A rare variant of mullerian agenesis: a case report and review of the literature

A 25-year-old unmarried Indian female presented to the emergency room with severe abdominal pain for 2 days without fever, vomiting, gastrointestinal, urinary, or any other associated systemic symptoms. She was hemodynamically stable, with mild tenderness in the right suprapubic region, but the rest of the examinations revealed no abnormalities. The past history was suggestive of PA, with well-developed secondary sexual characteristics and irregular abdominal pain. The rest of the history, including developmental, family, medical, surgical, and social, was normal. Investigation revealed a normal hemogram, a normal hormonal profile for an adult female, and a 46, XX karyotype. US and MRI revealed a rare variant of MRKH syndrome, polycystic ovaries, and adenomyotic changes in uterine elements. A diagnostic laparoscopy confirmed the mullerian abnormality. She was treated with analgesics and discharged with continuous OCPs as medical management. Psychological support and counseling were given, and surgical and fertility options were discussed. She is being followed up by a multidisciplinary team, is currently asymptomatic, and continuing medical management.

Mullerian agenesis is the most common cause of PA with well-developed secondary sexual characteristics. There are various forms of mullerian agenesis. Most of the cases are managed by a multidisciplinary team. Rare variants warrant an individualized approach to management.

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The differential diagnosis was PA with thelarche appropriate for age pointing to an obstructive etiology or complete androgen insensitivity syndrome (AIS). In MRKH syndrome, the individual is reared like a female with phenotypically normal external genitalia. They go on to develop normal secondary sexual characteristics with normal pubarche. However, they lack menstruation owing to the absence of a uterus or cervix or upper vagina, or a combination of all [ 11 ]. On vaginal examination or probing, there is usually a short, blind vaginal pouch (Table  1 ). Table 1 Differential diagnosis of primary amenorrhea with developed secondary sexual characteristics Parameters Conditions MRKH syndrome AI Syndrome Transverse vaginal septum Imperforate hymen Symptoms Primary amenorrhea Primary amenorrhea Primary amenorrhea with cyclical abdominal pain urinary retention (rare) Primary amenorrhea with cyclical abdominal pain urinary retention (rare) Examination findings Normal height external genitalia–normal female Thelarche–normal Pubarche–normal Usually taller than normal females for their age. External genitalia–normal female, unilateral or bilateral mass in the inguinal canal thelarche–normal pubarche–sparse hair or absent Normal height external genitalia–normal female Thelarche–normal Pubarche–normal Normal height external genitalia–bluish, bulging membrane Thelarche–normal Pubarche–normal Karyotype 46, XX 46, XY 46, XX 46, XX Imaging Absence of uterus, cervix, upper vagina, or all, normal ovaries Absence of uterus, cervix, and upper vagina, absence of internal Wolffian duct elements, testicular tissue in the inguinal canal Hematocolpos with or without hematometra empty lower vagina septa may be seen Hematocolpos with or without hematometra collection up to the opening of the introitus Hormonal levels Normal FSH, LH testosterone–female levels Normal FSH, LH testosterone–male levels Normal FSH, LH testosterone–female levels Normal FSH, LH testosterone–female levels Differential diagnosis of primary amenorrhea with developed secondary sexual characteristics Primary amenorrhea with cyclical abdominal pain urinary retention (rare) Primary amenorrhea with cyclical abdominal pain urinary retention (rare) Normal height external genitalia–normal female Thelarche–normal Pubarche–normal Usually taller than normal females for their age. External genitalia–normal female, unilateral or bilateral mass in the inguinal canal thelarche–normal pubarche–sparse hair or absent Normal height external genitalia–normal female Thelarche–normal Pubarche–normal Normal height external genitalia–bluish, bulging membrane Thelarche–normal Pubarche–normal Hematocolpos with or without hematometra empty lower vagina septa may be seen Hematocolpos with or without hematometra collection up to the opening of the introitus Normal FSH, LH testosterone–female levels Normal FSH, LH testosterone–male levels Normal FSH, LH testosterone–female levels Normal FSH, LH testosterone–female levels Individuals with complete AIS are also generally reared like a female as the external genitalia resemble a normal female. They can also show thelarche owing to the conversion of testosterone to estrogen. However, morphologically they show sparse or absent terminal hair in the pubic region and axilla. They may show a mass in the inguinal canal representing the testis unilaterally or bilaterally owing to the absence of a scrotum [ 12 , 13 ]. On vaginal examination or probing there is usually a short blind vaginal pouch. In both the imperforate hymen and transverse vaginal septum, there is an obstruction of the outflow tract in an individual with a normally functioning hypothalamic–pituitary–ovarian (HPO) axis and a normal uterus. They present with cyclical abdominal pain and PA. While the former presents with a bluish, bulging membrane at the introitus, the latter presents with an obstructed vaginal canal. In both conditions, there is a collection of menstrual blood in the vagina (hematocolpos) above the level of obstruction. A detailed history and thorough examination help in the provisional diagnosis of specific conditions. Investigations are done for confirmation of the diagnosis and to formulate a management plan. MRI is recommended in patients to show the presence of the uterus or remnants, the presence or absence of gonads (testis or ovary), the location of the gonads, and the collection of blood [ 14 , 15 ]. Karyotype helps to differentiate AIS (46, XY) from those with MRKH (46, XX). Assessment of serum levels of FSH, LH, and testosterone further helps in confirming AIS, wherein the testosterone levels will resemble those of a male individual. The American Society for Reproductive Medicine (ASRM) Mullerian Anomalies Classification 2021 (MAC2021) divides it into nine categories while allowing for an overlap of abnormalities [ 11 ]. When the abnormalities of our patient were interpreted in the context of the MAC2021, the abnormalities belonged to mullerian agenesis (MA), right-side uterine remnant with functional endometrium, left-side remnant with nonfunctional endometrium, and cervical hypoplasia/agenesis. There was also adenomyosis in the remnant with functional endometrium, and bilateral polycystic ovaries. There were no other features of polycystic ovary syndrome [ 10 ]. Furthermore, patients with MA and hematocolpos usually present earlier in their teens. Hence, it is a rare combination of abnormalities and poses significant challenges for diagnosis as well as management. A previous cohort study of 284 women with MRKH reported various combinations for abnormalities but not in the combination seen in our patient [ 8 ]. Another review of 11 patients from a center also revealed bilateral uterine remnants in patients with MRKH syndrome [ 16 ]. However, it did not match these abnormalities. Patients with MRKH syndrome might very rarely present with inguinal hernia and associated complications [ 17 ]. However, hernial orifices were normal in our patient. The diagnosis of MRKH syndrome poses psychological distress for the patient. Hence, treatment is normally done by a multidisciplinary team comprising gynecologists, fertility specialists, and psychological counselors. Support groups can also help the patient alleviate the associated stress [ 13 ]. Treatment for MRKH syndrome normally includes progressive vaginal dilators, surgical creation of a neovagina, or other complex procedures and should be referred to specialized centers [ 9 , 12 , 18 ]. Fertility options include adoption, surrogacy with the use of an ovum from the woman herself, or UT [ 6 , 9 , 19 ]. When biologically related offspring is planned (surrogacy, UT), genetic analysis should be done and inheritance risk should be considered [ 20 ]. Moreover, all the options may not be available in all countries owing to sociocultural or ethical issues [ 19 ].

Menstruation is a developmental milestone and usually marks healthy and normal pubertal changes in females. Menarche refers to the onset of first menstruation in a female. Amenorrhea is the absence of menses and can be primary or secondary. In primary amenorrhea (PA), there is an absence of menarche, whereas secondary amenorrhea (SA) refers to the cessation of previously regular menses for 3 months or irregular menses for 6 months [ 1 ]. According to the American College of Obstetricians and Gynecologists (ACOG), the evaluation of PM should be started if there is no menstruation by 15 years of age or 3 years after the onset of pubertal changes such as thelarche [ 1 , 2 ]. Delayed puberty should be suspected and investigated if there is a lack of any pubertal development by 13 years of age [ 3 ]. The causes of PA include outflow tract abnormalities, resistant endometrium, primary ovarian insufficiency, and disorders of the hypothalamus, pituitary, or other endocrine glands. The most common cause of PA is gonadal dysgenesis, followed by mullerian duct agenesis [ 4 ]. While in gonadal dysgenesis, the secondary sexual characteristics are not well developed owing to a lack of estrogen production by dysgenetic (streak) ovaries, mullerian duct abnormalities with outflow tract obstruction should be suspected in females with otherwise well-developed secondary sexual characteristics. Müllerian agenesis (mullerian aplasia, vaginal agenesis) or Mayer–Rokitansky–Küster–Hauser syndrome is rare, with an incidence of 1 per 4500–5000 females [ 5 ]. Although chronic illnesses and iatrogenic causes are mostly attributable to SA, some of these pathologies present early in life and present as PA [ 1 , 6 – 10 ]. Here, we present a 25-year-old female with pain in the lower abdomen and PA. After a thorough history, clinical examination, imaging, and diagnostic laparoscopy, two small uteri, a blind upper half vagina, bilateral polycystic ovaries, and a blind transverse connection between the two uteruses—horseshoe band cervix—were detected, which confirmed the diagnosis of Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome. This is a rare form of Müllerian abnormality with an unusual presentation.