Chapter 548 Vulvovaginal and Müllerian Anomalies

The sequence of events that occur in a developing embryo and early fetus to create a normal reproductive system includes cellular differentiation, duct elongation, fusion, resorption, canalization, and programmed cell death. Any of these processes can be interrupted during formation of the reproductive system, creating gonadal, müllerian, and/or vulvovaginal anomalies (see Table 548-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). Genetic, epigenetic, enzymatic, and environmental factors all have some role in the process (see Table 548-2 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). Most clinicians use the standard classification system adopted by the American Society for Reproductive Medicine (originally the American Fertility Society [AFS] classification). Others have proposed modified and more-detailed anatomic classification systems such as the modified AFS system or the VCUAM (vagina, cervix, uterus, and adnexa-associated malformation) system.

ANOMALY	DESCRIPTION
Hydrocolpos	Accumulation of mucus or nonsanguineous fluid in the vagina
Hemihematometra	Atretic segment of vagina with menstrual fluid accumulation
Hydrosalpinx	Accumulation of serous fluid in the fallopian tube, often an end result of pyosalpinx
Didelphic uterus	Two cervices, each associated with one uterine horn
Bicornuate uterus	One cervix associated with two uterine horns
Unicornuate uterus	Result of failure of one müllerian duct to descend

Table 548-2 HERITABLE DISORDERS ASSOCIATED WITH MÜLLERIAN ANOMALIES

MODE OF INHERITANCE	DISORDER	ASSOCIATED MÜLLERIAN DEFECT
Autosomal dominant	Camptobrachydactyly	Longitudinal vaginal septa
Autosomal dominant	Hand-foot-genital	Incomplete müllerian fusion
Autosomal recessive	Kaufan-McCusick	Transverse vaginal septa
	Johanson-Blizzard	Longitudinal vaginal septa
	Renal-genital-middle ear anomalies	Vaginal atresia
	Fraser syndrome	Incomplete müllerian fusion
	Uterine hernia syndrome	Persistent müllerian duct derivatives
Polygenic/multifactorial	Mayer-Rokitansky-Küster-Hauser syndrome	Müllerian aplasia
X linked	Uterine hernia syndrome	Persistent müllerian duct derivatives

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.