Stefan P. Renner

High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia

Background Congenital malformations involving the Müllerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Müllerian aplasia or Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at different genomic loci. Methods In order to obtain an overview of the contribution of copy number variation to both isolated and syndromic forms of Müllerian aplasia, copy number assays were performed in a series of 63 cases, of which 25 were syndromic and 38 isolated. Results A high incidence (9/63, 14%) of recurrent copy number variants in this cohort is reported here. These comprised four cases of microdeletion at 16p11.2, an autism susceptibility locus not previously associated with Müllerian aplasia, four cases of microdeletion at 17q12, and one case of a distal 22q11.2 microdeletion. Microdeletions at 16p11.2 and 17q12 were found in 4/38 (10.5%) cases with isolated Müllerian aplasia, and at 16p11.2, 17q12 and 22q11.2 (distal) in 5/25 cases (20%) with syndromic Müllerian aplasia. Conclusion The finding of microdeletion at 16p11.2 in 2/38 (5%) of isolated and 2/25 (8%) of syndromic cases suggests a significant contribution of this copy number variant alone to the pathogenesis of Müllerian aplasia. Overall, the high incidence of recurrent copy number variants in all forms of Müllerian aplasia has implications for the understanding of the aetiopathogenesis of the condition, and for genetic counselling in families affected by it.

Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)

BackgroundThe aim of this retrospective study was to describe the spectrum of genital and associated malformations in women with Mayer-Rokitansky-Küster-Hauser syndrome using evaluated diagnostic procedures and the Vagina Cervix Uterus Adnex – associated Malformation classification system (VCUAM).Methods290 women with MRKH syndrome were clinically evaluated with using clinical examinations, abdominal and perineal/rectal ultrasound, MRI, and laparoscopy.ResultsClassification of female genital malformation according to the Vagina Cervix Uterus Adnex – associated Malformation classification system was possible in 284 women (97.9%). Complete atresia of Vagina (V5b) and bilateral atresia of Cervix (C2b) were found in 284 patients (100%). Uterus: bilateral rudimentary or a plastic uterine horns were found in 239 women (84.2%). Adnexa: normal Adnexa were found in 248 women (87.3%). Malformations: associated malformations were found in 126 of 282 evaluable women (44.7%), 84 women (29.6%) had malformations of the renal system. Of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome 212 women (74.7%) could be classified as V5bC2bU4bA0. The most frequent classification was V5bC2bU4bA0M0 (46.8%) diagnosed in 133 of 284 women.ConclusionsComplete atresia of vagina and cervix were found in all patients, variable malformations were found with uterus and adnexa. A variety of associated malformations were present, predominantly of the renal system. It is therefore recommended that all patients with genital malformations should be evaluated for renal abnormalities.

Hysterectomy—A Comparison of Approaches

BACKGROUND The advantages and disadvantages of the various surgical techniques for hysterectomy are currently a topic of debate, with particular controversy over leaving the cervix in situ in the laparoscopic supracervical hysterectomy (LASH) procedure. METHODS In a retrospective single-center study, medical history and clinical characteristics were compared in patients who had undergone hysterectomy for benign disease in the period 2002-2008 at the Department of Obstetrics and Gynecology, Erlangen University Hospital. Postoperative satisfaction and the frequency of secondary operations for prolapse or incontinence in women with surgery between 2002 and 2007 were surveyed by means of a questionnaire. RESULTS The longest hospital stay was observed after abdominal hysterectomy (AH; 10 days), followed by vaginal hysterectomy (VH; 7.8 days) and laparoscopy-assisted vaginal hysterectomy (LAVH; 7.2 days). The shortest stays in hospital were seen after LASH (5.9 days) and total laparoscopic hysterectomy (TLH; 5.7 days). The shortest operating time was noted with VH (87 min) and the longest with LAVH (122 min). The lowest rates of blood loss were with LASH (1.38 g/dL) and TLH (1.51 g/dL). The highest rate of postoperative complications occurred after AH (8.9%). No differences were found in relation to postoperative satisfaction or surgery for prolapse or incontinence. CONCLUSION No postoperative benefits were found for leaving the cervix in situ when performing LASH. However, this was not a controlled randomized study.

Comparison of total laparoscopic hysterectomy (TLH) and laparoscopy-assisted supracervical hysterectomy (LASH) in women with uterine leiomyoma

OBJECTIVE To compare total laparoscopic hysterectomy (TLH) using the Hohl instrument with laparoscopy-assisted supracervical hysterectomy (LASH) in women with uterine leiomyoma. STUDY DESIGN 231 women underwent laparoscopic hysterectomy for the treatment of symptomatic leiomyoma between January 2005 and December 2007. A total of 113 women decided to undergo complete hysterectomy with removal of the cervix (TLH group) and 118 women wished to preserve the cervix; LASH was carried out in the latter group (LASH group). RESULTS No ureteral or bladder injury occurred in any of the patients. Two intraoperative complications and one postoperative complication occurred in the TLH group, while no complications occurred in the LASH group. When the TLH group was compared with the LASH group, the mean loss of hemoglobin was 1.6+/-1.1g/dL (95% CI 1.4-1.8) vs. 1.5+/-1.4g/dL (95% CI 1.2-1.7); the mean operating time was 114.0+/-33.8min (95% CI 107.6-120.2) vs. 116.5+/-40min (95% CI 109.3-124.0); and the mean uterus weight was 264.8+/-133.6g (95% CI 239.8-289.6) vs. 286.2+/-209.3g (95% CI 247.4-324.4). Hospital stay and use of analgesia in both groups were equal. No statistically significant differences were found. CONCLUSIONS TLH using the Hohl instrument is an option comparable with laparoscopy-assisted supracervical hysterectomy for women with uterine leiomyoma. However, the complication rates may be lower when LASH is performed.

HOXA10 and HOXA13 sequence variations in human female genital malformations including congenital absence of the uterus and vagina

Congenital genital malformations occurring in the female population are estimated to be 5 per 1000 and associate with infertility, abortion, stillbirth, preterm delivery and other organ abnormalities. Complete aplasia of the uterus, cervix and upper vagina (Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome) has an incidence of 1 per 4000 female live births. The molecular etiology of congenital genital malformations including MRKH is unknown up to date. The homeobox (HOX) genes HOXA10 and HOXA13 are involved in the development of human genitalia. In this investigation, HOXA10 and HOXA13 genes of 20 patients with the MRKH syndrome, 7 non-MRKH patients with genital malformations and 53 control women were sequenced to assess for DNA variations. A total of 14 DNA sequence variations (10 novel and 4 known) within exonic and untranslated regions were detected in HOXA10 and HOXA13 among our cohorts. Four HOXA10 and two HOXA13 DNA sequence variations were found solely in patients with genital malformations. In addition to mutations resulting in synonymous amino acid substitutions, in the HOXA10 gene a missense mutation was identified and predicted by computer analysis as probably damaging to protein function in two non-MRKH patients, one with a bicornate and the other patient with a septated uterus. A novel exonic HOXA10 cytosine deletion was also identified in a non-MRKH patient with a septate uterus and renal malformations resulting in a premature stop codon and loss of the homeodomain helix 3/4. This cytosine deletion and the missense mutation in HOXA10 were analysed by real time PCR and sequencing, respectively, in two additional larger cohorts of 103 patients with MRKH and 109 non-MRKH patients with genital malformations. No other patients were found with the cytosine deletion however one additional patient was identified regarding the missense mutation. Rare DNA sequence variations in the HOXA10 gene could contribute to the misdevelopment of female internal genitalia.

Higher incidence of linked malformations in siblings of Mayer–Rokitansky–Küster–Hauser-syndrome patients

BACKGROUND Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a malformation of the female genital tract (vaginal aplasia, rudimentary uterus, normal fallopian tubes and high ovaries). The incidence is one in 4000 female newborns. The aim of the present study was to record genital and associated malformations among siblings and relatives of MRKH patients in order to draw possible conclusions regarding the etiology of the syndrome: heredity (dominant versus recessive) or spontaneous malformation. METHODS Using a standardized questionnaire, affected MRKH patients were asked about other cases of MRKH and/or associated malformations among siblings and relatives. RESULTS No other cases of MRKH syndrome had occurred among the siblings or relatives of 73 MRKH patients; however, 13 associated malformations were recorded among a total of 103 siblings. Musculoskeletal malformations were markedly increased (3.27 times higher) in comparison with the prevalence of congenital malformations among newborns in the normal population. CONCLUSIONS This study shows that dominant inheritance cannot play a role in the etiology of MRKH syndrome, as no further cases of MRKH syndrome occurred among any of the siblings. The study provides support for the view that the syndrome has a multifactorial pathogenesis. Siblings/relatives of MRKH patients should be examined for associated musculoskeletal/urogenital malformations.

Evaluation of high-sensitivity C-reactive protein in comparison with C-reactive protein as biochemical serum markers in women with endometriosis

OBJECTIVE To compare high-sensitivity C-reactive protein (hs-CRP) with CRP as a soluble serum marker for the diagnosis of women with endometriosis. DESIGN Prospective nonrandomized controlled trial (Canadian Task Force classification II-1). SETTING University hospital. PATIENT(S) Eighty-two women were laparoscopically evaluated. No endometriosis was diagnosed in 34 women (the non-E group). Endometriosis was confirmed by histology in 48 women (the E group). Eighty-two women did not undergo laparoscopic evaluation (the unknown-E group). Afterward, the women were staged according to the revised American Society for Reproductive Medicine criteria (r-ASRM). INTERVENTION(S) CRP and hs-CRP were measured initially before laparoscopy. MAIN OUTCOME MEASURE(S) The hs-CRP and CRP levels and the correlation of those parameters with the stage of the disease. RESULT(S) There was a trend toward higher CRP levels and higher hs-CRP levels in the E group, while the lowest levels of both markers were found in the non-E group. There was a significantly lower hs-CRP level in the non-E group in comparison with the CRP level in this group. No differences between the different stages of the disease were found with either marker. CONCLUSION(S) Measurement of the two markers did not appear to be advantageous for the diagnosis of endometriosis independent of the stage of the disease. Nevertheless, a very low hs-CRP level might serve as a marker for an absence of endometriosis.

Awareness of general and personal risk factors for uterine cancer among healthy women.

Participation rates in gynaecological cancer screening are influenced by different factors. The knowledge of general and personal risk factors for uterine cancer among women might influence their interest in gynaecological cancer screening. Two thousand nine hundred women in 23 gynaecological outpatient services were invited to answer a structured questionnaire regarding general and personal risk factors for cervical and endometrial carcinoma; 2108 women participated. Women with a history of cancer were excluded from the study. It was found that levels of knowledge about uterine carcinoma were low. Only 47.4% of women knew the difference between the sites of origin of cervical and endometrial cancer. Seventy-seven per cent of participants assessed their knowledge about uterine malignancies as insufficient; 96.3% would appreciate more information about uterine cancer. Younger women were significantly less well informed than postmenopausal women. Known risk factors such as smoking or human papillomavirus (HPV) infection as factors for cervical cancer were underestimated; most women assessed genetic factors as most important for the development of uterine cancer. The level of information about risk factors as well as general facts about gynaecological cancer in women is low. Ameliorating this lack of information might influence the perception of uterine cancer and result in higher participation rates in gynaecological cancer screening.

Hormone replacement therapy and prognosis in ovarian cancer patients.

Estrogen exposure has at least a moderate effect on the risk for ovarian cancer, and antiestrogen therapy may be helpful in treating the disease. It is known from breast cancer that previous hormone replacement therapy (HRT) may influence the molecular profile and prognostic behavior of these tumors. The aim of this study was therefore to investigate the influence of previous HRT on the prognosis in a cohort of patients with invasive epithelial ovarian cancer. Among 547 patients who were treated for ovarian malignancies at a single institution from 1995 to 2008, a total of 244 postmenopausal patients with epithelial cancer and under the age of 75 were identified for whom information about HRT before the onset of the disease was available. HRT was correlated with tumor and patient characteristics. Analyses of overall survival and progression-free survival were carried out using Cox proportional hazards models. Age, tumor stage, and resection status correlated significantly with HRT in the univariate analysis. Patients with previous HRT were more likely to have a lower stage, to be younger, and to have optimal debulking. With regard to survival, HRT had a positive effect on overall survival, specifically in the subgroup of patients with optimal debulking. No correlation was seen in relation to progression-free survival. Sex hormone exposure through HRT may influence the behavior of ovarian cancers after the onset of the disease. This study supports the hypothesis that ovarian cancer is a hormonally influenced tumor.

Comparison of different diagnostic procedures for the staging of malformations associated with Mayer-Rokitansky-Küster-Hauser syndrome.

OBJECTIVE To compare different diagnostic procedures for staging malformations associated with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. DESIGN Retrospective two-center cohort study (Canadian Task Force classification II-2). SETTING University hospital. PATIENT(S) One hundred and thirty-eight women with MRKH. INTERVENTION(S) Clinical examinations, abdominal or perineal/rectal ultrasound, magnetic resonance imaging (MRI), and laparoscopy. MAIN OUTCOME MEASURE(S) Agreement between the results obtained with the other methods and the results obtained with the reference methods for correct staging of malformations, presented as kappa values (κ). RESULT(S) The VCUAM (vagina cervix uterus adnex-associated malformation) classification system was used to classify genital malformations in 138 women with MRKH. The reference methods for examining the individual organs were: vagina-clinical examination; cervix/uterus and adnexa-laparoscopy; and urinary tract malformations-MRI. The values obtained were as follows. Vagina was κ 0.74 for MRI versus clinical examination; ultrasound and laparoscopy did not allow adequate description of vaginal malformations. Cervical findings were rarely detailed with any of the imaging methods. Uterus was κ 0.93 for MRI versus laparoscopy, and κ 0.83 for ultrasound. For adnexa, only laparoscopy was able to describe the morphology adequately. The urinary tract was κ 0.87 for ultrasound versus MRI. CONCLUSION(S) For the correct staging of malformations associated with MRKH, MRI or a combination of clinical examination and ultrasound are equivalent. However, none of the imaging methods adequately describes adnexal morphology.