RESUMEN
D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.
Asunto(s)
Proteína Trifuncional Mitocondrial/deficiencia , Proteína-2 Multifuncional Peroxisomal , Humanos , Proteína-2 Multifuncional Peroxisomal/deficiencia , Proteína-2 Multifuncional Peroxisomal/genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Recién Nacido , Lactante , Masculino , Femenino , Secuenciación del Exoma , Mutación del Sistema de Lectura , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , 17-Hidroxiesteroide Deshidrogenasas/genética , Configuración de Recursos Limitados , Miopatías Mitocondriales , Cardiomiopatías , Enfermedades del Sistema Nervioso , RabdomiólisisRESUMEN
Hydroxysteroid (17ß) dehydrogenase (HSD17B) enzymes convert 17-ketosteroids to 17beta-hydroxysteroids, an essential step in testosterone biosynthesis. Human XY individuals with inactivating HSD17B3 mutations are born with female-appearing external genitalia due to testosterone deficiency. However, at puberty their testosterone production reactivates, indicating HSD17B3-independent testosterone synthesis. We have recently shown that Hsd17b3 knockout (3-KO) male mice display a similar endocrine imbalance, with high serum androstenedione and testosterone in adulthood, but milder undermasculinization than humans. Here, we studied whether HSD17B1 is responsible for the remaining HSD17B activity in the 3-KO male mice by generating a Ser134Ala point mutation that disrupted the enzymatic activity of HSD17B1 (1-KO) followed by breeding Hsd17b1/Hsd17b3 double-KO (DKO) mice. In contrast to 3-KO, inactivation of both HSD17B3 and HSD17B1 in mice results in a dramatic drop in testosterone synthesis during the fetal period. This resulted in a female-like anogenital distance at birth, and adult DKO males displayed more severe undermasculinization than 3-KO, including more strongly reduced weight of seminal vesicles, levator ani, epididymis, and testis. However, qualitatively normal spermatogenesis was detected in adult DKO males. Furthermore, similar to 3-KO mice, high serum testosterone was still detected in adult DKO mice, accompanied by upregulation of various steroidogenic enzymes. The data show that HSD17B1 compensates for HSD17B3 deficiency in fetal mouse testis but is not the enzyme responsible for testosterone synthesis in adult mice with inactivated HSD17B3. Therefore, other enzymes are able to convert androstenedione to testosterone in the adult mouse testis and presumably also in the human testis.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas , Ratones Noqueados , Testículo , Testosterona , Animales , Masculino , Testículo/metabolismo , Testículo/embriología , Ratones , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , 17-Hidroxiesteroide Deshidrogenasas/genética , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , Femenino , Testosterona/sangre , Testosterona/metabolismo , Feto/metabolismo , Estradiol Deshidrogenasas/metabolismo , Estradiol Deshidrogenasas/genéticaRESUMEN
Introduction: Individuals with 17-beta-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) deficiency face a multitude of challenges, primarily concerning genital appearance, potential malignancy risks, and fertility issues. This study reports our findings from an investigation involving five individuals affected by 17ß-HSD3 deficiency, ranging in age from pre-adolescence to adolescence. Notably, we identified four previously unreported mutations in these subjects. Methods: Our study included a comprehensive evaluation to determine the potential occurrence of testicular tumors. The methods involved clinical examinations, genetic testing, hormone profiling, and patient history assessments. We closely monitored the progress of the study subjects throughout their treatment. Results: The results of this evaluation conclusively ruled out the presence of testicular tumors among our study subjects. Moreover, four of these individuals successfully underwent gender transition. Furthermore, we observed significant improvements in genital appearance following testosterone treatment, particularly among patients in the younger age groups who received appropriate treatment interventions. Discussion: These findings underscore the critical importance of early intervention in addressing concerns related to genital appearance, based on our extensive clinical experience and assessments. In summary, our study provides insights into the clinical aspects of 17ß-HSD3 deficiency, emphasizing the vital significance of early intervention in addressing genital appearance concerns. This recommendation is supported by our comprehensive clinical assessments and experience.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/deficiencia , Trastorno del Desarrollo Sexual 46,XY , Ginecomastia , Errores Congénitos del Metabolismo Esteroideo , Neoplasias Testiculares , Masculino , Adolescente , Humanos , Trastorno del Desarrollo Sexual 46,XY/genética , Mutación , 17-Hidroxiesteroide Deshidrogenasas/genéticaRESUMEN
The 17-beta-hydroxysteroid dehydrogenase type 3 (17-ß-HSD3) enzyme converts androstenedione to testosterone and is encoded by the HSD17B3 gene. Homozygous or compound heterozygous HSD17B3 mutations block the synthesis of testosterone in the fetal testis, resulting in a Disorder of Sex Development (DSD). We describe 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 (c.608C>T, p.Ala203Val, and c.645A>T, p.Glu215Asp). Furthermore, we review all HSD17B3 mutations published so far in cases of 17-ß-HSD3 deficiency. A total of 70 different HSD17B3 mutations have so far been reported in 239 patients from 187 families. A total of 118 families had homozygous mutations, 63 had compound heterozygous mutations and six had undetermined genotypes. Mutations occurred in all 11 exons and were missense (55%), splice-site (29%), small deletions and insertions (7%), nonsense (5%), and multiple exon deletions and duplications (2%). Several mutations were recurrent and missense mutations at codon 80 and the splice-site mutation c.277+4A>T each represented 17% of all mutated alleles. These findings may be useful to those involved in the clinical management and genetic diagnosis of this disorder.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas , Desarrollo Sexual , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , 17-Hidroxiesteroide Deshidrogenasas/genética , Niño , Trastorno del Desarrollo Sexual 46,XY , Femenino , Ginecomastia , Humanos , Masculino , Mutación , Errores Congénitos del Metabolismo Esteroideo , TestosteronaRESUMEN
Congenital anomalies of the female reproductive tract that present with primary amenorrhea involve Müllerian aplasia, also known as Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS), and cervical and vaginal anomalies that completely obstruct the reproductive tract. Karyotype abnormalities do not exclude the diagnosis of MRKHS. Familial cases of Müllerian anomalies and associated malformations of the urinary and skeletal systems strongly suggest a complex genetic etiology, but so far, the molecular mechanism in the vast majority of cases remains unknown. Primary amenorrhea may also be the first presentation of complete androgen insensitivity syndrome, steroid 5α-reductase type 2 deficiency, 17ß-hydroxysteroid dehydrogenase type 3 deficiency, and Leydig cells hypoplasia type 1; therefore, these disorders should be considered in the differential diagnosis of the congenital absence of the uterus and vagina. The molecular diagnosis in the majority of these cases can be established.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/patología , Amenorrea/genética , Amenorrea/patología , Cuello del Útero/anomalías , Anomalías Congénitas/patología , Conductos Paramesonéfricos/anomalías , Vagina/anomalías , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , 17-Hidroxiesteroide Deshidrogenasas/genética , Síndrome de Resistencia Androgénica/genética , Síndrome de Resistencia Androgénica/patología , Cuello del Útero/embriología , Colestenona 5 alfa-Reductasa/deficiencia , Colestenona 5 alfa-Reductasa/genética , Anomalías Congénitas/diagnóstico , Trastorno del Desarrollo Sexual 46,XY/genética , Trastorno del Desarrollo Sexual 46,XY/patología , Femenino , Humanos , Masculino , Conductos Paramesonéfricos/patología , Testículo/anomalías , Testículo/patología , Vagina/embriologíaRESUMEN
BACKGROUND AND AIMS: 17-Beta hydroxysteroid dehydrogenase 13 (HSD17B13) is genetically associated with human nonalcoholic fatty liver disease (NAFLD). Inactivating mutations in HSD17B13 protect humans from NAFLD-associated and alcohol-associated liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma, leading to clinical trials of anti-HSD17B13 therapeutic agents in humans. We aimed to study the in vivo function of HSD17B13 using a mouse model. APPROACH AND RESULTS: Single-cell RNA-sequencing and quantitative RT-PCR data revealed that hepatocytes are the main HSD17B13-expressing cells in mice and humans. We compared Hsd17b13 whole-body knockout (KO) mice and wild-type (WT) littermate controls fed regular chow (RC), a high-fat diet (HFD), a Western diet (WD), or the National Institute on Alcohol Abuse and Alcoholism model of alcohol exposure. HFD and WD induced significant weight gain, hepatic steatosis, and inflammation. However, there was no difference between genotypes with regard to body weight, liver weight, hepatic triglycerides (TG), histological inflammatory scores, expression of inflammation-related and fibrosis-related genes, and hepatic retinoid levels. Compared to WT, KO mice on the HFD had hepatic enrichment of most cholesterol esters, monoglycerides, and certain sphingolipid species. Extended feeding with the WD for 10 months led to extensive liver injury, fibrosis, and hepatocellular carcinoma, with no difference between genotypes. Under alcohol exposure, KO and WT mice showed similar hepatic TG and liver enzyme levels. Interestingly, chow-fed KO mice showed significantly higher body and liver weights compared to WT mice, while KO mice on obesogenic diets had a shift toward larger lipid droplets. CONCLUSIONS: Extensive evaluation of Hsd17b13 deficiency in mice under several fatty liver-inducing dietary conditions did not reproduce the protective role of HSD17B13 loss-of-function mutants in human NAFLD. Moreover, mouse Hsd17b13 deficiency induces weight gain under RC. It is crucial to understand interspecies differences prior to leveraging HSD17B13 therapies.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/deficiencia , Dieta Alta en Grasa/efectos adversos , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Dieta Occidental/efectos adversos , Etanol/efectos adversos , Hígado Graso/etiología , Lípidos/análisis , Hígado/química , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Aumento de PesoRESUMEN
BACKGROUND: Deficiency of 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is a rare autosomal recessive 46,XY disorder of sex development (DSD). It is due to pathogenetic variants in the HSD17B3 gene. Mutated genes encode an abnormal enzyme with absent or reduced ability to convert Δ4-androstenedione (Δ4-A) to testosterone (T) in the fetal testis. Affected individuals are usually raised as females and diagnosis is made at puberty, when they show virilization. METHODS: A girl with a presumptive diagnosis of complete androgen insensitivity syndrome underwent endocrine and genetic assessment. Long-term follow-up was reported. RESULTS: The diagnosis of 17ß-HSD3 deficiency was made (stimulated T/Δ4-A ratio: 0.15; HSD17B3 gene analysis: c.277+4A>T in intron 3/c.640_645del (p.Glu214_Glu215del) in exon 9. After extensive information, parents decided to maintain female sex. Gonadal removal was performed and histological evaluation demonstrated deep fibrosis of testicular tissue. Follow-up till 8.5 years of age showed somatic and neuro-psychological development fitting with the female sex. CONCLUSIONS: Management of a child with the rare 17ß-HSD3 deficiency remains challenging. Any decision must be carefully evaluated with parents. Long-term follow-up must be warranted by a multidisciplinary DSD team to evaluate the adequacy of the choices made on quality of life in later life.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , Síndrome de Resistencia Androgénica/genética , Síndrome de Resistencia Androgénica/terapia , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , Niño , Desarrollo Infantil/fisiología , Preescolar , Trastorno del Desarrollo Sexual 46,XY/genética , Femenino , Estudios de Seguimiento , Humanos , Italia , Masculino , Procedimientos de Reasignación de Sexo/métodos , Testículo/cirugíaRESUMEN
Hydroxysteroid (17ß) dehydrogenase type 3 (HSD17B3) deficiency causes a disorder of sex development in humans, where affected males are born with female-appearing external genitalia, but are virilized during puberty. The hormonal disturbances observed in the Hsd17b3 knockout mice (HSD17B3KO), generated in the present study, mimic those found in patients with HSD17B3 mutations. Identical to affected humans, serum T in the adult HSD17B3KO mice was within the normal range, while a striking increase was detected in serum A-dione concentration. This resulted in a marked reduction of the serum T/A-dione ratio, a diagnostic hallmark for the patients with HSD17B3 deficiency. However, unlike humans, male HSD17B3KO mice were born with normally virilized phenotype, but presenting with delayed puberty. In contrast to the current belief, data from HSD17B3KO mice show that the circulating T largely originates from the testes, indicating a strong compensatory mechanism in the absence of HSD17B3. The lack of testicular malignancies in HSD17B3KO mice supports the view that testis tumors in human patients are due to associated cryptorchidism. The HSD17B3KO mice presented also with impaired Leydig cell maturation and signs of undermasculinization in adulthood. The identical hormonal disturbances between HSD17B3 deficient knockout mice and human patients make the current mouse model valuable for understanding the mechanism of the patient phenotypes, as well as endocrinopathies and compensatory steroidogenic mechanisms in HSD17B3 deficiency.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/fisiología , Hormonas Esteroides Gonadales/sangre , Infertilidad Masculina/patología , Células Intersticiales del Testículo/patología , Mutación , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , 17-Hidroxiesteroide Deshidrogenasas/genética , Animales , Femenino , Infertilidad Masculina/etiología , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Disorders of sex development (DSD) are defined as discrepancy between chromosomal, gonadal and anatomic sex. The basic principles for the management of DSD include a multidisciplinary approach for gender assignment. Clinical assessment includes a detailed history and examination of external genitalia. Most of the disorders with symmetrical gonades indicate hormonal cause while asymmetrical gonades are found in chromosomal DSDs. Karyotyping will indicate a 46XX DSD, 46 XY DSD or mosicism. Internal anatomy is defined by ultrasonography, genitoscopy and laparoscopy. Human chorionic gonadotrophins (hCG) stimulation test is carried out in under-virilised males to see the function of Leydig cells in testes. The Most common cause of 46XX DSD is congenital adrenal hyperplasia (CAH). The decision of gender assignment surgery is to be taken in a multidisciplinary environment and with informed consent of the parents. Most of 46 XX CAH patients, even if markedly virilised, and 46 XY complete androgen insensitivity syndrome are raised as females. Similarly, most of 5-α reductase deficiency and 17-ß hydroxysteroid dehydrogenase deficiency patients are assigned to the male gender. The decision in cases of mixed gondal dysgenesis and ovotesticular DSD is based on the development of external and internal genitalia. Patients with androgen biosynthetic defects, partial androgen insensitivity syndrome are usually assigned to the male gender.
Asunto(s)
Trastornos del Desarrollo Sexual/diagnóstico , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , Hiperplasia Suprarrenal Congénita/diagnóstico , Síndrome de Resistencia Androgénica/diagnóstico , Colestenona 5 alfa-Reductasa/deficiencia , Trastorno del Desarrollo Sexual 46,XY/diagnóstico , Femenino , Disgenesia Gonadal/diagnóstico , Ginecomastia/diagnóstico , Humanos , Cariotipificación , Masculino , Errores Congénitos del Metabolismo Esteroideo/diagnósticoRESUMEN
17ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3) deficiency is an autosomal recessive disorder of male sex development that results in defective testosterone biosynthesis. Although mutations in the cognate HSD17B3 gene cause a spectrum of phenotypic manifestations, the majority of affected patients are genetic males having female external genitalia. Many cases do not present until puberty, at which time peripheral conversion of androgen precursors causes progressive virilization. Measurement of the testosterone-to-androstenedione ratio is useful to screen for 17ßHSD3 deficiency, and genetic analysis can confirm the diagnosis. As some individuals with 17ßHSD3 deficiency transition from a female sex assignment to identifying as males, providers should ensure stable gender identity prior to recommending irreversible treatments. Gonadectomy is indicated to prevent further virilization if a female gender identity is established. The risk of testicular neoplasia is unknown, a point which should be discussed if patients elect to transition into a male gender role.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/deficiencia , Neoplasias de Células Germinales y Embrionarias/enzimología , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Dihidrotestosterona/metabolismo , Humanos , Mutación/genética , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/fisiopatologíaRESUMEN
Hydroxysteroid (17ß) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13-knockout (HSD17B13KO) mice deficient in Hsd17b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcarnitines, suggesting impaired mitochondrial ß-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsd17b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.-Adam, M., Heikelä, H., Sobolewski, C., Portius, D., Mäki-Jouppila, J., Mehmood, A., Adhikari, P., Esposito, I., Elo, L. L., Zhang, F.-P., Ruohonen, S. T., Strauss, L., Foti, M., Poutanen, M. Hydroxysteroid (17ß) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/deficiencia , Hígado Graso/enzimología , Metabolismo de los Lípidos , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo , Animales , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo , Hígado Graso/genética , Hígado Graso/patología , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/metabolismo , Inflamación/enzimología , Inflamación/genética , Inflamación/patología , Ratones , Ratones Noqueados , Mitocondrias Hepáticas/enzimología , Mitocondrias Hepáticas/genética , Mitocondrias Hepáticas/patología , Oxidación-Reducción , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismoRESUMEN
17-beta hydroxysteroid dehydrogenase type 3 (17ßHSD-3) enzyme catalyzes the conversion of androstenedione (Δ4) to testosterone (T) in the testes of the developing fetus, thus playing a crucial role in the differentiation of the gonads and in establishing the male sex phenotype. Any mutation in the encoding gene (HSD17B3) can lead to varying degrees of undervirilization of the affected male, ranging from completely undervirilized external female genitalia to predominantly male with micropenis and hypospadias. We present here an infant who was referred to our clinic because of ambiguous genitalia at birth. Gonads were palpable in the inguinal canal bilaterally and no Müllerian structures were identified on pelvic ultrasound. Because of a low T/Δ4 ratio after a human chorionic gonadotropin stimulation test, a tentative diagnosis of 17ßHSD-3 deficiency was made which was confirmed after genetic analysis of the HSD17B3 gene of the patient. The molecular analysis identified compound heterozygosity of two previously described mutations and could offer some further validation for the idea of a founder effect for 655-1;GâA mutation in the Greek population.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/deficiencia , Trastorno del Desarrollo Sexual 46,XY , Ginecomastia , Errores Congénitos del Metabolismo Esteroideo , 17-Hidroxiesteroide Deshidrogenasas/genética , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Trastorno del Desarrollo Sexual 46,XY/diagnóstico , Trastorno del Desarrollo Sexual 46,XY/genética , Trastorno del Desarrollo Sexual 46,XY/metabolismo , Grecia , Ginecomastia/diagnóstico , Ginecomastia/genética , Ginecomastia/metabolismo , Humanos , Recién Nacido , Masculino , Errores Congénitos del Metabolismo Esteroideo/diagnóstico , Errores Congénitos del Metabolismo Esteroideo/genética , Errores Congénitos del Metabolismo Esteroideo/metabolismoRESUMEN
17ß-Hydroxysteroid dehydrogenase 3 deficiency is a rare autosomal recessive cause of 46, XY disorders of sex development resulting from HSD17B3 gene mutations, however, no case has been reported in East Asia. The aim of this study was to report three Chinese 46, XY females with 17ß-HSD3 deficiency in a single center and perform a systematic review of the literature. Clinical examination, endocrine evaluation and HSD17B3 gene sequencing were performed in the three Chinese phenotypically females (two sisters and one unrelated patient). Relevant articles were searched by using the term "HSD17B3" OR "17beta-HSD3 gene" with restrictions on language (English) and species (human) in Pubmed and Embase. All the three phenotypically female subjects showed 46, XY karyotype, inguinal masses, decreased testosterone and increased androstenedione. Two novel homozygous mutations (W284X and c.124_127delTCTT) in HSD17B3 gene were identified. A systematic review found a total of 121 pedigrees/158 patients, with 78.5% (124/158) of patients assigned as females, 15.2% (24/158) from females to males, and 5.1% (8/158) raised as males. The most common mutation was c.277+4C>T (allele frequency: 25/72) for patients from Europe, and R80Q (allele frequency: 21/54) for patients from West Asia. The testicular histology showed normal infantile testicular tissue in 100% (9/9) infantile patients, normal quantity germ cells in 44.4% (8/18) prepubertal patients and 19.0% (4/21) pubertal and adult patients. We reported the first East Asian 17ß-hydroxysteroid dehydrogenase 3 deficiency cases. Additional literature reviews found founder effects among patients with different ethnic background and early orchiopexy may benefit fertility in patients assigned as males. These findings may significantly expand the clinical, ethnic and genetic spectrum of 17ß-hydroxysteroid dehydrogenase 3 deficiency.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/deficiencia , Trastorno del Desarrollo Sexual 46,XY/genética , Adolescente , Pueblo Asiatico/genética , Niño , Femenino , Humanos , MutaciónRESUMEN
17ß-hydroxysteroid dehydrogenase 3 deficiency consists of a defect in the last phase of steroidogenesis, in which androstenedione is converted into testosterone and estrone into estradiol. External genitalia range from female-like to atypical genitalia and most affected males are raised as females. Virilization in subjects with 17ß-HSD3 deficiency occurs at the time of puberty and several of them change to male social sex. In male social sex patients, testes can be safely maintained, as long as they are positioned inside the scrotum The phenotype of 46,XY DSD due to 17ß-HSD3 deficiency is extremely variable and clinically indistinguishable from other causes of 46,XY DSD such as partial androgen insensitivity syndrome and 5α-reductase 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio due to high serum levels of androstenedione and low levels of testosterone. The disorder is caused by a homozygous or compound heterozygous mutations in the HSD17B3 gene that encodes the 17ß-HSD3 isoenzyme leading to an impairment of the conversion of 17-keto into 17-hydroxysteroids. Molecular genetic testing confirms the diagnosis and provides the orientation for genetic counseling. Our proposal in this article is to review the previously reported cases of 17ß-HSD3 deficiency adding our own cases.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/deficiencia , Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , Trastornos del Desarrollo Sexual/genética , 17-Hidroxiesteroide Deshidrogenasas/genética , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/deficiencia , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , Adolescente , Adulto , Síndrome de Resistencia Androgénica/genética , Niño , Preescolar , Trastorno del Desarrollo Sexual 46,XY/genética , Exones , Femenino , Pruebas Genéticas , Genotipo , Homocigoto , Humanos , Hipospadias/genética , Masculino , Mutación , Fenotipo , Estudios Retrospectivos , Errores Congénitos del Metabolismo Esteroideo/genética , Virilismo/genética , Adulto JovenRESUMEN
BACKGROUND: 17ß-hydroxysteroid dehydrogenase (17ß-HSD) type 3 deficiency is an autosomal recessive disorder with diminished testosterone synthesis and consequently underandrogenisation. 46,XY patients with 17ß-HSD type 3 deficiency are often assigned a female sex at birth but have a high virilisation potential at the time of puberty. METHODS: We studied four 46,XY patients with 17ß-HSD type 3 deficiency at puberty with regard to the underlying mutations, the hormone values, and the clinical findings. RESULTS: 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 17ß-HSD type 3. One of the latter patients changed to male gender. CONCLUSION: All 4 patients with 17ß-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.â©.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/deficiencia , Trastorno del Desarrollo Sexual 46,XY , Ginecomastia , Mutación , Pubertad , Errores Congénitos del Metabolismo Esteroideo , Virilismo , 17-Hidroxiesteroide Deshidrogenasas/genética , Adolescente , Trastorno del Desarrollo Sexual 46,XY/genética , Trastorno del Desarrollo Sexual 46,XY/patología , Trastorno del Desarrollo Sexual 46,XY/fisiopatología , Femenino , Ginecomastia/genética , Ginecomastia/patología , Ginecomastia/fisiopatología , Humanos , Masculino , Errores Congénitos del Metabolismo Esteroideo/genética , Errores Congénitos del Metabolismo Esteroideo/patología , Errores Congénitos del Metabolismo Esteroideo/fisiopatología , Virilismo/genética , Virilismo/patología , Virilismo/fisiopatologíaRESUMEN
This study aimed at the detection of HSD17B3 gene mutations in Egyptian patients with suspected diagnosis of 46,XY DSD due to 17-ß-HSD-3 deficiency and at evaluation of phenotype/genotype relationship of these mutations. The study was conducted on 11 patients of 10 families which were provisionally diagnosed to have 17-ß-HSD-3 enzyme deficiency. Karyotyping, hormonal evaluation of testosterone, x0394;4-androstenedione, and dihydrotestosterone, and sequencing analysis of the 11 exons of the HSD17B3 gene were done. Mutations in HSD17B3 were detected in exons 2, 7, 8, 10, and 11, and 6 novel mutations were determined in exons 1, 2, 7, and 8. Two patients showed compound heterozygous mutations, while 8 families had probands with homozygous mutations. The current study shows that 17-ß-HSD-3 deficiency is not an uncommon disorder among Egyptian DSD cases. It was evidenced that the mutational profile of the disease is rather heterogeneous, relatively different from those reported in other populations, and has a high degree of novel genetic defects.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , Trastorno del Desarrollo Sexual 46,XY/sangre , Trastorno del Desarrollo Sexual 46,XY/genética , Mutación/genética , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Adolescente , Adulto , Androstenodiona/sangre , Androstenodiona/metabolismo , Niño , Preescolar , Dihidrotestosterona/sangre , Dihidrotestosterona/metabolismo , Trastorno del Desarrollo Sexual 46,XY/metabolismo , Egipto , Exones/genética , Femenino , Homocigoto , Humanos , Masculino , Testosterona/sangre , Testosterona/metabolismo , Adulto JovenRESUMEN
Hydroxysteroid (17ß)-dehydrogenase type 1 (HSD17B1) catalyzes the conversion of low active 17-ketosteroids, androstenedione (A-dione) and estrone (E1) to highly active 17-hydroxysteroids, testosterone (T) and E2, respectively. In this study, the importance of HSD17B1 in ovarian estrogen production was determined using Hsd17b1 knockout (HSD17B1KO) mice. In these mice, the ovarian HSD17B enzyme activity was markedly reduced, indicating a central role of HSD17B1 in ovarian physiology. The lack of Hsd17b activity resulted in increased ovarian E1:E2 and A-dione:T ratios, but we also observed reduced progesterone concentration in HSD17B1KO ovaries. Accordingly with the altered steroid production, altered expression of Star, Cyp11a1, Lhcgr, Hsd17b7, and especially Cyp17a1 was observed. The ovaries of HSD17B1KO mice presented with all stages of folliculogenesis, while the corpus luteum structure was less defined and number reduced. Surprisingly, bundles of large granular cells of unknown origin appeared in the stroma of the KO ovaries. The HSD17B1KO mice presented with severe subfertility and failed to initiate pseudopregnancy. However, the HSD17B1KO females presented with normal estrous cycle defined by vaginal smears and normal puberty appearance. This study indicates that HSD17B1 is a key enzyme in ovarian steroidogenesis and has a novel function in initiation and stabilization of pregnancy.