Ovarian and uterine development and hormonal feedback mechanism in a 46 XX patient with CYP19A1 deficiency under low dose estrogen replacement

Burckhardt, Marie‐Anne; Obmann, Verena Carola; Wolf, Rainer; Janner, Marco; Flück, Christa E.; Mullis, Primus-Eugen

doi:10.3109/09513590.2014.995619

Cited by 9 publications

(8 citation statements)

References 31 publications

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“…Thirty patients (0.2‐32 years) were included in the review, 8,10‐28 and the specific information is shown in Table 2 and Table S1. Most 46, XX patients were diagnosed in childhood based on virilized external genitalia, and three patients were initially misdiagnosed with CAH because of briefly elevated ACTH or 17α‐OHP levels.…”

Section: Resultsmentioning

confidence: 99%

“…10 Bone density is reported to be increased upon oestrogen administration. 7,17 The 9.2-year-old girl showed mild low TBLH BMD, and she started oestradiol therapy during the investigation. We will closely monitor her BMD during follow-up.…”

Section: Laboratory Investigationmentioning

confidence: 99%

“…Oestrogen therapy led to the normalization of metabolic abnormali- oestrogen. 17 Therefore, the researchers postulated that low doses of 17β-oestradiol (50-100 µg/d) are needed beginning in early childhood. 17,19 This approach appears to conform to the physiological rationale: the normal mid-childhood ovary is not entirely quiescent, as plasma oestradiol levels in healthy prepubertal girls, although they are low, are up to eight times higher than the levels in age-matched boys.…”

Section: Oestrogen Replacement Therapymentioning

confidence: 99%

“…17 Therefore, the researchers postulated that low doses of 17β-oestradiol (50-100 µg/d) are needed beginning in early childhood. 17,19 This approach appears to conform to the physiological rationale: the normal mid-childhood ovary is not entirely quiescent, as plasma oestradiol levels in healthy prepubertal girls, although they are low, are up to eight times higher than the levels in age-matched boys. 32,33 Adverse events, such as delayed bone age, slightly low BMD and ovarian dysplasia, were present in our patients, which provides evidence supporting the administration of a low-dose oestrogen treatment at an early age.…”

Section: Oestrogen Replacement Therapymentioning

confidence: 99%

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

Fan

Zhang

et al. 2020

Clinical Endocrinology

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Laboratory Investigationmentioning

confidence: 99%

Section: Oestrogen Replacement Therapymentioning

confidence: 99%

Section: Oestrogen Replacement Therapymentioning

confidence: 99%

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

Fan

Zhang

et al. 2020

Clinical Endocrinology

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“…Even though in this aromatase-deficient patient serum inhibin B levels were not measured, it is unlikely that the lack of suppression of the serum FSH level might be related to a low level of serum inhibin B. Accordingly, in a recent aromatase-deficient patient, reported by Burckhardt et al [32], the upper normal serum inhibin B levels detected were unable to suppress serum FSH levels under low E 2 dose treatment. In addition, a high dose of estrogen replacement therapy was required to suppress serum FSH.…”

Section: Discussionmentioning

confidence: 99%

An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues

et al. 2015

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Background/Aims: Splicing CYP19 gene variants causing aromatase deficiency in 46,XX disorder of sexual development (DSD) patients have been reported in a few cases. A misbalance between normal and aberrant splicing variants was proposed to explain spontaneous pubertal breast development but an incomplete sex maturation progress. The aim of this study was to functionally characterize a novel CYP19A1 intronic homozygote mutation (IVS9+5G>A) in a 46,XX DSD girl presenting spontaneous breast development and primary amenorrhea, and to evaluate similar splicing variant expression in normal steroidogenic tissues. Methods: Genomic DNA analysis, splicing prediction programs, splicing assays, and in vitro protein expression and enzyme activity analyses were carried out. CYP19A1 mRNA expression in human steroidogenic tissues was also studied. Results: A novel IVS9+5G>A homozygote mutation was found. In silico analysis predicts the disappearance of the splicing donor site in intron 9, confirmed by patient peripheral leukocyte cP450arom and in vitro studies. Protein analysis showed a shorter and inactive protein. The intron 9 transcript variant was also found in human steroidogenic tissues. Conclusions: The mutation IVS9+5G>A generates a splicing variant that includes intron 9 which is also present in normal human steroidogenic tissues, suggesting that a misbalance between normal and aberrant splicing variants might occur in target tissues, explaining the clinical phenotype in the affected patient.

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Human Aromatase Deficiency

Guercio¹,

Saraco²,

Costanzo³

et al. 2019

Encyclopedia of Endocrine Diseases

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Ovarian and uterine development and hormonal feedback mechanism in a 46 XX patient with CYP19A1 deficiency under low dose estrogen replacement

Abstract: Complete aromatase deficiency provides an excellent model of how ovarian and uterine development in relation to E2, LH, FSH and inhibin B feedback progresses from infancy to adolescence.

Cited by 9 publications

References 31 publications

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

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

An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues

Human Aromatase Deficiency

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