Abnormalities of the müllerian ducts produce a wide range of gynecologic and urologic disorders. The clinician must manage these problems and be prepared to counsel affected individuals concerning the recurrence risks to other family members. In this chapter, we consider the cause and pathogenesis of müllerian duct anomalies. Techniques for surgically correcting these anomalies are discussed elsewhere in these volumes and in other texts.¹

Sex begins at conception. The zygote contains the genetic material—46,XX or 46,XY—that determines its future sex; however, male and female embryos are morphologically indistinguishable until 7 weeks of embryogenesis, when the male gonads first become distinct. The reproductive duct systems remain sexually indifferent until 12 weeks of gestation (10 weeks' embryogenesis). The embryo initially has two sets of paired ducts. The first are the mesonephric (wolffian) ducts, which in the male develop into the vas deferens, seminal vesicles, and epididymides. The second are the paramesonephric ( müllerian) ducts, which in the female develop into the fallopian tubes, uterus, and upper vagina. Both sexes retain embryologic remnants of the duct that regresses in their sex. Because perturbations of embryogenesis are responsible for the disorders to be discussed later in this chapter, a review of normal reproductive embryology seems appropriate.^2,3,4

The undifferentiated embryo at 3 embryonic weeks contains a hindgut, a tube that runs from the dorsal aspect of what later will become the pelvic cavity, along the middle of the inferior pole, up the midline of the ventral embryo, and out the umbilical cord. The hindgut dilates as it passes along the inferior pole of the embryo, and at this point it is called the cloaca. The tube narrows again as it runs up the ventral embryo and here is called the allantois (Fig. 1). Between 4 and 6 embryonic weeks, a solid sheet of cells, the urorectal fold, grows downward to the cloacal membrane, indenting the hindgut-cloacaallantois tube and separating the cloaca from the hindgut (Fig. 2). The hindgut later develops into the sigmoid colon and rectum. Shortly after the urorectal fold meets it, the cloacal membrane breaks down and allows the urogenital sinus to open separately from the rectum.

At 4 weeks of embryogenesis, tubes extend bilaterally from the embryonic mesonephros to the cloaca. These mesonephric ducts later become the vas deferens and epididymis in the male, but in the female, they eventually regress. Tubular buds arising from the dorsal surface of the mesonephric ducts grow upward to meet the metanephros, becoming the metanephric ducts (Fig. 3). The portion of mesonephric duct between the metanephric duct and cloaca dilates becomes incorporated into the cloacal wall (Fig. 3) and later contributes to the formation of the bladder trigone. The metanephric ducts form the ureters.

Embryonic development of males and females is similar. Subsequently, however, divergence occurs. Differential development of the male and female tubules is directed by the gonads. The principle is that all embryos develop female internal genitalia unless a functioning testis is present. Sertoli cells in the fetal testes produce müllerian-inhibiting factor (MIF), a glycoprotein that inhibits development of the paramesonephric ( müllerian) ducts. Leydig cells in the fetal testes produce testosterone, which stabilizes the mesonephric (wolffian) ducts and promotes further development of vasa deferentia, epididymides, and seminal vesicles. Genital virilization is accomplished by dihydrotestosterone, which is converted from testosterone by 5-reductase.

After 37 postovulatory days, celomic epithelium invaginates into the tissue lateral and cranial to the mesonephric duct. This solid mass of tissue grows caudally along the length of the mesonephric duct. Near the mesonephric-metanephric junctures, solid cords of tissue grow medially on both sides of the embryo toward the midline to fuse with each other. As the cords are growing caudally, a lumen appears in their cranial portion, extending toward the growing tip. These cords become the paramesonephric ( müllerian) ducts, which fuse with the dorsal wall of the urogenital sinus to produce an elevation, the müllerian tubercle. In the presence of MIF these ducts do not develop further. In the absence of MIF (i.e. in normal females), paramesonephric ducts differentiate into fallopian tubes, uterus, and superior vagina.

Proliferation of the müllerian tubercle increases the distance between the urogenital sinus and the uterovaginal lumen. Concomitant with this elongation, tissue lateral to the fused paramesonephric ducts and lying at the base of the urogenital sinus proliferates to form sinovaginal bulbs. The sinovaginal bulbs grow caudally toward the urogenital diaphragm. When canalized, these bulbs form the vestibule of the vagina. The vagina is formed caudally from the sinovaginal bulbs of the urogenital sinus and cranially from the fused paramesonephric ducts. The precise proportion of vagina derived from each embryologic structure is uncertain, although most investigators believe the point of juncture lies at or slightly above the hymeneal ring. Most of the vagina is derived from the paramesonephric ducts. However, near-normal vaginal length in most patients with müllerian aplasia attests to the uncertainty or variable embryologic derivation.

Early fusion of the paramesonephric ducts is incomplete, with a septum persisting in the early uterus. By 9 embryologic weeks, the septum is no longer present; the uterocervical junction has developed. In the female, the mesonephric ducts by this time have begun to degenerate. Remnants of the mesonephric ducts persist in the broad ligament in females and are called Gartner ducts. The upper urogenital sinus develops into the bladder and the lower portion becomes the urethra.

Vaginal Atresia

The vagina is shortened or absent in many females whose external genitalia are ambiguous (pseudohermaphrodites), but in the present context, we consider only those females who lack a vagina and whose external genitalia are otherwise normal. Two groups of individuals fulfill these characteristics: those with absence of most of the vagina and all or almost all of the uterus ( müllerian aplasia) and those with absence of a portion of the vagina but presence of a normal uterus (vaginal atresia). The two conditions are embryologically and anatomically distinct (Fig. 4). Of individuals with an absent vagina, 80% to 90% have müllerian aplasia; the remainder have vaginal atresia.^5,6,7,8,9,10

In vaginal atresia the urogenital sinus fails to contribute the caudal portion of the vagina. The lower fifth to third of the vagina is replaced by 2 to 3 cm of fibrous tissue, above which lie a well-differentiated upper vagina, cervix, uterine corpus, and fallopian tubes (Fig. 4). Ultrasound, magnetic resonance imaging, or rectal examination may verify presence of müllerian derivatives. Hydrometrocolpos can develop.

Familial aggregates of isolated vaginal atresia are rare if not nonexistent. However, vaginal atresia is often reported as part of a large series of patients with absence of vagina. Analysis of a heterogeneous sample of patients might obscure findings that would be evident if the two disorders were analyzed separately.

Vaginal Atresia in the Multiple Malformation Syndromes

Etiologically distinct from vaginal atresia in otherwise normal women is vaginal atresia present as one component of a multiple malformation complex. Table 1 summarizes several syndromes. Winter and coworkers described four siblings with a previously unrecognized autosomal recessive syndrome characterized by vaginal atresia, renal hypoplasia or agenesis, and middle ear anomalies (malformed incus, fixation of the malleus and incus).¹¹ A second malformation syndrome in which vaginal atresia occurs is the Fraser syndrome, characterized by vaginal atresia and by cryptophthalmus with its resultant blindness.¹² Other syndromes include Antley-Bixler and Bardet-Biedl (Table 1).

TABLE 1. Multiple Malformation Syndromes Associated With Vaginal Atresia

Transverse vaginal septa occur at several locations and may be complete or incomplete. These septa are usually about 2 cm thick and located near the junction of the upper third and lower two thirds of the vagina;^1,2,13 however, septa may be present in the middle or lower third of the vagina¹³ (Fig. 5). Perforations are usually central but may be eccentric in location.^14,15,16,17 If no perforation exists, mucus and menstrual fluid cannot egress; hydrocolpos or hydrometrocolpos may develop. Other pelvic organs are usually normal, although occasionally the uterus is bicornuate.

Vaginal septa presumably result from failure of urogenital sinus derivatives and the müllerian duct derivatives to fuse or canalize. This explanation is deduced from the location of the septa, which is usually at the predicted sites of urogenital sinus müllerian fusion, and the histologic nature of the septa. The cranial surfaces of septa are usually lined by columnar ( müllerian) epithelium, whereas caudal surfaces are lined by squamous epithelium (i.e. urogenital sinus invagination).

Many patients have transverse vaginal septa, polydactyly, and cardiac defects.¹⁸ The original description and most subsequent cases have been in the Amish. The eponym McKusick-Kaufman syndrome is applied to such subjects.¹⁸ The latter cases could indicate that the postulated mutant is pleiotropic, a suggestion to which Pinsky subscribes.¹⁹ Alternatively, presence of multiple abnormalities may indicate a different mutant gene. Familial aggregates are rarely observed in non-Amish kindreds; it is difficult to distinguish between these possibilities.

In support of the thesis of a single pleiotropic gene is the analysis of 54 cases by Chitayat and colleagues.²⁰ Hydrometrocolpos was estimated to be present in 95% of Amish cases, polydactyly in 93%, and cardiovascular malformations in 9%. Amish individuals may show all three anomalies, various pairwise combinations of two, or only one.²¹ Sonte and colleagues estimated penetrance to be 70% for hydrometrocolpos in females, 60% for polydactyly in both sexes, and 15% for cardiovascular defects.²² Given these probabilities, 9% of males and 3% of females could be expected to have the gene in completely nonpenetrant state.

The gene has been localized to chromosome 20p12. Homozygosity mapping for short tandem repeat polymorphism (STRP) was performed in two large Amish pedigrees; 385 markers were analyzed.²² The peak two-point logarithm of odds (LOD) score was 3.33, and the peak three-point LOD score was 5.21. Region 20p12 includes the locus for the Alagille syndrome, an autosomal recessive multiple malformation syndrome characterized by cardiac anomalies, hepatic ductal hypoplasia, and abnormal (“butterfly”) vertebrae. Alagille syndrome is thought to be caused by a perturbation of jagged1 (JAG-1).²³ However, no sequence abnormalities in jagged1 were found in two Amish cases of transverse vaginal septum (i.e. McKusick-Kaufman).²²

Two mouse mutants show urogenital and skeletal anomalies: dominant hemimelia (dh) and loop tail (lp). Both loci map to mouse chromosome 1, a region not syntenic to human 20p.^24,25,26 These mouse mutants are probably not good models for transverse vaginal septa or at least the McKusick-Kaufman syndrome variant if distinct. Another possible mouse model is ivp (imperforate vagina), an autosomal recessive mutant not yet mapped.²⁷

Vaginal Longitudinal Septa

Vaginal septa may be longitudinal (sagittal or coronal) (Fig. 6) or transverse. Longitudinal septa, which rarely produce clinical problems, probably result from abnormal mesodermal proliferation or persisting epithelium. Occasionally, these septa impede the second stage of labor. Heritable tendencies are not obvious, although no systematic studies have been reported.

Edwards and Gale reported an autosomal dominant syndrome characterized by longitudinal vaginal septum, hand anomalies, and urinary incontinence possibly because of a bladder neck anomaly.²⁸ Longitudinal vaginal septa also occurs in the Johanson-Blizzard syndrome, which is probably an autosomal recessive disorder²⁹ (Table 2).

TABLE 2. Syndromes Associated With Longitudinal Vaginal Septa

Isolated absence or hypoplasia of the cervix associated with a normal uterine corpus and a normal vagina is rare. Relatively few cases have been described, and there have been no reports of multiple affected family members.^30,31 The disorder presumably results from failure of müllerian duct canalization or increased local epithelial proliferation after canalization. Hydrometrocolpos should be anticipated. The cervical canal may also be absent in true hermaphrodites.³²

In 1997, Fujimoto and colleagues reported 7 new cases and reviewed the 51 previously reported cases.³³ They concluded that one half of all cases with cervical absence or atresia had normal vaginas; one half had complete or partial vaginal atresia (Fig. 7). Surgically created uterovaginal canalization led to menstruation in 60% of cases overall but more often if concomitant vaginoplasty was not concurrently needed (68% versus 43%). After surgical correction, pregnancies have occurred only exceptionally.^31,32,33,34

Müllerian Aplasia

Aplasia of the müllerian ducts leads to absence of the uterine corpus, the uterine cervix, and the upper portion of the vagina (Fig. 4). The foreshortened 1 to 2 cm vagina is presumably derived exclusively from invagination of the urogenital sinus. Individuals with müllerian aplasia usually consult physicians because of primary amenorrhea. Secondary sexual development is normal, but no uterine structures are palpable. Uterine remnants may exist in the form of bilateral cords. The term Rokitansky-Küster-Hauser syndrome, is often applied, sometimes if remnants persists and sometimes synonymously with müllerian aplasia.

The only disorder that ordinarily needs to be considered in the differential diagnosis is complete androgen insensitivity. Androgen insensitivity can be excluded on the basis of chromosomal studies and gonadal composition. Puberal patients with müllerian aplasia invariably have pubic hair, whereas those with androgen insensitivity usually do not.

Renal anomalies are associated with müllerian aplasia more frequently than expected by chance^{9,35,36,37,38} (Table 3). The most frequent renal anomalies are pelvic kidney, renal ectopia, and unilateral aplasia. Skeletal anomalies, especially vertebral anomalies, are not uncommon. Excretory urography and vertebral roentgenograms are obligatory in the clinical evaluation of müllerian aplasia.

TABLE 3. Urologic Anomalies in Müllerian Aplasia

Familial aggregates of müllerian aplasia have been reported, namely affected siblings.^{39,40,1,42,43} However, Lischke and associates observed three sets of discordant monozygotic twins, and autosomal recessive inheritance therefore is an unlikely explanation for all cases.⁴⁴

Autosomal dominant inheritance was considered by Shokeir to exist in Saskatchewan families in which the proband had müllerian aplasia.⁴³ In 13 of 16 families, the proband showed complete absence of the uterine cervix and corpus; in the remaining 3, uterine remnants ( Rokitansky-Küster-Hauser) were present. None of the 3 individuals with uterine remnants had an affected relative, but 10 of the 13 with complete absence of the uterine cervix and corpus did. Two of these 10 had affected siblings, whereas the other 8 had other affected paternal relatives (i.e. aunts, first cousins, second cousins, or great-aunts). Such observations suggest sex-limited (female) autosomal dominant inheritance, although other genetic mechanisms cannot be excluded. Females with the postulated mutant would manifest müllerian abnormalities, whereas males would show no deleterious effect.

In contrast to the conclusions of Shokeir were 23 U.S. families reported by Carson and coworkers.³⁸ Not a single relative was affected. Absence of affected relatives among 30 postpubertal sisters, 31 paternal aunts, and 41 maternal aunts makes sex-limited autosomal dominant inheritance at least uncommon; however, dominant genes could be restricted to certain populations, and fresh dominant mutations can never be excluded. However, absence of affected siblings and lack of paternal consanguinity speaks against autosomal recessive inheritance.

Women with müllerian aplasia have normal ovaries. A current strategy is to obtain oocytes from affected women, perform fertilization in vitro with their husband's sperm, and transfer fertilized embryos to surrogate uteri of another woman in hormonal synchrony. Resulting offspring would genetically reflect the affected woman. Petrozza and colleagues⁴⁵ surveyed U.S. assisted reproductive technology (ART) programs to accumulate 34 pregnancies in women with müllerian aplasia. Of the 34 offspring, 17 were female, and none was affected; one male child had a middle ear defect and hearing loss.

These data suggest that the most logical explanation for müllerian aplasia is polygenic/multifactorial inheritance. This is the usual mode of inheritance for malformations affecting a single organ system or embryologically related systems. Müllerian aplasia clearly fulfills these characteristics. Polygenic/multifactorial inheritance could explain the occasional reports of multiple affected siblings. After the birth of one child with a polygenic/multifactorial disorder, the recurrence risk for first-degree relatives of affected probands approximates the square root of the incidence of the trait in the population. Because müllerian aplasia is rare, the recurrence risk for siblings should be low. A theoretical recurrence risk could be calculated if accurate incidence data existed. (Risk equals square root of incidence of the trait.) Failure to detect affected sibs in a relatively small sample is consistent with polygenic/multifactorial inheritance and a low (1% to 2%) recurrence risk for first-degree relatives.

Another plausible explanation is genetic (etiologic) heterogeneity. A dominant or recessive gene could explain a minority of cases, perhaps those in certain populations; nongenetic factors or polygenic/multifactorial inheritance could explain the remainder. Genetic heterogeneity could account for the discordant results between the study of Carson and associates³⁸ and that of Shokeir.⁴³ The latter sample was derived from a different population in which a different gene could have been segregating.

Genetic heterogeneity could be deduced if some individuals affected with a given malformation show a distinctive somatic anomaly that others lack. Renal and vertebral differentiation and therefore anomalies are apparently embryologically related, but a few patients display fusion of cervical vertebrae (Klippel-Feil anomalad). However, coexistence of müllerian aplasia and Klippel-Feil anomalad is sometimes associated with middle ear anomalies.^{9,46,47,48,49,50} This triad could indicate an entity distinct from more common forms of müllerian aplasia, especially given that renal anomalies were not present in individuals with Klippel-Feil anomalad. Neurosensory hearing loss in the high-frequency range has been observed.⁵¹

In several multiple malformation syndromes, müllerian aplasia is one component (Table 4). The mechanisms presumably reflect perturbation of genes different from those responsible for müllerian aplasia in otherwise normal individuals.

TABLE 4. Syndromes Associated With Müllerian Aplasia

True duplication of the uterus is a rare anomaly that probably results from division of one or both müllerian ducts early in embryogenesis. Affected individuals have two separate uteri, each of which may have two fallopian tubes.² One or both uteri may be rudimentary or bicornuate. True duplication should be distinguished from incomplete müllerian fusion, the much more frequent condition in which each of two hemiuteri is associated with only a single fallopian tube. Understandable because hemiuteri are so much more common than true duplications, the frequent practice of referring to bicornuate uteri as a “double uterus” actually constitutes a misnomer. No familial aggregates have been reported.

Incomplete Müllerian Fusion

The müllerian ducts are originally paired organs that fuse and canalize to form the upper vagina, uterus, and fallopian tubes. Failure of fusion results in two hemiuteri, each associated with no more than one fallopian tube. Sometimes one müllerian duct fails to contribute to the definitive uterus, leading to a rudimentary horn. Figure 8 shows the different varieties of incomplete müllerian fusion. Renal anomalies coexist with all. If one uterine horn is atretic, ipsilateral renal agenesis is especially common.

Familial aggregates of incomplete müllerian fusion include multiple affected siblings and affected mothers and daughters.^{52,53,54,55,56,57,58,59,60} Individuals in the same kindred may show different forms of incomplete müllerian fusion.⁶⁰ In the only formal genetic study reported,⁶¹ only 1 (2.7%) of 37 sisters had a clinically symptomatic uterine anomaly. There were no affected mothers (0 of 24), maternal aunts (0 of 44), or paternal aunts (0 of 50). The 2.7% prevalence in siblings constitutes a minimum frequency because relatives could have been a minor uterine anomaly in asymptomatic form. Ideally, hysteroscopy, hysterosalpingography, or surgical exploration could be performed on relatives. Female relatives in some families had not yet attempted pregnancy, limiting the opportunity to manifest symptoms that would suggest an anomaly. Even with such inherent limitations, the likelihood of first-degree female relatives being similarly affected with müllerian fusion anomalies would seem to be too low to be compatible with an autosomal dominant or autosomal recessive origin. That approximately 3% of female siblings were affected in the one formal study is consistent with predictions based on polygenic/multifactorial cause, assuming further studies confirm the previously given data.

Hand-Foot-Genital Syndrome

The hand-foot-genital (HFG) syndrome is an autosomal dominant disorder in which incomplete müllerian fusion is a major component. First reported by Stern and associates, multiple kindreds have now been recognized.^62,63,64 A family first identified by our group⁵⁵ was updated by Donnenfeld and colleagues.⁶⁵ The syndrome is characterized by skeletal (hand and foot) malformations and incomplete müllerian fusion in females or hypospadias in males (with “hand-foot-genital” replacing the original appellation of “hand-foot-uterus”).^65,66 Limb abnormalities include short first metacarpals, small distal phalanges on the thumbs, short middle phalanges on the small finger and fusion of the wrist bones. Analogously, the great toe is short because of a shortened metatarsal, and the phalanx is small and pointed.

Urinary system anomalies include urinary incontinence (female), ventral displaced urethral meatus (male and female), and malposition of the ureteral orifices in the bladder wall (female).⁶⁷ These urologic anomalies differ from those usually associated with incomplete müllerian fusion. Vertebral anomalies do not seem characteristic of the HFG syndrome.

HFG syndrome should be sought in all females with uterine anomalies, because offspring of affected women have a 50% likelihood of inheriting the mutant gene. Inquiry should be made concerning the presence or absence of skeletal anomalies or genital anomalies in male and female relatives. Even in the absence of a positive family history, HFG syndrome may be considered to be present if an individual displays characteristic skeletal and genital anomalies. Such an individual would probably represent a new mutation. It is also relevant to recall that varied expressivity is characteristic of all autosomal dominant disorders. It is possible that some females with the HFG gene may manifest only uterine anomalies or only skeletal anomalies, whereas others in the same kindred show both.

That the skeletal anomalies in HFG syndrome were reminiscent of the hypodactyly (Hd) mutant in the mouse was recognized by Mortlock and colleagues,⁶⁸ who had earlier detected a deletion in murine exon 1 of HOXA13.⁶⁹ HOXA13 was a good candidate gene for human HFG. A HOXA13 nonsense mutant was observed in a member of the original HFG family reported by Stern and coworkers.⁶³ The manner by which perturbation of HOXA13 produces HFG is still uncertain, but HOXA13 is integral for differentiation or fusion/canalization of müllerian derivatives.

Incomplete Müllerian Fusion in Other Multiple Malformation Syndromes

HFG is not the only one multiple malformation syndrome associated with incomplete müllerian fusion. Table 5 shows a more complete list. Many different genes and nonmendelian factors must remain intact for normal uterine development. Whether wild-type genes for these syndromes are integral for normal müllerian differentiation is unclear. In some of these syndromes uterine anomalies may arise secondary to connective tissue or vascular perturbations. The wild-type genes are not part of the normal müllerian differentiation cascade.

TABLE 5. Syndromes Associated With Incomplete Müllerian Fusion

Ordinarily, the central portion of the hymen is patent (perforate), allowing outflow of mucus and blood. If the hymen is imperforate, mucus and blood accumulate in the vagina or uterus (i.e. hydrocolpos or hydrometrocolpos). An imperforate hymen is not uncommon. Fortunately, the anomaly is easily corrected by surgical incisions, preferably cruciform. McIlroy and Ward reported siblings who possibly had the disorder, but no other familial aggregates have been described.⁷⁰

Isolated Absence of Fallopian Tubes

Absence of a fallopian tube in an otherwise normal female is rare.^2,71 Fallopian tubes usually persist despite regression of all other müllerian derivatives (i.e. uterus, cervix, and upper vagina). Unilateral absence of the ovary may accompany ipsilateral absence of the fallopian tube.⁵⁶ This implies pathogenesis involves a vascular accident or torsion after completion of gonadal and ductal differentiation, perhaps analogous to the cause of anorchia.⁷² No familial aggregates have been reported.

Persistence of Müllerian Derivatives in Otherwise Normal Males

The uterus and fallopian tubes ( müllerian derivatives) may persist in ostensibly normal males (PMD males). External genitalia, wolffian (mesonephric) derivatives, and testes develop as expected; pubertal virilization occurs. Infertility is common, and about 5% of reported individuals develop a seminoma or other germ cell tumor. The disorder is sometimes ascertained because the uterus and fallopian tubes are found in inguinal hernias; the appellation hernia uteri inguinale has been applied. Multiple affected siblings or monozygotic twins have been recognized.⁷³ In one family, maternal half-siblings were affected, and in another maternal first cousins.^74,75

Two genes are integral to pathogenesis. One codes for anti müllerian hormone (AMH) (i.e. müllerian inhibitory substance); the other codes for the AMH receptor. The AMH gene is located on 19p, is 2800 bp long, and consists of five exons.⁷⁶ AMH can be measured by enzyme-linked immunosorbent assay, but the assay is informative only before sexual maturation, because AMH production is suppressed thereafter. When AMH is absent in PMD males, a mutation is the structural gene can usually be demonstrated. Imbeaud and colleagues⁷⁷ studied 38 PMD cases. Mutations in the AMH structural gene were found in 16, all of whom had low or nondetectable AMH levels. Fifteen different mutations were found, involving every exon except number 4. The PMD cases due to the AMH gene mutations were found by the French investigators to be predominately their Arab or Mediterranean patients. The rate of consanguinity was high, consistent with 81% of patients being homozygous for the mutation. The first three exons are most consistently involved.⁷⁸

The AMH receptor gene is located on 12q13 and consists of 11 exons. Imbeaud and colleagues⁷⁹ were the first to report a mutation in the AMH receptor in PMD, finding at that time one case among 21 AMH-positive cases. Later, this group reported 16 AMH receptor mutations. In contrast to AMH-negative cases, AMH-positive cases were not Arab or Mediterranean, but French or European. A total of 45% were homozygous for a given mutation, but consanguinity was still infrequent. In 10 of the 16 in which a mutation was found, it involved a deletion of 27 bp in exon 10. The relative molecular homogeneity is attractive diagnostically. Miniature Schnauzer dogs provide an informative animal model for AMH receptor mutations.⁸⁰

Wolffian Aplasia and Congenital Absence of the Vas Deferens

Wolffian ducts differentiate in vas 9 deferentia, epididymides and seminal vesicles. Absence of wolffian derivatives (i.e. wolffian aplasia) may be an isolated defect, or it or may be associated with absence of the upper urinary tract. The latter circumstance—absence of wolffian duct derivatives and the upper urinary tract—implies total failure of mesonephric development. Absence of wolffian derivatives without upper urinary tract anomalies implies resorption of wolffian elements after the wolffian duct reaches the cloaca. Regardless of whether absence of wolffian derivatives is accompanied by abnormalities of the upper urinary tract, the gonads are only rarely involved. More frequently, upper urinary tract is normal in individuals who lack an epididymis, vas deferens, or seminal vesicle. If wolffian aplasia is bilateral, affected individuals are infertile because of azoospermia. If the defect is unilateral, patients are usually asymptomatic.

Cystic fibrosis is the result of a mutation in the cystic fibrosis transmembrane regulation (CFTR) gene on chromosome 7, which functions as a chloride channel. It has long been known that almost all cystic fibrosis (CF) homozygotes are infertile, usually because of congenital absence of the vas deferens (CAVD). Cystic fibrosis correlates with the absence of the vas deferens. Up to 70% of males with CAVD have cystic fibrosis,⁸⁴ usually in the form of compound heterozygosity. Two mutant CFTR alleles should be assumed to be present, even if only one can be detected molecularly. The most common mutations are ΔF508 and R117H. If only one (or no) CF for CF mutations are evident, a polymorphism may exist in which five thymidines are present in a particular sequence of intron 8.⁸⁵ The presence of seven or nine thymidines has no effect. This 5-thymidine polymorphism at the site results in low (10%) transcription of CFTR protein on that (cis) chromosome. This is the result of improper exon-intron splicing loss of exon 9 and CFTR mutant protein incapable of functioning as a chloride channel. If neither CFTR mutants nor a 5-thymidine polymorphism is evident in CAVD, a rare mutation (“private”) may still exist.⁸⁵

Several older reports have described affected sibs having congenital absence of the vas deferens.^86,87,88 These familial aggregates could reflect polygenic/multifactorial cause, but it seems more likely that mutations in the CFTR locus explain familial aggregates of CAVD. If upper tract anomalies coexist, this statement would not apply.

Failure of Fusion of Epididymis and Testis

Another relatively common urologic defect is failure of the testicular rete cords of the testis to fuse with the mesonephric tubules destined to form the ductule efferentia. Spermatozoa cannot exit. If the defect is bilateral, infertility results. One or both testes may also fail to descend.

Fusion defects of this type occur in about 1% of cryptorchid and in about 1% of azoospermic men. Familial aggregates have not been reported. Fertility is achievable by aspirating sperm from the testes or epididymis and using assisted reproductive technologies like intracytoplasmic sperm injection.

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