The role of the sex-determining region Y gene in the etiology of 46,XX maleness.

The condition of 46,XX maleness is characterized by testicular development in subjects who have two X chromosomes but who lack a normal Y chromosome. Several etiologies have been proposed to explain 46,XX maleness: 1) translocation of the testis-determining factor from the Y to the X chromosome, 2) mutation in an autosomal or X chromosome gene which permits testicular determination in the absence of TDF, and 3) undetected mosaicism with a Y-bearing cell line. We evaluated 10 affected subjects who were ascertained for different reasons and who had several distinct phenotypes. Six subjects had inherited sequences from the short arm of the Y chromosome including the sex-determining region Y gene (SRY). Five of the subjects were pubertal at the time of evaluation and had a phenotype similar to that of Klinefelter syndrome with evidence of Sertoli cell and Leydig cell dysfunction. One subject had evidence from Southern blot analysis and in situ hybridization for the presence of an intact Y chromosome in approximately 1% of cells. Three subjects lacked Y sequences by Southern blot analysis and by polymerase chain reaction amplification of SRY. These subjects were ascertained in the newborn period because of congenital anomalies. One had multiple anomalies including cardiac abnormalities; one had cardiac anomalies alone; and one had ambiguous genitalia. Our data confirm the genetic heterogeneity of 46,XX maleness, in which some subjects have SRY while other subjects lack it. In addition, there is phenotypic heterogeneity among subjects who lack SRY suggesting that there is also genetic heterogeneity within this subgroup.

A clinical syndrome of mild androgen insensitivity.

We studied four patients from three kindreds who had normal male body habitus and external genitalia except for short penile length and gynecomastia. Prostate size was small in all patients and spermatogenesis was decreased markedly in one and absent in three. Testicular biopsies in two patients revealed normal histology but evidence of spermatogenic arrest at the spermatocyte stage. Circulating levels of testosterone and LH were increased and the testosterone-dihydrotestosterone ratios were normal. Plasma estradiol was elevated in three of the four patients. Serum FSH levels were significantly elevated in only one patient. The response of LH and FSH to LHRH stimulation was normal in the two patients who were tested. Despite the normal male phenotype, the laboratory studies suggested the diagnosis of androgen insensitivity. This was confirmed in two patients by finding decreased dihydrotestosterone-binding capacity in genital skin fibroblasts. Two of the patients had normal levels of androgen receptor binding, suggesting that their defect represented a mild form of androgen insensitivity with normal receptor activity. These results demonstrated that mild forms of androgen insensitivity exist in which the only obvious clinical manifestations may be the presence of reduced penile length, gynecomastia, and/or infertility. The incidence of androgen insensitivity among men with these subtle phenotypic abnormalities, including infertility, remains to be determined.

17 alpha-hydroxylase deficiency in a genetic male and female sibling pair.

The diagnosis of congenital adrenal hyperplasia due to a deficiency of the enzyme 17 alpha-hydroxylase was made in a genetic male and female sibling pair born of parents who were first cousins. The genetic male was a phenotypic female who presented with primary amenorrhea and mild hypertension. The genetic female exhibited absence of secondary sexual characteristics and severe hypertension. The plasma steroid data confirmed the diagnosis of 17 alpha-hydroxylase deficiency in both subjects: low 17 alpha-hydroxyprogesterone, elevated desoxycorticosterone, elevated corticosterone and elevated progesterone. These are the first case reports of 17 alpha-hydroxylase deficiency in a male-female sibling pair, and they add support to the hypothesis that this is an autosomal recessive disorder.

Dissecting aortic aneurysm in childhood and adolescence. Case report and literature review.

A 15-year-old adolescent male with dissecting aortic aneurysm is presented. His young age, lack of predisposing factors, and fulminant course with rapid progression to death precluded a correct antemortem diagnosis. Review of the literature reveals that most instances of dissecting aortic aneurysm in childhood and adolescence are associated with predisposing conditions, especially congenital cardiovascular anomalies. The clinical picture is generally characteristic. Prompt evaluation and therapy may be lifesaving.

Micropenis. II. Hypogonadotropic hypogonadism.

This paper documents the case histories of 14 patients with hypogonadotropic hypogonadism and micropenis (penile length below 2.5 SD from the mean for the patient's chronlogical age, or for age corresponding to stage of sexual development). Nine of the patients were raised as males. Five of them received androgen for the purpose of stimulating penile growth: two realized normal adult penile length (-0.2 and -2.1 SD from normal mean length) whereas the other three had penile lengths significantly below the mean (-3.6, -4.6 and -5.2 SD from normal mean length). These data suggest that among hypogonadotropic patients with micropenis, those with prepubertal penile lengths between 2.5 and 3 SD below the mean may develop an adult penis of a length within the normal range. However, for those presenting with a shorter phallus, the expectation is that penile length will remain greater than 2 SD below the mean.

Antibody method for measurement of dihydrotestosterone receptors in cultured human skin fibroblasts.

We have adapted the method of Castañeda and Liao to the assay of DHT receptors in cultured fibroblasts arising from human skin. An antitestosterone antibody (100% crossreactivity for DHT) was coupled to CNBr-activated Sepharose. Confluent monolayers of fibroblasts were incubated with 3H-DHT (2 nM) at 37 degrees C for 30 min. Fibroblasts were then collected, sonicated, and centrifuged at 1200 x g for 15 min. The receptor assay was carried out on the supernatant; the antibody-sepharose was used to remove both unbound and nonspecifically bound DHT. Experience showed that the antibody did not entirely remove the nonspecifically bound and free DHT. A blank (sample heated at 60 degrees C for 3 min) was therefore subtracted to obtain an accurate value of specifically bound DHT. In spite of this, the antibody method, when compared to the gel filtration method, was more rapid and more convenient. Its reproducibility was similar to that of the gel filtration method, and its sensitivity was somewhat greater in patients with low levels of DHT-receptor complex. Improved sensitivity could be particularly useful when dealing with partial AIS.

Studies of androgen production and binding in 13 male pseudohermaphrodites and 13 males with micropenis.

We studied androgen production by morphologic and biochemical criteria plus androgen binding by skin fibroblasts in 13 male pseudohermaphrodites and 13 males with micropenis, none of whom had evidence of androgen insensitivity. Seventeen of the 26 patients had evidence of deficient androgen production, suggesting this as the cause of their incomplete virilization in utero. Fibroblasts from all 26 patients demonstrated normal androgen binding and affinity of the steroid for the receptor. Although these results exclude a deficiency of androgen binding in these individuals, other end organ defects are possible. Guidelines for diagnosis and management of such patients are presented.

Partial androgen insensitivity: the Reifenstein syndrome revisited.

We investigated eight patients with the Reifenstein syndrome to define the hormonal basis for this condition. The patients had normal or elevated concentrations of plasma androgens, normal production rates of testosterone and dihydrotestosterone, elevated serum levels of luteinizing hormone and normal 5alpha-reductase activity in skin fibroblasts. These findings indicate that the syndrome results from defective androgen action rather than from decreased androgen synthesis. The term "partial androgen insensitivity syndrome" describes this condition more accurately than a term based on clinical phenotype. Dihydrotestosterone binding studies in skin fibroblasts demonstrated two genetic variants similar to those reported in complete androgen insensitivity syndrome. One patient had a partial deficiency of cytoplasmic dihydrotestosterone binding, and four others had normal binding activity. The cause of the androgen insensitivity in the last four cases is unknown. Treatment with testosterone suppressed serum luteinizing hormone levels and promoted mild virilizing effects.

Androgen insensitivity in man: evidence for genetic heterogeneity.

We have studied ten phenotypically similar patients with complete androgen insensitivity. All of the patients tested had significantly elevated serum luteinizing hormone and plasma androgens within or above the normal adult male range. On the basis of specific dihydrotestosterone binding by skin fibroblasts, we identified two subgroups. Six patients from five different families had undetectable dihydrotestosterone binding, while four patients from two families had normal binding activity. Our results indicate that within the clinical syndrome of androgen insensitivity there are at least two distinct genetic variants. These variants may result from allelic mutations of the same X-linked gene specifying the dihydrotestosterone receptor or, alternatively, from mutations of separate genes both being essential for androgen action in responsive cells.