👤 Olaf Hiort

17β-Hydroxysteroid dehydrogenase 3 deficiency (17β-HSDD) and 5α-reductase type 2 deficiency (5α-RD) are rare 46,XY differences of sex development (DSD). This study aims to enlarge the limited knowledge on long-term gonadal function and gonadal pathology in these conditions. Retrospective multicentre cohort study. Data on phenotype, laboratory results, and hormone treatment were collected from patients aged ≥16 years at time of data collection with genetically confirmed 17β-HSDD and 5α-RD from 10 centres via the I-DSD Registry. If gonadectomy or gonadal biopsy had been performed, pathology reports and/or gonadal tissue or images were collected. All 16 patients with 17β-HSDD were raised female; 1 (6%) changed to male gender at age 14. Three females were treated with gonadotrophin-releasing hormone agonists (GnRHa) to prevent virilisation. Thirteen underwent gonadectomy at median age 8 (range 0-17). None had germ cell (pre)malignancies. Of 14 patients with 5α-RD, 10 (71%) were raised female. Five changed gender at age 7-23, of whom 4 to male gender. One was treated with GnRHa. Six underwent gonadectomy at median age 10 (range 0-31). None had germ cell (pre)malignancies. With gonads in situ, puberty spontaneously progressed. Three were treated with dihydrotestosterone. A significant percentage of individuals with 17β-HSDD and 5α-RD changed gender, and some were treated with GnRHa to prevent virilisation before making a definitive decision about gonadectomy. When left in situ, spontaneous puberty occurs and germ cell (pre)malignancies seem uncommon at least until early adulthood. Together, these data support delaying a decision about gonadectomy until late adolescence in these conditions. Show less

17β-hydroxysteroid dehydrogenase (17β-HSD) type 3 deficiency is an autosomal recessive disorder with diminished testosterone synthesis and consequently underandrogenisation. 46,XY patients with 17β-HSD type 3 deficiency are often assigned a female sex at birth but have a high virilisation potential at the time of puberty. We studied four 46,XY patients with 17β-HSD type 3 deficiency at puberty with regard to the underlying mutations, the hormone values, and the clinical findings. Three patients were initially assigned a female sex and 1 was assigned a male sex. All had relevant mutations in the HSD17B3 gene. The 2 patients with deleterious mutations had lower testosterone values at the time of puberty than the patients with possible residual activity of 17β-HSD type 3. One of the latter patients changed to male gender. All 4 patients with 17β-HSD type 3 deficiency synthesized relevant amounts (>0.7 µg/L) of testosterone at puberty, which lead to variable androgenisation. In patients with presumable residual activity of the mutated enzyme, testosterone values in the male reference range can be achieved, thereby inducing male pubertal development. These patients should possibly be assigned a male sex. Any surgical intervention should be avoided until the patients are old enough to consider their options of medical and surgical intervention.
. Show less

17-β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an important enzyme involved in the final steps of androgen synthesis and is required for the development of normal male external genitalia. 46,XY individuals with deficiency of this enzyme present a wide clinical spectrum from a female appearance of the external genitalia through ambiguous genitalia to a predominantly male genitalia with micropenis or hypospadias. This paper reports a one-year-old 46,XY patient with 17β-HSD3 deficiency who presented with female external genitalia and bilaterally palpable gonads in the inguinal region. The low T/Δ4 ratio after human chorionic gonadotropin (hCG) stimulation suggested 17β-HSD3 deficiency. A homozygous mutation, c.761₇₆₂delAG, was determined at the intron 9/exon 10 splice site of the HSD17B3 gene. To the best of our knowledge, this mutation has not been reported thus far, but its localization and type would imply a complete disruption of the 17β-HSD3 which may explain the phenotype of our patient. Show less

In this study, we present a Sudanese 46,XY patient raised as a female and diagnosed at the age of 20 years with having 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency. She presented with primary amenorrhea, undeveloped breasts and a male pattern of secondary sexual characteristics. Examination of her external genitalia showed type IV genital circumcision. Steroid measurements both in urine and serum pointed to 17β-HSD3 deficiency. A novel homozygous splice-site mutation [c.524 + 2T>A] was detected in intron 7 of the HSD17B3 gene. In this patient, steroid concentration clearly supported both the clinical diagnosis of 17β-HSD3 deficiency and the functional relevance of the mutation. Interestingly, despite of the type IV genital circumcision, the patient expressed her interest in reassigning her sex from female to male. Show less

17-beta-Hydroxysteroid dehydrogenase type 3 (17betaHSD-3) converts delta4 androstenedione (A) to testosterone (T) in the testes. This enzyme plays a key role in androgen synthesis and it is essential for normal fetal development of male genitalia. 17betaHSD-3 deficiency is a rare cause of 46,XY disorders of sexual development. Here, we report a 16-year-old 46,XY patient with 17betaHSD-3 deficiency raised as a female and significantly virilized in puberty. A homozygous 7 base pair deletion on exon 10 was determined in HSD17B3 gene (c.777-783del_GATAACC). Our patient had one of the very rare mutations, which was previously unencountered in Turkish patients with 17betaHSD type 3, and she is the second reported case with this deletion. Show less

The growing use of prenatal investigations allows an early detection of several inborn disorders, including disorders of sexual development. The management of these conditions is an arising problem. 46,XY karyotype and female phenotype were detected in a fetus; 5α-reductase and androgen receptor gene analysis on chorionic villi revealed no relevant mutation. The newborn was assigned to female sex. The diagnosis of 17β-hydroxysteroid dehydrogenase-3 β-OL deficiency was reached at four months of age, by means of a low testosterone/Δ 4-androstenedione ratio after HCG test and HSD17B3 gene analysis. A 46,XY fetus with female external genitalia suggests different conditions, some very rare. Specific genetic investigations should be performed prenatally when possible. A complete evaluation is mandatory after delivery to reach a correct diagnosis. Show less

Aim of this study is to report on basal clinical phenotype and follow up after diagnosis, of patients with 17beta-hydroxysteroid-dehydrogenase type 3 (17beta-HSD3) deficiency in Italy. Pediatric Endocrine Departments, University Hospitals. The cases of 5 Italian subjects affected by 17beta-HSD3 deficiency are presented in this study. Laboratory and genetic assessment. Gonadectomy and female sex assignment (4 patients) or GnRH analog therapy to regress puberty and gender identity disorder (1 patient). Presentation lasted from pregnancy (pre-natal diagnosis of a 46,XY fetus with female external genitalia) to infancy (inguinal hernia containing testes/clitoromegaly) and adolescence (virilisation). All subjects but one (subject 1, Central-Northern Italy) were from small areas of Southern Italy. Endocrine data (baseline and/or stimulated testosterone/ Delta4-androstenedione ratio) were informative. Two girls were homozygous for 17beta-HSD3 gene mutations (G289S/G289S; R80W/R80W), while the others were compound heterozygous (IVS325+4 A>T/A203V; L212Q/M235V; R80W/A235E). Four patients were confirmed as females and were well-adjusted with assigned sex; gender identity disorder improved during treatment with GnRH analog in the last subject. 17betaHSD3 deficiency may present from pregnancy to puberty for different clinical issues. Albeit testosterone/Delta4-androstenedione ratio represents the most accurate endocrine marker to diagnose the disorder, hCGstimulation is mandatory in pre-puberty. Molecular analysis of 17beta-HSD3 gene should be performed to confirm the diagnosis. Temporary GnRH analog treatment may regress gender identity disorder and provide time to confirm or change the birth sex assignment. Female individuals seems to be compliant with their sex, providing that virilisation does not occur. In Italy, the disorder seems to be more prevalent in the Southern regions and shows genetic heterogeneity. Show less

Deficiency of 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3), due to mutations in the gene encoding the enzyme, results in a rare autosomal recessive form of male-to-female sex reversal. Mutated genes encode an abnormal enzyme with absent or reduced ability to convert Delta4-androstenedione to testosterone in the testis. Affected individuals are genetically males who developed internal male Wolffian structures but female external genitalia. Such individuals are usually raised as females and diagnosis is made at puberty, when they show virilization. Correct diagnosis is mandatory to optimize treatment and follow-up. In the present paper we report the clinical history, endocrine evaluation and molecular genetics of a prepubertal girl affected by 17beta-HSD3 deficiency, in whom an erroneous diagnosis of androgen insensitivity syndrome was made. The clinical, endocrine and genetic features of 17beta-HSD3 deficiency are also reviewed. Show less

Children with 17beta-hydroxysteroid-dehydrogenase-3 (17beta-HSD-3) deficiency have a defect of testosterone biosynthesis with subsequent diminished virilization in XY individuals. Some are raised as girls and some as boys. There were two purposes of this case report: First, it analyzed the process of decision-making in a family with a pair of siblings with identical mutations leading to 17beta-HSD-3 deficiency whose parents chose to raise one child as a boy and one as a girl. This analysis was based on narrative interviews with the parents. Second, we assessed the gender role behavior and gender identity in the children to examine if the psychosexual development of these children correspond with the sex of rearing their parents chose. When participating in the study, the children were 7 (boy) and 5 (girl) years old. Parents described a difficult process of decision-making and voiced concerns about lack of appropriate and understandable information, and anticipated decision regret. However, they did not feel that the decision to "normalize" the external genitalia should have been deferred. Both children appeared to show age-typical gender-related behavior and did not show any signs of physical or mental distress. Show less