Clinical And Molecular Genetics Of Vaginal Septal Syndrome

BackgroundHerlyn-Werner-Wunderlich syndrome (HWWS) is a rare congenital anomaly, characterized by uterus didelphys, obstructed hemivagina and ipsilateral renal anomaly. It is caused by abnormal development of Wolffian and Mullerian ducts, with the exact-etiology still unknown. The classic clinical manifestations include dysmenorrhea, abdominal mass, irregular vaginal hemorrhage and intermittent mucopurulent discharge. Besides, it is classified into three types by Peking Union Medical College Hospital (PUMCH). After the diagnosis and classification is confirmed by pelvic and urological ultrasounds, vaginal septum resection and drainage of hematocolpos during menstruation is strongly recommended. Surgery is effective and safe. Only small amounts of sporadic cases have been reported, and familial clustering has never been described. Consequently, it is very difficult to analyze the mode of inheritance and molecular genetics underlying HWWS.MethodsIn this retrospective study, all patients, who were diagnosed of HWWS and admitted for surgery at Department of Obstetrics and Gynecology, PUMCH, Beijing, China between January 1986 and August 2015, were reviewed. After informed consent of patients and their relatives, clinical records and peripheral blood were collected. Supplemental data, clinical prognosis and pregnant outcomes were obtained through follow-up. DNA, collected from blood specimens, was for whole exome sequencing and further biological information analysis. Synonymous mutations and ordinary mutations were excluded, meanwhile deleterious and shared variations were preferred.ResultsOne hundred and nine patients with complete clinical data and confirmed diagnosis of HWWS were reviewed, including 39 cases of type I,68 cases of type Ⅱ and 3 cases of type Ⅲ. Patients, who were categorized as type I, were significantly younger than patients of type II and Ⅲ at onset and diagnosis (P<0.05). The mean time between menarche and onset of syndromes of type I was also significantly shorter than that of type Ⅱ and Ⅲ (P<0.05). Patients of type I tended to have dysmenorrhea, hematometra, hematosalpinx and hemoperitoneum, and progression to secondary endometriosis and pelvic adhesion. Meanwhile, patients of type II and III were more likely to intermittent mucopurulent discharge, acute pelvic inflammation and progression to pyocolpos and pyosalpinx.All patients had ipsilateral renal atresia, with relatively bigger opposite kidney. Of all the renal atresia,60.6% occurred at the right side. Few patients were combined with vertebral, cardiac and anal malformations.Most patients underwent vaginal septum resection and drainage of hematocolpos during menstruation, which was safe and with good clinical prognosis. As for the pregnancy outcomes, about 80% of patients were able to get pregnant with live birth rate of 69.4%. No pathological pregnancy was discovered.DNA was collected from 25 sporadic patients and underwent whole exome sequencing. After primary filtration unqualified, synonymous and ordinary mutations, the quantity of variations was decreased from 456894 to 744. After further analysis, LRP5、 CHD7、 DNAH14、PLEC and PDE4DIP were considered as possible virulence genes.ConclusionsHWWS has various clinical manifestations, depending on the classification. Therefore, the classification from PUMCH is important and helpful to understand the diagnosis of HWWS. Besides, surgery is an effective and safe way to relive symptoms and retain fertility.With the application of whole exome sequencing technique and analysis of pathogenicity, the possible virulence genes of 25 sporadic HWWS patients are LRP5、 CHD7, DNAH14 and PLEC. However, further functional studies are still demanded.