‘Idiopathic’ partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?

Gaspari, Laura; Paris, Florentin; Philibert, Pascal; Audran, Françoise; Orsini, Mattéa; Servant, Nadège; Maı̈moun, Laurent; Kalfa, Nicolas; Sultan, Charles

doi:10.1530/eje-11-0580

Cited by 34 publications

(22 citation statements)

References 66 publications

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“…Thus, despite the presumptive diagnosis of AIS, while 22% of all and 15% of index patients carried AR mutations, 12% of all and 11% of index patients carried SRD5A2 mutations. Concurring with our data, Gaspari et al (2011) found four cases with SRD5A2 mutations in their cohort of newborns presenting with ambiguous genitalia and normal plasma T values and an initial diagnosis of PAIS. It may be concluded that a 5a-reductase defect should be considered in all XY newborns with ambiguous genitalia and normal plasma T secretion.…”

Section: Discussionsupporting

confidence: 87%

AR and SRD5A2 gene mutations in a series of 51 Turkish 46,XY DSD children with a clinical diagnosis of androgen insensitivity

et al. 2014

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SUMMARY46,XY disorders of sex development (DSD) are caused by disorders of gonadal development, androgen biosynthesis and receptor (AR) defects. Although, clinical/biochemical features help in distinguishing specific aetiologies, there are overlaps which necessitate molecular analyses for the definitive diagnosis. To test precision of our clinical diagnosis of androgen insensitivity (AIS) by analysing AR and then SRD5A2 genes, patients were recruited at Marmara University Hospital and molecular analyses were performed at Vall d'Hebron Research Institute. Among 101 46,XY DSD patients, 46 index and five siblings (nine complete, 42 partial) with clinical/biochemical data suggestive of AIS and stimulated T/DHT ratio <25 were selected. AR and then SRD5A2 genes were sequenced. We detected AR mutations in 11 patients [seven index and four siblings (22% of all and 15% of index patients)] and SRD5A2 mutations in six [five index and one sibling (12% of all and 11% of index)]. AR mutation detection rate was 6/9 in all CAIS and 4/7 in the index (67 and 57% respectively) and 5/42 in all PAIS and 3/40 in the index (12 and 7.5% respectively).

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Section: Discussionsupporting

confidence: 87%

AR and SRD5A2 gene mutations in a series of 51 Turkish 46,XY DSD children with a clinical diagnosis of androgen insensitivity

et al. 2014

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“…Specifically, the higher occurrence of hypospadias and cryptorchidism may result from alterations of the function of fetal Leydig cells. Indeed, Leydig cells produce testosterone that is responsible for the masculinization of the male urogenital system and external genitalia (26,(34)(35)(36)(37). An important finding in relation to the TDS hypothesis is that androgens must act before the phenotypic masculinization (38,39).…”

Section: Fetal Testis Is a Major Target Of Endocrine Disruptorsmentioning

confidence: 99%

A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound

Eladak

Grisin

Moison

et al. 2015

Fertility and Sterility

580

278

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Bisphenol A (BPA) is a widely studied typical endocrine-disrupting chemical, and one of the major new issues is the safe replacement of this commonly used compound. Bisphenol S (BPS) and bisphenol F (BPF) are already or are planned to be used as BPA alternatives. With the use of a culture system that we developed (fetal testis assay [FeTA]), we previously showed that 10 nmol/L BPA reduces basal testosterone secretion of human fetal testis explants and that the susceptibility to BPA is at least 100-fold lower in rat and mouse fetal testes. Here, we show that addition of LH in the FeTA system considerably enhances BPA minimum effective concentration in mouse and human but not in rat fetal testes. Then, using the FeTA system without LH (the experimental conditions in which mouse and human fetal testes are most sensitive to BPA), we found that, as for BPA, 10 nmol/L BPS or BPF is sufficient to decrease basal testosterone secretion by human fetal testes with often nonmonotonic dose-response curves. In fetal mouse testes, the dose-response curves were mostly monotonic and the minimum effective concentrations were 1,000 nmol/L for BPA and BPF and 100 nmol/L for BPS. Finally, 10,000 nmol/L BPA, BPS, or BPF reduced Insl3 expression in cultured mouse fetal testes. This is the first report describing BPS and BPF adverse effects on a physiologic function in humans and rodents.

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“…So far, MAMLD1 mutations have only been described in patients with hypospadias, a less severe phenotype of 46,XY DSD. Most patients display normal testosterone production after birth [Gaspari et al, 2011], and it is hypothesized that MAMLD1 has only a transient effect on Leydig cell function and testosterone synthesis during embryonic development. So far, MAMLD1 mutations have been identified in 11 out of 250 cases with hypospadias (4.4%), and 5 of them have been functionally characterized: 3 nonsense mutations in exon 3 (p.E197X, p.Q270X, and p.S143X) have shown a complete loss of transactivation function, 1 missense mutation (p.P384L in exon 3) has shown a significant reduction in transactivation function, and 1 nonsense mutation (p. R726X in exon 5) retains normal transactivating activity but seems to exert a deleterious effect through early degradation by nonsense-mediated mRNA decay.…”

Section: Discussionmentioning

confidence: 99%

A Novel Hemizygous Mutation of <b><i>MAMLD1</i></b> in a Patient with 46,XY Complete Gonadal Dysgenesis

Ruiz-Arana¹,

Hübner²,

Cetingdag³

et al. 2015

Sex Dev

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MAMLD1 is suggested to play a role in the development of 46,XY disorders of sexual development (46,XY DSD). So far, mutations in this gene have been detected in several cases of hypospadias with normal testosterone levels at birth. From in vitro studies it was concluded that Mamld1 might transiently affect testosterone synthesis during genital development. We describe the first MAMLD1 mutation in a 46,XY patient with complete gonadal dysgenesis. The novel MAMLD1 missense mutation (p.P677L) results in a severely reduced transactivation in vitro of the promoter of the MAMLD1 target gene HES3/Hes3. However, as knowledge about the functional role of MAMLD1 in gonadal development is limited, we suggest that additional factors (digenic or oligogenic cause) play a role in the development of complete gonadal dysgenesis in this patient.

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‘Idiopathic’ partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?

Cited by 34 publications

References 66 publications

AR and SRD5A2 gene mutations in a series of 51 Turkish 46,XY DSD children with a clinical diagnosis of androgen insensitivity

AR and SRD5A2 gene mutations in a series of 51 Turkish 46,XY DSD children with a clinical diagnosis of androgen insensitivity

A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound

A Novel Hemizygous Mutation of <b><i>MAMLD1</i></b> in a Patient with 46,XY Complete Gonadal Dysgenesis

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