17β hydroxysteroid dehydrogenase 3 deficiency in 46,XY disorders of sex development: Our experience and a gender role‐focused systematic review

Abstract

Objectives: To describe Asian Indian patients with 17β hydroxysteroid dehydrogenase 3 (17βHSD3) deficiency and to perform a systematic review to determine the factors influencing gender role in 46,XY disorder of sex development (DSD) due to 17βHSD3 deficiency. Patients and Design:We present the phenotypic and genotypic data of 10 patients (9 probands and 1 affected family member) with 17βHSD3 deficiency from our 46,XY DSD cohort (N = 150; Western India) and a systematic review of 152 probands with genetically proven, index 17βHSD3 deficiency patients from the world literature to identify the determinants of gender role.Results: 17βHSD3 deficiency was the third most common (6%) cause of nondysgenetic 46,XY DSD in our cohort. Five patients each had prepubertal (atypical genitalia) and pubertal (primary amenorrhoea) presentations. Six patients were initially reared as female of whom two (one each in prepubertal and pubertal age) changed their gender role. Ten pathogenic molecular variants (six novel) were observed. In the systematic review, initial male sex of rearing was uncommon (10.5%) and was associated with atypical genitalia, higher testosterone/androstenedione (T/A) ratio and Asian origin. Gender role change to male was seen in 10.3% of patients with initial female sex of rearing and was associated with Asian origin but unrelated to pubertal androgens or molecular variant severity. It has not been reported in patients of European origin. Conclusions:We report the first Indian case series of 17βHSD3 deficiency, the third most common cause of 46,XY DSD, with six novel molecular variants. Distinct geographical differences in the frequency of initial male sex of rearing and gender role change to male in those initially reared as females in 17βHSD3 deficiency were noted which needs further evaluation for the underlying molecular mechanisms.

Changes in the clinical management of 5α-reductase type 2 and 17β-hydroxysteroid dehydrogenase type 3 deficiencies in France

“…It is however worth noticing that this cohort reported only two cases of adult patients who have requested female-to-male reassignment. The overall 10 % rate of post-pubertal female-to-male reassignment was thus relatively low, but similar to that reported in some other samples of patients with SRD5A2 deficency ( 4 ) and HSD17B3 deficiency ( 41 ). The contrast with studies reporting high rates of sex reassignment in patients with these conditions may be explained by cultural factors ( 10 , 41 ) but also by the fact that high rates of sex reassignment used to concern mostly patients who were not diagnosed during infancy and thus underwent unexpected virilization at adolescence ( 11 , 42 ).…”

“…The overall 10 % rate of post-pubertal female-to-male reassignment was thus relatively low, but similar to that reported in some other samples of patients with SRD5A2 deficency ( 4 ) and HSD17B3 deficiency ( 41 ). The contrast with studies reporting high rates of sex reassignment in patients with these conditions may be explained by cultural factors ( 10 , 41 ) but also by the fact that high rates of sex reassignment used to concern mostly patients who were not diagnosed during infancy and thus underwent unexpected virilization at adolescence ( 11 , 42 ). However, in this cohort, one of the patients who requested female-to-male reassignment had been diagnosed early and underwent gonadectomy during infancy, which confirms that the development of a male gender identity does not strictly rely on such virilization ( 43 ).…”

“…This study was the first to describe a cohort of patients with a molecular diagnosis of SRD5A2 or HSD17B3 deficiency in France and clearly showed how the changes in diagnostic and clinical practices over the past two decades have impacted the general picture of these conditions. First, in contrast with previous studies ( 1 , 4 , 6 , 21 , 41 ), the majority of the cases reported herein were diagnosed in newborns, or prenatally. Since the beginning of 2000s, making a diagnosis during adolescence has become the exception rather than the rule.…”

“…First, in contrast with previous studies (1,4,6,21,41), the majority of the cases reported herein were diagnosed in newborns, or prenatally. Since the beginning of the years 2000s, making a diagnosis during adolescence has become the exception rather than the rule.…”

“…For 58% (n=30) of patients, the diagnostic process began during the perinatal period, as they exhibited atypical genitalia. Among them, 7 had an antenatal diagnosis due to a discordance between external genitalia and the karyotype: 2 had SRD5A2 deficiency (cases 8 and 27) and 5 had HSD17B3 deficiency (cases 38,41,44,46,52). Overall, 33% (n=17) of patients were diagnosed during infancy, as they exhibited atypical genitalia or inguinal palpable gonads; and 9% (n=5) of patients were diagnosed during adolescence or adulthood, due to virilization or primary amenorrhea (Table 3).…”