Embryological observations on the female genital tract.

The embryology of the genital tract and urinary system is described, and the hypothesis is advanced that the vagina is an organ embryologically derived from the mesonephric or Wolffian ducts in addition to the Müllerian tubercle. This is based on experimental studies and case reports in the literature and our own cases of genital malformations, especially in patients with unilateral renal agenesis and an ipsilateral blind vagina. The importance of the mesonephric ducts as guides or 'inductor' elements for adequate Müllerian development is emphasized. A new embryological classification of female genital malformations is proposed, based on these embryological concepts.     

Experimental contributions to the study of the embryology of the vagina

BACKGROUND: Acién's hypothesis, deduced from patients with malformations of the female genital tract, especially those with renal agenesis and ipsilateral blind hemivagina, affirms the embryology of the human vagina as deriving from the Wolffian ducts and the Müllerian tubercle and could explain the embryological origin of all the female genital malformations reported. In this study, we investigated the hypothesis in rats. METHODS: Twenty-five pregnant rats were used to analyse female embryos (64) from day 15 (stage indifferent) to day 20 postcoitum (vagina completely formed). We performed transverse and longitudinal sections of embryos, haematoxylin-eosin tinction and immunohistochemical staining using markers specific to Wolffian derivatives. We also analysed the presence of these markers in the vagina of four adult rats. RESULTS: The Müller ducts converge until they fuse into one tube, but caudally they diverge and finally they fuse with the 'urogenital sinus bulbs' that are actually the distal portion of the Wolffian ducts according to the immunohistochemical marking with GZ1 and GZ2. The Müllerian tubercle is observed between those elements. Then, the immunohistochemical staining can be seen all along the completely formed vagina, which is also observed in the vagina of the adult rat. CONCLUSION: We prove the participation of Müller tubercle and Wolffian ducts in the formation of the vagina in rats, so we confirm experimentally Acién's hypothesis about the human vagina embryology.     

Double vagina, cardiac, pulmonary, and other genital malformations with 46,XY karyotype.

We have studied two unrelated genetic males with a novel constellation of genital, cardiac, and pulmonary malformations. The genital abnormalities consisted of a true double vagina, retention of Müllerian structures, and undervirilization of the external genitalia. Both infants had complex cyanotic congenital heart defects, hypoplastic right lungs, anomalous pulmonary venous return, and abnormalities of the diaphragm. One patient had rhabdomyomatous dysplasia of the lungs. The cause of this malformation pattern is unknown. There was no family history of similar defects, no consanguinity, no known exposure to teratogens, and no chromosome abnormality. The retention of Müllerian structures and undervirilization of male genitalia in these cases could be the result of failure in production of adequate amounts of testosterone and Müllerian inhibitory factor at appropriate times in gestation. Because the developing human vagina is at no stage a duplicate structure, a double vagina cannot be the result of arrested genital differentiation. The unusual occurrence of a true double vagina should lead to careful pulmonary and cardiac evaluation.     

Müllerian remnants of male mice exposed prenatally to diethylstilbestrol

Prenatal exposure of males to diethylstilbestrol (DES) results in reproductive tract teratogenesis, ie, retention of Müllerian duct remnants. The potential of these remnants to develop pathological changes has not been studied. Therefore, pregnant outbred CD-1 mice were subcutaneously injected with daily doses of DES (100 micrograms/kg) on days 9 through 16 of gestation. DES-exposed male offspring and age-matched control male mice were sacrificed at 10 to 18 mo of age and examined for reproductive tract abnormalities. Prominent Müllerian remnants were observed in 268 out of 277 (97%) of the DES-exposed male mice. These remnants differentiated into "femalelike structures" homologous to oviduct and uterus. The Müllerian remnants were often enlarged and cystic and shared supporting connective tissue with adjacent male structures. Previously reported lesions, termed "epididymal cysts," were determined histologically to be cystic "oviductlike" structures and were, therefore, considered a Müllerian duct abnormality. Pathological changes in these male oviductal and uterine homologs included benign and malignant lesions. In addition, epididymal structures were altered. Inflammation and sperm granulomas were prevalent in DES-treated mice as young as 10 mo old but were only observed in control mice at 18 mos. Cysts of epididymal duct origin, hyperplasia, and adenoma of the epididymal duct were also observed. No comparable abnormalities were noted in 122 control males of corresponding ages. The data presented in this report demonstrated that transplacental exposure to DES affected the differentiation and normal development of the male genital tract involving both the Müllerian (paramesonephric) and Wolffian (mesonephric) ducts. The long-term changes in these tissues include lesions, some of which resembled neoplasia although the natural history of the lesions is not known. Moreover, some previously described abnormalities referred to as "epididymal cysts" were associated with tissues derived from embryonic female origin.     

The vagina is formed by downgrowth of Wolffian and Müllerian ducts. Graphical reconstructions from normal and Tfm mouse embryos

Summary We use the Tfm (testicular feminization) mutation of the mouse to reexamine the role of Wolffian and Müllerian ducts during formation of the vagina. Threedimensional graphical reconstructions of the lower genital tract are prepared from serial sections of male, female, and Tfm embryos from day 15 p.c. until 8 days after birth.The reconstructions show that in female and Tfm animats the caudal segments of Wolffian and Müllerian ducts fuse and migrate caudally, whereas in the male they do not fuse and remain in their original position. Following down-growth, separate Wolffian and Müllerian ducts emerge from the fused caudal tips of the ducts. The Wolffian ducts degenerate, while the Müllerian ducts fuse with each other and form the vagina. Wolffian and Müllerian ducts are connected to the urogenital sinus by the sinus ridges which in later stages are separated from the sinus by lateral furrows. The sinus ridges are replaced by the Müllerian ducts. We conclude that the vagina develops by down-growth of Wolffian and Müllerian ducts along the sinus ridges. Wolffian ducts and sinus ridges regress so that the definitive vagina is formed by the Müllerian ducts.In Tfm embryos the vagina forms as in the female but subsequently degenerates, probably due to the action of AMH. The vaginal pocket in the Tfm is the variable remainder of the vagina at the end of the degeneration process.Supported by Deutsche Forschungsgemeinschaft Dr 94/6-4 and Th 323/1-1     

Expanding the reproductive organ phenotype of CHD7-spectrum disorder

CHD7 disorder is a multiple congenital anomaly syndrome with a highly variable phenotypic spectrum, and includes CHARGE syndrome. Internal and external genital phenotypes frequently seen in CHD7 disorder include cryptorchidism and micropenis in males, and vaginal hypoplasia in females, both thought to be secondary to hypogonadotropic hypogonadism. Here, we report 14 deeply phenotyped individuals with known CHD7 variants (9 pathogenic/likely pathogenic and 5 VOUS) and a range of reproductive and endocrine phenotypes. Reproductive organ anomalies were observed in 8 of 14 individuals and were more commonly noted in males (7/7), most of whom presented with micropenis and/or cryptorchidism. Kallmann syndrome was commonly observed among adolescents and adults with CHD7 variants. Remarkably, one 46,XY individual presented with ambiguous genitalia, cryptorchidism with Müllerian structures including uterus, vagina and fallopian tubes, and one 46,XX female patient presented with absent vagina, uterus and ovaries. These cases expand the genital and reproductive phenotype of CHD7 disorder to include two individuals with genital/gonadal atypia (ambiguous genitalia), and one with Müllerian aplasia.     

Dynamic ultrasound imaging—A multivariate approach for the analysis and comparison of time-dependent musculoskeletal movements

Background

Herlyn-Werner-Wunderlich (HWW) syndrome is a very rare congenital anomaly of the urogenital tract involving Müllerian ducts and Wolffian structures, and it is characterized by the triad of didelphys uterus, obstructed hemivagina and ipsilateral renal agenesis. It generally occurs at puberty and exhibits non-specific and variable symptoms with acute or pelvic pain shortly following menarche, causing a delay in the diagnosis. Moreover, the diagnosis is complicated by the infrequency of this syndrome, because Müllerian duct anomalies (MDA) are infrequently encountered in a routine clinical setting.

Cases presentation

two cases of HWW syndrome in adolescents and a differential diagnosis for one case of a different MDA, and the impact of magnetic resonance (MR) imaging technology to achieve the correct diagnosis.

Conclusions

MR imaging is a very suitable diagnostic tool in order to perform the correct diagnosis of HWW syndrome.     

Familial occurrence of renal and Müllerian duct hypoplasia, craniofacial anomalies, severe growth and developmental delay.

Absence of the kidneys and of the Müllerian structures has been reported in many patients. We report on a brother and sister, born to nonconsanguineous parents, with renal hypoplasia, Müllerian duct hypoplasia, and strikingly similar facial abnormalities. Both sibs have severe growth and developmental retardation. We think that the unique clinical findings in these sibs represent a new syndrome. The embryological and genetic implications of this condition are discussed.     

Laparoscopic creation of a neovagina and recovery of menstrual function in a patient with Rokitansky syndrome: a case report

A 16-year-old woman experiencing primary amenorrhoea and cyclic pelvic pain was diagnosed with Rokitansky syndrome, which was characterized by the absence of the uterus and the upper two-thirds of the vagina, normal salpinges and ovaries and a 4 x 3 cm Müllerian remnant containing functioning endometrium located near the left adnexa. With a combined laparoscopic-vaginal operation, the remnant was anastomized with the apex of the retrohymenal fovea. The operation allowed not only the creation of a neovagina but also the recovery of a regular menstrual activity and the theoretical restoration of the reproductive capacity of this patient. An accurate pre- and intra-operative evaluation of patients with Rokitansky syndrome is necessary to identify those who might benefit from this procedure.     

Clinical aspects of Mayer-Rokitansky-Kuester-Hauser syndrome: recommendations for clinical diagnosis and staging

BACKGROUND: The Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome is a malformation of the female genitals (occurring in one in 4000 female live births) as a result of interrupted embryonic development of the Müllerian (paramesonephric) ducts. This retrospective study examined the issue of associated malformations, subtyping, and the frequency distribution of subtypes in MRKH syndrome. METHODS: Fifty-three MRKH patients were investigated using a newly developed standardized questionnaire. Together with the results of clinical and diagnostic examinations, the patients were classified into the three recognized subtypes [typical, atypical and MURCS (Müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia)]. RESULTS: The typical form was diagnosed in 25 patients (47%), the atypical form in 11 patients (21%), and the most marked form-the MURCS type-in 17 patients (32%). Associated malformations were notably frequent among the patients. Malformations of the renal system were the most frequent type of accompanying malformation, with 23 different malformations in 19 patients, followed by 18 different skeletal changes in 15 patients. CONCLUSIONS: In accordance with the literature, this study shows that associated malformations are present in more than a third of cases. Therefore, new basic guidelines for standard diagnostic classification involving patients with suspected MRKH are presented.     

Array‐comparative genomic hybridization analysis in patients with Müllerian fusion anomalies

Fusion anomalies of the Müllerian ducts are associated with an increased risk for miscarriage and premature labor. In most cases polygenic‐multifactorial inheritance can be assumed but autosomal‐dominant inheritance with reduced penetrance and variable manifestation should be considered. We performed array‐comparative genomic hybridization (CGH) analysis in a cohort of 103 patients with Müllerian fusion anomalies. In 8 patients we detected microdeletions and microduplications in chromosomal regions 17q12, 22q11.21, 9q33.1, 3q26.11 and 7q31.1. The rearrangement in 17q12 including LHX1 and HNF1β as well as in 22q11.21 have already been observed in MRKHS (Mayer‐Rokitansky‐Küster‐Hauser syndrome). In summary, we (1) detected causative micro‐rearrangements in patients with Müllerian fusion anomalies, (2) show that Müllerian fusion anomalies and MRKHS may have a common etiology, and (3) identified new candidate genes for Müllerian fusion anomalies.     

Familial occurrence of hereditary renal adysplasia with Müllerian anomalies

We report on a family with unilateral or bilateral renal agenesis and Müllerian anomalies (vaginal atresia or minor anomalies). This family provides support for an autosomal dominant pattern of inheritance with incomplete penetrance and variable expressivity in hereditary renal adysplasia (HRA) associated with Müllerian defects.     

Cytologic features of müllerian papilloma of the cervix: mimic of malignancy

Müllerian papilloma is a rare benign tumor of the cervix and/or vagina that occurs predominantly in young children. The cytologic features of benign müllerian papilloma have never been described. We report for the first time, to our knowledge, the cytologic findings of a benign müllerian papilloma from the vaginal fluid specimen of a 15-mo-old girl using touch prep, ThinPrep, and cell block preparations. The deceptive cytologic features of a cellular specimen with complex papillary fronds composed of overlapping and crowded small hyperchromatic cells, with a high nuclear:cytoplasmic ratio, and feathering in this case resembled a malignant neoplasm. The clinical findings and cytomorphology of a benign müllerian papilloma can mimic those of malignant lesions of the female lower genital tract such as sarcoma botryoides and adenocarcinoma. An awareness of this entity and its potential to mimic these more aggressive neoplasms is essential for accurate diagnosis and to avoid over-treatment.     

Familial lipoid adrenal hyperplasia: genetic marker data and an approach to prenatal diagnosis

Some of the anatomic endocrine, and genetic aspects of lipoid adrenal hyperplasia were studied in an inbred Israeli-Arab family with two affected sibs. One sib, a genetic female, presented with acute Addisonian crisis. Endocrine studies documented elevated ACTH levels and no detectable steroids of gonadal or adrenal origin. The other patient, a male pseudo-hermaphrodite, was found at autopsy to have typical lipoid adrenal hyperplasia and ectopic adrenal tissue adjacent to an intra-abdominal testicle. Complete vagina, uterus, and fallopian tubes were present in addition to the Wolffian structures. This unique observation supports the view that steroids may be necessary for Müllerian inhibitory factor to induce regression of Müllerian structures. The segregation of 27 autosomal markers was studied in one affected and five unaffected sibs. Genetic linkage to HLA, MNS, and GPT is unlikely. In addition, the affected sib is heterozygote for a haplotype of chromosome 1 which includes the Rh, Fy, PGM-1 systems. Determination of fetal gender by the combined use of ultrasonography and amniocentesis is suggested for prenatal diagnosis and improved risk counselling.     

Laparoscopic management of a unicornuate uterus with two cavitated, non-communicating rudimentary horns: case report.

An 18 year old nulligravid woman presented with severe dysmenorrhoea secondary to stage IV (revised American Fertility Society) endometriosis, right haematosalpinx, right endometrioma, unicornuate uterus and two cavitated, non-communicating rudimentary uterine horns. To our knowledge, this is the first reported case of a unicornuate uterus accompanied by two rudimentary horns. Operative video-laparoscopy proved a successful approach for treating this previously unreported variant of congenital Müllerian anomaly. A review of the world literature confirms the uniqueness of this case while demonstrating laparoscopy to be a viable alternative to laparotomy for management of congenital Müllerian anomalies. The case presented may help to elucidate Müllerian duct embryology further.     

Molecular cytogenetic characterization of a case of Müllerian adenosarcoma

Müllerian adenosarcoma is a distinctive type of mixed Müllerian tumor of the female genital tract. To our knowledge, no cytogenetic data have been documented on Müllerian adenosarcoma in the literature so far. We report here the chromosomal findings of a Müllerian adenosarcoma in a 15-year-old female. Cytogenetic and molecular cytogenetic analysis revealed a complex karyotype involving chromosomes 2, 8, 10, 13, 19, and 21. These numerical and structural abnormalities may be of etiologic significance. This report may highlight the potential value of molecular cytogenetic analysis in differential diagnosis of Müllerian tumors. More cases are warranted to further genetically characterize this type of neoplasm.     

Smith-Lemli-Opitz syndrome in two 46,XY infants with female external genitalia

Two infants with features of the Smith-Lemli-Opitz (SLO) syndrome were found to have a 46,XY karyotype and female external genitalia. Autopsies showed normal testes for age with normal Wolffian duct structures and without Müllerian duct derivatives. This failure of masculinization of the external genitalia is an unusual finding and may represent the extreme of a spectrum of the genital anomalies commonly seen in males with this autosomal recessive syndrome. An endocrine evaluation on one of these infants at 3 months suggested unusually low testosterone production and meagre response to stimulation with human chorionic gonadotropin (hCG). The failure of complete masculinization of external genitalia in some cases of SLO syndrome may be due to inadequate testosterone production in utero.     

Morphology and histology of the male reproductive tract of Caecilia thompsoni (amphibia: Gymnophiona)

We studied the male reproductive tract of individuals of different body sizes of Caecilia thompsoni to describe morphological characteristics in comparison to other Gymnophiona. The reproductive tract consists of paired testes segmented into chains of primary and secondary lobes, sperm ducts that empty to Wolffian ducts, the cloaca that receives the Wolffian ducts and possesses a phallodeum. Müllerian ducts are present and develop into paired glands that empty into the cloacal urodeum. Testicular secondary lobes contain lobules with cysts of the entire germinal cell line, whereas primary lobes, in the terminal ends of the chains, only have spermagonia, Sertoli cells, and connective tissue. The smallest individual examined (21 cm body length) was immature and only possessed a few testicular primary lobes. Once the individuals reach sexual maturity, the morphological characteristics are quite consistent at macroscopic and histological level among males of very different body sizes. The histological features of the Wolffian and Müllerian glands suggest a complementary secretory role between the two ducts. In the cloaca we found the propulsor muscle, venous sinuses, and blind sacs in the phallodeum, which differentiate C. thompsoni from other species of the genus. Despite these slight differences, the general morphological characteristics, both macroscopic and microscopic, of the reproductive tracts of adult males of C. thompsoni follow the pattern known for the reproductively active males of Gymnophiona.     

A female with complete lack of Müllerian fusion, postaxial polydactyly, and tetralogy of fallot: genetic heterogeneity of McKusick-Kaufman syndrome or a unique syndrome?

We report a 19-year-old, non-Amish Caucasian female patient with primary amenorrhea caused by complete lack of Müllerian fusion with vaginal agenesis or Müllerian aplasia (MA), postaxial polydactyly (PAP), and tetralogy of Fallot. The genital tract anomaly of MA with and without renal or skeletal anomalies comprises Mayer-Rokitansky-Kuster-Hauser syndrome, which has not been reported with tetralogy of Fallot. The phenotypic triad of anomalies most closely resembled McKusick-Kaufman syndrome (MKS; OMIM 236700), a rare multiple congenital anomaly syndrome comprised of hydrometrocolpos (HMC), PAP, and congenital heart malformation that is inherited in an autosomal recessive pattern. While upper reproductive tract anomalies have not been reported with MKS, they have been reported with Bardet-Biedl syndrome (BBS), a syndrome that significantly overlaps with MKS. Both MKS and BBS can be caused by mutations in the MKKS or BBS6 gene on chromosome 20p12 and BBS is also associated with mutations in other genes (BBS1, BBS2, BBS4, and BBS7). To address this heterogenity, we sequenced the causative genes in MKS and BBS but no mutations in these five genes were identified. Fluorescence in situ hybridization (FISH) excluded large deletions of chromosome 20p12 and microsatellite marker studies confirmed biparental inheritance for all of the known BBS loci. The dual midline fusion defects of tetralogy of Fallot and MA suggests that either this patient has a unique syndrome with a distinct genetic etiology or that she has a genetically heterogeneous or variant form of MKS.