Pelvic Organ Prolapse, Susceptibility To

Description

Female pelvic floor disorders, including pelvic organ prolapse (POP), urinary incontinence, and stress urinary incontinence, affect over one-third of adult women (Bump and Norton, 1998). These disorders are characterized by weakening of the tissues supporting and anchoring the pelvic organs, which can affect both structure and function of the vagina, uterus, bladder, anus, and intestines.

Clinical Features

Yip and Kirsner (1983) described a 69-year-old woman who developed vaginal prolapse at age 29 for which vaginal hysterectomy was performed, and rectal prolapse at age 57 for which Dolorme operation was performed at age 62. At age 67, she had recurrence of rectal prolapse and later fecal incontinence, seemingly from loss of control of her anal sphincter. Vaginal prolapse had occurred also in her mother and daughter but no other examples of rectal prolapse were known in the family. The possibility that this represents a manifestation of a form of the Ehlers-Danlos syndrome comes to mind (VAM).

Pathogenesis

Connell et al. (2008) found that the uterosacral ligaments of 18 women with pelvic organ prolapse showed approximately 75-fold and 17-fold lower expression of HOXA11 (142958) and collagen III (COL3A1; 120180), respectively, compared to controls. In addition, MMP2 (120360) was increased 2-fold in patient tissue. Histologic examination showed more loosely organized collagen architecture in the ligaments from patients with prolapse. In vitro studies on murine embryonic fibroblasts showed that Hoxa11 increased collagen III expression and decreased Mmp2 expression. The findings were consistent with a pathway of extracellular matrix metabolism involving HOX11A, COL3A1, and MMP2. Connell et al. (2008) concluded that HOXA11 is essential for the development of the uterosacral ligaments, and suggested that women with pelvic organ prolapse may have weakened connective tissue due to changes in this signaling pathway.

Population Genetics

Ethnic and racial variations in the incidence of female pelvic floor disorders support the role of genetic factors. Women of European and Hispanic descent may be at greater risk compared to women of Asian, African, and Native American ethnicity. Dietz (2003) concluded that Asian women have significantly less pelvic organ mobility, both antepartum and postpartum, as opposed to women of Caucasian ancestry.

Inheritance

Chiaffarino et al. (1999) in several studies reported that among women with POP, approximately 30% show a familial occurrence.

The risk factors for POP are multifactorial (Nikolova et al., 2007). Vaginal parity, increased infant birth weight, episiotomy, extended second stage of labor, previous surgery, obesity, age, hormonal status, smoking, and constipation have all been reported to contribute to increased risk of POP. However, environmental factors alone fail to fully explain the genesis and progression of the disorder. Severe female pelvic floor disorders have been observed on occasion in nulliparous women with minimal risk factors; furthermore, most multiparous women do not develop symptoms.

Mapping

Nikolova et al. (2007) described a family in which 7 women in 3 generations, including a set of identical twins, suffered from pelvic organ prolapse from a very young age. A genomewide linkage scan identified 10 regions with a lod score of 1.5, the maximum possible for this family. Candidate genes within these regions were analyzed for expression in vaginal tissue by RT-PCR. Of the genes confirmed to be expressed, LAMC1 (150290) was further evaluated by sequencing and SNP genotyping. One such SNP, rs10911193, for which a rare T variant was segregating with the condition in this family, was present at a frequency of 4.9% in the general population and 22% among probands from a cohort of families with early-onset familial pelvic organ prolapse. The SNP was located in the promoter region of LAMC1.

Animal Model

Connell et al. (2008) found that Hoxa11-null mice had no detectable uterosacral ligaments.