Persistent Mullerian Duct Syndrome, Types I And Ii

A number sign (#) is used with this entry because persistent mullerian duct syndrome (PMDS) is caused by heterozygous mutation in the gene encoding anti-mullerian hormone (AMH; 600957) or in the AMH receptor gene (AMHR; 600956). These 2 forms of persistent mullerian duct syndrome are referred to as type I and type II, respectively.

Description

The persistent mullerian duct syndrome is characterized by the persistence of mullerian derivatives, uterus and tubes, in otherwise normally virilized males (summary by Knebelmann et al., 1991).

Clinical Features

The typical case is that of a male with bilateral cryptorchidism and inguinal hernias but normal male external genitalia otherwise. At the time of hernia repair, a uterus and fallopian tubes are found in the inguinal canal. The gonads are testes (Nilson, 1939).

Harbison et al. (1991) reported a patient with PMDS who was born to healthy unrelated New York parents of Italian descent. A right inguinal hernia was noted at the age of 1 month. Surgery on the 79th day of life revealed that both gonads were within the right hernia sac. Attached to each gonad was an unremarkable epididymis, vas deferens, and fallopian tube. Between the fallopian tubes was what appeared to be an infantile uterus. No serum anti-mullerian hormone could be detected by enzyme-linked immunosorbent assay.

Pathogenesis

The AMH hormone, also known as mullerian inhibiting substance (MIS), is a glycoprotein homodimer produced by Sertoli cells not only during the period when it is responsible for regression of the mullerian ducts but also in late pregnancy, after birth, and even, although at a much reduced rate, in adulthood. In the female, low amounts of AMH are released into the follicular fluid by mature granulosa cells. (Sertoli cells, which produce AMH, require the presence of a Y chromosome; presumably it is the Sertoli cell alone that requires the presence of testis-determining factor (TDF). The Sertoli cell population in an XX/XY chimeric mouse is composed entirely of XY cells.) In a case of persistent mullerian duct syndrome, Rangnekar et al. (1990) found that 50% of metaphases showed premature centromeric divisions and hypoploid counts. The formation of sex cords populated by primordial germ cells precedes the differentiation of the gonads. Because granulosa and Sertoli cells both originate from bipotential sex-cord cells and produce MIS, Gustafson et al. (1992) hypothesized that sex-cord tumors might secrete large amounts of this hormone. In a woman with an ovarian sex-cord tumor with annular tubules, a rare tumor with the characteristics of both granulosa and Sertoli cells, they found a markedly elevated serum level of MIS and demonstrated the usefulness of measuring MIS in serum for detection of persistent or recurrent disease.

The H-Y ('male') antigens were defined originally in the mouse by graft rejection (Eichwald and Silsmer, 1955); see histocompatibility Y antigen (426000). The H-Y antigen identified by graft rejection is different from that identified by antibody, the latter being referred to as 'serologic H-Y' or 'serologically detectable male' (SDM) antigen. SDM antibodies are raised by sensitizing female rodents with skin grafts or lymphoid cells from syngeneic males. Typing for SDM is then accomplished by absorption of SDM antibody and testing of the absorbed antibody for residual activity on male cells or cell extracts. There appear to be at least 2 SDM antigens. One is an integral part of the membrane of male cells and one is a soluble factor secreted by the Sertoli cells of the testis. Testis-secreted SDM can sex-reverse ovarian cells, causing them to form tubular structures in slow rotation cultures. These and other similar data implied a role for Sertoli-cell-secreted SDM in the development of the mammalian testis. Muller et al. (1993) presented evidence that testis-secreted H-Y is identical to mullerian inhibiting substance (AMH). Both are released by Sertoli cells; both evidently are encoded by autosomal genes under the control of the Y chromosome; both are found in the mature rat ovary; both induce sex reversal of ovarian cells in vitro; both are implicated in the sex reversal of ovarian cells in vivo; and both react specifically with the same antibodies.

Inheritance

Guell-Gonzalez et al. (1971), Morillo-Cucci and German (1971), and Armendares et al. (1973) described affected brothers. Von Seemen (1927) observed parental consanguinity. Affected sibs and parental consanguinity suggested autosomal recessive inheritance.

Naguib et al. (1989) reported an Arab Bedouin family with 4 affected males, 2 brothers and 2 of their maternal uncles. Superficially the pedigree suggested X-linked recessive inheritance, but the consanguinity of the parents of the maternal uncles suggested autosomal recessive inheritance.

Sloan and Walsh (1976) reported 2 affected half brothers with different fathers, suggesting X-linked recessive inheritance rather than autosomal recessive inheritance with male sex limitation.

Molecular Genetics

Knebelmann et al. (1991) demonstrated a missense mutation in the AMH gene in a patient with AMH-negative persistent mullerian duct syndrome (600957.0001).

PMDS is biologically heterogeneous: in some cases, bioactive AMH is normally expressed by testicular tissue, while in others no AMH is produced. Imbeaud et al. (1994) performed molecular analysis of the AMH gene in 21 patients and their families. In 6 patients with normal serum concentration of AMH, the AMH was normal or contained only polymorphisms and silent mutations, supporting the hypothesis that the condition is due to end-organ resistance. In the 15 remaining patients with low or undetectable levels of serum AMH, 9 novel mutations were discovered. When present in homozygotes or compound heterozygotes, these mutations were associated with the PMDS phenotype, the same mutation never being observed in 2 different families. The first 3 exons of the AMH gene appeared particularly prone to mutation, although they are less GC rich than the last 2 exons and code for the N-terminal part of the AMH protein, which is not in itself essential to bioactivity.

Imbeaud et al. (1995) demonstrated a mutation in the gene encoding the AMH receptor (600956.0001) in a 3-month-old boy of Pakistani extraction. The AMH gene was normal by sequencing and the production of normal AMH was demonstrated by the fact that normal regression of fetal rat mullerian ducts was elicited by coculture with a small fragment of testis from the patient.

Imbeaud et al. (1996) reported results of molecular studies on 38 families with PMDS. They identified the basis of the condition, namely 16 AMH and 16 AMHR mutations in 32 families. Six of the patients were postpubertal and, since AMH production is normally repressed in these patients, determination of the level of AMH was no longer informative. In prepubertal patients, the type of genetic defect leading to PMDS could be predicted from the level of serum AMH, which is very low or undetectable in PMDS type I due to AMH mutations and at the upper limit of normal in receptor type II mutations. AMH mutations were extremely diverse. AMH mutations were identified in 16 families, including 9 previously reported families (Imbeaud et al., 1994). Imbeaud et al. (1996) reported that exon 1 and the 3-prime half of exon 5 of AMH are the main sites of deleterious changes including short deletions and missense mutations. AMH receptor mutations leading to type II PMDS were detected in 16 patients and 10 of these patients had a 27-bp deletion in exon 10 on at least one allele (600956.0002). This deletion was thus implicated in 25% of the PMDS patients analyzed by Imbeaud et al. (1996). This deletion was present in the homozygous state in 4 patients and it was coupled with missense mutations in 7 patients.

Lang-Muritano et al. (2001) reported 2 brothers with bilateral cryptorchidism in whom the diagnosis of persistent mullerian duct syndrome was made on the basis of laparoscopic evidence of uterus and tubes, undetectable plasma levels of AMH, and homozygosity for a 23-bp insertion in exon 5 of the AMH gene (600957.0004).