Androgen receptor disorder in three brothers with bifid prepenile scrotum and hypospadias

Abstract

Three brothers with congenital transposition of the penis, scrotal hypospadias, bifid scrotum, and bilateral undescended testes are described. Further signs of incomplete virilization, but no gynecomastia were seen. LH and FSH were elevated, whereas testosterone levels were reduced or in the normal range. Serum concentrations of 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, 5\g=a\-dihydrotestosterone and estradiol measured in two affected brothers were in the normal range. Fibroblasts from scrotal skin biopsies performed in two patients showed normal 5\g=a\-reductase activity (419 and 214 pmol \m=.\ (mg protei n)\m=-\1 \m=.\h\m=-\1; normal >1), whereas androgen receptors had reduced maximal binding capacity (Bmax 4 and 14 fmol \ m=. \ (mg protein)\m=-\1; normal \m=ge\ 18) and an increased equilibrium dissociation constant (0.7 and 1.26 nmol/l; normal 0.2\m=+-\0.08)indicating a quantitative and qualitative androgen receptor defect. These patients represent a further variant of androgen insensitivity.The term »male pseudohermaphroditism« covers a number of distinct clinical forms of intersexuality characterized by an XY genotypic individual with testes but without phenotypically normal male gen¬ italia. Disorders of testosterone biosynthesis, resis¬ tance of androgen target organs to the action of circulating androgens or a disturbance in the action of Müllerian-inhibiting-hormone may be the mo¬ lecular causes for male pseudohermaphroditism. Androgen resistance can be caused either by dis¬ turbed conversion of testosterone to 5ot-dihydrotestosterone (5a-DHT; 5a-reductase defect), a qualitative or quantitative defect in androgen re¬ ceptor binding or a postreceptor defect (1). We present another variant of incomplete androgen insensitivity which occurred spontaneously in 3 brothers. The syndrome is characterized by hypo¬ spadias, bifid and prepenile scrotum, maldescended testes, and a qualitatively and quantitatively abnormal androgen receptor. Patients and MethodsThe three patients were brothers and belonged to a family with eight siblings. Based on physical examination, hormone values and semen parameters the fourth brother was normal. The four sisters were normal fe¬ males. Consanguinity and abnormal relatives were not reported from the family. The individual clinical and en¬ docrine findings in the three affected brothers are listed in Table 1.Patient No. 1 attended our clinic because of underdevel¬ oped genitalia and erectile dysfunction. A first genital operation had been performed during childhood; how¬ ever, medical records were no longer available. Further surgical treatments for hypospadias by the technique of Denis Browne (see 2) followed at the ages of 8 and 9.Physical examination at the age of 26 revealed sparse body hair, weak facial hair and a very high-pitched voice. The divided scrotum was positioned in front of the penis which had a ventral deviation and an urethral opening in the lower third (Fig. 1). Thus intercourse was not possible. The right testis had a volume of 6 ml, the ...

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