Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

276 Section II • Clinical Endocrinology

and genitalia are divided into two halves on either side of an exposed segment of bowel; a number of variants have been described. 314 The disorder is believed to result from the failed migration of the lateral mesodermal folds of the infraumbili cal anterior abdominal wall, leading to an enlarged cloacal membrane that ruptures prematurely, before descent of the urorectal septum, sometime prior to 8 weeks of gestation. 314,315 Müllerian Agenesis (Mayer-Rokitansky-Küster-Hauser Syndrome) Müllerian agenesis is a disorder of genital development characterized by absence of the vagina, an absent or hypoplastic uterus, and normal or hypoplastic fallopian tubes. 316 The disorder is a relatively common cause of pri mary amenorrhea and is described in detail in Chapter 10 (Amenorrhea). Typically, the ovaries are entirely normal, although one or both also may be undescended, hypoplas tic, or associated with an inguinal hernia. Affected patients often also have urologic anomalies (unilateral renal agen esis, ectopic or horseshoe kidney, and duplication of the collecting systems) and skeletal malformations (e.g., hemi verterbrae and scoliosis or the Klippel-Feil syndrome, which includes a short neck, low hairline, limited range of motion, and neurologic symptoms, resulting from one or more fused vertebrae). 317,318 The cause is unknown, although some cases are associated with chromosomal translocations or occur in familial aggregates, suggesting a genetic basis. Logically, mül lerian agenesis might be attributed to an activating mutation in the gene encoding AMH or its receptor, causing excess AMH activity, but none have been identified. 319 Patients with müllerian agenesis typically present in late adolescence or as young adults with primary amen orrhea, exhibiting normal breast and pubic hair devel opment and no visible vagina. A few may have functional islands of endometrium, resulting in obstructed menses and symptoms of cyclic pain. 317,318 Evaluation should include a karyotype, renal ultrasonography, spinal x-rays, and pelvic ultrasonography or MRI when there is reason to suspect a functional uterine remnant. 320,321 Surgery generally is indi cated only for those with symptoms relating to hematome tra, endometriosis, or an inguinal hernia. When the time is appropriate, a functional vagina can be created by progres sive vaginal dilation, 322–324 traditional vaginoplasty, 325 or the modified Vecchietti operation, which is performed laparo scopically. 326,327 Women with müllerian agenesis are infertile but can expect normal sexual function and have their own genetic offspring via IVF using oocytes retrieved from their own normal ovaries and their partner’s sperms, with sub sequent transfer of embryos to a gestational surrogate. 328,329 While still experimental, uterine transplantation has become an option for patients with MRKH to carry their own preg nancy since the first report of successful live birth follow ing uterine transplant in 2015. 330 To date, approximately 40 live and deceased donor uterine transplants have been performed with numerous live births using IVF. Additional

optimization is ongoing with use of utero-ovarian vein pedi cles in live donor procedures and minimizing cold ischemia time in deceased donors. Consequently, uterine transplan tation is likely to become a more prevalent and accepted treatment. 331 Müllerian Renal Cervicothoracic Somite Dysplasia (The MURCS Association) The MURCS association is a syndrome characterized by müllerian (MU) aplasia or hypoplasia, unilateral renal (R) agenesis or ectopy and cervicothoracic somite (CS) dysplasia, which results in vertebral defects (e.g., Klippel-Feil anomaly, scoliosis), and abnormalities of the ribs, upper limbs, and scapula. 332 Other associated anomalies have included cleft lip and palate, ovarian agenesis, abnormal pulmonary fissures, tetralogy of Fallot, anorectal malformations, and transmis sive deafness. 333–336 The pathophysiology involved is unclear but logically may involve an event occurring very early in development when the blastemas of the pronephric buds and cervicothoracic buds are closely located. The disorder has similarities to the 22q11 deletion syndrome (aortic arch anomalies, facial deformities, nasal voice, mild learning difficulties, renal agenesis, autoimmune disease, and cervi cal spine anomalies) and to the Mayer-Rokitansky-Küster Hauser syndrome, suggesting a similar pathophysiology. 332,337 46,XY Disorders of Sexual Development DSD occurring in chromosomal males (46,XY) can result from abnormalities in gonadal development, from decreased fetal androgen synthesis relating to deficiencies of steroido genic enzymes or regulatory proteins, from androgen recep tor defects that prevent normal androgen action, from LH receptor defects causing Leydig cell hypoplasia, or from mutations affecting AMH or its receptor. Disorders of Gonadal (Testicular) Development Normal gonadal development requires normal germ cells and normal gonadal somatic cells. Disorders of testicular develop ment include complete gonadal dysgenesis (Swyer syndrome), partial gonadal dysgenesis (a variety of single-gene disorders and chromosomal abnormalities involving key genes), and the loss of otherwise normally developed testes during fetal life (testicular regression syndrome). In addition, a small pro portion of patients with ovotesticular DSD (discussed in an earlier section of this chapter) has a 46,XY karyotype.

Complete Gonadal Dysgenesis (Swyer Syndrome) Swyer syndrome is an uncommon form of gonadal dysgen esis, characterized by a 46,XY karyotype. 338 Despite the pres ence of a Y chromosome, the phenotype is female because the dysgenetic (streak) gonads produce neither AMH nor androgens. Consequently, the vagina, cervix, uterus, and fal lopian tubes develop normally and the internal and external genitalia do not masculinize. 339 In approximately 10–15% of Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.