RESUMO
Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans-activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Müllerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute.
Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/genética , Estudos de Associação Genética , Variação Genética , Fenótipo , Fator Esteroidogênico 1/genética , Alelos , Sequência de Aminoácidos , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Transtorno 46,XY do Desenvolvimento Sexual/genética , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Modelos Anatômicos , Mutação , Conformação Proteica , Domínios Proteicos/genética , Sítios de Splice de RNA , Análise de Sequência de DNA , Fator Esteroidogênico 1/químicaRESUMO
There is increasing interest in fertility and use of assisted reproductive technologies for women with Turner syndrome (TS). Current parenting options include adoption, surrogacy, and spontaneous and assisted reproduction. For women with TS, specific risks of pregnancy include higher than usual rates of spontaneous abortion, foetal anomaly, maternal morbidity and mortality. Heterologous fertility assistance using oocytes from related or unrelated donors is an established technique for women with TS. Homologous fertility preservation includes cryopreservation of the patient's own gametes prior to the progressive ovarian atresia known to occur: preserving either mature oocytes or ovarian tissue containing primordial follicles. Mature oocyte cryopreservation requires ovarian stimulation and can be performed only in postpubertal individuals, when few women with TS have viable oocytes. Ovarian tissue cryopreservation, however, can be performed in younger girls prior to ovarian atresia - over 30 pregnancies have resulted using this technique, however, none in women with TS. We recommend consideration of homologous fertility preservation techniques in children only within specialized centres, with informed consent using protocols approved by a research or clinical ethics board. It is essential that further research is performed to improve maternal and foetal outcomes for women with TS.
Assuntos
Fertilidade/fisiologia , Síndrome de Turner/fisiopatologia , Animais , Criopreservação , Feminino , Humanos , Oócitos/citologia , Folículo Ovariano/citologiaRESUMO
OBJECTIVE: To describe the experience of hormone treatment of gender identity disorder (GID) in children and adolescents within a specialist clinic. DESIGN, PATIENTS AND SETTING: Cohort study by medical record review of children aged 0-17 years referred during 2003-2011 for management at the GID clinic in a tertiary paediatric referral centre - the Royal Children's Hospital, Melbourne, Victoria. MAIN OUTCOME MEASURES: Clinical characteristics of the patient population, hormone treatment provided, frequency of referrals with time. RESULTS: Thirty-nine children and adolescents were referred for gender dysphoria. Seventeen individuals were pubertal with persistent GID, and were considered eligible for hormone treatment. Seven patients, comprising three biological males and four biological females, had legally endorsed hormone treatment. In this group, gender dysphoria was first noted at 3-6 years of age. Hormone treatment with GnRH analogue to suppress pubertal progression (phase 1) was given at 10-16 years of age. Treatment with cross-sex hormones (phase 2) was given at 15.6-16 years. One patient purchased cross-sex hormone treatment overseas. One patient received oestrogen and progesterone for menstrual suppression before phase 1. The annual frequency of new referrals increased continuously over the study period. CONCLUSIONS: Hormone treatment for pubertal suppression and subsequent gender transition needs to be individualised within stringent protocols in multidisciplinary specialist units.
Assuntos
Androgênios/uso terapêutico , Estrogênios/uso terapêutico , Hormônio Liberador de Gonadotropina/uso terapêutico , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Testosterona/uso terapêutico , Transexualidade/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Puberdade , Estudos Retrospectivos , Transexualidade/diagnóstico , Transexualidade/psicologia , Resultado do TratamentoRESUMO
Intense controversy surrounds the management of disorders of sex development, particularly in relation to the validity of parental consent for genital surgery and the removal of gonadal tissue carried out during infancy or childhood. Past practices have been heavily criticised on ethical grounds by patient advocacy organisations, who have demanded a moratorium on these kinds of operations unless authorised by a court. Some doctors and hospital administrators have been influenced by the controversy and have referred cases to the Family Court of Australia, where a series of judgements have now established legal precedents that apply across Australia, restricting the circumstances in which parents can give consent for surgery. An alternative approach is to use a hospital-based Clinical Ethics Response Group and, if necessary, Clinical Ethics Committee, which has lay and legal representatives as well as health professionals, as a semi-independent committee of review. Finding a solution that protects the human rights and best interests of children is an ongoing challenge.
Assuntos
Transtornos do Desenvolvimento Sexual/cirurgia , Direitos Humanos/legislação & jurisprudência , Consentimento dos Pais/ética , Consentimento dos Pais/legislação & jurisprudência , Procedimentos Cirúrgicos Urogenitais/ética , Fatores Etários , Austrália , Identidade de Gênero , Humanos , Lactente , Defesa do Paciente/ética , Defesa do Paciente/legislação & jurisprudênciaRESUMO
Disorders of sex development, congenital conditions in which chromosomal, gonadal or anatomic sex is atypical at birth, require urgent assessment by a multidisciplinary team, to define whether there is a life threatening disorder of congenital adrenal hyperplasia or a healthy child with a complex condition. Uncertainty, stigma and taboo complicate counselling which must be knowledgeable, comprehensive and sensitive to different circumstances, religions and cultures. This articles will discuss clinical and genetic diagnosis, decisions regarding sex of rearing, ethical dilemmas, medical management of the infant and of the child or adolescent presenting for the first time with a DSD. Surgical options, timing and management are outlined.
Assuntos
Transtornos do Desenvolvimento Sexual/terapia , Adolescente , Hiperplasia Suprarrenal Congênita/terapia , Aconselhamento , Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Puberdade , Desenvolvimento SexualAssuntos
Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/metabolismo , Cerebelo/irrigação sanguínea , Policitemia/complicações , Acidente Vascular Cerebral/etiologia , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/enzimologia , Biomarcadores/metabolismo , Cerebelo/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Hiperandrogenismo/diagnóstico , Cariotipagem , Masculino , Pessoa de Meia-Idade , Policitemia/sangue , Policitemia/etiologia , Fatores de Risco , Esteroide 21-Hidroxilase/urina , Acidente Vascular Cerebral/diagnóstico por imagem , Testosterona/sangue , Tomografia Computadorizada por Raios XRESUMO
We have characterized an unusual family with two different androgen receptor (AR) gene deletions, in which we propose a novel mechanism of deletion formation has occurred. Affected individuals have the X-linked disorder androgen insensitivity syndrome, and we previously showed that different family members have deletions of different exons of the AR gene. We have now fully sequenced the deletions from affected individuals, and confirmed the presence of different deletions in different affected family members. Most affected and heterozygote individuals have a 4,430-bp deletion of exon 5 that occurred between repeated GTGGCAT motifs in introns 4 and 5. One affected hemizygous individual has a 4,033-bp deletion of exons 6 and 7 that occurred between repeated CCTC motifs in introns 5 and 7. The intron 5 breakpoint junctions of the two deletions are only 11 bp apart. Surprisingly, the maternal grandmother of the original index case was found to be mosaic for both deletional events, as well as having the normal AR gene. Karyotyping ruled out 47,XXX trisomy, indicating triple mosaicism for the two different deleted AR alleles and a normal AR allele. This triple mosaicism must have occurred early in embryonic development, as both deletions were passed on to different children. Based on these findings, we propose a novel mechanism of deletion formation. We suggest that during AR gene replication, a double strand DNA break occurred in intron 5, and that a variant of replication slippage occurred on both newly synthesized strands between the repeat motifs of microhomology, leading to the formation of the two different AR gene deletions.
Assuntos
Reparo do DNA , Replicação do DNA/fisiologia , Deleção de Genes , Receptores Androgênicos/genética , Síndrome de Resistência a Andrógenos/genética , Cromossomos Humanos X , Análise Mutacional de DNA , Éxons , Feminino , Ligação Genética , Heterozigoto , Humanos , Cariotipagem , Masculino , Dados de Sequência Molecular , Mosaicismo , LinhagemRESUMO
Hormonal therapy forms part of the treatment of every intersex condition. For some conditions, such as salt-wasting congenital adrenal hyperplasia, hormonal replacement therapy is life saving because hormones necessary for survival (cortisol and aldosterone) are replaced. In contrast, other hormones such as androgens or mineralocorticoids are secreted in excessive amounts in congenital adrenal hyperplasia due to an enzyme imbalance, and the role of hormonal therapy is to suppress the unwanted hormone excess by exerting negative feedback. For patients with one of the many causes of hypogonadism, sex hormone replacement therapy may be prescribed to stimulate sexual development: growth of a hypoplastic penis in a young boy, pubertal changes (male or female), psychosexual development, and adult sexual behavior. It has equally important and highly beneficial effects on bone mineral density. Hormonal therapy is also used to treat the unborn child. For the last 20 years, prenatal dexamethasone treatment administered to the pregnant woman has been used to prevent the development of ambiguous genitalia in females with 21-hydroxylase deficiency. Outcome studies show this treatment to be well tolerated and, in general, efficacious. Intersex conditions are, however, difficult to treat because they may intrinsically perturb complex aspects of the person's gender identity, gender-role behavior, sexual orientation, sexual functioning, and psychologic adjustment. Furthermore, decisions made about the sex of an infant by doctors and parents do not always turn out to be correct; the person may grow up feeling uncertain about his or her gender identity, or worse still, harbor a sense of outrage about their life and treatment experiences. Such a person will have definite views about hormonal therapy when the time comes and skillful counseling will be needed. A vigorous debate about ethical aspects of current medical practices relating to intersex conditions has been waged for the last 7 years between certain patient advocacy organizations and the medical profession, and is expected to continue for some time. The quality of the debate will be improved by evidence. The results of a number of long-term follow-up studies have been published, and more are expected. The published studies show mixed, but mainly encouraging, results.
Assuntos
Transtornos do Desenvolvimento Sexual/tratamento farmacológico , Hormônios/uso terapêutico , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Di-Hidrotestosterona/uso terapêutico , Transtornos do Desenvolvimento Sexual/classificação , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/prevenção & controle , Estrogênios/uso terapêutico , Feminino , Genitália , Glucocorticoides/uso terapêutico , Humanos , Masculino , Mineralocorticoides/uso terapêutico , Cuidado Pré-Natal , Progestinas/uso terapêutico , Testosterona/uso terapêuticoRESUMO
OBJECTIVES: To investigate androgen receptor (AR) function in spinal and bulbar muscular atrophy (SBMA). METHODS: A kindred was identified with five individuals carrying the AR gene CAG repeat expansion that causes SBMA. Androgen binding was measured in cultured genital skin fibroblasts from three affected individuals. One newborn, pre-symptomatic, individual showed normal androgen binding, but two older, symptomatic individuals showed a decrease in androgen binding affinity. This difference was not related to AR CAG repeat size, as all affected individuals in this kindred had 49 repeats (normal range 6-35). Post-mortem analysis in one subject confirmed the signs of androgen insufficiency in the testis, with marked seminiferous tubule atrophy, and the absence of germinal cells. The characteristic neuronal depletion in the anterior horn gray matter was also observed. CONCLUSION: This report raises the possibility that age- or puberty-related changes in androgen binding could occur, which could potentially contribute to the progressive development of androgen resistance in affected men.
Assuntos
Envelhecimento/fisiologia , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Receptores Androgênicos/metabolismo , Repetições de Trinucleotídeos/genética , Adulto , Idoso , Southern Blotting , Saúde da Família , Feminino , Humanos , Masculino , Metribolona/farmacocinética , Pessoa de Meia-Idade , Atrofia Muscular Espinal/classificação , Atrofia Muscular Espinal/patologia , Reação em Cadeia da Polimerase/métodos , Mudanças Depois da Morte , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ensaio Radioligante/métodos , Receptores Androgênicos/genética , Testículo/fisiologia , Trítio/farmacocinéticaRESUMO
The effects of a monosomy of either the maternally or paternally derived X chromosome in Turner's syndrome (TS) on general neurocognitive status and some executive abilities were assessed using the maximum likelihood estimators for pedigree data. This method increases the power of analysis by accounting for the effect of background heritable variation on a trait. The sample comprised 42 females with regular non-mosaic X monosomy and their non-affected relatives. Wechsler neurocognitive scores and several executive function tests' scores, including the Behaviour Dyscontrol Scale (BDS-2), the Wisconsin Card Sorting Test (WCST), and the Rey Complex Figure Test (RCFT), were considered in the analysis. Results showed a significant effect of TS on all Wechsler index and subtest scores, with greatest deficits observed in Arithmetic, Block Design, Object Assembly and Picture Arrangement, and on the total BDS, RCFT and WCST scores, regardless of parental origin of the single X-chromosome. Our data also showed a significantly higher effect of a paternally derived X chromosome in diminishing the performance on several Wechsler scores relevant to verbal skills, which might suggest X-linked imprinting loci relevant to these skills. Possible reasons for the inconsistency of the results concerning X-linked imprinting of cognitive loci using TS patients are discussed, and the relevance of pedigree analysis to future studies of this problem is emphasized.
Assuntos
Cromossomos Humanos X , Cognição/fisiologia , Impressão Genômica , Síndrome de Turner/genética , Síndrome de Turner/fisiopatologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Linhagem , Escalas de WechslerRESUMO
Intersex occurs when the appearance of the internal or external genitalia is at variance with normal development for either sex. The first question asked by, and of new parents in relation to their offspring is often "Is it a boy or a girl"? A rational approach, based on knowledge of normal prenatal sexual development, and based on a careful physical examination to guide further investigation, is required to reach a diagnosis. We briefly review prenatal sexual development to provide a background to the assessment of genital ambiguity in the newborn. Aspects of physical examination are discussed in detail, with reference to published normative data where possible. We provide a classification of genital ambiguity and an approach to differential diagnosis. We highlight some of the many syndromes associated with genital ambiguity, with reference to their genetic basis where possible. In 46,XX individuals, the commonest cause of genital ambiguity is congenital adrenal hyperplasia due to 21-hydroxylase deficiency; however, in 46,XY individuals the differential diagnosis is wide, and may remain unexplained, even after extensive investigation. Two algorithms are presented, one of which provides an initial approach based on the presence of a uterus and palpable gonads alone, and a second illustrating a comprehensive differential diagnosis of the undervirilised 46,XY individual. We discuss our approach to sharing information on the diagnosis and management with the parents and highlight the early involvement of an experienced multidisciplinary team. Finally, we consider current controversial issues relating to gender assignment and management of genital ambiguity.
Assuntos
Aberrações Cromossômicas , Transtornos do Desenvolvimento Sexual/terapia , Genitália/anormalidades , Tomada de Decisões , Diagnóstico Diferencial , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/psicologia , Feminino , Genitália/embriologia , Genitália/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino , Relações Pais-Filho , Equipe de Assistência ao Paciente , Educação de Pacientes como Assunto , PrognósticoRESUMO
CONTEXT: Clinical management of intersex conditions is controversial because the available evidence is limited and conflicting, with no long-term population based studies comparing matched controls. OBJECTIVE: To assess the long-term psychological, sexual and social outcomes of patients with intersex compared with two matched control populations. DESIGN, SETTING AND PARTICIPANTS: Three different aged-matched (18-32 years) patient groups completed a self-administered questionnaire of established quality of life and well-being inventories measuring physical' health, psychological adjustment and sexuality, following a mail-out to all identified patients. The intersex group (n = 50) and the Hirschsprung disease, a congenital disorder, control group (n = 27), were patients who had attended the Royal Children's Hospital, a tertiary centre, for their clinical care. The insulin dependent diabetes mellitus control group was recruited from an adult tertiary hospital. The study was conducted at the hospital-based Murdoch Childrens Research Institute. MAIN OUTCOME MEASURES: Psychological, sexual and social outcomes. RESULTS: The intersex group did not differ from controls on physical or mental health, depression, state anxiety, neuroticism, psychoticism or stressful life events. Intersex participants were satisfied with their overall body appearance, although intersex males were less satisfied than controls with the size (p <0.05) and appearance (p <0.01) of their sex organs. The intersex group was less likely to experience orgasm (p <0.05), tended to experience more pain during intercourse (p = 0.06), had more difficulties with penetration (p <0.01) and were less likely to have sexual activity several times or more a week (p <0.05) than the combined control groups. Intersex participants did not differ from controls in level of sexual desire or enjoyment of sexual activities. CONCLUSIONS: Most patients with intersex had positive psychosocial and psychosexual outcomes, although some problems were reported with sexual activity. These results overall suggest that a model of care including early genital surgery carried out at a centre of excellence with a multidisciplinary team can minimize long-term complication rates.
Assuntos
Transtornos do Desenvolvimento Sexual/terapia , Adolescente , Adulto , Diabetes Mellitus Tipo 1/psicologia , Diabetes Mellitus Tipo 1/terapia , Transtornos do Desenvolvimento Sexual/psicologia , Relações Familiares , Feminino , Identidade de Gênero , Doença de Hirschsprung/psicologia , Doença de Hirschsprung/terapia , Humanos , Masculino , Casamento , Qualidade de Vida , Comportamento Sexual , Comportamento Social , Fatores Socioeconômicos , Inquéritos e Questionários , Resultado do TratamentoRESUMO
We have identified androgen receptor (AR) gene mutations in eight Australian subjects with complete androgen insensitivity syndrome (AIS). Four individuals, from three families, have novel mutations that introduce premature termination codons. Two siblings have the nonsense mutation Glu681X, and another subject has the nonsense mutation p.Ser884X. The other subject has a CA insertion at codon 829 (c.2847_2848insCA), causing a frameshift mutation that introduces four nonsense amino acids prior to a Stop codon. All the termination codons occur in the ligand binding domain, and cause reduced androgen binding in patient genital skin fibroblasts. Four further patients have missense mutations. One subject has two different mutations, p.Ala645Asp in the hinge region of the receptor, and p.Arg752Gln in the ligand binding domain. Both these mutations have previously been reported in patients with AIS, but the combination of these two mutations in one subject is unique. Another subject has a novel c.2533G>C transversion at the first nucleotide in exon 5, introducing the amino acid change p.Gly724Ala at a highly conserved residue in the ligand binding domain. Androgen binding is normal in fibroblasts from this subject, although other point mutations at this amino acid totally abolish binding. Two other subjects have mutations previously described as causing AIS, namely p.Arg779Trp and p.Val889Met substitutions in the ligand binding domain of the receptor. The p.Arg779Trp mutation is associated with the detection of a truncated AR protein in this patient's fibroblasts, suggesting the mutation renders the receptor susceptible to proteolysis.
Assuntos
Síndrome de Resistência a Andrógenos/genética , Mutação/genética , Receptores Androgênicos/genética , Adulto , Austrália , Criança , Pré-Escolar , Códon sem Sentido/genética , Códon de Terminação/genética , Feminino , Mutação da Fase de Leitura/genética , Disgenesia Gonadal 46 XY/genética , Humanos , MasculinoRESUMO
Differentiation of a testis or an ovary from a bipotential gonad is a complex developmental process involving various genes and hormones. Similarly, internal and external genital organs develop from an indeterminate stage from the complex differentiation of Wolffian and Müllerian ducts. Differentiation of the Wolffian ducts, urogenital sinus, and external genitalia is androgen dependent. Female sex differentiation appears to be a more passive process that is independent of estrogen. This article reviews the process of differentiation of the gonads and the genitalia and the factors affecting it. In addition, a clinical approach to patients with sexual ambiguity or sex reversal is discussed.
Assuntos
Diferenciação Sexual/fisiologia , Animais , Desenvolvimento Embrionário e Fetal , Genitália/embriologia , Hormônios/fisiologia , HumanosRESUMO
Massive ovarian edema is a rare tumor-like condition found predominantly in young women. Patients usually present with abdominal pain and/or abdominal mass. Pre-operative diagnosis is often difficult. Awareness of this rare and benign lesion in young women may allow conservative management and prevention of oophorectomy in some patients.