Embryology (Pathogenesis)

Phenotypic sexual differentiation, especially during formation of the vulvovaginal and müllerian systems, is determined from genetic (46,XX), gonadal, and hormonal influences (Chapter 576). The genetic sex of the embryo is determined at fertilization when the gamete pronuclei fuse. The primordial germ cells (oogonia or spermatogonia) migrate from the yolk sac to the gonadal ridges. The primitive gonads are indistinguishable until about the 7th wk of development. Gonadal development determines the progression or regression of the genital ducts and subsequent hormonal production and, thus, the external genitalia. Critical areas in the SRY region (sex-determining region on the Y chromosome) are believed to be the factors that drive the development of a testis from a primitive gonad as well as spermatogenesis. The testis begins to develop between 6 and 7 wk of gestation, first with Sertoli cells followed by Leydig cells, and testosterone production begins at about 8 wk of gestation. The genital tract begins to differentiate later than the gonads. The differentiation of the wolffian ducts begins with an increase in testosterone, and the local action of testosterone activates development of the epididymis, vas deferens, and seminal vesicle. Further male genital duct and external genital structures depend on the conversion of testosterone to dihydrotestosterone (DHT).

In a 46,XX embryo, female sexual differentiation occurs about 2 wk later than gonadal differentiation in the male. Because the ovaries develop prior to and separately from the müllerian ducts, females with müllerian ductal anomalies usually have normal ovaries and steroid hormone production. The regression of the wolffian ducts results from the lack of local gonadal testosterone production, and the persistence of the müllerian (or paramesonephric) ducts results from the absence of AMH (antimüllerian hormone or müllerian-inhibiting substance) production. The müllerian ducts continue to differentiate into the fallopian tubes, uterus, and upper vagina without interference from AMH. There are complex interactions among the mesonephric, paramesonephric, and metanephric ducts (the metanephros becomes the adult kidney) early in embryonic development, and normal development of the müllerian system depends on such interaction. If this process is interrupted, coexisting müllerian and renal anomalies are often discovered in the female patient at the time of evaluation. Differentiation along the female pathway is often referred to as the default pathway, but it is an extremely intricate process regulated by the absence, presence, or dosage compensation of numerous gene products (e.g., SRY, SF-1, WTI, SOX9, Wnt-4, GATA4, DAX-1, BMP4, HOX genes, etc.) and remains not entirely understood.

By 10 wk of gestation, the caudal portions of the müllerian ducts fuse together in the midline to form the uterus, cervix, and upper vagina, in a Y-shaped structure, with the open upper arms of the Y forming the primordial fallopian tubes. Initially the müllerian ducts are solid cords that gradually canalize as they grow along and cross the mesonephric ducts ventrally and fuse in the midline. The mesonephric ducts caudally open into the urogenital sinus, and the müllerian ducts contact the dorsal wall of the urogenital sinus, where proliferation of the cells at the point of contact form the müllerian tubercle. Cells between the müllerian tubercle and the urogenital sinus continue to proliferate, forming the vaginal plate. At the same time of the midline fusion of the müllerian ducts, the medial walls begin to degenerate and resorption occurs to form the central cavity of the uterovaginal canal. Uterine septal resorption is thought to occur in a caudal to cephalad direction and to be complete at approximately 20 wk of gestation. This theory has been scrutinized because some anomalies do not fit the standard classification system. It is possible that septal resorption starts at some point in the middle and proceeds in both directions. At about 16 wk of gestation the central cells of the vaginal plate desquamate and resorption occurs, forming the vaginal lumen. The lumen of the vagina is initially separated from the urogenital sinus by a thin hymenal membrane. The hymenal membrane undergoes central resorption and perforates before birth. The sequential steps in this intricate process could be interrupted at countless points along the pathway of differentiation.

Epidemiology

Müllerian anomalies can include abnormalities in portions or all of the fallopian tubes, uterus, cervix, and vagina. True estimates of prevalence are difficult due to the varied presentations and asymptomatic nature of some of the anomalies. Imaging techniques have made significant contributions to uterovaginal anomaly diagnoses, which has increased reporting of anomalies and led to additional combinations of anomalies. Most estimate that müllerian anomalies are present in 2-4% of the female population. The incidence increases in women with a history of adverse pregnancy outcomes or infertility: 5-10% of infertile women undergoing hysterosalpingogram, 5-10% of women with recurrent pregnancy loss, and 25% or more of women with late miscarriages and/or preterm delivery have müllerian defects.

Clinical Manifestations

Vulvovaginal and müllerian anomalies can manifest at a variety of chronological time points during a female’s life: from infancy, through childhood and adolescence, and adulthood (see Table 548-1). The majority of external genitalia malformations manifest at birth, and often even subtle deviations from normal in either a male or female newborn warrant evaluation. Structural reproductive tract abnormalities can be seen at birth or can cluster at menarche or any time during a woman’s reproductive life. Some müllerian anomalies are asymptomatic, whereas others can cause gynecologic, obstetric, or infertility issues.

Clinical manifestations and treatments depend on the specific type of müllerian anomaly and are varied. There may be a pelvic mass, which may or may not be associated with symptoms. A mass bulging at the introitus or within the vagina indicates complete or partial outflow tract obstruction. An adolescent can present with pelvic pain either in association with primary amenorrhea or several months after the onset of menarche. Patients also may be asymptomatic until they present with miscarriage, pregnancy loss, or preterm delivery. When presentation is acutely symptomatic, emergency management may be required. Obstruction can result from a number of distinct anomalies including an imperforate hymen, transverse vaginal septum, and noncommunicating rudimentary horn. As menstrual fluid accumulates proximal to the obstruction, the resulting hematocolpos and hematometra cause cyclic pain or a pelvic mass.

Laboratory Findings

Several radiographic studies have been used, often in combination, to aid in diagnosis including ultrasound, hysterosalpingogram (HSG), sonohysterography (saline-infusion sonography), and MRI. Laparoscopy and hysteroscopy was the gold standard for evaluation of müllerian anomalies, but the new standard may be MRI due to its noninvasive, high-quality capabilities. MRI is the most sensitive and specific imaging technique used for evaluating müllerian anomalies because it can image nearly all reproductive structures, blood flow, external contours, junctional zone resolution on T2 weighted images, and associated renal and other associated anomalies. MRI also has a high correlation with surgical findings because of its multiplanar capabilities and high spatial resolution. Three-dimensional ultrasound (3D US) is another useful diagnostic tool and may be superior to traditional pelvic ultrasound and HSG. Evaluation of the external contour of the uterus is important for differentiating types of uterine anomalies. This often requires a combination of radiologic modalities for uterine cavity, external contour, and possible tubal patency. Diagnostic laparoscopy or hysteroscopy may be necessary depending on the presentation, but it is used less with the advancement of MRI and other imaging.

Diagnosis of müllerian anomalies should include a physical exam, pelvic ultrasound, possibly MRI, and renal and skeletal inspections for associated anomalies. Renal anomalies are noted in 30-40% and skeletal anomalies are associated in 10-15% of patients with müllerian anomalies. Unilateral renal agenesis occurs in 15% of patients. The most common skeletal anomalies are vertebral. Patients usually have a normal female karyotype (46,XX), but several familial segregations and gene mutations and/or abnormal karyotypes have been reported (see Table 548-2). About 5-8% of patients with congenital müllerian anomalies have abnormal karyotypes. Most malformations are sporadic, with a polygenic mechanism and multifactorial etiology.

Adolescent patients can present with acute obstruction of the outflow tract due to a müllerian anomaly, which requires emergency evaluation and surgical treatment. A small percentage of girls present with concomitant urinary retention due to an altered urethral angle or pressure on the sacral plexus. Urinary hesitancy and incomplete emptying symptoms may be present before abdominopelvic pain from the obstruction in a patient of any age.

Uterine Anomalies

Anomalous development of the uterus may be symmetric or asymmetric and/or obstructed or nonobstructed. Patients can present with primary amenorrhea or have either irregular or regular menstrual cycles. There may be an asymptomatic pelvic mass or dysmenorrhea. In adolescents and adults, pregnancy loss can cause the first suspicion of a uterine anomaly. Treatment is highly specific to the specific anomaly.

Uterine Didelphys

A uterine didelphys is the result a complete failure of fusion and represents 5% of müllerian anomalies. There are 2 fallopian tubes, 2 completely separate uterine cavities, 2 cervices, and often 2 vaginal canals or 2 partial canals because of an associated longitudinal vaginal septum (75% of the time). Evaluation for renal anomalies should be pursued because they are common as well. At times, the longitudinal septum attaches to 1 sidewall and obstructs 1 side of the vagina (or hemivagina). The combination of uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis is a variant of the broad spectrum of müllerian anomalies that is referred to as the Heryln-Werner-Wunderlich syndrome (HWWS) or obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome in the literature (Fig. 548-1). Adolescents with this disorder usually present with abdominal pain shortly after menarche. Although there still may be a risk of adverse pregnancy outcomes with a uterine didelphys (preterm labor, malpresentation), overall pregnancy outcomes are generally good and are associated with less risk than in other uterine anomalies.

Figure 548-1 Occluded right hemivagina and absent right kidney. A, A 2 day old girl presented with a gray cystic mass at the vaginal introitus. B, Intravenous urography shows no right renal function (probably absent kidney). In a cystogram (not shown), the bladder was displaced forward by the mass. The patent left hemivagina could be catheterized and was found to be markedly displaced to the left. On frontal (C) and lateral (D) vaginograms, contrast material introduced through a needle inserted in the cystic mass at the introitus opacifies a markedly distended right hemivagina and uterus (unilateral hydrometrocolpos) (asterisks). Contrast material from previous studies is still present in the patent vagina (V) and bladder (b).

(From Slovis TL, editor: Caffey’s pediatric diagnostic imaging, ed 11, Philadelphia, 2008, Mosby, p 2438.)

Vaginal Anomalies

Cervical Anomalies

Congenital atresia or complete agenesis of the uterine cervix is extremely rare and often manifests at puberty with amenorrhea and pelvic pain. It is associated with significant renal anomalies in 5-10% of patients. A pelvic MRI is often warranted to completely define the abnormality. Usually, pain and obstruction are significant and a hysterectomy is necessary. Attempts to reconnect the uterus to the vagina are rarely successful and associated with significant morbidity and reoperation rates. As with most müllerian anomalies, the ovaries usually remain normal and future reproduction can still occur through the use of IVF and a gestational carrier.

Vulvar and Other Anomalies