Studying Müllerian duct anomalies – from cataloguing phenotypes to discovering causation

Abstract

Müllerian duct anomalies (MDAs) are developmental disorders of the Müllerian duct, the embryonic anlage of most of the female reproductive tract. The prevalence of MDAs is 6.7% in the general female population and 16.7% in women who exhibit recurrent miscarriages. Individuals affected by these anomalies suffer from high rates of infertility, first-trimester pregnancy losses, premature labour, placental retention, foetal growth retardation and foetal malpresentations. The aetiology of MDAs is complex and heterogeneous, displaying a range of clinical pictures that generally lack a direct genotype-phenotype correlation. De novo and familial cases sharing the same genomic lesions have been reported. The familial cases follow an autosomal-dominant inheritance, with reduced penetrance and variable expressivity. Furthermore, few genetic factors and molecular pathways underpinning Müllerian development and dysregulations causing MDAs have been identified. The current knowledge in this field predominantly derives from loss-of-function experiments in mouse and chicken models, as well as from human genetic association studies using traditional approaches, such as microarrays and Sanger sequencing, limiting the discovery of causal factors to few genetic entities from the coding genome. In this Review, we summarise the current state of the field, discuss limitations in the number of studies and patient samples that have stalled progress, and review how the development of new technologies provides a unique opportunity to overcome these limitations. Furthermore, we discuss how these new technologies can improve functional validation of potential causative alterations in MDAs.

Reassessment of Surgical Procedures for Complex Obstructive Genital Malformations: A Case Series on Different Surgical Approaches

“…Each of these steps is crucial for the unremarkable development of the female internal genitalia, and disruption at any point can cause different types of genital developmental disorders, including cervical agenesis or aplasia [ 1 , 2 , 3 ]. In general, Müllerian duct anomalies are described in 4–7% of the female population, although cases of cervical agenesis or aplasia (with or without a vagina) but with a functional uterus are rare [ 4 , 5 , 6 , 7 ].…”

Development and characterization of human fetal female reproductive tract organoids to understand Müllerian duct anomalies

“…Müllerian duct anomalies (MDAs) represent a group of developmental disorders related to abnormalities in female reproductive tract organs ( 1 ). The incidence rate of MDAs in the general population and fertile women is around 5% ( 2 , 3 ).…”

“…Müllerian ducts (MDs; also known as paramesonephric ducts) are the paired tubular structures that undergo a highly orchestrated and complex process of differentiation to give rise to the fallopian tubes (FTs), uterus, cervix, and upper vagina ( 4 , 5 ). In MDA patients, one or more MD-derived organs are either underdeveloped or missing completely ( 1 , 6 ). Such patients are usually of a normal karyotype 46, XX genetic females and often have functioning ovaries and age-appropriate external genitalia ( 1 ).…”

“…In MDA patients, one or more MD-derived organs are either underdeveloped or missing completely ( 1 , 6 ). Such patients are usually of a normal karyotype 46, XX genetic females and often have functioning ovaries and age-appropriate external genitalia ( 1 ). Therefore, these females are generally presented in the clinic in the postpubertal stages with a wide range of gynecological and obstetrical disorders, including infertility and recurrent first-semester miscarriages ( 3 ).…”

“…Therefore, these females are generally presented in the clinic in the postpubertal stages with a wide range of gynecological and obstetrical disorders, including infertility and recurrent first-semester miscarriages ( 3 ). The clinical presentation of patients is related to the severity of the anatomical defects in MD-derived organs, which range from agenesis of the uterus and vagina to minor uterine cavity malformations ( 1 ).…”