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Female genital malformations and their associated abnormalities
Female genital malformations and their associated abnormalities Peter Oppelt, M.D.,a Meike von Have, M.D.,a Mareike Paulsen, M.D.,a Pamela L. Strissel, Ph.D.,a Reiner Strick, Ph.D.,a Sara Brucker, M.D.,b Diethelm Wallwiener, M.D.,b and Matthias W. Beckmann, M.D.a a
Department of Gynecology and Obstetrics, University Hospital, Erlangen and b Department of Gynecology and Obstetrics, University Hospital, Tübingen, Germany
Objective: With an incidence of up to 5% in the general population, genital malformations are a frequent clinical occurrence. The aim of this study was to assess whether a connection could be demonstrated between various degrees of severity of genital malformations and associated abnormalities. Design: All patients were classified using the Vagina, Cervix, Uterus, Adnex, and Associated Malformation (VCUAM) classification. Setting: University hospital. Patient(s): Two hundred eleven premenopausal patients with female genital malformations. Intervention(s): The patients underwent diagnostic workup for genital malformations using laparoscopy as well as hysteroscopy. Associated malformations were detected by either magnetic resonance imaging (MRI) or ultrasound. Main Outcome Measure(s): Demonstration of a connection between various degrees of severity of genital malformations and associated abnormalities. Result(s): In 72 cases (36%) out of 202 patients with uterine malformations (VCUAM U1– 4) we found associated abnormalities. The predominant findings were alterations in the renal system. When vaginal abnormality (VCUAM V1–5) alone was taken into consideration, an associated developmental disturbance in the renal tract was found in 30% of cases (n ⫽ 32 from 107). Conclusion(s): A close connection was demonstrated between genital malformations and associated abnormalities. For this reason, the diagnostic workup in patients with malformations should always include the renal system. Depending on the severity of the clinical picture, examinations may need to be extended further. (Fertil Steril威 2007;87:335– 42. ©2007 by American Society for Reproductive Medicine.) Key Words: Uterine malformation, genital malformation, vaginal malformation, MRKH syndrome, VCUAM classification
In the general female population, genital malformations are reported to occur with an incidence of 1%–5%, in groups of patients with fertility up to 6.5 % (1–5). The etiology is possibly due to an aberrant developmental inhibition of the Muellerian ducts during embryogenesis. To date, various genetic factors have been investigated, but a precise cause has not been identified for any of the individual types of malformation (1, 6 – 8). Precise classification of the individual malformations reported in the literature is only possible from reports with sometimes small numbers of cases. Because symptoms only occur in approximately 50% of cases in connection with the malformations, it must be assumed that mild malformations in particular (VCUAM classification U1a– 1c) are often not diagnosed and that these subgroups are underrepresented (9, 10). Figure 1 shows the distribution Received February 5, 2006; revised and accepted July 5, 2006. Reprint requests: Peter Oppelt, M.D., Department of Gynecology and Obstetrics, University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen, Germany (FAX: 49-9131-8536185; E-mail: Peter.Oppelt@ gyn.imed.uni-erlangen.de
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.07.1501
of malformations in 1,392 patients with uterine malformations according to the review by Woelfler and Rimbach (11), using the American Fertility Society (AFS) classification (12). However, this classification did not include other associated malformations. Regarding genital anomalies, it is usually the pathology of the uterus that is the focus of attention. Depending on their extent, these changes may occur in combination with other genital and associated malformations. Isolated genital malformations without changes in the uterus may also occur (13–17). Our previous publication validated a specifically group of patients with MRKH (Mayer-Rokitansky-Kuester-Hauser) and a small sample of only a few additional genital malformations using the VCUAM Classification System defined by us (10). Therefore, the aim of the present study was to extend this validation using VCUAM to now include a total of 211 female patients with all types of genital malformations and also test the classification in relation to associated changes (10).
Fertility and Sterility姞 Vol. 87, No. 2, February 2007 Copyright ©2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
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FIGURE 1 Distribution of uterine malformations of 1392 patients by Woelfler and Rimbach (11).
2a, unilateral hypoplasia/gonadal streak (including tubal malformation if appropriate); 2b, bilateral hypoplasia/gonadal streak (including tubal malformation if appropriate); 3a, unilateral aplasia; 3b, bilateral aplasia. Associated malformation: 0, none; R, renal system; S, skeleton; C, cardiac; N, neurologic. In any group in the VCUAM classification, the symbol ⫹ can be used to indicate “unclassifiable” and the symbol # to indicate “unknown.” In the analysis, the malformation of the uterus was regarded as dominant and as the reference point in relation to other abnormalities such as those in the vagina (see Tables 1–3). In a further analytical step, the vagina was set as the reference point, as in the gynecological examination anomalies, those are noticeable first. In Table 4, the individual vaginal malformations are correlated with additional genital and associated abnormalities.
Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
MATERIALS AND METHODS Between January 2000 and June 2005, 211 patients contacted the Departments of Gynecology at the university hospitals in Erlangen and Tübingen because of sterility or genital malformations. In a few of the patients, the data had been obtained as asymptomatic incidental findings. For precise assessment of the genital and associated anomalies, patients’ records, general visual examination of the urinary tract, surgical reports, x-ray pictures, magnetic resonance tomography findings, and ultrasound findings were evaluated. All patients underwent diagnostic workup for genital malformations using laparoscopy as well as hysteroscopy and ultrasound examination of the kidneys. Symptomatic associated malformations were then further evaluated by magnetic resonance imaging (MRI). The final classification of each malformation was carried out using the new VCUAM classification (10). This classification makes it possible to record the pathological anatomy of genital developmental disturbances descriptively. Each is recorded in accordance with the following scheme. Vagina: 0, normal; 1a, partial hymenal atresia; 1b, complete hymenal atresia; 2a, incomplete septate vagina ⬍50%; 2b, complete septate vagina; 3, stenosis of the introitus; 4, hypoplasia; 5a, unilateral atresia; 5b, complete atresia; S1, sinus urogenitalis (deep confluence); S2, sinus urogenitalis (middle confluence); S3, sinus urogenitalis (high confluence); C, cloaca. Cervix: 0, normal; 1, duplex cervix; 2a, unilateral atresia/ aplasia; 2b, bilateral atresia/aplasia. Uterus: 0, normal; 1a, arcuate; 1b, septate, ⬍50% of the uterine cavity; 1c, septate, ⱖ50% of the uterine cavity; 2, bicornate; 3, hypoplastic uterus; 4a, unilaterally rudimentary or aplastic; 4b, bilaterally rudimentary or aplastic. Adnex: 0, normal; 1a, unilateral tubal malformation, ovaries normal; 1b, bilateral tubal malformation, ovaries normal; 336
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Approval for conducting basic research and compiling the relevant documentation on female genital malformations was received through Ethics Vote no. 3074 in the Faculty of Medicine at the University of Erlangen. RESULTS Among the 211 patients included in the study, 202 had uterine and 9 had isolated vaginal anomalies. Also included in this analysis for comparison were 56 patients with MRKH, previously published (10). To allow better assessment of the connection between pathological, embryological abnormalities and the associated malformations, all of the patients were categorized, using the VCUAM classification, first with regard to their uterine changes and second, in relation to their vaginal changes. VCUAM U1 Group (Arcuate Uterus, Subseptate Uterus) Overall, only a few concomitant malformations were found in 80 patients in this group (Table 1). Additional anomalies in the cervix were only seen in five cases. All five of these patients also had a complete septate uterus (VCUAM U1c). Among the patients included in the study, this was not observed with those in uterine categories U1a and U1b. The associated malformation described included five changes in the urogenital system, two anal atresias, one hernia, one auricular, and one cerebral artery aneurysm. Changes in the adnex area were only found in one patient, with unilateral tubal hypoplasia. VCUAM U2 Group (Bicornate Uterus) Thirty-eight patients of 202 had a bicornate uterus (Table 2). In 50% of the cases (n ⫽ 19), this was accompanied by a duplex cervix. An increased proportion of malformations in the adnex was also observed in comparison with the VCUAM U1 group. Overall, 39% of the patients had at least one associated anomaly. The largest group consisted of 11 Vol. 87, No. 2, February 2007
TABLE 1 Uterine malformations VCUAM U1 (80 patients; 19 patients previously published in Oppelt et al.). Patient 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21)
Vagina
Cervix
Uterus
Adnex
Associated malformations
V# V0 V0 V0 V0 V1a V0 V0 V0 V0 V0 V0 V0 V0 V0 V0 V0 V0 V2a V2b VC
C# C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C1 C0 C0 C1 C1 C2a
U1a U1a U1a U1a U1a U1a U1b U1b U1b U1b U1b U1b U1b U1c U1c U1c U1c U1c U1c U1c U1c
A0 A# A⫹ A0 A0 A0 A# A# A0 A0 A0 A0 A1a A# A0 A0 A0 A0 A0 A0 A0
M0 M0 M0 MR M0 M0 M0 M0 M⫹ M⫹ M0 MR M0 MR⫹ MR M0 M⫹ M0 M0 M0 MR⫹
Description associated malformations
Amount
Vesicourethral reflux 17 x
A Malformation auricula 37 x B Double ureter, B C (left) Cerebral aneurysm 7x 2x Horseshoe kidney; anal atresia
Note: A ⫽ inguinal hernia; B ⫽ unilateral renal aplasia; C ⫽ double kidney. Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
changes in the urogenital system. In addition, dysplasias in the ear and nose, mental retardation, and skeletal changes were also diagnosed.
the women. Overall, the VCUAM U4 major group included 11 patients with morphological changes in the adnex, ranging from unilateral tubal anomaly (VCUAM A1a) to bilateral gonadal aplasia (VCUAM A3b).
VCUAM U3 Group (Hypoplastic Uterus) Only 5 of 202 patients could be assigned to this group. Four of five patients in the group showed a close association between uterine and ovarian abnormalities. Bilateral hypoplastic ovaries (gonadal streaks) were documented in all but one patient. A skeletal anomaly was present in only one case.
At least one extragenital malformation was found in 41% (n ⫽ 32) of the patients in the VCUAM U4 group. The most frequent were anomalies of the urogenital system (n ⫽26), followed by skeletal malformations (n ⫽ 13) and heart defects (n ⫽ 4). The first case of a patient with an abnormal neurologic status was also observed (n ⫽ 1).
VCUAM U4 Group (Unilaterally or Bilaterally Rudimentary Uterus) With a total of 79 of 202 patients in this group, unilateral uterine horn aplasia or a rudimentary horn (VCUAM U4a) was present in six cases (Table 3). A substantial difference was observed between the latter group and those with bilateral uterine horn aplasia/bilateral rudimentary uterine horn (VCUAM 4b) with regard to cervical involvement. Although complete vaginal atresia was present in all patients in the VCUAM U4b group, vaginal atresia was seen in only one case in the VCUAM U4a group. Three patients had no cervical pathology. A duplex cervix was present in two of
VCUAM V1–5 Group (Hymenal Atresia, Septate Vagina, Stenosis of the Introitus, Hypoplasia, Atresia, Sinus Urogenitalis, Cloaca) A total of 107 from the total of 211 patients were found to have malformations of the vagina (Table 4). Although only two of eight patients in the VCUAM V1 group had associated abnormalities, more strongly marked vaginal were more frequently combined with other changes in the genitals or associated malformations. All women with a septate vagina (n ⫽ 19) also had a duplex cervix, which continued in 14 cases with duplex uterus and in 3 cases with a complete septate uterus. In this subgroup, renal anomalies were also diagnosed in 32% of the patients (n ⫽ 6), as well as mal-
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TABLE 2 Uterine malformations VCUAM U2 (38 patients; 20 patients previously published in Oppelt et al.). Patient
Associated malformations
Vagina
Cervix
Uterus
Adnex
1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11)
V# V# V0 V0 V0 V0 V0 V0 V0 V0 V1b
C# C0 C0 C0 C0 C0 C0 C0 C0 C1 C#
U2 U2 U2 U2 U2 U2 U2 U2 U2 U2 U2
A# A3b A# A# A# A0 A0 A0 A1a A0 A0
M# M⫹ M0 MR MR M0 MR MS M0 M0 M⫹
12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22)
V2a V2a V2a V2b V2b V2b V2b V2b V2b V4 VS1
C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C0
U2 U2 U2 U2 U2 U2 U2 U2 U2 U2 U2
A0 A0 A1a A0 A0 A0 A0 A2a A2a A2b A0
M0 MR M0 M0 MR MR MR M0 MR M0 MN⫹
Description associated malformations
Amount
A 2x C (right) B
2x 6x 2x
Pelvic kidney scoliosis
3x Dysmorphism ear-hand-foot, partial missing tooth germ 3x B 4x 2x
B Double renal pelvis Ureter fissure B Mental retardation, strabismus
Note: A ⫽ inguinal hernia; B ⫽ unilateral renal aplasia; C ⫽ double kidney. Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
formations of the adnex in 16% (two in VCUAM A2a, one in VCUAM A2b). In addition stenoses of the vaginal introitus (n ⫽ 1; VCUAM V3) or vaginal hypoplasia (n ⫽ 4; VCUAM V4) were basically associated with at least one additional genital change. All of the patients with complete vaginal atresia (n ⫽ 72; VCUAM V5b) had simultaneous bilateral cervical aplasia as well as a bilateral rudimentary uterus or uterine aplasia. In addition, there was a marked increase in the frequency of associated anomalies in this subgroup. The most frequent of these were malformations of the kidneys, occurring in 23 of 72 patients (32%), followed by 14 skeletal dysmorphisms (particularly in the vertebral bodies and hips). The proportion of malformations of the adnex (n ⫽10, 14%) and heart (n ⫽ 4, 6%) was also notably high. DISCUSSION In the examination of genital malformations, attention usually focuses primarily on changes in the uterus, and this is reflected in almost all classifications of deformation. Acien et al. (18) attempted to use an embryonic classification to document connections between genital and urologic alter338
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ations. However, the classification met with little acceptance due to the complexity involved in using it. In this present investigation we demonstrated that the VCUAM classification can now be used generally to include all female genital malformations. The VCUAM classification, designed for easy clinical use, makes it possible to record all anatomic malformations and associated abnormalities separately. This is very important, particularly for the description of syndromes with genital involvement. Examples include patients with MRKH, especially the MURCS syndrome (Muellerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia), which includes both genital and extragenital abnormalities (7, 19). When the individual uterine changes (VCUAM U1a–U4b) are compared with the associated genital and extragenital malformations, a connection is evident that can in part be explained on the basis of embryogenesis. For example, the close spatial relationship between the Wolffian duct (mesonephric duct) and the Muellerian duct is often regarded as explaining uterine malformations with accompanying renal developmental disturbances. Gruenwald (20) and Magee et al. (21) were able to show that there is a direct influence of Vol. 87, No. 2, February 2007
TABLE 3 Uterine malformations VCUAM U4 (79 patients; 59 patients previously published in Oppelt et al.). 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22) 23) 24) 25)
V⫹ V0 V0 V0 V3 V4 V4 V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b
C1 C1 C0 C0 C0 C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b
U4a U4a U4a U4a U4a U4a U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b
A0 A# A0 A2b A# A⫹ A0 A# A# A# A# A# A# A# A# A0 A0 A0 A0 A0 A0 A0 A0 A0 A0
MR⫹ M# M0 M0 MR⫹ M0 MR⫹ M# M0 MR MR MRC MRS MS MSN M⫹ M0 MC⫹ MR MR MR MR MR MRS MRS⫹
26) 27)
V5b V5b
C2b C2b
U4b U4b
A0 A0
MRSC⫹ MS
28) 29) 30) 31) 32) 33) 34) 35) 36) 37) 38)
V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b
C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b
U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b
A0 A1a A1b A1b A1b A1b A2a A2b A2b A3a A3a
MS⫹ MR MR⫹ MRS⫹ MRS⫹ MRSC⫹ MR MRS MRS M0 MRS
A, silent kidney left, double aorta
C, rectal atresia, double kidney right A, hearing loss 13 x 5x D C C, E C, G, talipes varus Absence of 1/3 of the left arm hearing loss, hypoplasia of the wrist A 24 x A, E D C B Malformation uretra Horseshoe kidney B, malformation HWS A, F, high blood pressure, hypoplasia of the wrist A, D, E, F G, radial aplasia–thrombocytopenia syndrome with bilateral club hand F, cataract B A, B B, C, dwarfism, fibroma A, C, F A, C, open duct, jaw anomaly B B, F F, G, deformed elbow
3x
B, C, F
Note: A ⫽ inguinal hernia; B ⫽ unilateral renal aplasia; C ⫽ pelvic kidney; D ⫽ nephrosclerosis; E ⫽ aorticopulmonary septal defect; F ⫽ scoliosis; G ⫽ congenital dysplasia of the hip. Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
the Wolffian duct, through induction, on the development of the Muellerian duct. A high incidence of renal abnormalities was found with uterine malformations.
other associated malformations, which are encountered most frequently in the VCUAM U4 group, particularly in connection with the MRKH syndrome.
Although only 5 renal abnormalities (6%) were observed in the VCUAM U1 group, 11 malformations of the renal system were seen in the VCUAM U2 group (29%) and 25 in the VCUAM U4 group (32%). The same also applies to
In contrast to the VCUAM groups U1, U2, and U4, only one associated malformation of the (VCUAM MS–scoliosis) was observed among the five cases of the VCUAM group U3. A genetic mutation is probably not the primary factor for
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TABLE 4 Vaginal malformations VCUAM V (107 patients; 62 patients previously published in Oppelt et al.). Associated Patient Vagina Cervix Uterus Adnex malformations 1) 2) 3) 4) 5) 6)
V1a V1a V1a V1b V1b V1b
C0 C0 C0 C# C0 C#
U# U0 U1a U0 U0 U2
A# A0 A0 A0 A0 A0
M0 M0 M0 M0 M0 M⫹
7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22) 23) 24) 25) 26) 27) 28) 29) 30) 31) 32) 33) 34) 35) 36) 37) 38) 39) 40) 41) 42)
V2a V2a V2a V2a V2a V2b V2b V2b V2b V2b V2b V2b V2b V3 V4 V4 V4 V4 V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b
C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C0 C0 C1 C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b
U0 U1c U2 U2 U2 U0 U1c U2 U2 U2 U2 U2 U2 U4a U0 U2 U4a U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b
A0 A0 A0 A0 A1a A# A0 A2a A0 A0 A0 A0 A2a A# A2b A2b A⫹ A0 A# A# A# A# A# A# A# A# A0 A0 A0 A0 A0 A0 A0 A0 A0 A0
M0 M0 MR M0 M0 M0 M0 MR MR MR MR M0 M0 MR⫹ MR M0 M0 MR⫹ M# M0 MR MR MRC MRS MS MSN M⫹ M0 MC⫹ MR MR MR MR MR MRS MRS⫹
43) 44)
V5b V5b
C2b C2b
U4b U4b
A0 A0
MRSC⫹ MS
45) 46)
V5b V5b
C2b C2b
U4b U4b
A0 A1a
MS⫹ MR
Description associated malformations
Amount 2x
2x Dysmorphism ear-hand-foot, partial missing tooth germ 2x B 3x
B B Double renal pelvis Ureter fissure
2x
4x C, rectal atresia, double kidney right B
A, hearing loss 13 x 5x D C C, E C, G, talipes varus absence of 1/3 of the left arm Hearing loss, hypoplasia of the wrist A 24 x A, E D C B Malformation uretra Horseshoe kidney B, malformation HWS A, F, high blood pressure, hypoplasia of the wrist A, D, E, F G, radial aplasia–thrombocytopenia syndrome with bilateral club hand F, cataract B
3x
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TABLE 4 Continued. Associated Patient Vagina Cervix Uterus Adnex malformations 47) 48) 49) 50)
V5b V5b VC VS1
C2b C2b C2a C0
U4b U4b U1c U2
A1b A1b A0 A0
MR⫹ MRS⫹ MR⫹ MN⫹
Description associated malformations
Amount
A, B B, C, dwarfism, fibroma Horseshoe kidney, anal atresia Anal atresia, strabismus
Note: A ⫽ inguinal hernia; B ⫽ unilateral renal aplasia; C ⫽ pelvic kidney; D ⫽ nephrosclerosis; E ⫽ aorticopulmonary septal defect; F ⫽ scoliosis; G ⫽ congenital dysplasia of the hip. Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
the hypoplastic uterus, but rather an endocrinologic failure, which in this group is likely to be found in the lack of hormone production in the ovaries (four cases of VCUAM A2b). Acien et al. (18) have attempted to infer an embryological link; however, a molecular– genetic explanation has not yet been identified. Also a close relationship between the Muellerian duct and the urogenital sinus was observed. Among 107 patients with vaginal malformations (development from the urogenital sinus, VCUAM V1–5), 90% (n ⫽ 96) had cervical, 92% (n ⫽ 98) had uterine, and 30% (n ⫽ 32) had renal abnormalities as concomitant findings. A close association was also demonstrated in 20 patients with duplex vagina (VCUAM V2a and b) who were all diagnosed with duplex cervix. In addition, 3 cases of the 20 patients had a complete intrauterine septa and 15 patients, a duplex uteri. The connection is seen most impressively in the context of the MRKH syndrome. All 72 patients with bilateral vaginal atresia had bilateral cervical and uterine aplasia as concomitant findings (10). In contrast, when one starts primarily from the malformation that originates in the Muellerian duct, a malformation with its origin in the urogenital sinus is not found in all cases. In 202 patients with uterine malformations (Muellerian duct; VCUAM U1– 4), only 96 abnormalities of the vagina (urogenital sinus) were found. Another notable observation is the structure of the VCUAM U2 subgroup. Among the 38 patients with bicornate uterus (VCUAM U2), no abnormalities of the cervix or vagina were found in 15 cases (40%). A further observation is that 5 (33%) of these 15 patients were suffering from malformations of the renal system (two with pelvic kidney, two with renal agenesis, and one with unilateral double kidney). The conclusion might be that there is a direct influence of the sinus urogenitalis, through induction, on the development of the Muellerian duct and in some cases also of the Wolffian duct. Regarding all genital malformations and their associated abnormalities it can be concluded that other superordinated Fertility and Sterility姞
induction pathways must be available for this type of abnormal development. These results contribute to the hypothesis that organogenesis primarily takes place independently, but that there are higher level regulatory mechanisms that can have common effects on both the Muellerian and Wolffian ducts and the urogenital sinus. On the basis of genetic studies in mice, particularly in the knock-out mouse model, a fundamental role in the development of the urogenital tract has been attributed to the HOXA genes. Several mouse models have shown that Hoxa10 is essential for uterine development, Hoxa11 for the caudal uterine and cervical area, Hoxa13 for the upper vagina, and Hoxa9 for the development of the fallopian tubes (22, 23). A nonsense HoxA13 mutation is known to exist in the “hand– foot– genital” syndrome in humans (24, 25). However, no mutations were found in 32 patients with Muellerian aplasia (26). In a case report of an 18-year-old woman with MRKH syndrome, Biason-Lauber et al. (27) detected a loss-of-function mutation in the WNT4 gene. The WNT4 gene appears to be important for the regulation of Muellerian duct formation and control of ovarian steroidogenesis. But genetic analyses by Clément-Ziza et al. (28) exclude WNT4 as the major responsible gene in this malformation. The question of whether MRI is capable of replacing hysteroscopy and laparoscopy in the diagnostic workup is a matter of controversy (3, 29). In our own experience, we have noted incorrect interpretations based on the MRI findings, particularly in cases of complex female urogenital malformation. Finally, it should be pointed out that female genital malformations are frequently associated with other abnormalities. During the diagnosis of malformations, an ultrasound examination of at least both kidneys should also be carried out in addition to the assessment of the small pelvis. The extent to which the diagnosis and workup may need to be extended further should be determined in relation to the extent of the malformations and the patient’s symptoms. In this context, clinical pictures in the areas of urology, neurology, orthopedics, and cardiology should be considered. 341
REFERENCES 1. Nahum GG. Uterine anomalies. How common are they, and what is their distribution among subtypes? J Reprod Med 1998;43:877– 87. 2. Raga F, Bauset C, Remohi J, Bonilla-Musoles F, Simon C, Pellicer A. Reproductive impact of congenital Müllerian anomalies. Hum Reprod 1997;12:2277– 81. 3. Marten K, Vosshenrich R, Funke M, Obenauer S, Baum F, Grabbe E. MRI in the evaluation of müllerian duct anomalies. Clin Imaging 2003;27:346 –50. 4. Byrne J, Nussbaum-Blask A, Taylor WS, Rubin A, Hill M, O’Donnell R, et al. Prevalence of Müllerian duct anomalies detected at ultrasound. Am J Med Genet 2000;94:9 –12. 5. Acien P. Incidence of Müllerian defects in fertile and infertile women. Hum Reprod 1997;12:1372– 6. 6. Lee DM, Osathanondh R, Yeh J. Localization of Bcl-2 in the human fetal müllerian tract. Fertil Steril 1998;70:135– 40. 7. Oppelt P, Strissel PL, Kellermann A, Seeber S, Humeny A, Beckmann MW, et al. DNA sequence variations of the entire anti-Müllerian hormone (AMH) gene promoter and AMH protein expression in patients with the Mayer–Rokitansky–Küster–Hauser syndrome. Hum Reprod 2004;20:149 –57. 8. Simpson JL. Genetics of the female reproductive ducts. Am J Med Genet 1999;89:224 –39. 9. Troiano RN, McCarthy SM. Müllerian duct anomalies: imaging and clinical issues. Radiology 2004;233:19 –34. 10. Oppelt P, Renner SP, Brucker S, Strissel P, Strick R, Oppelt PG, et al. The VCUAM (vagina cervix uterus adnex-associated malformation) classification: a new classification for genital malformations. Fertil Steril 2005;84:1493–7. 11. Woelfler MM, Rimbach S. Morphologische Ursachen als Faktor beim habituellen Abort. Gynäkol Endokrinol 2005;3:18 –24. 12. American Fertility Society. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion secondary due to tubal ligation, tubal pregnancies, müllerian anomalies and intrauterine adhesions. Fertil Steril 1988;49:944 –55. 13. Pittock ST, Babovic-Vuksanovic D, Lteif A. Mayer–Rokitansky– Kuster–Hauser anomaly and its associated malformations. Am J Med Genet A 2005;135:314 – 6. 14. Hauser GA, Schreiner WE. Mayer–Rokitansky–Küster syndrome: rudimentary solid bipartite uterus with solid vagina (in German). Schweiz Med Wochenschr 1961;91:381– 4. 15. Schmid-Tannwald I, Hauser GA. Atypical forms of the Mayer–Rokitansky–Küster syndrome (in German). Geburtshilfe Frauenheilkd 1977; 37:386 –92.
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16. Fedele L, Bianchi S, Zanconato G, Raffaelli R. Laparoscopic creation of a neovagina in patients with Rokitansky syndrome: analysis of 52 cases. Fertil Steril 2000;74:384 –9. 17. Creatsas G, Deligeoroglou E, Makrakis E, Kontoravdis A, Papadimitriou L. Creation of a neovagina following Williams vaginoplasty and the Creatsas modification in 111 patients with Mayer–Rokitansky– Küster–Hauser syndrome. Fertil Steril 2001;76:1036 – 40. 18. Acien P, Acien M, Sánchez-Ferrer M. Complex malformations of the female genital tract: new types and revision of classification. Hum Reprod 2004;19:2377– 84. 19. Duncan PA, Shapiro LR, Stangel JJ, Klein RM, Addonizio JC. The MURCS association: Müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia. J Pediatr 1979;95:399 – 402. 20. Gruenwald P. The relation of the growing Müllerian duct to the Wolffian duct and its importance for the genesis of malformations. Anat Rec 1941;81:1–19. 21. Magee MC, Lucey DT, Fried FA. A new embryologic classification for uro-gynecologic malformations: the syndromes of mesonephric duct induced müllerian. J Urol 1979;121:265–7. 22. Warot X, Fromental-Ramain C, Fraulob V, Chambon P, Dolle P. Gene dosage-dependent effects of the Hoxa-13 and Hoxd-13 mutations on morphogenesis of the terminal parts of the digestive and urogenital tracts. Development 1997;124:4781–91. 23. Taylor HS, Vanden Heuvel GB, Igarashi P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod 1997;57:1338 – 45. 24. Mortlock DP, Innis JW. Mutation of HOXA13 in hand–foot– genital syndrome. Nat Genet 1997;15:179 – 80. 25. Goodman FR, Bacchelli C, Brady AF, Brueton LA, Fryns JP, Mortlock DP, et al. Novel HOXA13 mutations and the phenotypic spectrum of hand–foot– genital syndrome. Am J Hum Genet 2000;67:197–202. 26. Stelling JR, Bhagavah B, Gray MR, Reindollar RH. HOXA13 homeodomain mutation analysis in patients with Müllerian system anomalies. J Soc Gynecol Invest 1998;5:140A. 27. Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Mullerian-duct regression and virilization in a 46,XX woman. N Engl J Med 2004;351:792– 8. 28. Clement-Ziza M, Khen N, Gonzales J, Cretolle-Vastel C, Picard JY, Tullio-Pelet A, et al. Exclusion of WNT4 as a major gene in Rokitansky-Kuster-Hauser anomaly. Am J Med Genet A 2005;137:98 –9. 29. Troiano RN, McCarthy SM. Müllerian duct anomalies: imaging and clinical issues. Radiology 2004;233:19 –34.
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Department of Gynecology and Obstetrics, University Hospital, Erlangen and b Department of Gynecology and Obstetrics, University Hospital, Tübingen, Germany
Objective: With an incidence of up to 5% in the general population, genital malformations are a frequent clinical occurrence. The aim of this study was to assess whether a connection could be demonstrated between various degrees of severity of genital malformations and associated abnormalities. Design: All patients were classified using the Vagina, Cervix, Uterus, Adnex, and Associated Malformation (VCUAM) classification. Setting: University hospital. Patient(s): Two hundred eleven premenopausal patients with female genital malformations. Intervention(s): The patients underwent diagnostic workup for genital malformations using laparoscopy as well as hysteroscopy. Associated malformations were detected by either magnetic resonance imaging (MRI) or ultrasound. Main Outcome Measure(s): Demonstration of a connection between various degrees of severity of genital malformations and associated abnormalities. Result(s): In 72 cases (36%) out of 202 patients with uterine malformations (VCUAM U1– 4) we found associated abnormalities. The predominant findings were alterations in the renal system. When vaginal abnormality (VCUAM V1–5) alone was taken into consideration, an associated developmental disturbance in the renal tract was found in 30% of cases (n ⫽ 32 from 107). Conclusion(s): A close connection was demonstrated between genital malformations and associated abnormalities. For this reason, the diagnostic workup in patients with malformations should always include the renal system. Depending on the severity of the clinical picture, examinations may need to be extended further. (Fertil Steril威 2007;87:335– 42. ©2007 by American Society for Reproductive Medicine.) Key Words: Uterine malformation, genital malformation, vaginal malformation, MRKH syndrome, VCUAM classification
In the general female population, genital malformations are reported to occur with an incidence of 1%–5%, in groups of patients with fertility up to 6.5 % (1–5). The etiology is possibly due to an aberrant developmental inhibition of the Muellerian ducts during embryogenesis. To date, various genetic factors have been investigated, but a precise cause has not been identified for any of the individual types of malformation (1, 6 – 8). Precise classification of the individual malformations reported in the literature is only possible from reports with sometimes small numbers of cases. Because symptoms only occur in approximately 50% of cases in connection with the malformations, it must be assumed that mild malformations in particular (VCUAM classification U1a– 1c) are often not diagnosed and that these subgroups are underrepresented (9, 10). Figure 1 shows the distribution Received February 5, 2006; revised and accepted July 5, 2006. Reprint requests: Peter Oppelt, M.D., Department of Gynecology and Obstetrics, University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen, Germany (FAX: 49-9131-8536185; E-mail: Peter.Oppelt@ gyn.imed.uni-erlangen.de
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.07.1501
of malformations in 1,392 patients with uterine malformations according to the review by Woelfler and Rimbach (11), using the American Fertility Society (AFS) classification (12). However, this classification did not include other associated malformations. Regarding genital anomalies, it is usually the pathology of the uterus that is the focus of attention. Depending on their extent, these changes may occur in combination with other genital and associated malformations. Isolated genital malformations without changes in the uterus may also occur (13–17). Our previous publication validated a specifically group of patients with MRKH (Mayer-Rokitansky-Kuester-Hauser) and a small sample of only a few additional genital malformations using the VCUAM Classification System defined by us (10). Therefore, the aim of the present study was to extend this validation using VCUAM to now include a total of 211 female patients with all types of genital malformations and also test the classification in relation to associated changes (10).
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FIGURE 1 Distribution of uterine malformations of 1392 patients by Woelfler and Rimbach (11).
2a, unilateral hypoplasia/gonadal streak (including tubal malformation if appropriate); 2b, bilateral hypoplasia/gonadal streak (including tubal malformation if appropriate); 3a, unilateral aplasia; 3b, bilateral aplasia. Associated malformation: 0, none; R, renal system; S, skeleton; C, cardiac; N, neurologic. In any group in the VCUAM classification, the symbol ⫹ can be used to indicate “unclassifiable” and the symbol # to indicate “unknown.” In the analysis, the malformation of the uterus was regarded as dominant and as the reference point in relation to other abnormalities such as those in the vagina (see Tables 1–3). In a further analytical step, the vagina was set as the reference point, as in the gynecological examination anomalies, those are noticeable first. In Table 4, the individual vaginal malformations are correlated with additional genital and associated abnormalities.
Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
MATERIALS AND METHODS Between January 2000 and June 2005, 211 patients contacted the Departments of Gynecology at the university hospitals in Erlangen and Tübingen because of sterility or genital malformations. In a few of the patients, the data had been obtained as asymptomatic incidental findings. For precise assessment of the genital and associated anomalies, patients’ records, general visual examination of the urinary tract, surgical reports, x-ray pictures, magnetic resonance tomography findings, and ultrasound findings were evaluated. All patients underwent diagnostic workup for genital malformations using laparoscopy as well as hysteroscopy and ultrasound examination of the kidneys. Symptomatic associated malformations were then further evaluated by magnetic resonance imaging (MRI). The final classification of each malformation was carried out using the new VCUAM classification (10). This classification makes it possible to record the pathological anatomy of genital developmental disturbances descriptively. Each is recorded in accordance with the following scheme. Vagina: 0, normal; 1a, partial hymenal atresia; 1b, complete hymenal atresia; 2a, incomplete septate vagina ⬍50%; 2b, complete septate vagina; 3, stenosis of the introitus; 4, hypoplasia; 5a, unilateral atresia; 5b, complete atresia; S1, sinus urogenitalis (deep confluence); S2, sinus urogenitalis (middle confluence); S3, sinus urogenitalis (high confluence); C, cloaca. Cervix: 0, normal; 1, duplex cervix; 2a, unilateral atresia/ aplasia; 2b, bilateral atresia/aplasia. Uterus: 0, normal; 1a, arcuate; 1b, septate, ⬍50% of the uterine cavity; 1c, septate, ⱖ50% of the uterine cavity; 2, bicornate; 3, hypoplastic uterus; 4a, unilaterally rudimentary or aplastic; 4b, bilaterally rudimentary or aplastic. Adnex: 0, normal; 1a, unilateral tubal malformation, ovaries normal; 1b, bilateral tubal malformation, ovaries normal; 336
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Approval for conducting basic research and compiling the relevant documentation on female genital malformations was received through Ethics Vote no. 3074 in the Faculty of Medicine at the University of Erlangen. RESULTS Among the 211 patients included in the study, 202 had uterine and 9 had isolated vaginal anomalies. Also included in this analysis for comparison were 56 patients with MRKH, previously published (10). To allow better assessment of the connection between pathological, embryological abnormalities and the associated malformations, all of the patients were categorized, using the VCUAM classification, first with regard to their uterine changes and second, in relation to their vaginal changes. VCUAM U1 Group (Arcuate Uterus, Subseptate Uterus) Overall, only a few concomitant malformations were found in 80 patients in this group (Table 1). Additional anomalies in the cervix were only seen in five cases. All five of these patients also had a complete septate uterus (VCUAM U1c). Among the patients included in the study, this was not observed with those in uterine categories U1a and U1b. The associated malformation described included five changes in the urogenital system, two anal atresias, one hernia, one auricular, and one cerebral artery aneurysm. Changes in the adnex area were only found in one patient, with unilateral tubal hypoplasia. VCUAM U2 Group (Bicornate Uterus) Thirty-eight patients of 202 had a bicornate uterus (Table 2). In 50% of the cases (n ⫽ 19), this was accompanied by a duplex cervix. An increased proportion of malformations in the adnex was also observed in comparison with the VCUAM U1 group. Overall, 39% of the patients had at least one associated anomaly. The largest group consisted of 11 Vol. 87, No. 2, February 2007
TABLE 1 Uterine malformations VCUAM U1 (80 patients; 19 patients previously published in Oppelt et al.). Patient 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21)
Vagina
Cervix
Uterus
Adnex
Associated malformations
V# V0 V0 V0 V0 V1a V0 V0 V0 V0 V0 V0 V0 V0 V0 V0 V0 V0 V2a V2b VC
C# C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C0 C1 C0 C0 C1 C1 C2a
U1a U1a U1a U1a U1a U1a U1b U1b U1b U1b U1b U1b U1b U1c U1c U1c U1c U1c U1c U1c U1c
A0 A# A⫹ A0 A0 A0 A# A# A0 A0 A0 A0 A1a A# A0 A0 A0 A0 A0 A0 A0
M0 M0 M0 MR M0 M0 M0 M0 M⫹ M⫹ M0 MR M0 MR⫹ MR M0 M⫹ M0 M0 M0 MR⫹
Description associated malformations
Amount
Vesicourethral reflux 17 x
A Malformation auricula 37 x B Double ureter, B C (left) Cerebral aneurysm 7x 2x Horseshoe kidney; anal atresia
Note: A ⫽ inguinal hernia; B ⫽ unilateral renal aplasia; C ⫽ double kidney. Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
changes in the urogenital system. In addition, dysplasias in the ear and nose, mental retardation, and skeletal changes were also diagnosed.
the women. Overall, the VCUAM U4 major group included 11 patients with morphological changes in the adnex, ranging from unilateral tubal anomaly (VCUAM A1a) to bilateral gonadal aplasia (VCUAM A3b).
VCUAM U3 Group (Hypoplastic Uterus) Only 5 of 202 patients could be assigned to this group. Four of five patients in the group showed a close association between uterine and ovarian abnormalities. Bilateral hypoplastic ovaries (gonadal streaks) were documented in all but one patient. A skeletal anomaly was present in only one case.
At least one extragenital malformation was found in 41% (n ⫽ 32) of the patients in the VCUAM U4 group. The most frequent were anomalies of the urogenital system (n ⫽26), followed by skeletal malformations (n ⫽ 13) and heart defects (n ⫽ 4). The first case of a patient with an abnormal neurologic status was also observed (n ⫽ 1).
VCUAM U4 Group (Unilaterally or Bilaterally Rudimentary Uterus) With a total of 79 of 202 patients in this group, unilateral uterine horn aplasia or a rudimentary horn (VCUAM U4a) was present in six cases (Table 3). A substantial difference was observed between the latter group and those with bilateral uterine horn aplasia/bilateral rudimentary uterine horn (VCUAM 4b) with regard to cervical involvement. Although complete vaginal atresia was present in all patients in the VCUAM U4b group, vaginal atresia was seen in only one case in the VCUAM U4a group. Three patients had no cervical pathology. A duplex cervix was present in two of
VCUAM V1–5 Group (Hymenal Atresia, Septate Vagina, Stenosis of the Introitus, Hypoplasia, Atresia, Sinus Urogenitalis, Cloaca) A total of 107 from the total of 211 patients were found to have malformations of the vagina (Table 4). Although only two of eight patients in the VCUAM V1 group had associated abnormalities, more strongly marked vaginal were more frequently combined with other changes in the genitals or associated malformations. All women with a septate vagina (n ⫽ 19) also had a duplex cervix, which continued in 14 cases with duplex uterus and in 3 cases with a complete septate uterus. In this subgroup, renal anomalies were also diagnosed in 32% of the patients (n ⫽ 6), as well as mal-
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TABLE 2 Uterine malformations VCUAM U2 (38 patients; 20 patients previously published in Oppelt et al.). Patient
Associated malformations
Vagina
Cervix
Uterus
Adnex
1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11)
V# V# V0 V0 V0 V0 V0 V0 V0 V0 V1b
C# C0 C0 C0 C0 C0 C0 C0 C0 C1 C#
U2 U2 U2 U2 U2 U2 U2 U2 U2 U2 U2
A# A3b A# A# A# A0 A0 A0 A1a A0 A0
M# M⫹ M0 MR MR M0 MR MS M0 M0 M⫹
12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22)
V2a V2a V2a V2b V2b V2b V2b V2b V2b V4 VS1
C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C0
U2 U2 U2 U2 U2 U2 U2 U2 U2 U2 U2
A0 A0 A1a A0 A0 A0 A0 A2a A2a A2b A0
M0 MR M0 M0 MR MR MR M0 MR M0 MN⫹
Description associated malformations
Amount
A 2x C (right) B
2x 6x 2x
Pelvic kidney scoliosis
3x Dysmorphism ear-hand-foot, partial missing tooth germ 3x B 4x 2x
B Double renal pelvis Ureter fissure B Mental retardation, strabismus
Note: A ⫽ inguinal hernia; B ⫽ unilateral renal aplasia; C ⫽ double kidney. Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
formations of the adnex in 16% (two in VCUAM A2a, one in VCUAM A2b). In addition stenoses of the vaginal introitus (n ⫽ 1; VCUAM V3) or vaginal hypoplasia (n ⫽ 4; VCUAM V4) were basically associated with at least one additional genital change. All of the patients with complete vaginal atresia (n ⫽ 72; VCUAM V5b) had simultaneous bilateral cervical aplasia as well as a bilateral rudimentary uterus or uterine aplasia. In addition, there was a marked increase in the frequency of associated anomalies in this subgroup. The most frequent of these were malformations of the kidneys, occurring in 23 of 72 patients (32%), followed by 14 skeletal dysmorphisms (particularly in the vertebral bodies and hips). The proportion of malformations of the adnex (n ⫽10, 14%) and heart (n ⫽ 4, 6%) was also notably high. DISCUSSION In the examination of genital malformations, attention usually focuses primarily on changes in the uterus, and this is reflected in almost all classifications of deformation. Acien et al. (18) attempted to use an embryonic classification to document connections between genital and urologic alter338
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ations. However, the classification met with little acceptance due to the complexity involved in using it. In this present investigation we demonstrated that the VCUAM classification can now be used generally to include all female genital malformations. The VCUAM classification, designed for easy clinical use, makes it possible to record all anatomic malformations and associated abnormalities separately. This is very important, particularly for the description of syndromes with genital involvement. Examples include patients with MRKH, especially the MURCS syndrome (Muellerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia), which includes both genital and extragenital abnormalities (7, 19). When the individual uterine changes (VCUAM U1a–U4b) are compared with the associated genital and extragenital malformations, a connection is evident that can in part be explained on the basis of embryogenesis. For example, the close spatial relationship between the Wolffian duct (mesonephric duct) and the Muellerian duct is often regarded as explaining uterine malformations with accompanying renal developmental disturbances. Gruenwald (20) and Magee et al. (21) were able to show that there is a direct influence of Vol. 87, No. 2, February 2007
TABLE 3 Uterine malformations VCUAM U4 (79 patients; 59 patients previously published in Oppelt et al.). 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22) 23) 24) 25)
V⫹ V0 V0 V0 V3 V4 V4 V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b
C1 C1 C0 C0 C0 C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b
U4a U4a U4a U4a U4a U4a U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b
A0 A# A0 A2b A# A⫹ A0 A# A# A# A# A# A# A# A# A0 A0 A0 A0 A0 A0 A0 A0 A0 A0
MR⫹ M# M0 M0 MR⫹ M0 MR⫹ M# M0 MR MR MRC MRS MS MSN M⫹ M0 MC⫹ MR MR MR MR MR MRS MRS⫹
26) 27)
V5b V5b
C2b C2b
U4b U4b
A0 A0
MRSC⫹ MS
28) 29) 30) 31) 32) 33) 34) 35) 36) 37) 38)
V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b
C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b
U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b
A0 A1a A1b A1b A1b A1b A2a A2b A2b A3a A3a
MS⫹ MR MR⫹ MRS⫹ MRS⫹ MRSC⫹ MR MRS MRS M0 MRS
A, silent kidney left, double aorta
C, rectal atresia, double kidney right A, hearing loss 13 x 5x D C C, E C, G, talipes varus Absence of 1/3 of the left arm hearing loss, hypoplasia of the wrist A 24 x A, E D C B Malformation uretra Horseshoe kidney B, malformation HWS A, F, high blood pressure, hypoplasia of the wrist A, D, E, F G, radial aplasia–thrombocytopenia syndrome with bilateral club hand F, cataract B A, B B, C, dwarfism, fibroma A, C, F A, C, open duct, jaw anomaly B B, F F, G, deformed elbow
3x
B, C, F
Note: A ⫽ inguinal hernia; B ⫽ unilateral renal aplasia; C ⫽ pelvic kidney; D ⫽ nephrosclerosis; E ⫽ aorticopulmonary septal defect; F ⫽ scoliosis; G ⫽ congenital dysplasia of the hip. Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
the Wolffian duct, through induction, on the development of the Muellerian duct. A high incidence of renal abnormalities was found with uterine malformations.
other associated malformations, which are encountered most frequently in the VCUAM U4 group, particularly in connection with the MRKH syndrome.
Although only 5 renal abnormalities (6%) were observed in the VCUAM U1 group, 11 malformations of the renal system were seen in the VCUAM U2 group (29%) and 25 in the VCUAM U4 group (32%). The same also applies to
In contrast to the VCUAM groups U1, U2, and U4, only one associated malformation of the (VCUAM MS–scoliosis) was observed among the five cases of the VCUAM group U3. A genetic mutation is probably not the primary factor for
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TABLE 4 Vaginal malformations VCUAM V (107 patients; 62 patients previously published in Oppelt et al.). Associated Patient Vagina Cervix Uterus Adnex malformations 1) 2) 3) 4) 5) 6)
V1a V1a V1a V1b V1b V1b
C0 C0 C0 C# C0 C#
U# U0 U1a U0 U0 U2
A# A0 A0 A0 A0 A0
M0 M0 M0 M0 M0 M⫹
7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22) 23) 24) 25) 26) 27) 28) 29) 30) 31) 32) 33) 34) 35) 36) 37) 38) 39) 40) 41) 42)
V2a V2a V2a V2a V2a V2b V2b V2b V2b V2b V2b V2b V2b V3 V4 V4 V4 V4 V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b V5b
C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C0 C0 C1 C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b C2b
U0 U1c U2 U2 U2 U0 U1c U2 U2 U2 U2 U2 U2 U4a U0 U2 U4a U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b U4b
A0 A0 A0 A0 A1a A# A0 A2a A0 A0 A0 A0 A2a A# A2b A2b A⫹ A0 A# A# A# A# A# A# A# A# A0 A0 A0 A0 A0 A0 A0 A0 A0 A0
M0 M0 MR M0 M0 M0 M0 MR MR MR MR M0 M0 MR⫹ MR M0 M0 MR⫹ M# M0 MR MR MRC MRS MS MSN M⫹ M0 MC⫹ MR MR MR MR MR MRS MRS⫹
43) 44)
V5b V5b
C2b C2b
U4b U4b
A0 A0
MRSC⫹ MS
45) 46)
V5b V5b
C2b C2b
U4b U4b
A0 A1a
MS⫹ MR
Description associated malformations
Amount 2x
2x Dysmorphism ear-hand-foot, partial missing tooth germ 2x B 3x
B B Double renal pelvis Ureter fissure
2x
4x C, rectal atresia, double kidney right B
A, hearing loss 13 x 5x D C C, E C, G, talipes varus absence of 1/3 of the left arm Hearing loss, hypoplasia of the wrist A 24 x A, E D C B Malformation uretra Horseshoe kidney B, malformation HWS A, F, high blood pressure, hypoplasia of the wrist A, D, E, F G, radial aplasia–thrombocytopenia syndrome with bilateral club hand F, cataract B
3x
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TABLE 4 Continued. Associated Patient Vagina Cervix Uterus Adnex malformations 47) 48) 49) 50)
V5b V5b VC VS1
C2b C2b C2a C0
U4b U4b U1c U2
A1b A1b A0 A0
MR⫹ MRS⫹ MR⫹ MN⫹
Description associated malformations
Amount
A, B B, C, dwarfism, fibroma Horseshoe kidney, anal atresia Anal atresia, strabismus
Note: A ⫽ inguinal hernia; B ⫽ unilateral renal aplasia; C ⫽ pelvic kidney; D ⫽ nephrosclerosis; E ⫽ aorticopulmonary septal defect; F ⫽ scoliosis; G ⫽ congenital dysplasia of the hip. Oppelt. Female genital malformations diagnosis. Fertil Steril 2007.
the hypoplastic uterus, but rather an endocrinologic failure, which in this group is likely to be found in the lack of hormone production in the ovaries (four cases of VCUAM A2b). Acien et al. (18) have attempted to infer an embryological link; however, a molecular– genetic explanation has not yet been identified. Also a close relationship between the Muellerian duct and the urogenital sinus was observed. Among 107 patients with vaginal malformations (development from the urogenital sinus, VCUAM V1–5), 90% (n ⫽ 96) had cervical, 92% (n ⫽ 98) had uterine, and 30% (n ⫽ 32) had renal abnormalities as concomitant findings. A close association was also demonstrated in 20 patients with duplex vagina (VCUAM V2a and b) who were all diagnosed with duplex cervix. In addition, 3 cases of the 20 patients had a complete intrauterine septa and 15 patients, a duplex uteri. The connection is seen most impressively in the context of the MRKH syndrome. All 72 patients with bilateral vaginal atresia had bilateral cervical and uterine aplasia as concomitant findings (10). In contrast, when one starts primarily from the malformation that originates in the Muellerian duct, a malformation with its origin in the urogenital sinus is not found in all cases. In 202 patients with uterine malformations (Muellerian duct; VCUAM U1– 4), only 96 abnormalities of the vagina (urogenital sinus) were found. Another notable observation is the structure of the VCUAM U2 subgroup. Among the 38 patients with bicornate uterus (VCUAM U2), no abnormalities of the cervix or vagina were found in 15 cases (40%). A further observation is that 5 (33%) of these 15 patients were suffering from malformations of the renal system (two with pelvic kidney, two with renal agenesis, and one with unilateral double kidney). The conclusion might be that there is a direct influence of the sinus urogenitalis, through induction, on the development of the Muellerian duct and in some cases also of the Wolffian duct. Regarding all genital malformations and their associated abnormalities it can be concluded that other superordinated Fertility and Sterility姞
induction pathways must be available for this type of abnormal development. These results contribute to the hypothesis that organogenesis primarily takes place independently, but that there are higher level regulatory mechanisms that can have common effects on both the Muellerian and Wolffian ducts and the urogenital sinus. On the basis of genetic studies in mice, particularly in the knock-out mouse model, a fundamental role in the development of the urogenital tract has been attributed to the HOXA genes. Several mouse models have shown that Hoxa10 is essential for uterine development, Hoxa11 for the caudal uterine and cervical area, Hoxa13 for the upper vagina, and Hoxa9 for the development of the fallopian tubes (22, 23). A nonsense HoxA13 mutation is known to exist in the “hand– foot– genital” syndrome in humans (24, 25). However, no mutations were found in 32 patients with Muellerian aplasia (26). In a case report of an 18-year-old woman with MRKH syndrome, Biason-Lauber et al. (27) detected a loss-of-function mutation in the WNT4 gene. The WNT4 gene appears to be important for the regulation of Muellerian duct formation and control of ovarian steroidogenesis. But genetic analyses by Clément-Ziza et al. (28) exclude WNT4 as the major responsible gene in this malformation. The question of whether MRI is capable of replacing hysteroscopy and laparoscopy in the diagnostic workup is a matter of controversy (3, 29). In our own experience, we have noted incorrect interpretations based on the MRI findings, particularly in cases of complex female urogenital malformation. Finally, it should be pointed out that female genital malformations are frequently associated with other abnormalities. During the diagnosis of malformations, an ultrasound examination of at least both kidneys should also be carried out in addition to the assessment of the small pelvis. The extent to which the diagnosis and workup may need to be extended further should be determined in relation to the extent of the malformations and the patient’s symptoms. In this context, clinical pictures in the areas of urology, neurology, orthopedics, and cardiology should be considered. 341
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