Pubertal development in 46,XY patients with NR5A1 mutations

Abstract Purpose Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age. Methods We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition. Results Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty. Conclusion Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.

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Up-to-Date Clinical and Biochemical Workup of the Child and the Adolescent with a Suspected Disorder of Sex Development

Hormone Research in Paediatrics ◽

10.1159/000519895 ◽

2021 ◽

pp. 279-290 ◽

Cited By ~ 1

Author(s):

Romina P. Grinspon ◽

Sebastián Castro ◽

Rodolfo A. Rey

Keyword(s):

External Genitalia ◽

Ambiguous Genitalia ◽

Diagnostic Approach ◽

Reproductive Hormone ◽

Imaging Studies ◽

Disorder Of Sex Development ◽

Surgical Exploration ◽

Sex Development ◽

Internal Genitalia ◽

17 Hydroxyprogesterone

Background: The suspicion of a disorder of sex development (DSD) often arises at birth, when the newborn presents with ambiguous genitalia, or even during prenatal ultrasound assessments. Less frequently, the aspect of the external genitalia is typically female or male, and the diagnosis of DSD may be delayed until a karyotype is performed for another health issue, or until pubertal age when a girl presents with absence of thelarche and/or menarche or a boy consults for gynaecomastia and/or small testes. Summary: In this review, we provide a practical, updated approach to clinical and hormonal laboratory workup of the newborn, the child, and the adolescent with a suspected DSD. We focus on how to specifically address the diagnostic approach according to the age and presentation. Key Message: We particularly highlight the importance of a detailed anatomic description of the external and internal genitalia, adequate imaging studies or surgical exploration, the assessment of reproductive hormone levels – especially testosterone, anti-Müllerian hormone, 17-hydroxyprogesterone, and gonadotropins – and karyotyping.

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Cytogenetics and sex determination in man and mammals

Journal of Biosocial Science ◽

10.1017/s0021932000023427 ◽

1970 ◽

Vol 2 (S2) ◽

pp. 7-30 ◽

Cited By ~ 26

Author(s):

C. E. Ford

Keyword(s):

Y Chromosome ◽

External Genitalia ◽

Mutant Gene ◽

Normal Female ◽

Human Female ◽

Present Evidence ◽

Male Development ◽

Sex Development ◽

Internal Genitalia ◽

Male External Genitalia

SummarySex in man and probably throughout the class mammalia is normally determined by the presence of a Y chromosome (male) or its absence (female). The presence of genetic loci on both the long and the short arm of the X chromosome in double dose appears to be essential for the development of mature functional ovaries in the human female though a single X suffices in the female mouse.The development of masculine genital anatomy and phenotype is a consequence of prior formation of testes. In the absence of gonads of either kind, female internal and external genitalia are formed but secondary sex development fails. In rare human families a mutant gene suppresses the development of male external genitalia in 46, XY embryos but permits the development of testes and male internal genitalia. The external phenotype is normal female (syndrome of testicular feminization). A sex-linked mutant gene in the mouse has a similar effect.The locus or loci directly concerned with male development might lie wholly on the Y chromosome or might be located on another chromosome or chromosomes. In the latter case it (or they) must be repressed in the female and normally activated by a locus or loci on the Y chromosome in the male. Present evidence does not permit the exclusion of either possibility.

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45,X/46,XY mosaicism: report on 14 patients from a Brazilian hospital. A retrospective study

Sao Paulo Medical Journal ◽

10.1590/1516-3180.2014.1326729 ◽

2014 ◽

Vol 132 (6) ◽

pp. 332-338 ◽

Cited By ~ 17

Author(s):

Rafael Fabiano Machado Rosa ◽

Willy Francisco Bartel D'Ecclesiis ◽

Raquel Papandreus Dibbi ◽

Rosana Cardoso Manique Rosa ◽

Patrícia Trevisan ◽

...

Keyword(s):

Retrospective Study ◽

Turner Syndrome ◽

Early Recognition ◽

External Genitalia ◽

Ambiguous Genitalia ◽

Referral Hospital ◽

Clinical Genetics ◽

Sex Development ◽

Genital Ambiguity ◽

The Individual

CONTEXT AND OBJECTIVE: 45,X/46,XY mosaicism, or mixed gonadal dysgenesis, is considered to be a rare disorder of sex development. The aim of our study was to investigate the clinical and cytogenetic characteristics of patients with this mosaicism.DESIGN AND SETTING: A retrospective study in a referral hospital in southern Brazil.METHODS: Our sample consisted of patients diagnosed at the clinical genetics service of a referral hospital in southern Brazil, from 1975 to 2012. Clinical and cytogenetic data were collected from the medical records.RESULTS: Fourteen patients were included in the sample, with ages at the first evaluation ranging from 2 days to 38 years. Nine of them had female sex of rearing and five, male. Regarding the external genitalia, most were ambiguous (n = 10). One patient presented male phenotype and was treated for a history of azoospermia, while three patients presented female phenotype, of whom two had findings of Turner syndrome and one presented secondary amenorrhea alone. Some findings of Turner syndrome were observed even among patients with ambiguous genitalia. None presented gonadal malignancy. One patient underwent surgical correction for genital ambiguity and subsequent exchange of sex of rearing. Regarding cytogenetics, we did not observe any direct correlation between percentages of cell lines and phenotype.CONCLUSIONS: 45,X/46,XY mosaicism can present with a wide variety of phenotypes resulting from the involvement of different aspects of the individual. All these observations have important implications for early recognition of these patients and their appropriate management.

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SRY-negative in 46, XX Male Testicular DSD: a case report

Journal of Biomedicine and Translational Research ◽

10.14710/jbtr.v6i3.9088 ◽

2020 ◽

Vol 6 (3) ◽

pp. 97-100

Author(s):

Nurin Aisyiyah Listyasari ◽

Ardy Santosa ◽

Achmad Zulfa Juniarto

Keyword(s):

Ambiguous Genitalia ◽

Pcr Analysis ◽

Molecular Testing ◽

Cell Hyperplasia ◽

Signaling Mechanism ◽

Comprehensive Management ◽

Sex Development ◽

Determination Process ◽

Precise Diagnosis ◽

Differences Of Sex Development

Background: The sex determination process requires distinct signaling pathways to generate either testis or ovaries from the same precursor structures, the primordial gonad. Deviations of this signaling mechanism may result in disorders/differences of sex development (DSD). The 46, XX testicular DSD is a rare genetic condition identified by a discrepancy between genetic and phenotypic sex caused sex reversal syndrome. Case Presentation: We describe the case of a 5 years-old 46, XX boy with ambiguous genitalia. On physical examination he had severe hypospadias, bifid scrotum, micropenis and palpable bilateral testes. Cytogenetic analysis of patient reveals a 46, XX karyotype. Hormonal assay showed low level of FSH, LH and Testosterone and there was no evidence of Mullerian structures based on pelvic imaging. The histopathology of gonadal tissue showed a Leydig cell hyperplasia which gives the impression of Sertoli cell nodule. Polymerase chain reaction (PCR) analysis failed to identify the presence of SRY gene, therefore a diagnosis of 46, XX Testicular DSD with SRY-negative was established. Conclusion: This report presents a rare case of SRY-negative 46, XX Testicular DSD in a boy with ambiguous genitalia. A comprehensive management including clinical, cytogenetic and molecular analyses have indicated that undiscovered genetic or environmental factors needs to be elucidated. It is important to carry out further molecular testing to establish precise diagnosis of DSD and to provide appropriate genetic counseling for patients and their family.

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Combined homozygous 21 hydroxylase with heterozygous P450 oxidoreductase mutation in a Saudi boy presented with hypertension

BMJ Case Reports ◽

10.1136/bcr-2019-233942 ◽

2020 ◽

Vol 13 (9) ◽

pp. e233942

Author(s):

Aida Aljabri ◽

Fatimah Alnaim ◽

Yasin Alsaleh

Keyword(s):

Adrenal Insufficiency ◽

Clinical Manifestations ◽

Ambiguous Genitalia ◽

Sterol Synthesis ◽

Gene Encoding ◽

Key Enzymes ◽

P450 Oxidoreductase ◽

Sex Development ◽

Skeletal Malformations ◽

New Variant

Congenital adrenal hyperplasia (CAH) comprises a group of inherited autosomal recessive disorders characterised by defective cortisol biosynthesis, compensatory increases in corticotrophin secretion and adrenocortical hyperplasia. The characteristics of the biochemical and clinical phenotype depend on the specific enzymatic defect. 21-hydroxylase deficiency is estimated to account for 90%–95% of all CAH cases. Although there are many variants of CAH, a new variant is found secondary to a mutation in the gene encoding the protein P450 oxidoreductase (POR) in which the electron is granted to all microsomal P450 enzymes type II. In 2004, it was discovered that this new CAH disease was attributable to the POR gene mutation. POR facilitates electron transfer from Nicotinamide adenine dinucleotide phosphate (NADPH) to key enzymes involved in steroid and sterol synthesis and metabolism. POR deficiency causes partial and combined impairment of the key enzymes involved in steroidogenesis: P450c17 (17α-hydroxylase/17,20 lyase), P450c21 (21-hydroxylase) and P450aro (aromatase). Clinically, mutant POR manifests with disordered sex development, adrenal insufficiency and skeletal malformations. However, each enzyme may be differently compromised in the same patient. This difference in the clinical manifestations secondary to the variability in enzymatic impairments ranges from ambiguous genitalia in both sexes, adrenal insufficiency associated or not to bone malformations, to abnormal laboratory results in the neonatal screening test of asymptomatic newborns. We report here a case of a 46, XY patient with normal male genitalia associated with hypertension not related to fludrocortisone in which genetic study showed that a homozygous mutation in the CYP21A2 also carries the heterozygous missense variant of unclear pathogenicity in the POR gene.Although there are many variants of CAH, a new variant is found secondary to a mutation in the gene encoding the protein P450 oxidoreductase (POR) which therefore the electron is granted to all microsomal P450 enzymes type II. In 2004, it was mentioned by Fluck and his colleagues that this new CAH disease was attributable to the POR gene mutation.POR facilitates electron transfer from NADPH to key enzymes involved in steroid and sterol synthesis and metabolism.POR deficiency causes partial and combined impairment of the key enzymes involved in steroidogenesis: P450c17 (17α- hydroxylase/17,20 lyase), P450c21 (21-hydroxylase) and P450aro (aromatase).Clinically, Mutant POR manifests with disordered sex development, adrenal insufficiency and skeletal malformations.However, each enzyme may be differently compromised in the same patient. This difference in the clinical manifestations secondary to the variability in enzymatic impairments, it is ranging from ambiguous genitalia in both sexes, adrenal insufficiency associated or not to bone malformations, to abnormal laboratory results in the neonatal screening test of asymptomatic newborns.

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CBX2-dependent transcriptional landscape: implications for human sex development and its defects

Scientific Reports ◽

10.1038/s41598-019-53006-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Patrick Sproll ◽

Wassim Eid ◽

Anna Biason-Lauber

Keyword(s):

Next Generation Sequencing ◽

Rna Sequencing ◽

Current Knowledge ◽

Next Generation ◽

Steroidogenic Factor 1 ◽

Sex Development ◽

New Genes ◽

Differences Of Sex Development ◽

Generation Sequencing ◽

Transcriptional Landscape

Abstract Sex development, a complex and indispensable process in all vertebrates, has still not been completely elucidated, although new genes involved in sex development are constantly being discovered and characterized. Chromobox Homolog 2 (CBX2) is one of these new additions and has been identified through a 46,XY girl with double heterozygous variants on CBX2.1, causing Differences of Sex Development (DSD). The mutated CBX2.1 failed to adequately regulate downstream targets important for sex development in humans, specifically steroidogenic factor 1 (NR5A1/SF1). To better place CBX2.1 in the human sex developmental cascade, we performed siRNA and CBX2.1 overexpression experiments and created a complete CRISPR/Cas9-CBX2 knockout in Sertoli-like cells. Furthermore, we deployed Next Generation Sequencing techniques, RNA-Sequencing and DamID-Sequencing, to identify new potential CBX2.1 downstream genes. The combination of these two next generation techniques enabled us to identify genes that are both bound and regulated by CBX2.1. This allowed us not only to expand our current knowledge about the influence of CBX2.1 in human sex development, but also to advance our insight in the mechanisms governing one of the most important decisions during embryonal development, the commitment to either female or male gonads.

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Parents’ experiences of having a baby with ambiguous genitalia

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2014-0457 ◽

2015 ◽

Vol 28 (7-8) ◽

Cited By ~ 7

Author(s):

Mailme de Souza Oliveira ◽

Roberto Benedito de Paiva-e-Silva ◽

Gil Guerra-Junior ◽

Andréa Trevas Maciel-Guerra

Keyword(s):

Health Professionals ◽

Disorders Of Sex Development ◽

Ambiguous Genitalia ◽

Initial Management ◽

Sex Development ◽

Personal Belief ◽

Sex Assignment ◽

Previous Assignment ◽

The Moment ◽

The Impact

AbstractHealth professionals must be aware of the impact on parents of the birth of children with ambiguous genitalia. This study aimed to analyze the experiences and perceptions of such parents. Parents of 30 children who were evaluated in a reference center for disorders of sex development (DSD) were interviewed. The questionnaire covered the prenatal period, the moment they were told about the disorder, initial management by health professionals, and problems they experienced. Only two cases were detected during pregnancy. The news was usually given to the mother alone by pediatricians. Most parents kept it secret and avoided exposing the baby to the prejudice of others. Parents of children who were referred without sex assignment usually held a personal belief of their child’s sex. Previous assignment was based on clinical examination and/or karyotype. Spreading knowledge about DSD could increase awareness of this issue, thus reducing parents’ shock and societal stigma. Training of neonatal care teams is required to avoid assignment before evaluation.

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Disorders/Differences of Sex Development Presenting in the Newborn With 46,XY Karyotype

Frontiers in Pediatrics ◽

10.3389/fped.2021.627281 ◽

2021 ◽

Vol 9 ◽

Author(s):

Silvano Bertelloni ◽

Nina Tyutyusheva ◽

Margherita Valiani ◽

Franco D'Alberton ◽

Fulvia Baldinotti ◽

...

Keyword(s):

Disorders Of Sex Development ◽

Gender Assignment ◽

Salt Wasting ◽

Personalized Care ◽

Sex Development ◽

Sex Assignment ◽

Differences Of Sex Development ◽

Life Threatening

Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions, resulting in discordance between an individual's sex chromosomes, gonads, and/or anatomic sex. The management of a newborn with suspected 46,XY DSD remains challenging. Newborns with 46,XY DSD may present with several phenotypes ranging from babies with atypical genitalia or girls with inguinal herniae to boys with micropenis and cryptorchidism. A mismatch between prenatal karyotype and female phenotype is an increasing reason for presentation. Gender assignment should be avoided prior to expert evaluation and possibly until molecular diagnosis. The classic diagnostic approach is time and cost-consuming. Today, a different approach may be considered. The first line of investigations must exclude rare life-threatening diseases related to salt wasting crises. Then, the new genetic tests should be performed, yielding increased diagnostic performance. Focused imaging or endocrine studies should be performed on the basis of genetic results in order to reduce repeated and invasive investigations for a small baby. The challenge for health professionals will lie in integrating specific genetic information with better defined clinical and endocrine phenotypes and in terms of long-term evolution. Such advances will permit optimization of counseling of parents and sex assignment. In this regard, society has significantly changed its attitude to the acceptance and expansion beyond strict binary male and female sexes, at least in some countries or cultures. These management advances should result in better personalized care and better long-term quality of life of babies born with 46,XY DSD.

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Neonatal Sex Assignment in Disorders of Sex Development: A Philosophical Introspection

Journal of Neonatal Surgery ◽

10.21699/jns.v6i3.604 ◽

2017 ◽

Vol 6 (3) ◽

pp. 58 ◽

Cited By ~ 7

Author(s):

V Raveenthiran

Keyword(s):

Gender Bias ◽

Personal Experience ◽

Disorders Of Sex Development ◽

Ambiguous Genitalia ◽

Third Parties ◽

Sex And Gender ◽

Sex Development ◽

Consensus Conferences ◽

Sex Assignment ◽

And Gender

Management of ambiguous genitalia is highly controversial. This condition was known previously as intersex and presently as disorders of sex development (DSD). There is no consensus regarding the choice, timing and method of sex assignment in neonates with DSD. Consensus conferences could not unify the views of various stakeholders and third parties. This article philosophically examines the nature and origin of such controversies. Misconception, bias and conflicting priorities are identified as the three cardinal sources of controversies. Conceptual duality of sexes, confused notion of sex and gender, bias towards penetrative intercourse, conflict between utopian ideals and reality, unwillingness to compromise are identified as perpetuators of controversies. Suggestions are made regarding sex assignment in various types of DSD based on the understanding of published literature and the author’s personal experience.

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Illness Uncertainty Longitudinally Predicts Distress Among Caregivers of Children Born With DSD

Journal of Pediatric Psychology ◽

10.1093/jpepsy/jsaa069 ◽

2020 ◽

Vol 45 (9) ◽

pp. 1053-1062

Author(s):

Caroline M Roberts ◽

Christina M Sharkey ◽

Dana M Bakula ◽

Megan N Perez ◽

Alexandria J Delozier ◽

...

Keyword(s):

Depressive Symptoms ◽

Critical Time ◽

The United States ◽

Ambiguous Genitalia ◽

Study Entry ◽

Cross Sectional ◽

Illness Uncertainty ◽

Sex Development ◽

Differences Of Sex Development ◽

Parent Illness

Abstract Objective A subset of parents of children with disorders/differences of sex development (DSD) including ambiguous genitalia experience clinically elevated levels of anxious and depressive symptoms. Research indicates that uncertainty about their child’s DSD is associated with parent psychosocial distress; however, previous studies have been cross-sectional or correlational in nature. The current study is the first to examine the longitudinal trajectory of the relationship between caregiver-perceived uncertainty about their child’s DSD and caregiver anxious and depressive symptoms across the first 12 months following genital surgery in young children, or if surgery was not performed, the first 12 months following study entry. Methods One hundred and thirteen caregivers (Mage = 32.12; 57.5% mothers; 72.6% Caucasian) of children (N = 70; Mage = 9.81 months; 65.7% female) with DSD were recruited from 12 DSD specialty clinics in the United States. Caregivers completed psychosocial measures at baseline, 6 and 12 months following genitoplasty, or study entry if parents elected not to have surgery for their child. Results Caregiver illness uncertainty and both anxious and depressive symptoms were highest at baseline and decreased over time (ps < .05). Caregiver illness uncertainty predicted symptoms of anxious and depressive symptoms across all time points (ps < .05). Conclusions Caregivers’ perceptions of uncertainty about their child’s DSD are highest soon after diagnosis, and uncertainty continues to predict both anxious and depressive symptoms across time. Thus, the initial diagnostic period is a critical time for psychological assessment and intervention, with parent illness uncertainty being an important clinical target.

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