Prepubertal male pseudohermaphroditism due to 17-ketosteroid reductase deficiency: diagnostic value of a hCG test and lack of HLA association

Abstract

Most patients with male pseudohermaphroditism (MPH) due to 17-ketosteroid reductase (17-KSR) deficiency were diagnosed at or after puberty when significant virilization occurred. We report 2 prepubertal sibs (Case 1, 4 yr and Case 2, 10 yr) unambiguously raised as females, with clitoral enlargement, separate urethral and vaginal orifices and gonads palpable at the inguinal canal bilaterally. Basal serum LH, FSH, 17-hydroxyprogesterone, testosterone (T), dihydrotestosterone and dehydroepiandrosterone (DHEA) were normal for age. delta 4-Androstenedione (delta 4-A) was slightly elevated in Case 2 but nondiagnostic. Steroid measurements after human chorionic gonadotropin (hCG) stimulation were compared with those of boys with male external genitalia submitted to the same hCG protocol: peak T was subnormal (Case 1, 80, Case 2, 91, vs normal 329 +/- 129 ng/dl, mean +/- 1SD), peak delta 4-A elevated (Case 1, 477, Case 2, 264, vs normal 44 +/- 26 ng/dl) resulting in an abnormally elevated delta 4-A/T ratio (Case 1, 6.0, Case 2, 2.9, vs normal 0.12 +/- 0.09) and establishing the diagnosis of 17-KSR deficiency. This diagnosis was confirmed in vitro by minimal T production when testicular tissue of both patients was incubated with tritiated delta 4-A. The 2 sibs did not share a single haplotype for the HLA complex indicating lack of association between HLA and the locus of the gene for 17-KSR. In conclusion, in 2 sibs with MPH the subnormal T and elevated delta 4-A response to the hCG test indicated the diagnosis of 17-KSR deficiency followed by orchiectomy to avoid later virilization at puberty.

The testosterone:androstenedione ratio in male undermasculinization

“…Our observation that the T:A ratio rises following hCG stimulation agrees with earlier reports of testosterone and androstenedione levels following hCG (Rosenfield et al ., 1974; Forest, 1979; Toscano et al ., 1983) and supports the view that the altered T:A ratio in affected infants and children may only become biochemically obvious following hCG stimulation (Arnhold et al ., 1988; Boehmer et al ., 1999). The T:A ratio did not rise markedly in cases of abnormal testes and the median ratio remained below the cut‐off value of 0·8.…”

“…Early identification may obviate the need for surgery as these children may virilize with the help of testosterone treatment or spontaneously during puberty (Eckstein et al ., 1989). Affected infants and children should show an altered testosterone:androstenedione (T:A) ratio but this imbalance may only become biochemically obvious following hCG stimulation (Arnhold et al ., 1988; Boehmer et al ., 1999). While Campo et al .…”

The Use of Genetics for Reaching a Diagnosis in XY DSD

“…In many cases, 17β-HSD3 deficiency can be identified by the increased concentrations of androstenedione and reduced levels of testosterone and subsequently confirmed by the genetic analysis of the HSD17B3 gene [Boehmer et al, 1999;Mendonca et al, 2017]. A T/A ratio below 0.8 has been proposed as a reliable cut-off for 17β-HSD3 deficiency for all age groups [Arnhold et al, 1988;Boehmer et al, 1999;Ahmed et al, 2000b]. In prepubertal individuals, a human chorionic gonadotropin (hCG) test may be required as an abnormal T/A ratio may only become biochemically evident following this stimulus [Kulle et al, 2017;Mendonca et al, 2017].…”

Deficiency of 17-Ketoreductase Presenting Before Puberty

“…The bio chemical diagnosis is confirmed by the presence of de creased basal plasma testosterone and elevated basal plas ma androstenedione concentrations [1,2,[5][6][7][8][9][10] which are accentuated by hCG provocation [2], There are few published reports of cases presenting before puberty, and information about the biochemical features at this age is limited [3,8,[10][11][12][13][14][15][16]. Diagnosis of 17-ketoreductase deficiency is frequently complicated by the presence of normal basal steroid levels [8,[10][11][12][13], An hCG stimulation test has been suggested as the most appropriate way of making the diagnosis [2,8,10,13,15,16]. We present biochemical data from two cases in whom the diagnosis was made before puberty.…”