General Medical Information

Müllerian Aplasia

Joe Leigh Simpson

Aplasia of the müllerian ducts leads to absence of the uterine corpus, uterine cervix, and upper portion of the vagina. The foreshortened 1- to 2-cm vagina presumably is derived exclusively from invagination of the urogenital sinus. Individuals with müllerian aplasia usually consult physicians because of primary amenorrhea. Secondary sexual development is normal, no uterine structures are palpable, but uterine remnants may exist in the form of bilateral cords. The term Rokitansky-Küster-Hauser syndrome often is applied, sometimes only if remnants persist and sometimes synonymously with müllerian aplasia.

Only one other disorder ordinarily needs to be considered in the differential diagnosis of CAI. Müllerian aplasia is about twice as common. Androgen insensitivity can be excluded on the basis of chromosomal studies and gonadal composition (testes rather than ovaries). Pubertal patients with müllerian aplasia invariably show pubic hair, whereas those with androgen insensitivity usually do not. Renal (pelvic kidney, renal ectopia, and unilateral aplasia), skeletal, and vertebral anomalies are not uncommon.

Affected siblings with müllerian aplasia have been reported. However, Lischke and associates observed three sets of discordant monozygotic twin. Thus, autosomal recessive inheritance is not the explanation for all cases. In 1978, autosomal dominant inheritance was proposed by Shokeir based on 16 Saskatchewan families. In 13 of 16 families, the proband showed complete absence of the uterine cervix and corpus; in the remaining three, uterine remnants were present. None of the three individuals with uterine remnants had an affected relative, but ten of the 13 with complete absence of the uterine cervix and corpus did. Two of these ten had affected siblings, whereas the other eight had other affected paternal relatives (aunts, first cousins, second cousins, or great-aunts). These observations suggest sex-limited (female) autosomal dominant inheritance. Females with the postulated mutant would manifest müllerian abnormalities, whereas males would show no deleterious effect.

In contrast to the conclusions of Shokeir were the findings of Carson and co-workers. Not a single relative was affected in 23 U.S. families, encompassing 30 postpubertal sisters, 31 paternal aunts, and 41 maternal aunts. This makes sex-limited autosomal dominant inheritance unlikely; absence of affected siblings and lack of paternal consanguinity speaks against autosomal recessive inheritance.

The data of Carson are consistent with those of Petrozzi, who studied women with müllerian aplasia who underwent assisted reproductive technologies (ART). Because women with müllerian aplasia have normal ovaries, one strategy is to obtain oocytes from affected women, perform fertilization in vitro with their husband’s sperm, and transfer fertilized embryos to a surrogate uterus of another woman in hormonal synchrony. Offspring would reflect genetic constitution of the woman with müllerian aplasia. Petrozza surveyed U.S. ART programs and collected 34 pregnancies involving oocytes of women with müllerian aplasia. Of the 34 offspring, 17 were female. None were affected; one male child had a middle ear defect and hearing loss.

The most logical explanation for müllerian aplasia is polygenic/multifactorial inheritance, the usual mode of inheritance for malformations affecting either a single organ system or embryologically related systems. Polygenic/multifactorial inheritance is consistent with the occasional reports of multiple affected siblings. After the birth of one child with a polygenic/multifactorial disorder, the recurrence risk for first-degree relatives of affected probands approximates the square root of the incidence of the trait in the population. Given that müllerian aplasia is rare, one would expect the recurrence risk in siblings to be low. Failure to detect affected siblings in a relatively small sample is consistent with polygenic/multifactorial inheritance and a low (1% to 2%) recurrence risk for first-degree relatives.

No significant progress has been reported in the molecular elucidation of müllerian aplasia. Reindollar and colleagues have searched for perturbations in several potential candidate genes. Large deletions, insertions, or rearrangements have not been detected in the genes WT-1 (Wilms’ tumor), PAX 2, HOXA13, and AMH (MIS). There is no increase in the N314 allele of galactose-1-phosphate uridyl transferase

In several multiple malformation syndromes, müllerian aplasia is one component. The etiology presumably reflects perturbation of genes different from those responsible for müllerian aplasia in otherwise normal individuals.