Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

Chapter 8 • Normal and Abnormal Sexual Development 285

abortions have a 45,X karyotype. 490,491 The incidence of Turner syndrome among newborn girls ranges around 1 in 2,000–5,000 live-born phenotypic females. 492–494 Although Turner syndrome classically is associated with a 45,X karyotype, more than half of patients are mosaics (e.g., 45,X/46,XX). The prevalence of mosaicism varies directly with the method used for detection, ranging from 34% with conventional cytogenetics, to 60% with fluorescence in situ hybridization, to nearly 75% when a reverse transcriptase PCR assay is used. 495 Some patients with Turner syndrome lack only part of one X chromosome or exhibit one of a vari ety of structural abnormalities of the X, including ring chro mosomes, isochromosomes, and terminal deletions. Clinical Features The sine qua non of Turner syndrome is short stature. It is the only abnormality present in virtually all patients and can be attributed to deletion of the short stature homeobox-contain ing gene (SHOX), which is located in the pseudoautosomal region at the distal end of the short arm of the X chromosome (Xp22.33). 496,497 The classical phenotype of Turner syndrome also includes the absence of sexual development, a webbed neck, low set ears and posterior hairline, widely spaced nipples (“shield chest”), short fourth metacarpals, and an increased carrying angle at the elbow (“cubitus valgus”). The phenotype of patients with Turner syndrome relates, in part, to the parental origin of their X chromosome; most with a 45,X karyotype retain the maternal X. 498 Most women with Turner syndrome have no pubertal devel opment and primary amenorrhea. However, some develop normally and later present with secondary amenorrhea. Approximately 15% of patients with Turner syndrome begin but do not complete pubertal development and approximately 5% complete puberty and begin menstruation. 499 The streak gonads in women with Turner syndrome characteristically are com posed of connective tissue with no follicles or only a few atretic follicles. About one-third have ovaries that can be imaged with pelvic ultrasonography, and those who do more commonly exhibit spontaneous breast development at puberty. 500 Although a few women with Turner syndrome conceive naturally, preg nancies are rare and associated with a relatively high risk for sex chromosome aneuploidy and spontaneous abortion.

duct development is impaired (reflecting the decreased level of testosterone production), and the testes fail to descend, because normal descent requires the actions of testosterone and insulin-like factor 3, both deriving from Leydig cells. 484,485 The phenotype of patients with Leydig cell hypoplasia oth erwise generally correlates with the level of residual LH/ hCG receptor activity, ranging from completely female external genital development to nearly normal male geni talia. Those having no significant testosterone production appear female at birth and present at puberty with primary amenorrhea and sexual infantilism, lacking both pubic hair development (due to the lack of testosterone) and breast development (due to the absence of aromatizable substrate); the serum LH concentration is elevated and testosterone lev els are abnormally low. Others in whom LH receptor func tion is only partially impaired and testosterone production is decreased but still significant can present with ambiguous genitalia, hypospadias, or micropenis. 481,483 The hernia uterine inguinale syndrome is a rare autoso mal recessive disorder that results from a failure of mülle rian duct regression, due to mutations in the genes encoding AMH or its receptor. 486,487 Affected patients appear as normal males having an inguinal hernia containing relatively well differentiated müllerian duct structures, usually including a uterus and fallopian tubes. They have normal male inter nal and external genitalia and, usually, cryptorchid testes. In affected families, genetic studies have identified mutations in the AMH gene in 45% and in the AMHR2 receptor gene in another 39%; in the remaining 15%, no mutation was detected, implicating genes coding for other factors in the AMH transduction cascade. 488 Sex chromosome DSD describes a group of disorders asso ciated with an abnormal karyotype, including 45,X (Turner syndrome and variants), 47,XXY (Klinefelter syndrome and variants), 45,X/46,XY mosaicism (mixed gonadal dysgene sis), and 46,XX/46,XY mosaicism (chimerism). Ovotesticular DSD (true hermaphroditism), discussed in the earlier sec tion of this chapter devoted to 46,XX DSD, also can be asso ciated with a mosaic 45,X/46,XY or 46,XX/46,XY karyotype. 45,X (Turner Syndrome and Variants) Turner syndrome was first described in 1938 489 and now is recognized as important cause of short stature in girls and primary amenorrhea in young women. The disorder also is discussed in Chapter 10, as a cause of amenorrhea. Turner syndrome results from loss of all or part of an X chromosome and is very common; approximately 15% of all spontaneous Disorders of Antimüllerian Hormone and Its Receptor Sex Chromosome Disorders of Sexual Development

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Approximately 30–50% of patients with Turner syndrome have renal anomalies; horseshoe kidney is the most common and predisposes to hydronephrosis due to obstruction. 501,502 Cardiac malformations also are common. Approximately 20–30% of patients have aortic valve disease (bicuspid aortic valve, aortic root dilation) and 3–10% have coarctation 503–506 ; The prevalence of cardiac anomalies may be higher in those with a 45,X karyotype than in mosaics. 504 Other cardiovascu lar anomalies include elongation of the transverse aortic arch (49%), persistent left superior vena cava (13%), anomalous pul monary venous return (13%), and an aberrant right subclavian artery (8%); their prevalence is higher in patients with abnormal neck and chest development. 507 A prolonged QT interval can be Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.