Disorders of sex development: effect of molecular diagnostics

Achermann, John C.; Domenice, Sorahia; Bachega, Tânia A. S. S.; Nishi, Mirian Yumie; Mendonca, Berenice B.

doi:10.1038/nrendo.2015.69

Cited by 90 publications

(87 citation statements)

References 123 publications

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“…The new next-generation sequencing will permit more precocious diagnosis in comparison with classic single gene sequencing [14, 35, 36] and avoid a high rate of missed diagnoses still present in females with 46,XY GD [24]. In addition, the two 46,XX women with homozygous DHH mutation reported in this paper and by Sato e al.…”

Section: Resultsmentioning

confidence: 79%

Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

Baldinotti¹,

Cavallaro²,

Dati³

et al. 2018

Horm Res Paediatr

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Background: In humans, Desert Hedgehog (DHH) gene mutations are a very rare cause of 46,XY gonadal dysgenesis (GD), eventually associated with peripheral neuropathy. Patients and Methods: Clinical records of 12 patients with 46,XY GD and unknown genetic background were reviewed and a 46,XY woman with peripheral neuropathy was individuated. Her 46,XX sister affected by similar neuropathy was also investigated. Genomic DNA was extracted and DHH exons sequenced and analyzed. A comparative genomic hybridization array was also performed. Results: In both the 46,XY and 46,XX sisters, a homozygous c.554C>A mutation in exon 2 of the DHH gene was found, determining a premature termination codon (p.Ser 185*). Heterozygous consanguineous carrier parents showed neither reproductive problems nor peripheral neuropathy. In the proband and her sister, a 499-kb duplication in 9p22.1 was also found. Conclusion: A 46,XY European woman with 46,XY GD and a novel homozygous DHH pathogenic variant is reported, confirming that this gene plays a key role in male gonadal development. Her 46,XX sister, harboring the same mutation, showed normal internal and external female phenotype. Thus, DHH seems not to be involved in the ovarian development pathway or its postpubertal function. Homozygous DHH mutations cause a specific peripheral neuropathy in humans with both 46,XY and 46,XX karyotypes.

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Section: Resultsmentioning

confidence: 79%

Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

Baldinotti¹,

Cavallaro²,

Dati³

et al. 2018

Horm Res Paediatr

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“…If the use of WGS in the clinical front has been so far limited to the diagnosis of severe complex phenotypes 29 , WES is now easily available as a diagnostic test and can be very useful for obtaining a molecular diagnosis in endocrinopathies for which several candidate genes exist, such as disorders of sex development 6,30 . Indeed, implementing MPS in endocrine research has allowed the discovery of new molecular mechanisms in rare and common disorders, such as precocious puberty and obesity, respectively 2,31 .…”

Section: Massive Parallel Sequencingmentioning

confidence: 99%

Diagnóstico molecular na prática clínica: visão do endocrinologista

Ferraz-de-Souza¹

2015

Rev. Med. (São Paulo)

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Endocrinology is one of several medical specialities that have been gradually transformed by a deeper understanding of the molecular bases of disorders. Genetic testing with the purposes of defining a precise molecular diagnosis has increasingly gained space in the routine assessment of patients with endocrinopathies, and the advent of massive parallel sequencing (MPS) is boosting the incorporation of molecular information in the clinic. The main benefit of genetic testing is diagnostic precision, resulting in improved and individualized care for patients and family members, and better disease prevention. However, genetic tests are not infallible and may bear several potential risks, being thus indicated when clinical suspicion is strong and the benefit of determining a molecular diagnosis is unambiguous. In this review, these evolving concepts and current indications for molecular diagnosis in endocrinology will be explored. Molecular tools will be revised and contextualised, including those aimed at identifying changes in gene dosage (karyotpe, FISH, MLPA, aCGH, SNParray) or in the DNA nucleotide sequence (allele-specific PCR, RFLP, Sanger sequencing, MPS or NGS). Finally, matters surrounding the complex attribution of biologically relevant functional impact to identified DNA variants will be explored, together with the challenges brought by high throughput molecular analysis. These are exciting times for molecular endocrinology, and hopefully soon a translation to multiple benefits for patients will be self-evident.Keywords: Genetic testing; Endocrinology; Mutation; DNA mutation analysis; Transcription, genetic; Genetic markers; Sequence analysis, DNA/methdos; Molecular sequence data. RESUMO:A endocrinologia é uma de muitas especialidades médicas que vem sendo transformada pelo maior conhecimento das bases moleculares das doenças. O teste genético com o propósito de definir o diagnóstico molecular vem ganhando espaço na avaliação rotineira de pacientes com endocrinopatias, e o advento do sequenciamento paralelelo em larga escala (SPLE) está ampliando o potencial de incorporação da informação molecular na prática clínica. O principal benefício do teste genético é a precisão diagnóstica, resultando em melhora e individualização do tratamento de pacientes e seus familiares, e da prevenção de doenças. Entretanto, testes genéticos não são infalíveis e podem trazer alguns riscos potenciais, estando portanto indicados quando a suspeita clínica é forte e o benefício do diagnóstico molecular é claro. Nesta revisão serão explorados conceitos genéticos em evolução e as atuais indicações de diagnóstico molecular em endocrinologia. Ferramentas moleculares serão revisadas, incluindo aquelas visando a identificação de alterações no número de cópias gênicas (cariótipo, FISH, MLPA, aCGH, SNParray) ou na sequencia nucleotídica do DNA (PCR alelo-específica, RFLP, sequenciamento Sanger, SPLE ou NGS). Ainda, serão discutidos os percalços da difícil atribuição de impacto funcional e relevância biológica a variantes de DN...

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“…A primeira etapa do desenvolvimento sexual é constituída pelo sexo cromossômico (pela presença do cromossomo X ou do Y) 2 . Este cromossomo influenciará a determinação do sexo gonadal, diferenciando a gônada bipotencial em ovário ou testículo.…”

Section: -Desenvolvimento Sexual Em Humanosunclassified

Aspectos comportamentais e do desenvolvimento psicossexual dos pacientes com distúrbios do desenvolvimento sexual 46,XY na idade adulta

Batista¹

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AgradecimentosA todos os pacientes cujas histórias estão -em parte -contadas aqui.À professora Berenice Bilharinho de Mendonça, pela liberdade para a minha curiosidade. Por me apresentar o universo encantador do desenvolvimento, com o qual eu já me identificava antes mesmo de saber. Por ensinar que, tão importante quanto um diagnóstico, é entender como a pessoa se sente.À Marlene Inácio, pela generosidade em partilhar seus dados, seu conhecimento, sua alegria. Pela leveza. Cada pedaço desta tese é também desenhado por você.À Dra Sorahia Domenice e à Dra Elaine Frade Costa, por todos os ensinamentos, pelo acolhimento, por tantas oportunidades. We found an association between prenatal androgen exposure and major prevalence of male psychosexual outcomes and a higher incidence of female to male gender dysphoria. There was not difference in the psychosexual outcomes according by external genitalia virilization in male and in female individuals. There was an incidence of 19% of gender dysphoria (27 out from 144). In 93% (n=25), the gender change was from female to male (F to M). The ethological diagnosis related with F to M GD were 5α-RD2 deficiency (5ARD2) in 16/32 (50%), followed by 5/15 (33%) in 17β-HSD3 deficiency (17βHSD3). Others diagnosis related with F to M GD were: partial gonadal dysgenesis (n=3/24; 12%) and 3βHSD2 (n=1/3; 33%). Both cases of male to female (M to F) GD occurred in partial gonadal dysgenesis (8%; n=2/24). The median of GD age (desire to belong to another gender) was 8 years old (5-9), and the median of gender change itself was 15 years old (10.5 -20). In F to M GD, gender change was associated with prenatal androgen exposure (p<.001; V=0,461). The psychosexual components showed higher concordance index with final gender (GI -k=0.81; GI -k=0.65 and SO -k=0.85) then with the assigned sex (GI -k=0.1; GI -k=0.25 and SO -k=0.15). Conclusion: Prenatal androgen exposure affects the psychosexual development, favoring more male outcomes. This influence was observed in GI, GR and SO. The degree of external genitalia virilization did not influence the psychosexual development. Female to Male GD is common in 46,XY DSD raised in female social sex, especially in 5ARD2 and 17βHSD3 deficiencies. There is a strong relationship between prenatal androgen exposure and F to M GD. On the other hand, M to F gender change was rare in 46,XY DSD and occurred only in partial gonadal dysgenesis patients.

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Disorders of sex development: effect of molecular diagnostics

Cited by 90 publications

References 123 publications

Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

Diagnóstico molecular na prática clínica: visão do endocrinologista

Aspectos comportamentais e do desenvolvimento psicossexual dos pacientes com distúrbios do desenvolvimento sexual 46,XY na idade adulta

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