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1.
Hum Genet ; 140(4): 667-680, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33469725

RESUMO

PURPOSE: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome consists of congenital absence of the uterus and vagina and is often associated with renal, skeletal, cardiac, and auditory defects. The genetic basis is largely unknown except for rare variants in several genes. Many candidate genes have been suggested by mouse models and human studies. The purpose of this study was to narrow down the number of candidate genes. METHODS: Whole exome sequencing was performed on 111 unrelated individuals with MRKH; variant analysis focused on 72 genes suggested by mouse models, human studies of physiological candidates, or located near translocation breakpoints in t(3;16). Candidate variants (CV) predicted to be deleterious were confirmed by Sanger sequencing. RESULTS: Sanger sequencing verified 54 heterozygous CV from genes identified through mouse (13 CV in 6 genes), human (22 CV in seven genes), and translocation breakpoint (19 CV in 11 genes) studies. Twelve patients had ≥ 2 CVs, including four patients with two variants in the same gene. One likely digenic combination of LAMC1 and MMP14 was identified. CONCLUSION: We narrowed 72 candidate genes to 10 genes that appear more likely implicated. These candidate genes will require further investigation to elucidate their role in the development of MRKH.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Útero/anormalidades , Vagina/anormalidades , Transtornos 46, XX do Desenvolvimento Sexual/patologia , Animais , Anormalidades Congênitas/patologia , Feminino , Variação Genética , Humanos , Masculino , Camundongos , Ductos Paramesonéfricos/patologia , Translocação Genética , Sequenciamento Completo do Exoma
2.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
3.
Adv Clin Exp Med ; 29(4): 505-511, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32348039

RESUMO

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also known as Müllerian agenesis or aplasia, is a congenital disease manifested by the aplasia of the uterus and the upper 2/3 of the vagina; its incidence is 1 in 4,000-5,000 female live births. We can distinguish 2 types of the MRKH syndrome: type I, which is characterized by an isolated absence of 2/3 of the vagina and uterus; and type II or MURCS (Müllerian duct aplasia, unilateral renal agenesis and cervicothoracic somite anomalies), which is also associated with other symptoms. The treatment of the MRKH syndrome patients aims at creating a neovagina and enabling sexual intercourse. Non-surgical techniques are the first-choice methods, and more than 90% of patients notice an anatomical and functional improvement if they are well-prepared emotionally. If non-surgical treatment does not bring about the expected results, a surgical procedure remains an option. The surgical method is mainly determined by the surgeon's experience. There are a few types of operations, though none of them seems superior to others. The next challenge is to provide these patients with a chance to become parents. Nowadays, a uterine transplant, a surrogate or adoption are the available solutions. An interdisciplinary approach is required, and the treatment should consist of medical and psychological support. This review presents the current knowledge about the MRKH syndrome with regard to the current methods of non-surgical and surgical treatment as well as a summary of the associated psychological problems.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual , Anormalidades Congênitas , Ductos Paramesonéfricos/anormalidades , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtornos 46, XX do Desenvolvimento Sexual/cirurgia , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Anormalidades Congênitas/cirurgia , Feminino , Humanos , Ductos Paramesonéfricos/cirurgia , Útero/anormalidades , Vagina/anormalidades
4.
J Clin Res Pediatr Endocrinol ; 12(1): 109-112, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30968679

RESUMO

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.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Aromatase/deficiência , Ginecomastia/genética , Infertilidade Masculina/genética , Erros Inatos do Metabolismo/genética , Transtornos 46, XX do Desenvolvimento Sexual/complicações , Transtornos 46, XX do Desenvolvimento Sexual/etiologia , Adolescente , Aromatase/genética , Criança , Feminino , Ginecomastia/complicações , Humanos , Infertilidade Masculina/complicações , Masculino , Erros Inatos do Metabolismo/complicações , Irmãos
5.
Biomedica ; 39(4): 622-630, 2019 12 01.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31860174

RESUMO

In most cases, male sexual differentiation occurs with SRY gene mediation. However, exceptional genotypes have been identified, as shown in this paper. This was a male adult patient seen at the Servicio de Paternidades, Instituto de Genética, Universidad Nacional de Colombia. The following procedures were carried out: Amelogenin gene and short tandem repeat analyses using human identification commercial kits, conventional karyotype, SRY fluorescent in situ hybridization, PCR analysis for Y chromosome microdeletions, clinical evaluation, and genetic counseling. We present an adult male with unambiguous genitalia, karyotype 46,XX, and an SRY negative and ZFY positive molecular profile. The diagnosis of nonsyndromic 46,XX testicular disorder of sex development (DSD) -a rare genetic condition- was established. Only 20 % of similarly diagnosed patients are SRY negative and exhibit diverse molecular profiles. Until now, available evidence seems to indicate that, even in the absence of SRY, the ZFY factor is involved in male sexual differentiation.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/genética , Genes sry , Genitália Masculina/anatomia & histologia , Adulto , Amelogenina/análise , Deleção Cromossômica , Cromossomos Humanos Y/genética , Eletroforese Capilar , Genótipo , Humanos , Hibridização in Situ Fluorescente , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/genética , Cariotipagem , Fatores de Transcrição Kruppel-Like/análise , Fatores de Transcrição Kruppel-Like/genética , Masculino , Repetições de Microssatélites , Técnicas de Amplificação de Ácido Nucleico , Linhagem , Reação em Cadeia da Polimerase/métodos , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética
6.
Ceska Gynekol ; 84(5): 386-392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31826637

RESUMO

OBJECTIVE: Evaluation of existing knowledge of etiopathogenesis, clinical manifestations and treatment options to increase quality of life in women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH). DESIGN: Review article. SETTING: Department of Obstetrics and Gynaecology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague. METHODS: Literature search using the Web of Science, Google Scholar and Medline databases with keywords (absolute uterine infertility factor, AUFI, Mayer-Rokitansky-Küster-Hauser syndrome, MRKH, uterine transplantation) and analysis of articles published in impact and reviewed journals. RESULTS: MRKH syndrome is defined as congenital agenesis of the upper two-thirds of vagina and uterus in women with normal secondary sexual characteristics and female karyotype (46, XX). The incidence of the syndrome is 1 : 4500 births of female sex children. It is the second most common cause of primary amenorrhea. Recent research has focused on elucidating the genetic origin of the disease, focusing on the research of candidate genes that could be participating in the genesis of Müllerian ducts and their derivatives. CONCLUSION: MRKH syndrome now appears as a multifactorial congenital developmental defect based on a combination of genetic predisposition and environmental factors. Modern medicine can help girls with MRKH syndrome to a quality sexual life. It is also able to offer different possibilities of achieving motherhood. In the future, however, further research is needed, in particular on the etiology and pathogenesis of this syndrome to detect a possible genetic basis of the disease.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual , Anormalidades Congênitas/genética , Vagina/anormalidades , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/genética , Criança , Feminino , Humanos , Qualidade de Vida , Útero
7.
JNMA J Nepal Med Assoc ; 57(216): 119-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31477946

RESUMO

Gonadal dysgenesis is a rare genetically heterogeneous disorder characterized by underdeveloped ovaries with consequent, impuberism, primary amenorrhea, and hypergonadotropic hypogonadism. Mullerian agenesis or Mayer­Rokitansky­Kuster­Hauser syndrome is characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in a woman with normal development of secondary sexual characteristics and a normal 46 XX karyotype. The association of gonadal dysgenesis and Mayer-Rokitansky-Kuster-Hauser syndrome is very rare and appears to be coincidental. We report a case of a 24-years old woman who presented with primary amenorrhea. The endocrine study revealed hypergonadotrophic hypogonadism. The karyotype was normal, 46,XX. Internal genitalia could not be identified on the pelvic ultrasound and pelvic MRI. There were no other morphological malformations. Keywords: Gonadal dysgenesis; Mayer Rokitansky Kuster Hauser syndrome; Mullerian agenesis; primary amenorrhea; 46,XX.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Amenorreia/etiologia , Anormalidades Congênitas/diagnóstico , Disgenesia Gonadal 46 XX/diagnóstico , Ductos Paramesonéfricos/anormalidades , Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Feminino , Disgenesia Gonadal 46 XX/genética , Humanos , Cariótipo , Útero/anormalidades , Vagina/anormalidades , Adulto Jovem
8.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533357

RESUMO

The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for some conditions of 46,XX DSD where hyperandrogenism interferes with chromosomal and gonadal sex development. Congenital adrenal hyperplasias (CAHs) are disorders of steroidogenesis that mainly involve the adrenals (21-hydroxylase and 11-hydroxylase deficiencies) and sometimes the gonads (3-beta-hydroxysteroidodehydrogenase and P450-oxidoreductase); in contrast, aromatase deficiency mainly involves the steroidogenetic activity of the gonads. This review describes the main genetic, biochemical, and clinical features that apply to the abovementioned conditions. The activities of the steroidogenetic enzymes are modulated by post-translational modifications and cofactors, particularly electron-donating redox partners. The incidences of the rare forms of CAH vary with ethnicity and geography. The elucidation of the precise roles of these enzymes and cofactors has been significantly facilitated by the identification of the genetic bases of rare disorders of steroidogenesis. Understanding steroidogenesis is important to our comprehension of differences in sexual development and other processes that are related to human reproduction and fertility, particularly those that involve androgen excess as consequence of their impairment.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtornos 46, XX do Desenvolvimento Sexual/metabolismo , Androgênios/metabolismo , Estudos de Associação Genética , Predisposição Genética para Doença , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Alelos , Biomarcadores , Regulação Enzimológica da Expressão Gênica , Testes Genéticos , Humanos , Padrões de Herança , Redes e Vias Metabólicas , Fenótipo , Esteroides/metabolismo
9.
BMJ Case Rep ; 12(8)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466990

RESUMO

Goldenhar syndrome, also known as oculo-auriculo-vertebral syndrome, has been described since 1952. Traditionally, the syndrome has been described as having eye, ear, facial and vertebral anomalies. However, numerous case reports and reviews have highlighted multi-organ involvement, including cardiovascular, gastrointestinal, respiratory system and urinary abnormalities. We describe a 13 years old who has a reproductive tract abnormality, which has not been reported previously as a finding of Goldenhar syndrome.


Assuntos
Amenorreia/etiologia , Síndrome de Goldenhar/diagnóstico , Anormalidades Urogenitais/complicações , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/genética , Adolescente , Amenorreia/diagnóstico , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Diagnóstico Diferencial , Feminino , Síndrome de Goldenhar/genética , Síndrome de Goldenhar/patologia , Humanos , Cariótipo , Ductos Paramesonéfricos/anormalidades , Equipe de Assistência ao Paciente , Ultrassonografia/métodos , Anormalidades Urogenitais/diagnóstico por imagem
10.
Hum Reprod ; 34(9): 1838-1846, 2019 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-31424080

RESUMO

The aetiology of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members leading to the identification of a novel pathogenic (CADD = 33) c.705G>T missense variant in GREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which support GREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/complicações , Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Rim Único/complicações , Rim Único/genética , Sequenciamento Completo do Exoma/métodos , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Adulto , Idoso , Anormalidades Congênitas/diagnóstico , Família , Feminino , Humanos , Recém-Nascido , Masculino , Linhagem , Rim Único/diagnóstico , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/genética , Útero/anormalidades , Vagina/anormalidades
11.
Hum Reprod ; 34(6): 1117-1125, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31111890

RESUMO

STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives? SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism. WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences. STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant. PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data. MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse. LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Quimerismo , Anormalidades Congênitas/genética , Genes Ligados ao Cromossomo Y/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Transtornos 46, XX do Desenvolvimento Sexual/sangue , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Adulto , Biomarcadores/análise , Estudos de Casos e Controles , Anormalidades Congênitas/sangue , Anormalidades Congênitas/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
12.
Hum Mol Genet ; 28(14): 2319-2329, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30985895

RESUMO

Disorders of sex development (DSDs) are defined as congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. In many DSD cases, genetic causes remain to be elucidated. Here, we performed a case-control exome sequencing study comparing gene-based burdens of rare damaging variants between 26 DSD cases and 2625 controls. We found exome-wide significant enrichment of rare heterozygous truncating variants in the MYRF gene encoding myelin regulatory factor, a transcription factor essential for oligodendrocyte development. All three variants occurred de novo. We identified an additional 46,XY DSD case of a de novo damaging missense variant in an independent cohort. The clinical symptoms included hypoplasia of Müllerian derivatives and ovaries in 46,XX DSD patients, defective development of Sertoli and Leydig cells in 46,XY DSD patients and congenital diaphragmatic hernia in one 46,XY DSD patient. As all of these cells and tissues are or partly consist of coelomic epithelium (CE)-derived cells (CEDC) and CEDC developed from CE via proliferaiton and migration, MYRF might be related to these processes. Consistent with this hypothesis, single-cell RNA sequencing of foetal gonads revealed high expression of MYRF in CE and CEDC. Reanalysis of public chromatin immunoprecipitation sequencing data for rat Myrf showed that genes regulating proliferation and migration were enriched among putative target genes of Myrf. These results suggested that MYRF is a novel causative gene of 46,XY and 46,XX DSD and MYRF is a transcription factor regulating CD and/or CEDC proliferation and migration, which is essential for development of multiple organs.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Proteínas de Membrana/genética , Fatores de Transcrição/genética , Transtornos 46, XX do Desenvolvimento Sexual/patologia , Adolescente , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Pré-Escolar , Estudos de Coortes , Biologia Computacional , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Feminino , Ontologia Genética , Gônadas/crescimento & desenvolvimento , Haploinsuficiência , Humanos , Masculino , Proteínas de Membrana/metabolismo , Mutação , Mutação de Sentido Incorreto , Análise de Célula Única , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem
13.
J Obstet Gynaecol Res ; 45(7): 1386-1390, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30912224

RESUMO

Coexistence of Mayer-Rokitansky-Küster-Hauser syndrome and gonadal dysgenesis is extremely rare, and a case of Mayer-Rokitansky-Küster-Hauser syndrome with a uterine cervix and normal vagina has not been reported. Here, we report such a case associated with gonadal dysgenesis. A 17-year-old female presented with primary amenorrhea and undeveloped secondary sexual characteristics. Genital examination revealed a uterine cervix and normal vagina without a uterine body and ovaries. An endocrine study showed hypergonadotrophic hypogonadism. The karyotype was 46,XX. Laparoscopy revealed a rudimentary uterus, normal fallopian tubes and bilateral streak ovaries. There were no other associated malformations. Hormonal substitution therapy was started for development of secondary sexual characteristics and prevention of osteoporosis, but the problem of infertility is unresolved.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/patologia , Anormalidades Congênitas/patologia , Disgenesia Gonadal 46 XX/patologia , Ductos Paramesonéfricos/anormalidades , Transtornos 46, XX do Desenvolvimento Sexual/genética , Adolescente , Colo do Útero/patologia , Anormalidades Congênitas/genética , Feminino , Disgenesia Gonadal 46 XX/genética , Humanos , Ductos Paramesonéfricos/patologia , Vagina/patologia
14.
Sex Dev ; 13(2): 60-66, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30739115

RESUMO

SRY-negative 46,XX testicular disorders of sex development (DSD) are very rare conditions. Recently, we identified a novel heterozygous NR5A1 mutation, p.Arg92Trp (c.274C>T, p.R92W), in 2 unrelated cases of 46,XX testicular/ovotesticular DSD. We report the clinical course from infancy to puberty in a Japanese male with SRY-negative 46,XX testicular DSD, carrying this p.Arg92Trp mutation in NR5A1. The patient naturally acquired the development of a penis and pubic hair during puberty. However, hypergonadotropic hypogonadism subsequently developed. More clinical cases will be needed to fully understand the effects of the p.Arg92Trp mutation on the ability to maintain testosterone secretion in 46,XX testicular DSD.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Mutação/genética , Puberdade/genética , Proteína da Região Y Determinante do Sexo/metabolismo , Fator Esteroidogênico 1/genética , Testículo/crescimento & desenvolvimento , Testículo/patologia , Transtornos 46, XX do Desenvolvimento Sexual/sangue , Adolescente , Criança , Pré-Escolar , Seguimentos , Heterozigoto , Humanos , Lactente , Masculino , Testosterona/sangue
15.
Sex Dev ; 13(1): 35-40, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30739119

RESUMO

Müllerian anomalies comprise the Mayer-Rokitansky-Küster-Hauser syndrome as well as fusion defects of the müllerian ducts. Recurrent micro-aberrations like deletions in 16p11.2 encompassing TBX6 were found to be causative in these patients. TBX6 encodes a transcription factor which plays a role in paraxial mesoderm differentiation/specification. In previous studies, we and other groups found possibly pathogenic variants in TBX6 in patients with müllerian anomalies. Since we suggested TBX6 as a strong candidate, we performed sequential analysis of the TBX6 gene in additional 125 patients with müllerian anomalies, and 2 possibly pathogenic missense variants and 1 nonsense substitution in TBX6 in 4/125 patients were found. The missense variant c.484G>A, which we have described in a previous study, was reidentified but with no higher frequency as in our controls. We detected 3 possibly pathogenic variants in TBX6 and could show that the variant c.484G>A is not causative for disorders of the müllerian ducts in the non-Finnish European population. In summary, we present increasing evidence for association of variants in TBX6 with malformations of the müllerian ducts.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Predisposição Genética para Doença , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/patologia , Mutação/genética , Proteínas com Domínio T/genética , Sequência de Bases , Estudos de Casos e Controles , Feminino , Humanos
16.
Andrologia ; 51(4): e13232, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30623467

RESUMO

To explore the clinical features and assisted reproductive technology (ART) outcomes of 46,XX disorders of sex development (DSD) males, 144 males with 46,XX DSD were recruited in this retrospective study. The baseline information, clinical characteristics and ART outcomes of the participants were collected and analysed. The mean age was 29.06 ± 4.50 years. The mean volumes (95% CI) of left and right testicles were 2.16 (1.82-2.49) ml and 2.16 (1.83-2.49) ml, respectively. Cryptorchidism and/or hypospadias appeared in 19 patients (13.19%). Elevated levels of follicle-stimulating hormone (FSH) were found in 136 patients (95.10%) and increased luteinising hormone (LH) values were detected in 125 patients (92.59%). Eighty subjects (62.99%) had low testosterone values. Among 86 patients with status of sex-determining region Y (SRY)-gene and azoospermia factor (AZF) region available, fifteen (17.44%) patients were SRY-negative and AZF region was absent in every patient without exception. Additionally, fertility achieved in 87 patients through ART using donor spermatozoa. In conclusion, hypergonadotropic hypogonadism appeared as the main presentation of 46,XX DSD males regardless of the SRY status. The available fertility option proved to achieve live birth was limited to ART using donor spermatozoa.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Cromossomos Humanos Y/genética , Hipogonadismo/genética , Técnicas de Reprodução Assistida , Proteína da Região Y Determinante do Sexo/genética , Transtornos 46, XX do Desenvolvimento Sexual/sangue , Transtornos 46, XX do Desenvolvimento Sexual/terapia , Adulto , Hormônio Foliculoestimulante/sangue , Testes Genéticos , Humanos , Hipogonadismo/sangue , Hipogonadismo/terapia , Cariotipagem , Hormônio Luteinizante/sangue , Masculino , Estudos Retrospectivos , Testosterona/sangue , Resultado do Tratamento
17.
Rom J Morphol Embryol ; 60(4): 1311-1316, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32239110

RESUMO

Prenatal diagnosis of disorder of sex development (DSD) is very rare and is estimated to occur in 1∕2500 pregnancies. A group of DSDs are the 46,XX testicular DSD. Today, the incidence of 46,XX testicular DSD is estimated at 1∕20 000 newborn males. A majority of males with DSD have an unbalanced X;Y exchange involving the pseudoautosomal region, with translocation of the sex-determining region of the Y (SRY) gene onto Xp23.3. We present a rare case of very early prenatal diagnosis and management of a fetus with SRY-positive 46,XX testicular DSD.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Genes sry , Processos de Determinação Sexual/genética , Adulto , Feminino , Feto/diagnóstico por imagem , Marcadores Genéticos , Humanos , Cariótipo , Masculino
18.
Clin Genet ; 95(1): 172-176, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30294972

RESUMO

Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Patologia Molecular , Doenças Testiculares/diagnóstico , Proteínas WT1/genética , Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtornos 46, XX do Desenvolvimento Sexual/patologia , Criança , Proteínas de Ligação a DNA/genética , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Mutação , Fenótipo , Desenvolvimento Sexual/genética , Doenças Testiculares/genética , Doenças Testiculares/patologia , Testículo/patologia
19.
J Pediatr Endocrinol Metab ; 32(1): 85-88, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30530883

RESUMO

Background Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder caused by CYP19A1 overexpression. Clinical manifestations of AEXS include pre- or peri-pubertal gynecomastia, advanced bone age and compromised adult height. Case presentation Here we report an 8-year-old boy diagnosed with AEXS by chromosomal array that revealed a 1.1 Mb novel de novo duplication at 15q21.2, with a predicted final height of 157.4 cm. We prescribed letrozole and growth hormone (GH) to maximize his linear growth. Without further bone age advancement, his height increased from 137.7 cm to 144 cm after an 8-month treatment period. Conclusions We identified a novel duplication at 15q21.2 in AEXS, and found that aromatase inhibitor (AI) plus GH might provide a better growth-promoting approach for AEXS patients.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtornos 46, XX do Desenvolvimento Sexual/patologia , Aromatase/genética , Cromossomos Humanos Par 15/genética , Duplicação Gênica , Ginecomastia/genética , Ginecomastia/patologia , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/patologia , Transtornos 46, XX do Desenvolvimento Sexual/tratamento farmacológico , Aromatase/química , Inibidores da Aromatase/uso terapêutico , Criança , Ginecomastia/tratamento farmacológico , Humanos , Infertilidade Masculina/tratamento farmacológico , Masculino , Erros Inatos do Metabolismo/tratamento farmacológico , Prognóstico
20.
Sex Dev ; 13(1): 26-34, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30504698

RESUMO

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a disorder of sex development which affects 1 in 4,500 females and is characterized by agenesis of müllerian structures, including the uterus, cervix, and upper vagina. It can occur in isolation (type 1) or in conjunction with various anomalies (type 2), with a subset of these comprising müllerian, renal, and cervicothoracic abnormalities (MURCS) association. The genetic causes of MRKH have been investigated previously yielding limited results, with massive parallel sequencing becoming increasingly utilized. We sought to identify genetic contributions to MRKH using a combination of microarray and whole exome sequencing (WES) on a cohort of 8 unrelated women with MRKH and MURCS. WES data were analysed using a candidate gene approach to identify potential contributing variants. Microarray analysis identified a 0.6-Mb deletion in the previously implicated 16p11.2 region in a patient with MRKH type 2. WES revealed 16 rare nonsynonymous variants in MRKH candidate genes across the cohort. These included variants in several genes, such as LRP10 and DOCK4, associated with disorders with müllerian anomalies. Further functional studies of these variants will help to delineate their biological significance and expand the genotypic spectrum of MRKH.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Estudos de Associação Genética , Genômica/métodos , Ductos Paramesonéfricos/anormalidades , Adulto , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Exoma , Adulto Jovem
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