosterone. Antimu¨ llerian hormone (AMH) is ly they are azoospermic or severely oligospermic. The synthesized, as it is in the normal testis. Cells respond clinical condition is called Klinefelter syndrome, the normally to AMH, for which reason mu¨ llerian derivatives incidence of which is about 1 per 1000 (0.1%) liveborn regress as predicted. As also expected on the basis of the males. As already noted, the demonstration in Klinefelter testes synthesizing oestrogens in unimpeded fashion, syndrome that the mammalian Y chromosome is capable affected individuals manifest breast development and of directing male differentiation irrespective of the number feminize at puberty. Partial androgen insensitivity results of X chromosomes was the first clear indication that sex in genital ambiguity. A mild form affects only spermato- determination was fundamentally different in mammals genesis. than in D. melanogaster. Both complete and partial androgen insensitivity result In the most common form of Klinefelter syndrome – from mutations in the androgen receptor gene on Xq11– 47,XXY – seminiferous tubules degenerate to be replaced Xq12. This gene consists of eight exons; exons 2 and 3 are with hyaline material. Spermatozoa are rare in semen DNA-binding domains, whereas exons 4 to 8 are andro- analysis, but a few can usually be recovered at testicular gen-binding domains. Many different mutations have been biopsy for use in intracytoplasmic sperm injections (ICSI). reported, involving all exons. It is not always possible to External genitalia are usually well differentiated. In 80– predict phenotype on the basis of the mutation. 90% of 47,XXY men penile size is in the normal range; however, after administration of androgens the 5a-Reductase deficiency penile length may still increase by 1–3 cm. The scrotum is usually well developed and vasa deferentia normal. The These genetic males show ambiguous external genitalia at prostate is smaller than usual, presumably reflecting birth, but paradoxically virilize at puberty like normal decreased androgen levels. Plasma testosterone is approxi- males. They experience phallic enlargement, increased mately half that of normal males. The decreased androgen facial hair, muscular hypertrophy, and voice deepening, production causes lack of normal secondary sexual yet no breast development. Their external genitalia consist development. 47,XXY patients are usually not retarded.

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If mental retardation exists in a 47,XXY male, his IQ is oogenesis and implications for human sterility. American Journal of usually 50–85. Human Genetics 62: 533–541. Klinefelter syndrome may be associated with 46,XY/ German J, Simpson JL, Chaganti RSK et al. (1978) Genetically 47,XXY mosaicism, the frequency of which is probably determined sex-reversal in 46,XY humans. Science 205: 53–56. Jirasek J (1976) Principles of reproductive embryology. In: Simpson JL underestimated. 46,XY/47,XXY patients are less likely (ed.) Disorders of Sexual Differentiation, pp. 51–110. New York: than 47,XXY patients to have azoospermia, small testes, or Academic Press. decreased facial or pubic hair. Mean plasma testosterone Koopman P, Gubbay J, Vivian N, Goodfellow P and Lovell-Badge R levels are also higher in 46,XY/47,XXY, and mature (1991) Male development of chromosomally female mice transgenic spermatozoa are more likely to be detected. The Klinefelter for SRY. Nature 351: 117–121. phenotype may also be associated with the complements Ottolenghi C, Veitia R, Nunes M, Souleyreau-Therville N and Marc 48,XXXY and 49,XXXY. In these forms mental retarda- Fellous (1998) Genetics of sex determination and its pathology in man. In: Kempers RD (ed.) Fertility and Reproductive Medicine, pp. 723– tion is consistently present. Somatic anomalies occur more 734. Amsterdam: Elsevier Science. often in 48,XXXY and 49,XXXXY than in 47,XXY. Simpson JL (1998) Genetics of oocyte depletion. In: Lobo RA (ed.) Mental retardation is often severe in the former two. Perimenopause, Serono Symposia USA, Norwell, MA, pp. 36–45. 48,XXYY patients share some features with 47,XXY New York: Springer-Verlag. and other features with 47,XYY. Testicular hypoplasia Simpson JL (2000) Genetics of sexual differentiation. In: Carpenter SEK results in poorly developed secondary sexual character- and Rock J (eds) Pediatric and Adolescent Gynecology. Philadelphia: istics, and many 48,XXYY patients have mental retarda- Lippincott Williams & Wilkins. Simpson JL, Christakos AC, Horwith M and Silverman FS (1971) tion. Somatic anomalies present are reminiscent of those Gonadal dysgenesis associated with apparently chromosomal com- occurring in 48,XXXY and 49,XXXXY. plements. Birth Defects 7(6): 215–228. Sinclair AH, Berta P, Palmer MS et al. (1990) A gene from the human References sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346: 240–244. Bione S, Sala C, Manzini C et al. (1998) A human homologue of the Yu RN, Ito M, Saunders TL, Camper SA and Jameson JL (1998) Role of Drosophila melanogaster diaphanous gene is disrupted in a patient Ahch in gonadal development and gametogenesis. Nature Genetics 20: with premature ovarian failure: evidence for conserved function in 353–357.

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