Aromatase deficiency caused by mutation of CYP19A1 gene: A case report. / CYP19A1åŸºå› çªå˜è‡´èŠ³é¦™åŒ–é ¶ç¼ºä¹ç—‡1例.

Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. CYP19A1 gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.

The role of CYP19A1 and ESR2 gene polymorphisms in female androgenetic alopecia in the Polish population.

Introduction: Androgenetic alopecia is the most common type of non-cicatricial alopecia both in male and female patients. The mechanism that leads to hair loss is similar in both sexes, but the underlying cause, and especially the role of genes and sex hormones in the pathogenesis of the disease in women has not fully been explained as of yet. So far, a few attempts have been made to assess selected SNPs for CYP19A1 and ESR2 genes, but their results are not unequivocal and fully reproducible. Aim: To investigate the association of 13 CYP19A1 and 11 ESR2 gene SNPs with female androgenetic alopecia (FAGA) in a population of Polish patients, including some already genotyped SNPs of possible importance for FAGA pathophysiology in other populations. Material and methods: Twenty-four genetic polymorphisms were analysed for the ESR2 and CYP19A1 genes in 117 patients with FAGA and 128 healthy subjects treated at the Department of Dermatology in Krakow. Results: In the studied Polish population, none of the selected SNPs, frequently detected in the Caucasian population and linked with the transformation pathway of sex hormones, showed a significant association with FAGA. Conclusions: Further studies into the genetic background of androgenetic alopecia are needed. Ethnic differences as well as the size of the studied population may be of great significance for the obtained results.

Association of ST6GAL1 and CYP19A1 polymorphisms in the 3'-UTR with astrocytoma risk and prognosis in a Chinese Han population.

BACKGROUND: Astrocytoma is a common type of central nervous system tumor. In this study, we investigated the correlation between ST6GAL1 and CYP19A1 polymorphisms and the risk and prognosis of astrocytoma. METHODS: A total of 365 astrocytoma patients and 379 healthy controls were genotyped using the Agena MassARRAY system. The correlation between ST6GAL1 and CYP19A1 variants and astrocytoma risk was calculated using logistic regression. The survival rate of patients with astrocytoma was analyzed to evaluate prognosis. RESULTS: We found that the ST6GAL1-rs2239611 significantly decreased the risk of astrocytoma in the codominant model (p = 0.044) and dominant model (p = 0.049). In stratified analyses, CYP19A1-rs2255192 might be associated with a higher risk of astrocytoma among the low-grade subgroup under recessive (p = 0.034) and additive (p = 0.030) models. However, CYP19A1-rs4646 had a risk-decreasing effect on the high-grade subgroup in the codominant model (p = 0.044). The results of Cox regression analysis showed that the CYP19A1-rs2239611 and -rs1042757 polymorphisms were significantly correlated with the prognosis of astrocytoma. CONCLUSION: Our results suggest that ST6GAL1 and CYP19A1 genes may be a potential biomarker of genetic susceptibility and prognosis to astrocytoma in the Chinese Han population.

MicroRNAs and Long Noncoding RNAs as Novel Therapeutic Targets in Estrogen Receptor-Positive Breast and Ovarian Cancers.

Aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane have shown to prevent metastasis and angiogenesis in estrogen receptor (ER)-positive breast and ovarian tumors. They function primarily by reducing estrogen production in ER-positive post-menopausal breast and ovarian cancer patients. Unfortunately, current AI-based therapies often have detrimental side-effects, along with acquired resistance, with increased cancer recurrence. Thus, there is an urgent need to identify novel AIs with fewer side effects and improved therapeutic efficacies. In this regard, we and others have recently suggested noncoding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), as potential molecular targets for utilization in modulating cancer hallmarks and overcoming drug resistance in several cancers, including ER-positive breast and ovarian cancer. Herein, we describe the disruptive functions of several miRNAs and lncRNAs seen in dysregulated cancer metabolism, with a focus on the gene encoding for aromatase (CYP19A1 gene) and estrogen synthesis as a novel therapeutic approach for treating ER-positive breast and ovarian cancers. Furthermore, we discuss the oncogenic and tumor-suppressive roles of several miRNAs (oncogenic miRNAs: MIR125b, MIR155, MIR221/222, MIR128, MIR2052HG, and MIR224; tumor-suppressive miRNAs: Lethal-7f, MIR27B, MIR378, and MIR98) and an oncogenic lncRNA (MIR2052HG) in aromatase-dependent cancers via transcriptional regulation of the CYP19A1 gene. Additionally, we discuss the potential effects of dysregulated miRNAs and lncRNAs on the regulation of critical oncogenic molecules, such as signal transducer, and activator of transcription 3, ß-catenin, and integrins. The overall goal of this review is to stimulate further research in this area and to facilitate the development of ncRNA-based approaches for more efficacious treatments of ER-positive breast and ovarian cancer patients, with a slight emphasis on associated treatment-delivery mechanisms.

Aromatase deficiency: A case series of 46, XX Chinese children and a systematic review of the literature.

BACKGROUND: Aromatase deficiency (AD) caused by cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1) variants is characterized by a deficiency in androgen-to-oestrogen conversion. OBJECTIVE: To investigate the clinical characteristics and accurate management of aromatase-deficient children. PATIENTS AND METHODS: We described three 46, XX aromatase-deficient children, searched PubMed with "(aromatase deficiency) AND (46, XX OR ovaries)" and manually searched citations in identified studies for the literature review. RESULTS: Two girls and one boy (3.4-9.2 years) with the 46, XX karyotype presented ambiguous genitalia and maternal antenatal virilization, normal-low height, delayed bone age, normal glucose and lipid profiles, markedly elevated follicle-stimulating hormone (FSH) levels and poor oestradiol responses to human menopausal gonadotropin stimulation. Ultrasound revealed normal-sized uterus and ovaries with undetectable follicles. Histopathology revealed primordial follicles and few primary follicles in ovaries. One patient presented granulosa and follicular membrane cell proliferation and interstitial sclerosis. We identified four CYP19A1 variants; c.146_158del and c.344G >A were unreported. We reviewed available data from thirty 46, XX patients (0.2-32 years). Some patients were not diagnosed until puberty/adulthood; three were initially misdiagnosed with congenital adrenocortical hyperplasia. The main characteristics were maternal antenatal virilization (21/29), ambiguous genitalia (mainly Prader IV or III, 19/23), delayed bone age (16/17), low bone mass (5/8), markedly elevated FSH levels and ovarian cysts (13/30). CONCLUSIONS: 46, XX AD is easily neglected or misdiagnosed. Ambiguous genitalia, maternal antenatal virilization and markedly elevated FSH levels are important diagnostic indicators. We described two novel variants, new histopathological features of ovaries and an early management strategy.

Effect of GnRH agonist before IVF on outcomes in infertile endometriosis patients: a randomized controlled trial.

RESEARCH QUESTION: Does 3-months of gonadotrophin releasing hormone agonist (GnRHa) treatment before IVF improve clinical pregnancy rate in infertile patients with endometriosis? DESIGN: Single-blind, placebo-controlled clinical trial of 200 infertile women with endometriosis assigned to use GnRHa (study group) or placebo (control group) for 3 months before IVF. Clinical, embryological outcomes and stimulation parameters were analysed. Clinical pregnancy rate was the primary endpoint. In a subgroup of 40 patients, follicular fluid levels of oestradiol, testosterone and androstendione were measured. Gene expression profile of CYP19A1 was analysed in cumulus and mural granulosa cells. RESULTS: Implantation or clinical pregnancy rate were not significantly different between the two groups. Clinical pregnancy rates were 25.3% and 33.7% in the study and control groups, respectively (P = 0.212). Cumulative live birth rate was not significantly different: 22.0% (95% CI 13.0 to 31.0) in the study group and 33.7% (95% CI 24.0 to 44.0) in the control group (P = 0.077). Ovarian stimulation was significantly longer and total dose of gonadotrophins significantly higher in the study group (both P < 0.001). Serum oestradiol levels on the day of HCG were significantly lower in the study group (P = 0.001). Cancellation rate was significantly higher in the study group (P = 0.042), whereas cleavage embryos were significantly more numerous in the control group (P = 0.023). No significant differences in the expression of CYP19A1 gene in mural or cumulus granulosa cells or steroid levels in follicular fluid between the two groups were observed, but testosterone was significantly lower in the study group (P < 0.001). CONCLUSION: Three-months of GnRHa treatment before IVF does not improve clinical pregnancy rate in women with endometriosis.

Down-regulation of the CYP19A1 gene in cumulus cells of infertile women with endometriosis.

Aromatase plays a fundamental role in the establishment of oocyte quality, which might be compromised in infertile women with endometriosis. The expression of the CYP19A1 gene (that encodes aromatase) was compared in cumulus cells and oestradiol concentrations in the follicular fluid of infertile women with and without endometriosis submitted to ovarian stimulation for intracytoplasmic sperm injection. Cumulus cells were isolated and the expression of the CYP19A1 was quantitated through real-time polymerase chain reaction. Oestradiol concentrations in follicular fluid were measured by chemiluminescence immunoassay. A lower expression of the CYP19A1 in the cumulus cells of infertile women with endometriosis was observed compared with controls (0.17 ± 0.13 and 0.56 ± 0.12, respectively), and no significant difference in the follicular fluid oestradiol concentrations was observed between groups. Our results show reduced expression of the CYP19A1 in cumulus cells of infertile women with endometriosis, which may play a role in the pathogenesis of endometriosis-related infertility.

Rare 15q21.1q22.31 Duplication Due to a Familial Chromosomal Insertion and Diagnostic Investigation in a Carrier of Balanced Chromosomal Rearrangement and Intellectual Disability.

Insertions are rare balanced chromosomal rearrangements with an increased risk of imbalances for the offspring. Moreover, balanced rearrangements in individuals with abnormal phenotypes may be associated to the phenotype by different mechanisms. This study describes a three-generation family with a rare chromosomal insertion. G-banded karyotype, chromosomal microarray analysis (CMA), whole-exome sequencing (WES), and low-pass whole-genome sequencing (WGS) were performed. Six individuals had the balanced insertion [ins(9;15)(q33;q21.1q22.31)] and three individuals had the derivative chromosome 9 [der(9)ins(9;15)(q33;q21.1q22.31)]. The three subjects with unbalanced rearrangement showed similar clinical features, including intellectual disability, short stature, and facial dysmorphisms. CMA of these individuals revealed a duplication of 19.3 Mb at 15q21.1q22.31. A subject with balanced rearrangement presented with microcephaly, severe intellectual disability, absent speech, motor stereotypy, and ataxia. CMA of this patient did not reveal pathogenic copy number variations and low-pass WGS showed a disruption of the RABGAP1 gene at the 9q33 breakpoint. This gene has been recently associated with a recessive disorder, which is not compatible with the mode of inheritance in this patient. WES revealed an 88 bp deletion in the MECP2 gene, consistent with Rett syndrome. This study describes the clinical features associated with the rare 15q21.1-q22.31 duplication and reinforces that searching for other genetic causes is warranted for individuals with inherited balanced chromosomal rearrangements and abnormal phenotypes.

A Novel Homozygous CYP19A1 Gene Mutation Causing Aromatase Deficiency.

Aromatase deficiency is a rare autosomal recessive disorder and its exact prevalence is not known. Aromatase enzyme catalyzes the conversion of androgens to estrogens in gonadal and extra-gonadal tissues. Deficiency of aromatase enzyme can lead to ambiguous genitalia in a female child and maternal virilization during pregnancy due to raised androgen levels in the mother. A 10-month-old child was referred to our outpatient department for the evaluation of ambiguous genitalia. There was a history of maternal virilization during pregnancy. Karyotype of the child was 46XX. Congenital adrenal hyperplasia was ruled out as serum cortisol, plasma adrenocorticotropic hormone, and 17-hydroxyprogesterone were within normal limits. Hormonal assays showed elevated follicle-stimulating hormone and luteinizing hormone, with raised testosterone and low estradiol levels. Based on these findings, aromatase deficiency was suspected. A novel homozygous mutation c.1376delA located on exon 10 was identified on the CYP19A1 gene. We identified a novel mutation in the CYP19A1 gene in a patient who presented with ambiguous genitalia and maternal virilization during pregnancy.

Aromatase Deficiency in Two Siblings with 46,XX Karyotype Raised as Different Genders: A Novel Mutation (p.R115X) in the CYP19A1 Gene

Aromatase deficiency rarely causes a 46,XX sexual differentiation disorder. The CYP19A1 gene encodes the aromatase enzyme which catalyses the conversion of androgens to oestrogens. In cases with 46,XX karyotype, mutations in the CYP19A1 gene can lead to disorders of sex development. Clinical findings in aromatase deficiency vary depending on the degree of deficiency. The effect of increased androgens, including acne, cliteromegaly and hirsutism, can be observed in mothers with placental aromatase deficiency. A decrease in maternal virilisation symptoms is observable in the postpartum period. It is rarely reported that there is no virilization in pregnancy. In this study, two 46,XX sibling having the p.R115X (c.343 C>T) novel pathogenic variant in the CYP19A1 gene and raised as different genders, with no maternal virilisation during pregnancy, are presented. In conclusion, 46,XX virilised females should be examined in terms of aromatase deficiency once congenital adrenal hyperplasia has been excluded, even if there is no history of maternal virilisation during pregnancy.

A Novel Homozygous CYP19A1 Gene Mutation: Aromatase Deficiency Mimicking Congenital Adrenal Hyperplasia in an Infant without Obvious Maternal Virilisation

Aromatase deficiency is a rare, autosomal recessive disorder in which affected patients fail to synthesize normal estrogen. Herein, we report a 46, XX patient born with virilised external genitalia. A novel homozygous mutation in the CYP19A1 gene, causing aromatase deficiency, was detected. A 30-day infant registered as a male was referred to pediatric endocrinology because of a uterus detected on ultrasonography. The infant was born at 23 gestational weeks by C-section because of preeclampsia and premature membrane rupture. The parents were consanginenous. There was no evidence of virilisation, such as acne, hirsutism, deep voice or clitoral enlargement in the maternal history. Physical examination of the infant revealed complete scrotal fusion and a single urogenital meatus, consistent with Prader stage-3. A standard dose adrenocorticotropic hormone (ACTH) test revealed an inadequate cortisol response and high 17-hydroxy progesterone levels, suggesting simple virilising congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. However, no mutation in the CYP21A2 gene was detected. At age 2.5 years the ACTH test was repeated, after suspension of hydrocortisone treatment for 48 hours, when resulting cortisol and androgen levels were normal. The patient was re-evaluated in terms of 46, XX disorders of sex development (DSD), especially with a suspicion of aromatase deficiency. A novel, homozygous, exon 6 deletion was identified in the CYP19A1 gene. Aromatase deficiency may be confused with CAH in the newborn period. In this case 46, XX DSD aromatase deficiency was present in the absence of a history of maternal virilisation or large and multicystic ovaries.

Aromatase Deficiency due to a Novel Mutation in CYP19A1 Gene

Aromatase deficiency is a rare autosomal recessive genetic disorder with an unknown incidence. Aromatase converts androgens into estrogen in the gonadal and extra-gonadal tissues. Aromatase deficiency causes ambiguous genitalia in the female fetus and maternal virilization (hirsutism, acne, cliteromegaly, deep voice) during pregnancy due to increased concentration of androgens. A 19 months old girl patient was assessed due to presence of ambiguous genitalia. There were findings of maternal virilization during pregnancy. The karyotype was 46,XX. Congenital adrenal hyperplasia was not considered since adrenocorticotropic hormone, cortisol, and 17-hydroxyprogesterone levels were within normal ranges. At age two months, follicle-stimulating hormone and total testosterone levels were elevated and estradiol level was low. Based on these findings, aromatase deficiency was suspected. A novel homozygous mutation IVS7-2A>G (c.744-2A>G) was identified in the CYP19A1 gene. Pelvic ultrasound showed hypoplasic ovaries rather than large and cystic ovaries. We identified a novel mutation in the CYP19A1 gene in a patient who presented with ambiguous genitalia and maternal virilization during pregnancy. Presence of large and cystic ovaries is not essential in aromatase deficiency.