Female pseudohermaphroditism with multiple caudal anomalies: Absence of Y‐specific DNA sequences as pathogenetic factors

Abstract

46,XX female pseudohermaphrodites have been previously described with nearly complete masculinization of the external genitalia and no apparent source of testosterone. Multiple malformations of internal genital, urinary, and gastrointestinal tracts are associated. We have evaluated four such infants with female pseudohermaphroditism and multiple caudal anomalies. Three cases had apparently normal chromosomes (46,XX); one had a 46,XX,del(10)(q25.3-->qter) chromosome constitution. The chromosome breakpoint is in the region of PAX2, a developmentally important paired box gene which is expressed in urogenital tissue. Using the polymerase chain reaction, we screened for the presence of multiple Y specific sequences, including SRY (sex determining region, Y chromosome), that could explain masculinization of the external genitalia. All were negative for Y centromeric sequences, ZFY (Zinc finger Y), and SRY. Furthermore, there was no evidence for adrenal or other sources of testosterone. We suggest that the masculinization in these cases is the result of abnormal expression of genes which would normally be regulated by testosterone.

Penislike clitorises with megalourethras in nonvirilized female fetuses and a newborn. A histopathologic study and its bearing on their pathogenesis

“…In the present cases 1 to 3 and in similar cases reported [1,2,[5][6][7][8][9][10][11][12], this reduction relates to the most serious variant of the "high-type" anorectal malformation that has been attributed to a very large defect of the posterior part of the cloacal membrane and adjacent cloaca [24]. In case 4, the narrow accessory phallic urethra was considered to be the anterior half of a urogenital sinus that was split longitudinally because of an earlier mesenchymal interruption of a very early cloacal membrane and adjacent part of the cloaca [25].…”

“…The female type of histologic feature of glans and corpora cavernosa and absence of major male elements in the penoclitoral organs contradict suggestions of (regional) masculinization made before [14,17] and are in line with the absence of androgenic factors [5,11]. The highly abnormal circular character of corpora cavernosa and/or glans in 3 cases, the formation of a megalourethra, and the formation of a relatively large penislike structure indicate a deviation at a very early embryonic stage.…”

“…This disorder is also characterized by maletype external genitalia, but in this category, most phallic structures are penislike, well-developed scrotums are uncommon, and the deformation is associated with other anomalies of the perineum. The penislike clitorises are occasionally part of a spectrum of multiple caudal anomalies that are considered to result from lower mesodermal defects [1,2,[5][6][7][8][9][10][11][12]. They are a consistent feature of accessory phallic urethra duplication [13][14][15][16][17][18][19][20][21][22][23] that was presumed to result from a temporary and regional masculinization during fetal development [14,17].…”

Rare association of female pseudohermaphroditism, phallic urethra, and posterior cloaca

“…Less frequently reported are 46,XX female pseudohermaphrodites with normal testosterone and complete androgenization of the external genitalia. A distinct form of this condition is associated with malformations of the internal genital, urinary, and gastrointestinal systems [5][6][7][8]. In addition, skeletal anomalies such as talipes equinovarus, vertebral defects, and sacral agenesis have been documented in certain cases [7].…”

Cloaca, Posterior Cloaca and Absent Penis Spectrum

“…Retrospectively, we found fi ve publications referring to this condition as "pseudohermaphroditism" [ 39 ]. Some authors used the term "caudal anomalies" [ 40 ], "ambiguous genitalia with VATER" [ 41 ], or "caudal developmental fi eld defect with female pseudohermaphroditism and VACTERL anomalies" [ 42 ] and fi nally "penis-like clitorises with megalourethra in non-virilized female fetus" [ 43 ]. Looking at the pictures of all those cases presented, it was obvious that all those patients suffered from cloacas with normal female gonads and chromosomes.…”