Asta Literature Retrieval: Pathophysiology and clinical mechanisms of 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogen...

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Papers retrieved: 17
Snippets retrieved: 20

Relevant Papers

[1] A case of 17-beta-hydroxysteroid dehydrogenase deficiency type 3 in adult endocrinologist practice

Authors: N. V. Molashenko, N. Kalinchenko, V. A. Ioutsi, O. Gurinovich, D. M. Babaeva et al.
Year: 2023
Venue: Obesity and metabolism
URL: https://www.semanticscholar.org/paper/3956fc73b438d160a4f6eecf9d0be41945a7d814
DOI: 10.14341/omet12942
Citations: 1
Summary: A clinical case of 17-βhydroxysteroid dehydrogenase type 3 deficiency with late diagnosis due to parental will is presented, which often result in a change of gender identity during puberty.
Evidence snippets:
Snippet 1 (score: 0.772) > 17β-Hydroxysteroid dehydrogenase 3 deficiency (17HSD3) is a rare autosomal recessive cause of 46, XY disorders of sex development resulting from HSD17B3 gene mutations, in which conversion of androstenedione to testosterone is impared. The clinical signs of 17HSD3 deficiency depend on the residual activity of the enzyme. The diagnosis of 17HSD3 deficiency is based on reduced testosterone/androstenedione ratio (T/AD < 0.8). Patients are usually assigned at birth and raise as female. If the diagnosis is made before puberty, gonadectomy is recommended, taking into account the risk of masculinization during the puberty and estrogen therapy initiation in this period. If the diagnosis of 17HSD3 deficiency is established during puberty, when virilization manifests, the therapeutic strategy is based on the results of comprehensive psychological testing and gender identity of a patient. In patients with more pronounced masculinization or diagnosis established shortly after birth, who are assigned at birth and raise as male, testosterone therapy is used to achieve a male phenotype. The 17HSD3 deficiency and virilization often result in a change of gender identity during puberty. The article presents a clinical case of 17-βhydroxysteroid dehydrogenase type 3 deficiency with late diagnosis due to parental will. The diagnostic approaches and management of the disease are also described.

[2] Identifying 17-β-HSD3 Deficiency in Patients with Karyotype 46,XY Misdiagnosed with Androgen Insensitivity Syndrome: A Pediatric Case Report

Authors: Beshaier Almulhem, Fatimah Mouayed AlJishi, Mohammad Al-Qahtani
Year: 2025
Venue: The American Journal of Case Reports
URL: https://www.semanticscholar.org/paper/8dcee4504eca99e5299ecb44e080ba2d548f4f9d
DOI: 10.12659/AJCR.948210
PMID: 41035179
PMCID: 12502987
Summary: Genetic and hormonal testing play a crucial role in differentiating among various types of disorders of sex development, thereby reducing the risk of diagnostic uncertainty.
Evidence snippets:
Snippet 1 (score: 0.707) > Disorders of sex development (DSD) include a spectrum of disorders in which chromosomal, genetic, gonadal, hormonal, or anatomic aspects of sex are atypical [1]. The incidence is estimated at 1 in 20 000 live births for 46,XY DSDs and 1 in 14 000-15 000 for 46,XX DSDs, most commonly due to congenital adrenal hyperplasia [2,3]. DSDs are classified into sex chromosome, 46,XX, and 46,XY categories [4]. Causes of 46,XY DSD include gonadal dysgenesis, androgen biosynthesis defects (eg, 17 beta-hydroxysteroid dehydrogenase type 3 (17b-HSD3) deficiency), and androgen insensitivity syndrome (AIS) [4,5]. Diagnosis requires a multidisciplinary approach involving clinical, hormonal, imaging, and genetic assessments [3]. Management is individualized, addressing gender identity, malignancy risk, and hormone therapy [5]. > Synthesis of sex steroids is controlled by multiple enzymes, which include 17-b-HSD3 [4]. 17-b-HSD3 is inherited as an autosomal recessive trait on chromosome 9q22.32 and expressed in the testes. In the testes, 17-b-HSD3 converts inactive steroid androstenedione to active testosterone [6]. > In males, homozygous or compound heterozygous mutations of 17-b-HSD3 result in a decrease of testicular testosterone and subsequently decreases the dihydrotestosterone level. The disorder manifests as under-masculinization, which is characterized by hypoplastic-to-normal internal male genitalia with an external female phenotype [4]. Therefore, the pathognomonic hallmark of this disorder is a decreased plasma testosterone-to-androstenedione ratio (T: A) [7]. However, homozygous or compound-heterozygous mutations in females are asymptomatic [8].
Snippet 2 (score: 0.674) > Patient: Male, 13-year-old Final Diagnosis: 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency Symptoms: Acne • clitoromegaly • hirsutism • virilization Clinical Procedure: — Specialty: Endocrinology and Metabolic • Pediatrics and Neonatology Objective: Rare disease Background Defects in androgen synthesis, such as 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) deficiency, can lead to ambiguous genitalia in people with karyotype 46,XY due to impaired testosterone and dihydrotestosterone production. This condition may be initially diagnosed as androgen insensitivity syndrome (AIS), an X-linked disorder characterized by female external genitalia, absence of Mullerian structures, inguinal testes, and primary amenorrhea in adolescence. This report describes the case of a 13-year-old phenotypic female with 46,XY karyotype and a history of virilization due to 17-β-HSD3 deficiency, previously diagnosed with AIS. Case Report We report the case of a 13-year-old phenotypic female who was initially diagnosed with AIS during early childhood at a rural hospital. Several years later, she presented to a pediatric endocrinology clinic with progressive signs of virilization, including hirsutism, deepening of the voice, and severe facial acne. Laboratory evaluation, including a human chorionic gonadotropin (hCG) stimulation test, revealed a markedly low testosterone-to-androstenedione (T/AND) ratio of 0.1, strongly suggestive of 17β-HSD3 deficiency. Whole-exome sequencing identified a homozygous missense variant of uncertain significance in exon 4 of the HSD17B3 gene. As the patient had been raised as a female, the parents chose to maintain her female gender assignment. Subsequently, the patient underwent bilateral orchiectomy along with clitoroplasty and labioplasty at another medical center. Conclusions Genetic and hormonal testing play a crucial role in differentiating among various types of disorders of sex development, thereby reducing the risk of

[3] P-05 17Β-HYDROXYSTEROID DEHYDROGENASE 3 DEFICIENCY: TWO CASE REPORTS

Authors: Ilknur Uzun, A. Hacıoğlu, Z. Karaca, Ulku Gul Siraz, Aslıhan Kiraz et al.
Year: 2025
Venue: JCEM Case Reports
URL: https://www.semanticscholar.org/paper/bbd2b72df1f5a6796e78aae7336539d4e82e970f
DOI: 10.1210/jcemcr/luae218.008
PMCID: 11771402
Summary: Although clinical evaluation and laboratory test results might point out to 17-β-HSD3 deficiency, the definite diagnosis is established with genetic testing and the diagnosis is confirmed by molecular genetic testing.
Evidence snippets:
Snippet 1 (score: 0.676) > Abstract Introduction 17-β-hydroxysteroid dehydrogenase type3 (17β-HSD3) is an enzyme that produces testosterone from androstenedione, encoded by the HSD17B3 gene. Its deficiency causes 46 XY disorder of sex development (DSD) with autosomal recessive inheritance. 46 XY individuals with this enzyme deficiency can exhibit a wide range of phenotypes, ranging from normal female external genitalia to ambiguous genitalia. In early childhood, the diagnosis might be clinically indistinguishable from other causes of 46 XY DSD such as partial androgen insensitivity syndrome (AIS) and 5α-reductase type 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio. The diagnosis is confirmed by molecular genetic testing. If the diagnosis is missed in early infancy, patients present with severe virilization symptoms and amenorrhea during puberty. We present two siblings followed and managed with a presumed diagnosis of AIS until the genetic testing was performed. Clinical Case 1 A 4-month-old patient with female external genitalia was operated on with suspicion of bilateral inguinal hernia, and pathologic investigation revealed immature testicular tissue. No uterus and ovaries could be detected by pelvic ultrasound. The karyotype analysis was consistent with 46 XY, and the patient was followed up with the diagnosis of AIS. The patient’s parents were first cousins. The patient was started on estradiol replacement when she was 13 years old. At the age of 21, she underwent vaginoplasty due to a 2 cm long vaginal canal. A genetic analysis was available when the patient was 21 years old. Next generation sequencing revealed a previously reported homozygous c.277+5g>A mutation in exon 3 of HSD17B3 gene. The diagnosis was established as 17β-HSD3 deficiency. Clinical Case 2 After the index case was diagnosed with AIS karyotype analyses were performed on three other siblings at the time. The patient’s 7 years old sibling, who had a complete female-appearing genitalia, had a karyotype of 46XY. As the presumed diagnosis was AIS, bilateral or

[4] Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients

Authors: Catarina I. Gonçalves, J. Carriço, M. Bastos, M. Lemos
Year: 2022
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/9438ad569ae4cd1acb03becebdec0d9dff849c90
DOI: 10.3390/ijms231710026
PMID: 36077423
PMCID: 9456484
Citations: 21
Summary: A child raised as a female in whom the discovery of testes in the inguinal canals led to a genetic study by whole exome sequencing (WES) and to the identification of a compound heterozygous mutation of the HSD17B3 gene is described.
Evidence snippets:
Snippet 1 (score: 0.662) > 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) deficiency (OMIM: 264300) is a rare autosomal recessive Disorder of Sex Development (DSD) [1]. 17-β-HSD3 is encoded by the HSD17B3 gene (chromosome 9q22.32) and expressed in the testis where it converts the inactive steroid androstenedione to the active androgen testosterone [2]. Homozygous or compound heterozygous HSD17B3 mutations block the synthesis of testosterone in the fetal testis, resulting in undervirilized genitalia in 46,XY newborns [3]. The clinical phenotype may range from the normal female appearance of the external genitalia to various degrees of genital ambiguity, including microphallus with hypospadias [1,4,5]. Due to normal anti-Mullerian hormone (AMH) secretion, patients lack Mullerian structures (uterus, fallopian tubes, cervix, and the upper part of the vagina), whereas Wolffian derivatives (epididymis, vas deferens, and seminal vesicles) are often normally developed and testes are located in the inguinal canal. As female external genitalia is common at birth, these children are usually assigned the female gender and raised as such [1,4,5]. The diagnosis may occur in childhood due to mild clitoromegaly, urogenital sinus or inguinal hernia with testes present along the inguinal canals or labioscrotal folds [1,4,5]. At the expected time of puberty, severe virilization usually occurs due to the significant increase in the testicular secretion of androstenedione that can presumably be partially converted to testosterone by 17-β-HSD3 residual activity or by other isoenzymes [6,7]. Thus, diagnosis before puberty allows early treatment by the removal of the abnormal testes, which should prevent the clinical signs of marked virilization.
Snippet 2 (score: 0.613) > Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients

[5] Genomic technologies and the diagnosis of 46, XY differences of sex development

Authors: Firman P. Idris, Andrew H Sinclair, K. Ayers
Year: 2024
Venue: Andrology
URL: https://www.semanticscholar.org/paper/515cc06a603661191269701fa387e11a5f16bff1
DOI: 10.1111/andr.13708
PMID: 39081229
PMCID: 12183017
Citations: 5
Summary: This review will discuss 46, XY differences/disorders of sex development, its molecular causes, and the genomic technologies currently utilized for diagnosis with focus on reports from the last 5 years.
Evidence snippets:
Snippet 1 (score: 0.636) > Differences/disorders of sex development can be caused by disruptions to the molecular and cellular mechanisms that control development and sex determination of the reproductive organs with 1:100 live births affected. Multiple genes are associated with 46, XY differences/disorders of sex development that can cause varying clinical phenotypes. An accurate genetic diagnosis is essential to guide clinical care for individuals with 46, XY differences/disorders of sex development and can contribute to family planning. The use of genomics in differences/disorders of sex development has grown, with several advances employed in genetic diagnosis; however, diagnostic rates have stagnated at less than 50% for these conditions. This review will discuss 46, XY differences/disorders of sex development, its molecular causes, and the genomic technologies currently utilized for diagnosis with focus on reports from the last 5 years. We also touch on the challenges in diagnosing 46, XY differences/disorders of sex development and discuss new and future technologies that promise to improved diagnostic rates for these difficult conditions.

[6] 17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency: Diagnosis, Phenotypic Variability and Molecular Findings

Authors: M. Faienza, L. Cavallo
Year: 2012
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/01f91cfd3e06683a9b6fd4fad1f3355eb286ef85
DOI: 10.5772/27190
Citations: 7
Summary: The steroid hormones are lipophilic compounds with low molecular weight, derived from cholesterol, which play a crucial role in differentiation, development and physiological functions of many tissues and influence the sexual differentiation of the genitalia and their functional state in adulthood, the development of secondary sexual characteristics, and sexual behavior.
Evidence snippets:
Snippet 1 (score: 0.622) > Disorders of sexual development (DSDs) are congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical (Houk et al., 2006;Hughes et al., 2006). These disorders are classified into three major categories: sex chromosome DSD, 46,XX DSD and 46,XY DSD. This designation was proposed to replace the former term of pseudohermaphroditism, according to the consensus statement on management of intersex disorders (Hughes et al., 2006). 46,XY DSD are a heterogeneous group of clinical conditions characterized by 46,XY karyotype, either norma l o r d y s g e n e t i c t e s t e s a n d f e m a l e o r ambiguous phenotype of external (and possibly internal) genitalia (Hughes et al., 2006). This disorder can have several etiologies, but more frequently is due to a disruption in androgen production and/or action. Defects in androgen action and metabolism include mutations in the androgen receptor gene (complete, partial or mild androgen insensivity syndrome-AIS and Kennedy syndrome), or in the steroid 5-reductase type 2 gene, encoding the enzyme which convert T into DHT in the uro-genital tract (Quigley et al., 1995;Wilson et al., 1993). Instead, disorders of androgens biosynthesis are rare and usually due to alteration of enzyme involved in the conversion of cholesterol to T, such as the steroidogenic acute regulatory (stAR) protein, the steroidogenic enzyme P450ssc, 3HDS type 2, 17hydroxylase/17-20 lyase and 17 -hydroxysteroid dehydrogenase type 3 (17-HSD3) (Gobinet et al., 2002;Miller et al., 2005), (Fig. 1) Fig. 1. Steroidogenic pathway and role of 17-HSD3

[7] Clinical Features of Unrecognized Congenital Adrenal Hyperplasia Due to 17α-hydroxylase Deficiency Since Adolescence: A Case Report

Authors: K. Rashmi, L. Ravichandran, Ayan Roy, Dukhabandhu Naik, S. Kamalanathan et al.
Year: 2023
Venue: Journal of the ASEAN Federation of Endocrine Societies
URL: https://www.semanticscholar.org/paper/557cfbeaaddd9fae397ae0cffcdcd6e2460d94dd
DOI: 10.15605/jafes.038.02.08
PMID: 38045661
PMCID: 10692439
Citations: 4
Summary: This is a case of a 51-year-old single female who was referred to us for the evaluation of new-onset hypertension and hypokalaemia of one-year duration and genetic analysis revealed a mutation in the CYP17A1 gene, thus confirming the diagnosis of 17α-hydroxylase deficiency.
Evidence snippets:
Snippet 1 (score: 0.615) > Disorders of sexual development (DSD) refer to a diverse group of congenital disorders that result in a discrepancy between an individual's sex chromosomes, gonads, and/or the anatomic sex. The 46, XY DSD could be due to a defect in gonadal development or androgen biosynthesis, an error in steroidogenesis as that found in congenital adrenal hyperplasia (CAH), or due to a defect in androgen action. > Congenital adrenal hyperplasia occurs due to enzyme defects involved in adrenal and gonadal steroid biosynthesis. Most CAH cases result from a deficiency of 21-hydroxylase or 11-beta-hydroxylase, accounting for 90% and 7% of cases, respectively. 1,2 Deficiency of 21-hydroxylase and 11-betahydroxylase affects only the adrenal steroidogenesis, whereas those with a mutation in 17α-hydroxylase/17,20lyase (CYP17A1) and 3-β-hydroxysteroid dehydrogenase type 2 (HSD3B2) have an additional impairment in gonadal steroid biosynthesis. Consequently, 21-hydroxylase and 11-beta-hydroxylase cause DSD exclusively in 46, XX individuals. Congenital adrenal hyperplasia due to a mutation in STAR protein, cholesterol side chain cleavage (CYP11A1), and CYP17A1 all cause DSD exclusively in 46, XY individuals. Moreover, deficiencies in HSD3B2 and P450 oxidoreductase cause DSD in both sexes. > Congenital adrenal hyperplasia caused by 17α-hydroxylase deficiency (17OHD) is extremely rare, occurring in approximately 1 in 50,000 individuals. 3 The classical description of 17OHD is that of a phenotypic female (46, XX or underandrogenized 46, XY) who presents at puberty with primary amenorrhea and lack of secondary sexual characteristics, with low-renin hypertension, and hypokalaemic metabolic alkalosis.

[8] So, and if it is not congenital adrenal hyperplasia? Addressing an undiagnosed case of genital ambiguity

Authors: R.L. de Omena Filho, R. Petroli, F. C. Soardi, Débora de Paula Michelatto, T. Mazzola et al.
Year: 2021
Venue: Italian Journal of Pediatrics
URL: https://www.semanticscholar.org/paper/ee166ffef7ef311090ebf2bb06444759926b5573
DOI: 10.1186/s13052-022-01284-9
PMID: 35689291
PMCID: 9188102
Citations: 3
Summary: This case exemplifies the families’ pilgrimage in cases of genital ambiguity due to a rare genetic condition andrecognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions.
Evidence snippets:
Snippet 1 (score: 0.613) > Background The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene. In this disorder/difference of sex development, the conversion of androstenedione into testosterone is impaired. The appearance of external genitalia of 46,XY individuals varies from typically male to almost female. Case presentation We report on a child presenting severe ambiguous genitalia. Due to access constraints, specialized care did not start until the child was 10 months old. Parents are consanguineous and were born in an area of high isonymy that is a cluster for rare recessive diseases. A new homozygous missense variant c.785G > T was found in exon 10 of the HSD17B3 gene. Conclusions Researchers-clinicians and researchers-researchers collaborative efforts to elucidate the genetic basis of this disease were critical since this etiologic investigation is not available through the public health system. This case exemplifies the families’ pilgrimage in cases of genital ambiguity due to a rare genetic condition. Recognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions.

[9] 46,XY disorder of sex development due to 17-beta hydroxysteroid dehydrogenase type 3 deficiency: a plea for timely genetic testing

Authors: C. Grimbly, O. Caluseriu, P. Metcalfe, M. Jetha, E. Rosolowsky
Year: 2016
Venue: International Journal of Pediatric Endocrinology
URL: https://www.semanticscholar.org/paper/1bf3ed5f49930e542c1acaa85db860524454f26d
DOI: 10.1186/s13633-016-0030-x
PMID: 27307783
PMCID: 4908721
Citations: 8
Influential citations: 1
Summary: Expedient genetic testing for the HSD17B3 gene provided the unequivocal diagnosis of 17βHSD3 deficiency and advocate for urgent genetic testing in rare causes of DSD as indeterminate hormone results can delay diagnosis and prolong intervention.
Evidence snippets:
Snippet 1 (score: 0.594) > 46,XY disorder of sex development due to 17-beta hydroxysteroid dehydrogenase type 3 deficiency: a plea for timely genetic testing
Snippet 2 (score: 0.547) > Background17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) deficiency is a rare cause of disorder of sex development (DSD) due to impaired conversion of androstenedione to testosterone. Traditionally, the diagnosis was determined by βHCG-stimulated ratios of testosterone:androstenedione < 0.8.Case presentationAn otherwise phenotypically female infant presented with bilateral inguinal masses and a 46,XY karyotype. βHCG stimulation (1500 IU IM for 2 days) suggested 17βHSD3 deficiency although androstenedione was only minimally stimulated (4.5 nmol/L to 5.4 nmol/L). Expedient genetic testing for the HSD17B3 gene provided the unequivocal diagnosis.ConclusionWe advocate for urgent genetic testing in rare causes of DSD as indeterminate hormone results can delay diagnosis and prolong intervention.

[10] Early and late diagnoses of 17β‐Hydroxysteroid dehydrogenase type‐3 deficiency in two unrelated patients

Authors: H. Manyas, B. Eroğlu Filibeli, İ. Ayrancı, M. S. Güvenç, B. Dündar et al.
Year: 2021
Venue: Andrologia
URL: https://www.semanticscholar.org/paper/fdad1718fba1b8f4a5e2c6cf5807a8e688091afb
DOI: 10.1111/and.14017
PMID: 33586216
Citations: 2
Summary: It is emphasised that patients with 17β‐hydroxysteroid dehydrogenase type 3 deficiency can present with heterogeneous clinical findings in different age groups and that early diagnosis is important to prevent future gender confusion and related problems.
Evidence snippets:
Snippet 1 (score: 0.582) > 17β‐hydroxysteroid dehydrogenase type 3 deficiency is a rare cause of 46 XY disorders of sexual development. Mutations in the HSD17B3 gene result in reduced activity of the 17β‐HSD3 enzyme, decreasing the conversion of androstenedione to testosterone. In this report, two cases, admitted with different clinical findings in the neonatal and adolescent periods and were decided to be raised in different genders are presented. The first case who had complete female external genitalia presented on the third postnatal day with the complaint of swelling in the groin. He was decided to be raised as a male and was treated successfully with parenteral testosterone in order to increase phallus size before surgical correction of the external genitalia. The second case was an adolescent girl who presented due to pubertal virilisation and primary amenorrhoea and chose female gender. Molecular genetic analyses of the HSD17B3 gene revealed two different previously reported homozygous variants. We emphasise that patients with 17β‐hydroxysteroid dehydrogenase type 3 deficiency can present with heterogeneous clinical findings in different age groups. Early diagnosis is important to prevent future gender confusion and related problems.

[11] Clinical, hormonal, and molecular-genetic characteristics of two cases of abnormal sex formation (ASF) in 46XY subjects caused by type 3 17-beta hydroxysteroid dehydrogenase deficiency

Authors: A. Kolodkina, N. Kalinchenko, A. Nizhnik, M. A. Nokel, A. Tiulpakov
Year: 2011
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/3f3e56a5bd3348a0efd750f5617ffc5224f324d4
DOI: 10.14341/PROBL201157325-30
Citations: 2
Summary: Two girls were born with the female-type of external genitalia and 46XY karyotype, but progressive virilization in the pubertal period gave reason to suspect diagnosis of 17HSD3 deficiency; this diagnosis was confirmed in molecular genetic studies.
Evidence snippets:
Snippet 1 (score: 0.582) > Type 3 17-beta hydroxysteroid dehydrogenase (17HSD3) deficiency is a rare form of abnormal sex formation (ASF) in 46XY subjects in which the conversion of androstendione to testosterone is blocked; this defect results in compromised masculinization of the external genitalia during the intrauterine development. A distinctive feature of this form of sex development is masculinization at puberty due to the extragonadal conversion of androstendione to testosterone. Two clinical cases are reported: both girls were born with the female-type of external genitalia and 46XY karyotype, but progressive virilization in the pubertal period gave reason to suspect diagnosis of 17HSD3 deficiency. In both cases, this diagnosis was confirmed in molecular genetic studies (the following mutations were identified in the HSD17B3 gene: c.728-734delGATAACCp.1244fsX254/c.277+4A>T and c.277+4A>T). These two cases are the first reports of 17HSD3 deficiency in the Russian literature.

[12] 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency

Authors: Unknown authors
Year: 2020
Venue: Definitions
URL: https://www.semanticscholar.org/paper/cf059fb7536a489106947e2a5eafad542bd40d48
DOI: 10.32388/n6esvs
Citations: 1
Summary: 17-beta-hydroxysteroid dehydrogenase isozyme 3 (17betaHSD III) deficiency is a rare disorder leading to male pseudohermaphroditism (MPH), a condition characterized by incomplete differentiation of the male genitalia in 46X,Y males.
Evidence snippets:
Snippet 1 (score: 0.564) > 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency

[13] Uniparental Isodisomy of Chromosome 1 Unmasking an Autosomal Recessive 3-Beta Hydroxysteroid Dehydrogenase Type II-Related Congenital Adrenal Hyperplasia

Authors: K. Panzer, O. Ekhaguere, B. Darbro, J. Cook, O. Shchelochkov
Year: 2017
Venue: Journal of Clinical Research in Pediatric Endocrinology
URL: https://www.semanticscholar.org/paper/ab44cfc2baf2cbd1f55d84af139c7f67254ddd16
DOI: 10.4274/jcrpe.3680
PMID: 27796263
PMCID: 5363168
Citations: 9
Influential citations: 1
Summary: Evidence of the existence of an uncommon mechanism for HSD3B2 gene-related CAH arising from UPD of chromosome 1 is provided, and a term undervirilized male whose newborn screen indicated borderline CAH is described.
Evidence snippets:
Snippet 1 (score: 0.564) > Deficiency of 3-beta hydroxysteroid dehydrogenase type II (3β-HSD2) is a rare autosomal recessive form of congenital adrenal hyperplasia (CAH). In humans, 3β-HSD2 is predominantly expressed in the adrenal glands and gonads (1) and its encoding gene, HSD3B2 (MIM*613890), is located on chromosome 1 (2,3). The enzyme 3β-HSD2 oxidizes and isomerizes Δ 5 -steroids, namely, pregnenolone, 17-hydroxypregnenolone (17-OH Preg) and dehydroepiandrosterone into corresponding Δ 4 -ketosteroids (4). Deficiency of the enzyme impacts the steroid hormone pathway by disrupting the biosynthesis of mineralocorticoid, corticosteroid, and sex hormones. Typically, 3β-HSD2 enzyme deficiency results in cortisol deficiency, salt wasting, and male undervirilization. However, depending on the degree of enzyme deficiency and activity of the 3-beta hydroxysteroid dehydrogenase type I (3β-HSD1) enzyme, a similar enzyme produced in the skin and placenta, milder presentation may occur (5). This variability in clinical presentation should prompt clinicians to seek clarification of the diagnosis using molecular methods. Increased utilization of single nucleotide polymorphism (SNP) array in clinical practice has led to the recognition of uniparental isodisomy (UPD) that either disrupts imprinting patterns or unmasks autosomal recessive alleles (6). Reports on UPD as an underlying molecular mechanism of CAH are scarce (7). There are reported cases of UPD involving the two most common forms of CAH, steroid 21-hydroxylase (8) and 11-β-hydroxylase deficiency (9). Here, we report the first patient affected by HSD3B2-related CAH uncovered by UPD of chromosome 1. In general, UPD of chromosome 1 has been infrequently reported in other disease conditions (10).

[14] Ambiguous Genitalia Due to 3β-Hydroxysteroid Dehydrogenase Type 2 Deficiency: Clinical, Genetic, and Functional Characterization of Two Novel HSD3B2 Variants

Authors: Jani Liimatta, Kay-Sarah Sauter, T. du Toit, André Schaller, Dagmar l'Allemand et al.
Year: 2025
Venue: JCEM Case Reports
URL: https://www.semanticscholar.org/paper/d75fcf172b99d7813296d04de04101725edb7b2f
DOI: 10.1210/jcemcr/luae245
PMID: 39839754
PMCID: 11744041
Citations: 2
Summary: A 46, XY child with ambiguous genitalia and CAH without apparent adrenal insufficiency due to 2 novel heterozygous variants in the HSD3B2 gene is described, suggesting that Virilization that already progresses prepubertally through peripheral conversion of androgen precursors by 3β-hydroxysteroid dehydrogenase 1 will pose an increasing challenge during puberty.
Evidence snippets:
Snippet 1 (score: 0.562) > Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting steroid biosynthesis [1,2]. Very rare causes of CAH include 3β-hydroxysteroid dehydrogenase 2 deficiency (3βHSD2D, OMIM 613890) [1]. In early steps of adrenal and gonadal steroidogenesis, 3βHSD2 converts precursors into metabolites of the mineralocorticoid, glucocorticoid, and sex steroid pathways (Fig. 1). Variants in the HSD3B2 gene lead to a variable degree of 3βHSD2D with mild to severe clinical signs of CAH and sexual ambiguity [3,4]. Precursors accumulating through 3βHSD2D reach peripheral tissues, where type 1 3βHSD (3βHSD1/HSD3B1) is expressed and able to convert these to bioactive androgens (see Fig. 1). > At birth, 3βHSD2D may manifest with a difference of sexual development (DSD) both in 46, XX and 46, XY individuals [1,3,4]. 46, XY individuals have incomplete male genital development (hypospadias, ambiguous genitalia) due to lower production of testosterone (T) and dihydrotestosterone (DHT). 46, XX individuals have normal or mildly virilized external genitalia (clitoromegaly, labial fusion) because of increased dehydroepiandrosterone (DHEA) being converted to T by 3βHSD1 peripherally. According to the severity of 3βHSD2D, adrenal insufficiency manifests with or without salt loss (hypoaldosteronism) or adrenal crisis (hypocortisolism). > Here, we describe the clinical presentation, steroid biochemistry, and molecular genetics of 3βHSD2D in a patient harboring 2 novel HSD3B2 variants. Additionally, we provide functional data for novel variants and discuss challenges in patient care.

[15] Molecular genetic diagnosis and surgical management in a cohort of children with 46,XY disorders/differences of sex development

Authors: Y. S. Wong, H. Luk, H. Yau, L. Wong, S. W. Poon et al.
Year: 2025
Venue: Frontiers in Pediatrics
URL: https://www.semanticscholar.org/paper/0f189d71bb4129ec6656df5733df393c73cd517c
DOI: 10.3389/fped.2025.1456227
PMID: 39936125
PMCID: 11810906
Citations: 3
Summary: Molecular genetic diagnosis enhances the understanding of etiology, improves diagnostic accuracy, and provides precise guidance in the counseling and surgical management of children with 46,XY DSD.
Evidence snippets:
Snippet 1 (score: 0.551) > Objective A firm diagnosis revealing the etiology of disorders/differences of sex development (DSD) is most helpful in guiding clinical management. The aim of this study is to investigate molecular genetic diagnoses and surgical treatment in a cohort of children with 46,XY DSD. Methods A retrospective study was conducted on children with 46,XY DSD. They were referred to a tertiary surgical center during the period between 2011 and 2022 and were found to have genetic alterations, which were considered etiologies for their DSD. Data on clinical presentations, sex of rearing, genetic findings, surgical treatment, and comorbidities were collected and reviewed. Results A total of 21 patients were included in the study: 11 and 10 were reared as male and female, respectively. Genetic alterations were found as the causes for androgen insensitivity syndrome (n = 4), 5-alpha reductase type II deficiency (n = 5), 17-beta hydroxysteroid dehydrogenase III deficiency (n = 1), 17-alpha hydroxylase deficiency (n = 1), and gonadal dysgenesis (n = 10). Of those with gonadal dysgenesis, the genetic alterations were NR5A1 mutation/deletion (n = 3), DMRT1 deletion (n = 4), WT1 mutation (n = 2), and DAX1 duplication (n = 1). A total of 20/21 patients underwent one or more surgical procedures including hypospadias repair (n = 10), gonadectomy (n = 11), gonadal biopsy (n = 4), hernia repair (n = 4), orchidopexy (n = 1), and feminizing genitoplasty (n = 1). A total of 5/21 had germ cell neoplasms in one or both gonads. A total of 8/10 patients with gonadal dysgenesis had comorbidities involving other systems. Of the whole group, seven patients were found to inherit genetic alterations from their parents. Conclusions Molecular genetic diagnosis enhances the understanding of etiology, improves diagnostic accuracy, and provides precise guidance in the counseling and surgical management of children with 46,XY DS

[16] Approach of Heterogeneous Spectrum Involving 3beta-Hydroxysteroid Dehydrogenase 2 Deficiency

Authors: A. Nicola, M. Carsote, A. Gheorghe, E. Petrova, A. Popescu et al.
Year: 2022
Venue: Diagnostics
URL: https://www.semanticscholar.org/paper/8db5969dc71adc0aac2f75f4ee1ebb03c5369b13
DOI: 10.3390/diagnostics12092168
PMID: 36140569
PMCID: 9497988
Citations: 8
Summary: Adequate case management underlines the recent shift from evidence-based medicine to individualized (patient-oriented) medicine, this approach being particularly applicable in this exceptional and challenging disorder.
Evidence snippets:
Snippet 1 (score: 0.551) > We aim to review data on 3beta-hydroxysteroid dehydrogenase type II (3βHSD2) deficiency. We identified 30 studies within the last decade on PubMed: 1 longitudinal study (N = 14), 2 cross-sectional studies, 1 retrospective study (N = 16), and 26 case reports (total: 98 individuals). Regarding geographic area: Algeria (N = 14), Turkey (N = 31), China (2 case reports), Morocco (2 sisters), Anatolia (6 cases), and Italy (N = 1). Patients’ age varied from first days of life to puberty; the oldest was of 34 y. Majority forms displayed were salt-wasting (SW); some associated disorders of sexual development (DSD) were attendant also—mostly 46,XY males and mild virilisation in some 46,XX females. SW pushed forward an early diagnosis due to severity of SW crisis. The clinical spectrum goes to: premature puberty (80%); 9 with testicular adrenal rest tumours (TARTs); one female with ovarian adrenal rest tumours (OARTs), and some cases with adrenal hyperplasia; cardio-metabolic complications, including iatrogenic Cushing’ syndrome. More incidental (unusual) associations include: 1 subject with Barter syndrome, 1 Addison’s disease, 2 subjects of Klinefelter syndrome (47,XXY/46,XX, respective 47,XXY). Neonatal screening for 21OHD was the scenario of detection in some cases; 17OHP might be elevated due to peripheral production (pitfall for misdiagnosis of 21OHD). An ACTH stimulation test was used in 2 studies. Liquid chromatography tandem–mass spectrometry unequivocally sustains the diagnostic by expressing high baseline 17OH-pregnenolone to cortisol ratio as well as 11-oxyandrogen levels. HSD3B2 gene sequencing was provided in 26 articles; around 20 mutations were described as “novel pathogenic mutation” (frameshift, missense or nonsense); many subjects had a consanguineous background. The current COVID-19 pandemic showed that CAH-

[17] SUN-159 17-beta Hydroxysteroid Dehydrogenase 3 Deficiency in 1 Month Old Infant

Authors: Deepa Mathew, P. Speiser, Aristotle Panayiotopoulos, Laura Pisani
Year: 2020
Venue: Journal of the Endocrine Society
URL: https://www.semanticscholar.org/paper/38b77d9dc2ce0f53f5f7168a6b973fe5e96e56bb
DOI: 10.1210/jendso/bvaa046.1375
PMCID: 7207273
Summary: Molecular genetic analysis utilizing a commercially available candidate gene panel for 46, XY disorders of sex development diagnosed 17 beta-HSD3 deficiency in this case where hormonal testing was not informative.
Evidence snippets:
Snippet 1 (score: 0.542) > Abstract Background: 17-beta hydroxysteroid dehydrogenase 3 deficiency is a rare autosomal recessive disorder caused by mutations in HSD17B3 encoding the enzyme which converts androstenedione to testosterone. It is characterized in 46, XY males by incomplete virilization, including micropenis and hypospadias. Clinical Case: We report a 1 month old infant who presented with ambiguous genitalia. Prenatal non-invasive screening showed a Y chromosome, however, fetal ultrasound revealed female genitalia. The infant was born with micropenis (~1.4 cm in length) and proximal hypospadius, with enlarged labioscrotal folds and palpable gonads bilaterally. The urethral meatus had been relocated surgically to the glans. There was an apparent vaginal orifice with a normally positioned anus. Initial testing revealed a normal serum 17-OHP (90 ng/dl, n<200 ng/dl) and normal electrolytes. Abdominal US showed normal kidneys. Pelvic US demonstrated no Mullerian structures; gonads thought to be testes were identified in the labioscrotal folds. At 3 months of age, the infant underwent a 3 day HCG stimulation testing with a borderline testosterone response to 132 ng/dl, androstenedione 78 ng/dl and DHT 25 ng/dl. T/A ratio was unremarkable at 1.7 (n>0.8). Thus, hormonal testing was unsupportive of a testicular steroidogenic enzyme deficiency or androgen insensitivity syndrome. Karyotype was confirmed as 46, XY with microarray evidence of multiple regions of homozygosity. Genotyping with a 46, XY DSD panel (GeneDx) revealed a homozygous pathogenic variant c.608 C>T (p.A203V) in exon 9 of the HSD17B3 gene, consistent with a diagnosis of autosomal recessive 17-beta hydroxysteroid dehydrogenase 3 deficiency. Parents are of Arabic descent and are consanguineous. An older brother was also born with ambiguous gen

Notes

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