Article

Ovarian differentiation and gonadal failure

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Ovarian failure can result from several different genetic mechanisms—X chromosomal abnormalities, autosomal recessive genes causing various types of XX gonadal dysgenesis, and autosomal dominant genes. The number and precise location of loci on the X are still under investigation, but it is clear that, in aggregate, these genes are responsible for ovarian maintenance, given that monosomy X shows germ cells that undergo accelerated atresia. Despite recent hypotheses, at present there is no evidence for a gene directing primary ovarian differentiation; this process may be constitutive. Phenotypic/karyotypic correlation and limited molecular confirmation have long shown that proximal Xp and proximal Xq contain regions of the most importance to ovarian maintenance. Terminal deletions at Xp11 result in 50% primary amenorrhea and 50% premature ovarian failure or fertility. Deletions at Xq13 usually produce primary amenorrhea. Terminal deletions nearer the telomeres on either Xp of Xq bring about premature ovarian failure more often than complete ovarian failure. The X-linked zinc finger gene (ZFX) and diaphanous 2 Drosophila homologue (DIAPH2) are the only candidate genes for ovarian maintenance that map to the X chromosome. Additional, as yet unidentified, genes along the X chromosome must be involved. The search for these genes in humans is hampered by the lack of candidate genes that map to the X chromosome, the scarcity of patients with fortuitous autosomal translocations, and small pedigrees, which hinder mapping of the loci. In addition, difficulties with human germ cell research also make it challenging to dissect genes important to ovarian development. Autosomal genes also are involved in ovarian differentiation and gonadal failure. Follicle-stimulating hormone receptor and ataxia telangiectasia are examples of autosomal genes known to cause human ovarian failure. Transgenic mouse models point to many other candidate autosomal genes, and sequencing of the human homologues in affected women should lead to the discovery of new genes responsible for human ovarian failure. Identification, functional analysis, and mapping of novel genes specifically expressed in the ovary of mice and women eventually should lead to fruitful dissection of essential genes in mammalian ovarian development and maintenance. Am. J. Med. Genet. (Semin. Med. Genet.) 89:186–200, 1999. © 2000 Wiley-Liss, Inc.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Gonadal dysgenesis, impaired development of the gonads, is a group of conditions where the gonads are underdeveloped and have a complete or partial loss of function. Most cases of ovarian dysgenesis are due to abnormalities in the X chromosome [24]. Individuals with 46, XX gonadal dysgenesis may present with primary amenorrhea, hypergonadotropic hypogonadism, and infertility. ...
... This mosaicism generally includes a 45, X cell line with another cell line of 46, XX, 47, XXX, or a number of other X-chromosome deletions [34]. These patients will exhibit a milder phenotype and might be diagnosed due to infertility [24]. The diagnosis of Turner Syndrome or mosaicism is done via karyotyping. ...
Article
Full-text available
The ovarian reserve is finite and begins declining from its peak at mid-gestation until only residual follicles remain as women approach menopause. Reduced ovarian reserve, or its extreme form, premature ovarian insufficiency, stems from multiple factors, including developmental, genetic, environmental exposures, autoimmune disease, or medical/surgical treatment. In many cases, the cause remains unknown and resulting infertility is not ultimately addressed by assisted reproductive technologies. Deciphering the mechanisms that underlie disorders of ovarian reserve could improve the outcomes for patients struggling with infertility, but these disorders are diverse and can be categorized in multiple ways. In this review, we will explore the topic from a perspective that emphasizes the prevention or mitigation of ovarian damage. The most desirable mode of fertoprotection is primary prevention (intervening before ablative influence occurs), as identifying toxic influences and deciphering the mechanisms by which they exert their effect can reduce or eliminate exposure and damage. Secondary prevention in the form of screening is not recommended broadly. Nevertheless, in some instances where a known genetic background exists in discrete families, screening is advised. As part of prenatal care, screening panels include some genetic diseases that can lead to infertility or subfertility. In these patients, early diagnosis could enable fertility preservation or changes in family-building plans. Finally, Tertiary Prevention (managing disease post-diagnosis) is critical. Reduced ovarian reserve has a major influence on physiology beyond fertility, including delayed/absent puberty or premature menopause. In these instances, proper diagnosis and medical therapy can reduce adverse effects. Here, we elaborate on these modes of prevention as well as proposed mechanisms that underlie ovarian reserve disorders.
... Cytogenetic abnormalities related to the X chromosome usually lead to early ovarian failure. A region of the long arm of the X chromosome known as "critical region Xq" -ranging from Xq13 to Xq28 -has been associated with the formation of the female gonad and ovarian function maintenance; therefore, the genes present in this chromosome are believed to be essential for normal ovarian function (Simpson & Rajkovic, 1999). ...
Article
Full-text available
This paper reports the case of a patient who sought assisted reproductive technology (ART) treatment and was referred to pre-implantation genetic diagnosis (PGD) on account of a chromosomal translocation presented with secondary infertility. The patient underwent a highly complex ART treatment and had 14 metaphase II oocytes collected on the day of follicular aspiration. The embryos were taken to extended culture and five were biopsied and vitrified. The embryo genetic report showed aneuploidy in four of the blastocysts, while the other resulted in 46, XX. In conclusion, chromosome translocations involving the X chromosome might result in the deregulation of gene expression and defective ovarian formation. Therefore, the genes present in the X chromosome are believed to be essential in normal ovarian function.
Article
Full-text available
Infertility rates increases day by day and major reason can be genetic disorders.Objective: To review the prevalence and effects of genetic defects that can cause infertility.10 to 20% of patients have severe infertility disorders. To find out whether genetic material defects are really major infertility cause or not? And what are their prevalence.. Infertility is common health condition. Genetic cause are majorly unexplained but 2300 genes expressed that can retranslate and their mutation can cause of infertility.Handfull of genes and genetic effects are associated with human genome to express genes. Mostly tests added to check male infertility annually.Methods: I analyse and evaluate 12 articles from (1997-2011) from Google scholar, PubMed etc. All data is reviewed from infertility complaints. The data is extracted from Medline, PubMed and Obsgyne online library.Results: Those studies which conducted between years 1985 to 2011 are included in review. The sample size included more than 300 men and women aged between 20 to 40 years. In this study we evaluated that genomic technologies and advent of fertility tips can help in fertile patients. Metabolic chromosomal defects can be genetic disorders by deletion of chromosomes abnormLly.SOX9 chromosome is also play basic role in men fertility. Semen collection and measurements done and proper advances can be seen through research to follow up infertile patients. Comprehensive diagnosis started to advance the research and to increase the prognostic information.Conclusions: Infertility can be caused by genomic abnormalities and chromosomal abnormalities. Molecular techniques can help to reduce the abnormalities. In reality we are unable to establish genotype phenotype relationship and various testicular pattern to see infertile men.
Article
Full-text available
Infertility rates increases day by day and major reason can be genetic disorders.Objective: To review the prevalence and effects of genetic defects that can cause infertility.10 to 20% of patients have severe infertility disorders. To find out whether genetic material defects are really major infertility cause or not? And what are their prevalence.. Infertility is common health condition. Genetic cause are majorly unexplained but 2300 genes expressed that can retranslate and their mutation can cause of infertility.Handfull of genes and genetic effects are associated with human genome to express genes. Mostly tests added to check male infertility annually.Methods: I analyse and evaluate 12 articles from (1997-2011) from Google scholar, PubMed etc. All data is reviewed from infertility complaints. The data is extracted from Medline, PubMed and Obsgyne online library.Results: Those studies which conducted between years 1985 to 2011 are included in review. The sample size included more than 300 men and women aged between 20 to 40 years. In this study we evaluated that genomic technologies and advent of fertility tips can help in fertile patients. Metabolic chromosomal defects can be genetic disorders by deletion of chromosomes abnormLly.SOX9 chromosome is also play basic role in men fertility. Semen collection and measurements done and proper advances can be seen through research to follow up infertile patients. Comprehensive diagnosis started to advance the research and to increase the prognostic information.Conclusions: Infertility can be caused by genomic abnormalities and chromosomal abnormalities. Molecular techniques can help to reduce the abnormalities. In reality we are unable to establish genotype phenotype relationship and various testicular pattern to see infertile men.
Article
Full-text available
Rationale: Turner syndrome (TS) is a genetic disorder associated with abnormalities of the X chromosome related to ovarian function, but whether it is associated with endometrial abnormalities is still not clear. Patient concerns: We report the case of a 26-year-old Han Chinese woman with TS and Xp11.2 deletion, presenting with short final stature, ovarian hypofunction, unexplained cystic dilatation of the entire endometrium, and endometrial thickening. Diagnoses: The patient was diagnosed with chromosome Xp11.2 deletion through cytogenetic analysis and ultrasonic and endometrial pathology. Interventions: The patient was treated with conventional in vitro fertilization preimplantation genetic testing for 1 cycle. Outcomes: Cytogenetic examination showed karyotype 45, X, del (X) del (p11, 2). Ultrasonic examination showed uneven endometrium thickness and a full-stage cystic dilation echo. After 1 cycle of in vitro fertilization treatment, 4 eggs were obtained without forming an available embryo. Lessons: To our knowledge, the present case is the first report of a patient with TS with Xp deletions and ultrasound imaging endometrial abnormalities. Our findings expand the phenotypic spectrum of TS and may provide a reference for other clinicians.
Chapter
Hypogonadotropic and hypergonadotropic forms of hypogonadism exist. In the hypogonadotropic phenotype, functional etiology originates from GnRH neurons in the hypothalamus unable to permit follicle-stimulating hormone (FSH) and luteinizing hormone to stimulate ovaries. Kallmann syndrome is canonical, characterized by anosmia and also somatic anomalies specific for a perturbed gene. In the hypergonadotropic phenotype, etiology originates in the ovaries, FSH elevated as result of negative feedback inhibition because sex steroids can be generated. Hypergonadotropic phenotypes can be caused by X-chromosome abnormalities, inability of primordial germ cells to develop into secondary follicles, defects in DNA repair, or defects in chromosomal segregation.
Article
Full-text available
This study aimed to evaluate the clinical characteristics, pregnancy outcomes and prognostic factors for pregnancy of female with chromosomal abnormalities (CAs) after artificial insemination with donor's sperm (AID) treatment.A retrospective case-control study was analyzed by using the data of 29 female patients with CA and 116 controlled patients with normal karyotype (1:4 ratio) who underwent AID cycles at Guangdong Family Planning Special Hospital from January 2011 to December 2017. In all cases, reproductive histories were collected, and the cytogenetic analysis was performed by Trypsin-Giemsa banding and karyotyping. The embryos were fertilized via intracervical or intrauterine insemination. Clinical characteristic variables were compared.The prevalence of CA was found to be 0.29% in the whole AID population. The live birth rates of CA group and controlled group were 41.4% and 31.0% (P = .29) respectively. Compared to normal karyotype group, patients with CA showed higher rate of primary infertility (93.1% vs 75.9%, P = .049); Multivariate analysis demonstrated that ovarian stimulation (odds ratio, 3.055; 95% confidence interval, 1.421-6.568; P = .004) was associated with adverse pregnancy outcomes in female patients with AID treatment.For the infertility CA patients who were phenotypically normal, AID was a suitable choice, whereas ovarian stimulation results in an improvement in the pregnancy rate.
Article
Full-text available
Chromosomal abnormalities are the main genetic risk factor associated with reproductive and sexual development disorders (DSD). The goal of this study is to retrospectively evaluate the frequency of chromosomal aberrations in Moroccan subjects with problems of procreation or sexual ambiguity. A total of 1005 individuals, including 170 infertile couples, underwent cytogenetic analysis in the Cytogenetic Laboratory of the Pasteur Institute of Morocco. Heparinized blood samples were processed according to the standard karyotype method. A total (81.5%) of the patients studied had a normal karyotype, while the remaining (18.5%) patients had an abnormal karyotype. Female patients had more chromosomal abnormalities (52%) than male patients (48%). These chromosomal aberrations included 154 cases (83%) of sex chromosomal abnormalities, the most common being Turner’s syndrome and Klinefelter’s syndrome, and 31 cases (17%) had autosomal aberrations, especially chromosome 9 reversal (inv(9)(p12;q13)). The present data shows that among 170 couples, 10.6% had chromosomal abnormalities mainly involved in the occurrence of recurrent miscarriages. Genotype-phenotype correlations could not be made, and therefore, studies using more resolutive molecular biology techniques would be desirable.
Chapter
This chapter explains the biology of sex determination and how science seeks to categorise sex. It also examines the legal definition of sex and questions the law’s assumption that there are only two sexes. In particular it considers the legal response to intersex people.
Article
In humans, FMR1 (Fragile X mental retardation 1) is strongly expressed in granulosa cells (GCs) of the female germline and apparently controls efficiency of folliculogenesis. Major control mechanism(s) of the gene transcription rate seem to be based on the rate of CpG-methylation along the CpG island promoter. Conducting CpG-methylation-specific bisulfite-treated PCR assays and subsequent sequence analyses of both gene alleles, revealed three variably methylated CpG domains (FMR1-VMR (variably methylated region) 1, -2, -3) and one completely unmethylated CpG-region (FMR1-UMR) in this extended FMR1-promoter-region. FMR1-UMR in the core promoter was exclusively present only in female GCs, suggesting expression from both gene alleles, i.e., escaping the female specific X-inactivation mechanism for the second gene allele. Screening for putative target sites of transcription factors binding with CpG methylation dependence, we identified a target site for the transcriptional activator E2F1 in FMR1-VMR3. Using specific electrophoretic mobility shift assays, we found E2F1 binding efficiency to be dependent on CpG-site methylation in its target sequence. Comparative analysis of these CpGs revealed that CpG 94-methylation in primary GCs of women with normal and reduced efficiency of folliculogenesis statistically significant differences. We therefore conclude that E2F1 binding to FMR1-VMR3 in human GCs is part of an epigenetic mechanism regulating the efficiency of human folliculogenesis. Our data indicate that epigenetic mechanisms may control GC FMR1-expression rates.
Article
Full-text available
Premature ovarian insufficiency (POI) is a rare disease, especially in children and adolescents. It was previously called premature ovarian failure (POF). It can be manifested as delayed puberty, primary or secondary amenorrhea that occurred before the age of 40 years with no less than two abnormal serum sex hormones (low estrogen and high gonadotropin). It is reported that the incidence rate is 1% at the age of 40 years and 0.01% at the age of 20 years. Although the disease usually occurs in middle-aged and elderly women, clinical practice in recent years has shown that it has also been found in adolescents and even children. It is generally believed that the etiology of POI includes genetic factors, immune factors, and iatrogenic factors. So far, several genetic mutations that may cause POI have been found clinically, but the etiology of 90% of POI is still unknown. In recent years, the incidence of POI in children and adolescents has increased, and there are more urgent requirements for its early diagnosis, treatment, and clinical management. Based on this, this article will mainly review the research progress of the etiology, treatment, and clinical management of POI in children and adolescents.
Chapter
Changes in our understanding of pathology have accelerated in recent years. The ability to approach a diagnostic problem from different points of view—clinical, morphologic, and molecular genetic—has led to an integrative approach to pathology. Nontumoral pathology of the testis has not been an exception. In this chapter, we start from a histophysiologic base that includes the development of the testicle, the descent of the prepubertal testis, and the adult testicle. The chapter continues with congenital anomalies of the testis and the alterations in sexual development, the classifications for which have not been uniformly accepted by those who study these matters. We focus on the undescended testis, a source of controversy regarding its best treatment—surgical versus hormonal. The problem of the infertile patient is addressed, bearing in mind not only the primary alterations, be these chromosomal or molecular, but also considering that efficient testicular function is only acquired when there is a harmonious interaction between different glands and organs. Vascular pathology of the testis is always interesting, whether focusing on a dramatic situation such as testicular torsion, or considering the relationship between varicocele and infertility. In the section on Inflammation and Infection, besides the classical processes, other lesser known processes are included in the section Other Testicular and Epidydima Lesions. Compared with the previous edition, this chapter incorporates a significant number of figures that properly document the text.
Chapter
The diagnosis of primary ovarian insufficiency (POI) has untold effects on women and a better understanding alongside potential treatments are paramount to improve quality of life of these women. Various causes have been linked to the development of POI with genetics playing a key role. A better understanding of the genetics of POI could lead to earlier diagnosis and broaden fertility options. This chapter discusses previously known and more recently discovered genes that have been implicated in the development of POI. It explores the varying phenotypic expressions of some genes in different populations and areas for further research in the genetics of POI.
Article
Aim: This comprehensive review article aims to comprehend the frequency and prevalence of chromosomal abnormalities in both primary amenorrhea (PA) and secondary amenorrhea (SA) cases and correlating it with their phenotypes, clinical features and hormonal profiles. Methods: Research publications on prevalence of chromosomal abnormalities in both PA and SA cases worldwide and its etiology, clinical features, hormonal profiles; their correlation with chromosomal profiles were searched for on the internet, including general search engines and respective scientific sites. Only published, relevant and authentic data conducted on phenotypically female patients were considered. Another aspect of amenorrhea occurs due to several clinical conditions apart from cytogenetic viewpoint were not considered or discussed in detail. Results: As literature study suggests; considering various etiology of amenorrhea counting anatomic defect of the hypothalamus or genetic defect, and various acquired causes of chromosomal anomalies contribute to be one of the major etiologies of both PA and SA; ranging from 15.9% to 63.3% in case of PA and from 3.9% to 44.4% in case of SA. In spite of the presence of any other factors responsible condition, the genetic factors need to be emphasized, which might include single gene disorders or chromosomal disorders. Individuals with chromosomal anomalies reported a wide range of abnormalities in phenotypes, as well as in other clinical features and hormonal profiles. Conclusion: This comprehensive review is the first structured review article that encompasses the cytogenetic profile of the amenorrhea cases and correlating it with their phenotypes, clinical features and hormonal profiles from Eastern India.
Article
Full-text available
This report describes a clinically rare and atypical case of 46,X,idic(X)(q21.32)/45,X-type Turner syndrome with rapidly progressive puberty development. After 11 months of treatment with recombinant human growth hormone (rhGH), the child’s height increased. After 18 months of treatment with rhGH, the child showed secondary sex characteristics. The child was followed up for 1 year after the appearance of the secondary sex characteristics, and regular menses were still present. This case indicates that modern molecular biology techniques should be used rationally to further investigate the existence of X-chromosome translocations and occult chimeras to prevent misdiagnosis.
Chapter
On the surface the genetics of Turner syndrome (TS) would appear straightforward, as many affected females have 45,X. This chapter reviews the structure and function of the sex chromosomes and the multitude of chromosomal differences that can be seen in females with TS, including sex chromosome mosaicism. This chapter also explores the unique features of the X chromosome, including X-chromosome inactivation, and evidence for and against the existence of imprinted genes on the X chromosome. In order to fully understand the clinical features seen in individuals with TS, mechanisms leading to structural rearrangements of the sex chromosomes are discussed, as is an overview of important genes that reside on the X chromosome. Finally, this chapter summarizes the recommended genetic testing when Turner syndrome is suspected in both a prenatal and a postnatal setting and recurrence risks when a family has had one girl with Turner syndrome.
Chapter
Premature ovarian insufficiency (POI) is defined as the loss of ovarian function before the age of 40 years. Secondary amenorrhea or prolonged oligomenorrhea and primary amenorrhea may be the first symptoms and are the most common complains of POI patients. Hypergonadotropic hypogonadism is the most characteristic abnormality in hormonal profile of those patients. The prevalence of POI is about 1% and is variable depending on the age: 1% of women younger than 40 years, 0.1% under 30 years, and 0.01% under the age of 20 years. Both spontaneous and iatrogenic causes may induce POI. Spontaneous causes of POI include genetic abnormalities, autoimmune disorders, infections, enzyme deficiency, metabolic diseases, or very often idiopathic causes. Induced or iatrogenic POI is often a result of oncological treatment: radiotherapy, chemotherapy, and surgery. It is necessary to highlight that POI along with associated hypoestrogenism contributes to many complications in women’s health. POI causes decrease in bone mineral density, impairment of metabolic health, and cardiovascular system functioning. Genitourinary tract, fertility, as well as emotional health and sexual life are also at influence of premature hypoestrogenism associated with POI. The mainstay of treatment of POI is hormone replacement therapy (HRT) until at least the age of natural menopause. HRT should be long term in POI patients; therefore issues of compliance as well as risk-benefit ratio are very important to maximize longer-term health.
Article
Purpose: Sex-biased expression of genes on the X chromosome is accomplished by a complex mechanism of dosage regulation that leads to anatomical and physiological differences between males and females. Copy-number variations (CNVs) may impact the human genome by either affecting gene dosage or disturbing a chromosome structural and/or functional integrity. Methods: We performed a high-resolution CNV profiling to investigate the X chromosome integrity in cohorts of 269 fertile females and 111 women affected with primary ovarian insufficiency (POI) and assessed CNVs impact into functional and nonfunctional genomic elements. Results: In POI patients, we observed a 2.5-fold enrichment for rare CNVs comprising ovary-expressed genes, and genes implicated in autoimmune response and apoptotic signaling. Moreover, there was a higher prevalence of deletions encompassing genes that escape X inactivation, noncoding RNAs, and intergenic DNA sequences among POI females, highlighting structural differences between X chromosomes of fertile and POI females. Furthermore, we discovered a ~4% carrier incidence for X-linked disorders among fertile women. Conclusion: We constructed a high-resolution map of female-specific CNVs that provides critical insights into the spectrum of human genetic variation, sex-specific disease risk factors, and reproductive potential. We discovered novel CNVs associated with ovarian dysfunction and support polygenic models for POI.
Article
Full-text available
Individuals with a 47,XXY karyotype usually present with a male phenotype due to the additional Y chromosome. In this paper, we describe a 47,XXY female who was pregnant with a fetus of the same karyotype based on chromosome analysis of amniotic fluid cells. Further analysis of her Y chromosome indicated that the additional Y chromosome contains no SRY gene on the short arm but carries the azoospermia factor region on the long arm, including azoospermia factor a, b and c (AZFa, AZFb, AZFc). This region may influence her female phenotype. Fertile females with a 47,XXY karyotype and loss of SRY are extremely rare. This paper is the first report of a 47,XXY pregnant woman with a normal phenotype and may enrich our knowledge on 47,XXY individuals.
Article
One of the traits most consistently seen in females with Turner syndrome is premature ovarian insufficiency (POI). The biological mechanisms underlying the germ cell atresia that leads to infertility in most women with Turner syndrome are unclear. Given that telomeres are important for proper chromosomal pairing and other early steps in meiosis and oogenesis, one can conjecture that perturbations in telomere length and/or function might contribute to the POI associated with Turner syndrome. Also, one can speculate that epigenetic modifications that arise in response to asynapsis, as well as the resetting of the epigenome during embryogenesis, could contribute to monosomy X‐related germ cell atresia. Moreover, errors in recombination‐based DNA repair might contribute to the failure of cells lacking all, or a portion of, a second sex chromosome to successfully complete oogenesis. This article presents a review of the extant literature related to telomere length and/or epigenetic patterns associated with POI in females with a monosomy X complement (in humans and animal models). A goal of this review is to inspire researchers to use new technological advances to better characterize the components of the biological cascade leading to early germ cell loss in females with Turner syndrome.
Chapter
Female reproductive tract development is a complex process intricately tied to the patterning of the male (Wolffian) reproductive tract and renal anlage. Development starts from undifferentiated mesoderm known as the genital ridge, with germ cells migrating to this location from the yolk sac. The müllerian duct begins as an invagination of the coelomic epithelium at the top of the genital ridge and elongates by active cell proliferation using the Wolffian duct as a guide. Many genes have been linked to female reproductive tract development, but only a few have been directly implicated by animal knockout models; this is because the simplex female reproductive tract pattern (i.e., one with a single cervix and uterus, with two separate fallopian tubes) is limited to humans and other primates. Most recently, genomic sequencing has identified more genes, mostly transcription factors and extracellular signaling molecules, and mutations in those genes, associated with malformations of the female reproductive tract. The most common congenital abnormality of the human female genital tract occurs when the paired müllerian ducts fail to fuse or the subsequent septum fails to resorb, yielding a spectrum of uterine anomalies, including uterus didelphys and bicornuate uterus. External female genital tract development requires both the absence of a key male determining factor (SRY) and presence of its antagonist (WNT4). Virilization of genetically female fetuses is due to excessive androgens from congenital adrenal hyperplasia or maternal blood.
Article
Full-text available
Key Clinical Message Unbalanced X‐autosome translocation can result in various phenotypic manifestations. We present the first case of 46,X,der(X)t(X;8)(q28;q13) in a 34‐year‐old female with relatively mild manifestations, including congenital heart disease, epicanthal fold, mild intellectual disability, and menstrual irregularity. Our findings expand the known spectrum of unbalanced X‐autosome translocations, for improved clinical management.
Article
Full-text available
In normal males, luteinizing hormone (LH) regulates the function of Leydig cells and, hence, male sexual differentiation, pubertal androgenization, male sexual function, and fertility. Abnormalities in the function of Leydig cells result in primary hypogonadism and varying degrees of male pseudohermaphroditism.1-5 In these patients, Leydig cells are absent, hypoplastic, or unresponsive to stimulation with human chorionic gonadotropin (hCG), and studies of testicular-biopsy samples from some patients have revealed the absence of LH receptors.2,3 In normal women, LH stimulates the theca cells to produce androgen precursors for aromatization to estradiol by granulosa cells during the follicular phase of the menstrual cycle. . . .
Article
Full-text available
A patient with a 46,XX chromosome constitution showed the following main characteristics: lack of secondary sexual development, female external genitalia with absence of vagina, no gonadal structures, and complete lack of internal genitalia. This is a variant of the gonadal agenesis syndrome so far only described in association with and XY chromosome component. Endrocinology demonstrated that in the absence of gonadal feedback the pituitary responsiveness to synthetic luteinizing hormone-releasing hormone was increased.
Article
Full-text available
A genetic analysis is necessary to gain a greater understanding of the complex developmental processes in mammals. Toward this end, an insertional transgenic mouse mutant has been isolated that results in abnormal germ-cell development. This recessive mutation manifests as infertility in both males and females and is specific for the reproductive organs, since all other tissues examined were histologically normal. A developmental analysis of the gonadal tissues demonstrated that the germ cells were specifically depleted as early as day 11.5 of embryonic development, while the various somatic cells were apparently unaffected. Therefore, the mutated locus must play a critical role in the migration/proliferation of primordial germ cells to the genital ridges of developing embryos. In addition, females homozygous for the mutation could potentially be a valuable animal model of a human syndrome, premature ovarian failure. This mutation has been named germ-cell deficient, gcd.
Article
Full-text available
The chromosomal breakage syndromes--ataxia-telangiectasia, Fanconi's anemia, and Bloom's syndrome--are associated with growth failure, neurologic abnormalities, immunodeficiency, and an increased incidence of malignancy. The relationship between these features is unknown. We recently evaluated a 21-year-old female with more severe chromosomal breakage, immunodeficiency, and growth failure than in any of the mentioned disorders. As of November 1985, the patient remains clinically free of malignancy. At age 18, the patient's weight was 22.6 kg (50th percentile for seven years), height was 129 cm (50th percentile for eight years), and head circumference was 42 cm (50th percentile for six months). Laboratory studies demonstrated a marked decrease in both B and T cell number and function. The peripheral blood contained 400 to 900 lymphocytes/microL with 32% T11 cells, 17% T4 cells, and 21% T8 cells. The proliferative responses to phytohemagglutinin (PHA), pokeweed mitogen, and concanavalin A were less than 10% of control. There were 1% surface IgM positive cells, and serum IgG was 185 mg/dL, IgM 7 mg/dL, IgA 5 mg/dL. In lymphocyte cultures stimulated with the T cell mitogens PHA, phorbol ester, and interleukin 2, 55% of the banded metaphases demonstrated breaks or rearrangements. The majority of the breaks involved four fragile sites on chromosomes 7 and 14, 7p13, 7q35, 14q11, and 14q32. These are the sites of the genes for the T cell-antigen receptor and the immunoglobulin heavy chain and are sites of gene rearrangement in lymphocyte differentiation. Epstein-Barr virus stimulated B cells and fibroblast cultures also demonstrated a high incidence of breaks, but the sites were less selective. These findings suggest that the sites of chromosomal fragility in the chromosomal breakage syndromes may be informative and that factors other than the severity of the immunodeficiency or the high incidence of chromosomal damage may contribute to the occurrence of malignancy in the chromosomal breakage syndromes.
Article
Full-text available
The association of microcephaly, mental retardation, cataracts, and hypogonadism is described in sibs (brother and sister) of consanguineous parents. These features are consistent with a diagnosis of Martsolf's syndrome. In addition, one sib had a cardiomyopathy while the other had cardiac failure.
Article
This chapter describes the genetics of ovarian failure and the genes that are involved for normal function, as well as those genes that may be implicated in premature ovarian failure. Failure of germ cell development is associated with complete ovarian failure, resulting in lack of secondary sexual pubertal development. Decreased number but not total absence of germ cells is more likely associated with premature ovarian failure, presenting with infertility or secondary amenorrhea. Yet complete and premature ovarian failure may be different manifestations of the same underlying pathogenic and etiologic processes. Chromosomal abnormalities, mutations of autosomal or X-linked genes, and polygenic/multifactorial elements all play a role. Clinical disorders associated with germ cell abnormalities are enumerated, deducing etiologic factors responsible for ovarian differentiation and oogenesis in normal females.
Article
We report on two Japanese sisters with Perrault syndrome, i.e., autosomal recessive ovarian dysgenesis associated with sensorineural deafness. They also had ataxic gait, pes equinovarus, nystagmus, limited extraocular movements, and short stature. One older affected sister had partial growth hormone deficiency. Our review included 21 patients from 8 families, including our patients; 16 are women with ovarian dysgenesis and deafness, 3 deaf males without gonadal defect, one a woman with ovarian dysgenesis without deafness, and one a girl with deafness in whom ovarian function was not evaluated. Perrault syndrome may not be uncommon; some cases may have gone unrecognized, especially when a single child in a family is affected.
Article
A 14 4/12-year-old white girl, evaluated for progressive virilization and clitoromegaly, was found to have the unusual combination of a 46, XX karyotype, well-developed Müllerian structures, and dysgenetic testes with Leydig cell hyperplasia. Although there have been previous case reports of 46, XX males, in all of these patients development of the Müllerian ducts had been suppressed. When contemporary classifications of human disorders of sexual differentation were reviewed, no report of a similar patient was found. We speculate that the genotype and phenotype in our patient correspond to the genetic intersexuality of the hornless goat, thereby raising the possibility that the human autosome may play a role in the control of sexual development.
Article
PROSTAGLANDINS have wide-ranging effects in the body and are thought to be important mediators of inflammation. Cyclooxygen-ase (COX) plays a key regulatory role in prostaglandin synthesis, and occurs in both constitutive (COX-1) and inducible (COX-2) isoforms1,2. COX-1 is thought to provide cytoprotective effects3, whereas COX-2 is both inducible and the major isoform of inflammatory cells4. Reduction of prostaglandin production by inhibition of cyclooxygenases appears to be the main mechanism of action of most non-steroidal anti-inflammatory drugs (NSAIDS)5. Here we present an animal model of COX-2 deficiency that was generated by gene targeting. Defects in null mice correlating with reduced viability included renal alterations, characteristic of renal dysplasia (100% penetrance), and cardiac fibrosis (50% penetrance). Female Cox-2 −/− mice were infertile. COX-2 deficiency failed to alter inflammatory responses in several standard models, but striking mitigation of endotoxin-induced hepatocellular cytotoxicity was observed.
Article
Pure gonadal dysgenesis with 46,XX genotype is a rare abnormality with unknown etiology. Although sensorineural deafness has been described with 46,XX gonadal dysgenesis, the majority of reported cases of 46,XX gonadal dysgenesis have no associated physical abnormalities. We report a patient with 46,XX gonadal dysgenesis associated with epibulbar dermoids and preauricular skin tags, the classic ocular and skin manifestations of Goldenhar sequence (oculoauricular vertebral dysplasia). We propose that our patient may represent a new and previously unreported syndrome.
Article
Gonadal (ovarian) dysgenesis with normal chromosomes (46,XX) clearly is a heterogeneous condition. In some forms, the defect is restricted to the gonads, whereas other affected females show neurosensory hearing loss (Perrault syndrome). In another form, brothers may have germ cell aplasia [Granat et al., Fertil Steril 1983; 40:215–219]. Nongenetic causes exist as well. To elucidate the proportion of XX gonadal (ovarian) dysgenesis due to autosomal recessive genes, we analyzed published (N = 17) and unpublished (N = 8) families having at least two female offspring. Analysis was restricted to cases in whom ovarian failure was documented by the presence of streak ovaries (published cases) or elevated gonadotropins (unpublished cases). We reasoned that the closer to that segregation ratio expected for an autosomal recessive trait (0.25), the lower the frequency of nongenetic forms. Segregation analysis utilized standard correction for single ascertainment, with only females included in the preliminary analysis. The segregation ratio estimate was 0.16. Our results suggest that many 46,XX females with gonadal (ovarian) dysgenesis represent a disorder segregating as an autosomal recessive trait, placing sisters of these cases at a 25% risk for this disorder. © 1996 Wiley-Liss, Inc.
Article
To understand better the pathogenesis of ovarian dysgenesis in individuals with abnormalities such as 45,X Turner syndrome, trisomy 13, and trisomy 18, we have examined microscopically the ovaries of 36 infants with a number of chromosomal abnormalities confirmed by karyotype analysis. All infants with trisomy 13, trisomy 18, triploidy, and 45,X were found to have severe ovarian dysgenesis characterized by a virtual absence of primary oocytes. The ovaries of individuals with 21 trisomy and of those with partial deletion or duplication of an autosome demonstrated variable findings, which ranged from complete absence of oocytes to a mild diminution of oocyte numbers. The results of this study suggest that the attrition of germ cells in these infants is a result of faulty meiotic pairing and that ovarian dysgenesis is a more frequent finding in children with karyotypic abnormalities than has been realized previously.
Article
We have undertaken a study of 35 patients with i(Xq) to determine whether those that are maternally derived originate by similar mechanisms to those that are paternally derived. Isochromosome formation is not associated with increased parental age and > 90% of i(Xq) contain proximal Xp sequences suggesting that centromere misdivision is not a common mechanism of formation. Our results indicate that the majority of i(Xq) originate from a single X chromosome and the usual mechanisms of formation do not appear to differ according to the parent of origin.
Article
The degree of follicular development was examined in a patient with 17 alpha-hydroxylase deficiency that accounted for impairment of estrogen and androgen biosynthesis. The ovarian content of P was markedly higher than those of any other steroids requiring 17 alpha-hydroxylation for synthesis. The morphologic analysis of the ovaries demonstrated that normal follicles could not develop to more than 2.2 mm in diameter, and most follicles with diameters of 1.0 mm or more yielded to atresia. It is known that estrogen and FSH act synergistically on the growth of the follicles. Our data suggest that the follicles can develop up to the size of 2.2 mm in diameter at most with the sole stimulation of gonadotropin.
Article
Two males and three females with ataxia telangiectasia aged from 4 6/12; to 23 years were subjected to an i.v. LH-RH test. All were found to have elevated basal levels of FSH and three had elevated basal levels of LH. In all the response of FSH to LH-RH was supranormal. In the pubertal and adult females the basal levels of estradiol were low. The laboratory and clinical findings in these patients as well as data reported by others indicate that the primary gonadal failure is an integral part of AT.
Article
The frequency of germ cell neoplasms in girls with 46-XY gonadal dysgenesis suggests that germ cells may persist in the dysgenetic gonads for many years. A phenotypic female infant with a karyotype of 46-XY in blood, skin, and gonads had a few ova in primordial follicles and numerous germ cells in her dysgenetic gonads at the age of 3 months. At 3 years and 10 months of age her gonads contained no primordial follicle and the only remaining germ cells were in a gonadoblastoma. We propose that germ cells are lost from dysgenetic gonads much more rapidly than from normal gonads, but that the rate of loss in patients with a karyotype of 46-XY may be less than the rate of loss in patients with a karyotype of 45-XO.
Article
In a routine cytogenetic investigation of the outpatients of a hospital for the mentally retarded, a 26-year-old women with a presumptive interstitial deletion of the short arm of one of the X chromosomes was found. The same aberration was found in her phenotypically normal mother and in one of her four sisters, all phenotypically normal. By GTG- and QFQ-banding methods, the deletion was interpreted to involve the entire band Xp21 and adjacent parts of p11 and p22. The karyotype is written 46,X,del(X)(pter leads to p22::p11 leads to qter). By autoradiography and Bud R acridine orange technique, the deleted X was the late replicating one in all three affected persons. The deletion apparently causes shortness of stature but no other phenotypic symptoms or signs. Hence a gene or genes controlling stature is located in band Xp21 or regions immediately adjacent to this band. Since the absence of this region does not cause streak gonads, it does not contain genes controlling the formation of the ovaries. This appears to be the first example of a heritable chromosome deletion compatible with a normal phenotype and reproduction.
Article
Mutations rendering mice deficient in germ cells provide a natural experimental system for investigation of the differentiation of Sertoli cells without the normal number of germ cells. In the present study, use was made of 2 viable mutants (atrichosis, at/at, and dominant spotting, W/W(v)) with testes grossly deficient in germ cells bacause of the failure of the genital ridges to become adequately populated with germ cells. Ultrastructural examination of prepuberal testes of such mice revealed that essentially normal, both structural and temporal, maturation of the Sertoli cells occurred. In particular, there was normal differentiation of the typical tripartite nucleolus, the Sertoli cell junctions and mitochondria. We conclude that the normal complement of differentiating germ cells is not a prerequisite for structural differentiation of Sertoli cells.
Article
Of a brother and two sisters with infertility, one female sibling was found to be mosaic for Turner's syndrome. The brother and the other sister, of average intelligence, were phenotypically normal, with no dysmorphic features or ambiguous genitalia, but both showed hypergonadotropic hypogonadism. It is suggested that the basic defect in these two siblings is the same and is of genetic origin. As the parents were consanguineous, the defect is most likely due to an autosomal recessive gene.
Article
INDIRECT evidence of the capacity of a Y-containing germ cell to become functional oocyte in ovarian tissue of a chimaeric XX/XY female mouse has been published1. This animal was one of two fertile XX/XY females obtained by aggregation of early morulae of the inbred strains AKR (albino) and CBA-T6 (agouti). Mated to a BALB/c (albino) male she had given birth to two litters that included one albino son, the remaining six young being agouti. Afterwards she had been retained for observation in connection with another investigation. In consequence she was more than 12 months old when her chromosomes were examined and she was found to contain both XX (CBA) and XY (AKR) cells. Only then was it realised that this implied that the egg that gave the albino son had come from a Y-bearing oocyte. Although ancillary evidence effectively excluded the possibility of erroneous recording or mixture of animals as explanations, there may have been some reluctance to accept the conclusion that a Y-bearing germ cell had become a functional oocyte. It is therefore satisfying to report here the direct observation of an XY oocyte at diakinesis in a preparation from another fertile, chimaeric XX/XY female mouse.
Article
THERE is considerable evidence that, as a result of some early embryonic event, the genes of one X chromosome in each somatic cell of the human female are not expressed1. Studies of somatic tissues and cultured cells (including fibroblast clones) from human embryos, heterozygous for the common electrophoretic variant of glucose-6-phosphate dehydrogenase (G6PD), indicate that a single active X is present in cells from various tissues, at least by 5 weeks from conception2. On the other hand, the presence of the heteropolymorphic form of the enzyme in oocytes of the heterozygous adult female3 and a 16-week-old foetus4 is compelling evidence that, in meiotic stage germ cells, there are two active X chromosomes; however, the basis for the two active chromosomes in oocytes is not clear. It is conceivable that germ cell progenitors escape inactivation because inactivation occurs when cells destined to become germ cells have already been imprinted. Alternatively, only a single X chromosome may be active in all cells of the early zygote, with the second X activated only in germ cells at some time after their differentiation. The third possibility, that germ cells are subject to inactivation, but that reactivation occurs when meiosis commences, has been suggested by Gartler et al. because they did not observe the heteropolymer in ovaries from a 12-week-old human foetus heterozygous for the G6PD variant5,6. The ovary at that developmental stage contains approximately 23% germ cells, with a preponderance of premeiotic and leptotene germ cells7. But the implication that two functional X chromosomes are required for the onset of mammalian meiosis is not supported by evidence that XO mice produce normal gametes8. Using human foetal material, we have now obtained evidence against the third possibility.
Article
A woman balanced carrier of a X/15 translocation gave birth to a balanced infertile son and three unbalanced Xp--fertile daughters. This family and the other eleven cases of Xp--fertile women found in the literature demonstrate that loss of the p21 leads to pter region of the X chromosome is compatible with fertility, probably because it leaves on Xp the region which is never inactivated.
Article
The purpose of this communication is to review the current status of phenotypic karyotypic correlations of human sex chromosomes. The data analyzed will include surveys of individuals with gonadal dysgenesis, 'Turner's syndrome,' primary amenorrhea, and sex chromosome anomalies, as well as isolated reports of individuals with more unusual rearrangements. In addition, the phenotypes associated with 45,X/46,XY mosaicism are discussed.
Article
Two kindreds with Marinesco-Sjögren's syndrome in three sibships are described. In five of the six affected, but in none of the unaffected sibs, a hypergonadotropic hypogonadism was observed. In one of the kindreds a high degree of inbreeding was revealed, and inbreeding likely also existed in the other kindred. The two families were not related. Marinesco-Sjögren's syndrome is known to be a distinct clinical entity, governed by autosomal recessive inheritance, and this also applies to hypergonadotropic hypogonadism. Several heredo-degenerative nervous disorders are accompanied by a hypogonadotropic hypogonadism, which is believed to be secondary to the neurological disorder, as in traumatic paraplegia. A hypergonadotropic hypogonadism cannot readily be explained in this way. We consider genetic linkage between two independent disorders as the most likely explanation for the observed concurrence.
Article
To determine the cause of absent sexual development in a 17-year-old girl with end-stage renal disease. Case study. Seventeen-year-old girl with end-stage renal failure. None. The patient had phenotypically normal external female genitalia, müllerian duct hypoplasia, and no ovaries. Her serum gonadotropin levels were in the castrate range at baseline and after gonadotropin-releasing hormone stimulation. Her karyotype, in lymphocytes and cultured fibroblasts, was 46,XX. Analysis of genomic DNA, following polymerase chain reaction-amplication with oligonucleotide primers corresponding to the Y-encoded zinc finger protein ZFY and the testis-determining SRY gene, showed Y chromosome material in a male control but none in the patient. The results suggest a diagnosis of Frasier syndrome, a disorder characterized by true gonadal dysgenesis and end-stage renal disease occurring in normal phenotypic girls. Although previously reported only in individuals with a 46,XX karyotype, our studies indicate that Frasier syndrome may also occur in 46,XX girls. Delayed puberty is not uncommon in renal failure. This case illustrates the importance of measuring gonadotropin levels in teenage girls with delayed puberty and renal failure, particularly if the origin of the renal disease is obscure.
Article
The parental origin of the single X in 45 cases (40 liveborns and 5 fetuses) with a 45,X karyotype was studied using polymorphic DNA probes. The single X was paternal in origin (Xp) in 10 cases (22.2%) and maternal (Xm) in 35 cases (77.8%). Y chromosome material was detected in 1 out of the 35 cases with a 45,Xm constitution. Analysis of parental ages and clinical data of the patients with respect to the origin of the single X revealed no significant differences between the origins.
Article
In the mothers of two girls with Turner syndrome due to a deletion of the short arm of an X chromosome, the same chromosomal anomaly was detected. Both mothers and daughters had short stature but normal pubertal development. Short parents and normal pubertal development do not exclude Turner syndrome in a girl with small stature.
Article
We have used X- and Y-linked RFLPs to determine the origin of the single X chromosome in 25 live-born individuals with Turner syndrome. We determined that 18 individuals retained a maternal X (Xm) and that seven retained the paternal X (Xp). No occult mosaicism was detected. We found no differences in either maternal or paternal ages for the two groups. The ratio of maternal X to paternal X is just over 2:1, which is consistent with the expected proportion of meiotic or mitotic products, with equal loss at each step, given the nonviability of 45,Y. Six phenotypic or physiologic characteristics were assessed: (1) birth weight, (2) height percentile at time of testing, (3) presence of a webbed neck, (4) cardiovascular abnormalities, (5) renal abnormalities, and (6) thyroid autoimmunity. There were no significant differences in birth weights or heights between the girls who retained the maternal X or the paternal X. In addition, no differences between the groups could be appreciated in the incidence of the physical, anatomic, or physiologic parameters assessed.
Article
Mice carrying mutations at the W (Dominant white spotting) and Sl (Steel) loci develop abnormalities in three independent systems: neural crest-derived melanocytes, primordial germ cells and haematopoietic stem cells. Consequently, homozygotes of viable mutant alleles have white coats and are sterile and severely anaemic. Tissue recombination studies predict that the W gene is expressed cell autonomously, whereas the product of the Sl locus affects the microenvironment in which the stem cells migrate, proliferate and differentiate. The W locus encodes the protoncogene c-kit, a member of the tyrosine kinase receptor family. The haematopoietic growth factor SCF (stem cell factor) has been identified as the product of the Sl locus and a ligand for c-kit. Here, we report that SCF is expressed during embryogenesis in cells associated with both the migratory pathways and homing sites of melanoblasts, germ cells and haematopoietic stem cells. Both SCF and c-kit are also expressed in a variety of other tissues, including the brain and spinal cord, suggesting that the receptor-ligand system has additional roles in embryogenesis.
Article
The W locus of mice encodes the c-kit tyrosine kinase receptor. In embryos homozygous for severe W mutations, the number of germ cells does not increase after 8 days of development, melanocytes do not appear, and production of erythrocytes and mast cells is deficient. To gain some insight into the role of the c-kit receptor, we have used in situ hybridization to explore the time period of expression of c-kit transcripts in early germ cells and melanoblasts. At 6 1/2 days of development, expression was not seen in the embryonic cylinder, but did appear in parietal endoderm. Germ cells displayed a low level of c-kit transcripts from their first appearance in the 7 1/2 -day embryo, continuing through early proliferation and migration to the gonad. During migration, surrounding tissues also expressed c-kit. Expression increased in gonia and then ceased as they became nonproliferative. Expression in presumptive melanoblasts was first seen in the cervical region of 10-day embryos and continued as they spread over the surface of the body, entered the epidermis, and differentiated in hair follicles after birth. The effects of mutations of c-kit on germ cells and melanoblasts can be interpreted as an absence of a proliferative signal shortly after their segregation from other cell types. This signal may be required throughout the proliferative phase of early germ cells [and also in postnatal stages of germ cell development (Manova et al. (1990). Development 110, 1057-1069]. In melanoblasts, c-kit may play a role during both proliferation and differentiation.
Article
A description is presented of the first documented case of placental aromatase deficiency. The deficiency caused maternal virilization during pregnancy and pseudohermaphroditism of the female fetus. A 24-yr-old primigravida showed progressive virilization during the third trimester. Urinary excretion of estrogen was less than 14 mumol/day between 35-38 weeks of pregnancy, although nonstress tests showed reactive patterns and serum levels of human placental lactogen were above 460 nmol/L. Maternal serum levels of estrogens were low, and those of androgens were high in the third trimester. A dehydroepiandrosterone sulfate loading test induced a marked increase in maternal serum levels of androgens, whereas no such increase was observed in estrogens. The woman delivered vaginally a live full-term infant who exhibited female pseudohermaphroditism. Cord serum levels of estrogens were extremely low, while those of androgens were high. The aromatase activity of the placenta, determined by the conversion of [7-3H]androstenedione to 17 beta-[7-3H]estradiol and [7-3H]estrone, were less than 0.03 fmol/microgram protein.min (control, 9.6 +/- 2.2 fmol/microgram protein.min). The sulfatase activity of the placenta was 0.63 pmol/microgram protein.min compared to 0.46 +/- 0.16 pmol/microgram protein.min in controls. The rate of aromatization by normal control placentas was the same as that obtained during coincubation of samples of normal placentas and that of the patient. Thus, the presence of aromatase inhibitor in the patient's placenta was excluded.
Article
A family is described in which both a mother and an infertile daughter had premature menopause at the ages of 31 and 28 years, respectively. Initially, an extensive investigation revealed no apparent cause for their conditions. However, when cytogenetic analysis in the daughter was performed, a terminal deletion in the long arm of one of the X-chromosomes was found. The karyotype was: 46,Xdel(X),(q25-qter). Chromosomal investigation in the mother showed an identical deletion. The karyotype of the patient's 35-year-old sister is normal. She has a normal menstrual cycle and two normal children. The presence of such familial cases suggests that chromosomal investigation should be considered in young women with oligomenorrhea, especially those whose mothers have experienced a premature menopause.
Article
Thirty-four families with a child or fetus with Turner's syndrome were studied using a series of polymorphic DNA probes. Analysis of the origin of the normal X chromosome was possible in all cases. In 16 families with 45,X (four fetuses and 12 livebirths), the observed X was maternal in each case, indicating a preferential loss of the paternal sex chromosome at, or before, conception. In the remaining 18 families with a variety of karyotypes, but especially in those where the child had an isochromosome of Xq or a ring X, there was again a strong tendency for the normal X to be maternal. Analysis of parental ages was performed with known origin of each abnormality, but no evidence for an increased or decreased parental age effect was detected.
Article
Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency in genotypic females is characterized by primary amenorrhea and the absence of sexual maturation due to inadequate biosynthesis of ovarian androgens and estrogens. We induced ovarian follicular development in a woman with this syndrome. Ovum pick-up, in vitro fertilization, and primary embryonic development were achieved despite undetectable plasma estradiol and extremely low ovarian androgen concentrations and minute concentrations of these hormones in the ovarian follicular fluid.
Article
Two sisters, ages 18 and 25, presented with primary amenorrhea and underwent clinical, hormonal, cytogenetic, and pathologic evaluation. Both were of normal stature and lacking of somatic stigmata. Both patients had normal 46,XX karyotype on peripheral blood. Streak gonads were seen in both patients and a rather scanty number of primordial follicles was found in one patient. FSH, LH, and urinary estrogens were consistent with streak gonad syndrome. Autosomal recessive inheritance has been suggested in familial aggregates with XX gonadal dysgenesis.
Article
Four sibs, three males and one female, had microcephaly, hypergonadotropic hypogonadism, short stature, and multiple congenital anomalies. They had five normal sibs and consanguineous parents. Findings in the affected sibs also included a narrow forehead, synophrys, micrognathia, abnormally folded pinnae, early loss of teeth in three, cubitus valgus in two, genu valgum, gynecomastia, and undescended testes in one. All sibs had normal chromosomes. Results of tests for growth hormone release and adrenocortical function were normal. Luteinizing hormone releasing hormone (LHRH) and human chorionic gonadotropin (hCG) stimulation tests were consistent with primary gonadal failure. Testicular biopsy, performed on two affected males, was normal in one and showed focal atrophy with decreased spermatogenesis in the other. The patients manifest a phenotype different from all other known types of hypergonadotropic hypogonadism and appear to represent a new MCA/MR syndrome.
Article
Following a previous study of human fetal oocytes analysed by light and electron microscope microspreading (Speed 1985), a further and more extensive analysis has now been carried out at electron microscope (EM) level. Some new anomalies not previously observed are described. More than one-third of all pachytene oocytes show degeneration (Z-cells) or synaptic errors which might lead to germ cell death. Meiotic pairing anomalies appear to be much more common among oocytes than spermatocytes, and could be significant factor in the high rate of atresia found between mid-term and birth in the human ovary.
Article
We report on an Arab family in which a mother and two of her daughters, despite having deletion Xq25, are fertile. So far, only one case of deletion Xq25 associated with fertility has been reported. Consistent inactivation of the deleted X chromosome in the proposita and early menopause in the mother were noted. The effect of Xq deletion on fertility and the CRH is discussed.
Article
A brother and sister with Martsolf syndrome are reported. The main characteristics of the syndrome are mental retardation, short stature, cataracts, hypogonadism and craniofacial anomalies including microcephaly, maxillary retrusion, pouting mouth, malaligned teeth and mildly dysplastic pinnae. The metacarpal and phalangeal bones are short. The occurrence of Martsolf syndrome in sibs of opposite sex suggests autosomal recessive inheritance.
Article
Two sisters with premature menopause and a small deletion of the long arm of one of their X chromosomes [del (X)(pter----q26.3:)] were investigated with polymorphic DNA probes near the breakpoint. The deleted chromosome retained the factor IX (F9) locus and the loci DXS51 (52A) and DXS100 (pX45h), which are proximal to F9. However, the factor VIII (F8) locus was not present, nor were two loci tightly linked to this locus, DXS52 (St14) and DXS15 (DX13). This deletion refines the location of the F9 locus to Xq26 or to the interface Xq26/Xq27, thus placing it more proximally than has been previously reported. The DNA obtained from these patients should be valuable in the mapping of future probes derived from this region of the X chromosome.
Article
We describe a family in which four women had menstrual irregularities and a partial deletion of the long arm of the X chromosome (Xq). Three of the four women had premature ovarian failure (at the ages of 24 to 37 years). Chromosome-banding studies initially suggested that a terminal portion of Xq was deleted. However, DNA-hybridization studies showed that an interstitial portion of Xq was deleted and that the affected women had a 46,XX,del(X)(pter-q21.3::q27-qter) karyotype. These findings help clarify the role of Xq in ovarian function and indicate that the accurate description of such abnormalities requires a combination of cytogenetic and DNA-hybridization analysis.
Article
The pairing characteristics of the X axis in XO human and mouse oocytes were studied by the spreading technique throughout meiotic prophase. In three human XO foetuses, germ cell development was seen to be largely blocked at the preleptotene stage. In XO mice on the other hand, oocytes surviving through pachytene increasingly show the X axis making a non-homologous association with itself or with an autosome. Such associations take the form hairpins or rings when self pairing occurs or triradial structures when involvement is with an autosome. Pairing initiation in the autosomes involved is disturbed by the X axis suggesting that the heterologous pairing seen is taking place at the earliest stage of synaptonemal complex formation, namely zygotene. It is suggested, that in the XO mouse, and perhaps also in rare fertile XO humans, survival, of a population of oocytes into the adult is ensured by the ability of the X axis to pair non-homologously at meiotic prophase, thus satisfying pairing requirements.
Article
We report on two sib fetuses with similar abnormalities detected prenatally by ultrasound. The first fetus had micrognathia, was without cleft palate, and had low-set ears, double outlet right ventricle with a ventricular septal defect, and 46,XY gonadal dysgenesis. The second sib fetus was born with cleft lip and palate, micrognathia, transposition of the great vessels, ventricular septal defect, a right-sided aorta arch, and bilateral cystic kidneys with hypospadias. We were able to identify 11 additional cases in the literature with similar findings. We think this set of defects is a recognizable syndrome that appears to be inherited either as an autosomal recessive or as an X-linked recessive and may overlap with the Smith-Lemli-Opitz syndrome.
Article
We report two new cases of Rothmund-Thomson syndrome which emphasize the less well-known non-dermatological complications, namely: hypodontia, soft tissue contractures, proportionate short stature, hypogonadism, anaemia and osteogenic sarcoma. Genetic analysis of these and previously reported pedigrees supports autosomal recessive inheritance.
Article
The embryonic testicular regression syndrome associated with severe mental retardation is reported in three 46,XY sibs each of whom has a 46,XY chromosome complement. A fourth sib, a sister, also is severely retarded mentally; her chromosome complement is 46,XX. The 46,XY individuals, who were raised as females, presented varying degrees of genital ambiguity, indicating that their gonadal activities had been arrested at different times during embryogenesis. No trace of gonadal tissue could be found in either patient. The coincidence of the embryonic testicular regression syndrome and severe mental retardation in the same sibship is discussed.
Article
We describe 3 sibs, two females and a male, with hypogonadism, defective Müllerian development in the sisters, and partial alopecia consisting of cranial hair only in the center of the scalp. One sister had absent gonads, the other had streak ovaries; both had markedly hypoplastic internal genitalia. Their brother had hormonal and histologic findings consistent with germinal cell aplasia. In view of the fact that the parents were consanguineous, autosomal recessive inheritance of the syndrome is likely.