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Primed in situ labeling (PRINS) can be used to localize DNA segments too small to be detected by fluorescence in situ hybridization. By PRINS we identified the SRY gene in two XX males, a woman with XY gonadal dysgenesis, and an azoospermic male with Xp-Yp interchange. Because PRINS has been used generally in the study of repetitive sequences, we modified the technique for study of the single copy 2. 1-kb SRY sequence. SRY signals were identified at band Yp11.31p11.32 in normal XY males and in the woman with XY gonadal dysgenesis. SRY signals were identified on Xp22 in one XX male but not in the other. They were identified in the corresponding region (Xp22) of the der(X) in the azoospermic male with Xp-Yp interchange. SRY signals were not observed in normal XX females. Presence of SRY in DNA samples from the various subjects was confirmed by polymerase chain reaction. We conclude that PRINS is ideal for rapid localization of single copy genes and small DNA segments in general.

Most phenotypic females with an XY male karyotype do not have significant extragenital anomalies; however, some patients with additional abnormalities have been described. We report on an individual with XY gonadal dysgenesis, mental retardation, microcephaly, growth retardation, and multiple pterygia. Although not previously reported, the possible relationship between these findings is discussed in the context of evident heterogeneity of XY gonadal dysgenesis.

We report on a group of 9 subjects who had a 46,XY karyotype, ambiguous genitalia, abnormalities of sexual duct formation, and lack of gonadal tissue on one or both sides. This is sometimes referred to as "embryonic testicular regression." Previous investigators have suggested that this condition results from loss of testes at a critical stage in development. We examined the possibility that the "embryonic testicular regression" is part of the clinical spectrum of 46,XY gonadal dysgenesis. Four subjects totally lacked gonadal tissue, three of them having ambiguous genitalia, and one a micropenis. The development of incongruous sexual ducts (presence of Müllerian ducts in the subject with micropenis, and absence of Müllerian and Wolffian ducts in two subjects with ambiguous genitalia) suggests that the embryonic gonads were intrinsically functionally abnormal before their disappearance. Five subjects had unilateral gonadal tissue, ambiguous genitalia, and a mix of Wolffian and Müllerian structures. The development of incongruous sexual ducts in 3 of them, the presence of ambiguous external genitalia in 5, and the presence of abnormal gonadal histology in 2 patients all indicate an underlying abnormality of gonadal differentiation in these subjects. The occurrence of testicular regression in several subjects in the family of one patient suggests a genetic basis for the condition. The presence of multiple congenital anomalies in other subjects in our study suggests either a mutation in a single gene that functions in several developmental pathways, or a defect of multiple genes that might be the result of a chromosome deletion.(ABSTRACT TRUNCATED AT 250 WORDS)

Using reverse genetics, a candidate for the sex determining gene from the Y chromosome has recently been cloned. We have used a DNA probe from this gene to assess the presence of this crucial region of the Y chromosome in patients with sexual ambiguity or gonadal dysgenesis. The DNA from 3 cases of gonadal dysgenesis, one complicated by somatic anomalies and mental retardation, reacted normally with this putative sex determining gene. A patient having a small phallus and pseudovaginal, perineoscrotal hypospadias (PPSH) also had normal Y chromosomal DNA. We hypothesize that the defect in sex determination in all 4 cases is most probably subsequent to the primary sex determining switch.

Although SRY was first identified 10 years ago, we still know remarkably little about its mode of action or downstream target genes. Recently, potential protein partners have been identified and there has been considerable activity to understand the roles of WT1, SF-1, DAX-1 and SOX9 in gonadogenesis. The emerging picture is one of complex interactions, involving both positive and negative regulatory signals that, depending on the cellular and promoter context, drive the expression of male-specific genes. Despite recent advances, however, we are still unable to explain the genetic cause of most cases of 46,XY gonadal dysgenesis or even a single case of Y-chromosome-negative 46,XX maleness.

A 16 1/2-year-old girl was studied because of ileitis, lack of pubertal development, and primary amenorrhea. She had a 46,XY chromosome constitution in lymphocytes in fibroblasts without structural defects of X or Y. She was H-Y antigen negative. This observation supports the concept of causal heterogeneity of XY gonadal dysgenesis (Swyer syndrome). Two groups have been established: (1) H-Y antigen-positive forms, which are more common, possibly due to gonad-specific receptor defects (total failure or reduced receptor affinity), (2) H-Y antigen-negative forms possibly due to mutation in the H-Y generating system, either of the structural gene (presumably autosomal) or of a controlling gene (on the sex chromosomes). The H-Y antigen status may be of value in determining which patients are at risk for gonadoblastoma or dysgerminoma.