RESUMEN
BACKGROUND: Chromosomal abnormalities (CAs) have been described in patients with secondary amenorrhea (SA). However, studies on this association are scarce. OBJECTIVES: To evaluate the frequency and types of CAs detected by karyotyping in patients with SA. DESIGN AND SETTING: This retrospective study was performed in a reference clinical genetic service in South Brazil. METHODS: Data were obtained from the medical records of patients with SA who were evaluated between 1975 and 2022. Fisher's bicaudate exact test and Student's t-test were used, and P < 0.05 was considered significant. RESULTS: Among 43 patients with SA, 14 (32.6%) had CAs, namely del (Xq) (n = 3), 45,X (n = 2), 46,X,r(X)/45,X (n = 2), 46,XX/45,X (n = 1), 46,X,i(q10)/45,X (n = 1), 47,XXX (n = 1), 46,XX/47,XXX (n = 1), 46,XX/47,XX,+mar (n = 1), 45,XX,trob(13;14)(q10;q10)/46,XXX,trob(13;14)(q10;q10) (n = 1), and 46,XX,t(2;21)(q23;q11.2) (n = 1). Additional findings were observed mostly among patients with CA compared with those without CA (P = 0.0021). No difference in the mean age was observed between the patients with SA with or without CAs (P = 0.268025). CONCLUSIONS: CAs are common among patients with SA, especially those with short stature and additional findings. They are predominantly structural, involve the X chromosome in a mosaic, and are compatible with the Turner syndrome. Patients with SA, even if isolated, may have CAs, particularly del (Xq) and triple X.
Asunto(s)
Amenorrea , Aberraciones Cromosómicas , Femenino , Humanos , Estudios Retrospectivos , Amenorrea/genética , CariotipificaciónRESUMEN
CONTEXT: Follicle-stimulating hormone (FSH) plays an essential role in gonadal function. Loss-of-function mutations in the follicle-stimulating hormone receptor (FSHR) are an infrequent cause of primary ovarian failure. OBJECTIVE: To analyze the molecular physiopathogenesis of a novel mutation in the FSHR identified in a woman with primary ovarian failure, employing in vitro and in silico approaches, and to compare the features of this dysfunctional receptor with those shown by the trafficking-defective D408Y FSHR mutant. METHODS: Sanger sequencing of the FSHR cDNA was applied to identify the novel mutation. FSH-stimulated cyclic adenosine monophosphate (cAMP) production, ERK1/2 phosphorylation, and desensitization were tested in HEK293 cells. Receptor expression was analyzed by immunoblotting, receptor-binding assays, and flow cytometry. Molecular dynamics simulations were performed to determine the in silico behavior of the mutant FSHRs. RESULTS: A novel missense mutation (I423T) in the second transmembrane domain of the FSHR was identified in a woman with normal pubertal development but primary amenorrhea. The I423T mutation slightly impaired plasma membrane expression of the mature form of the receptor and severely impacted on cAMP/protein kinase A signaling but much less on ß-arrestin-dependent ERK1/2 phosphorylation. Meanwhile, the D408Y mutation severely affected membrane expression, with most of the FSH receptor located intracellularly, and both signal readouts tested. Molecular dynamics simulations revealed important functional disruptions in both mutant FSHRs, mainly the loss of interhelical connectivity in the D408Y FSHR. CONCLUSIONS: Concurrently, these data indicate that conformational differences during the inactive and active states account for the distinct expression levels, differential signaling, and phenotypic expression of the I423T and D408Y mutant FSHRs.
Asunto(s)
Insuficiencia Ovárica Primaria/genética , Receptores de HFE/genética , Adulto , Amenorrea/genética , Amenorrea/metabolismo , Sustitución de Aminoácidos , Familia , Femenino , Hormona Folículo Estimulante/farmacología , Células HEK293 , Humanos , Isoleucina/genética , Mutación con Pérdida de Función/genética , Modelos Moleculares , Mutación Missense , Linaje , Insuficiencia Ovárica Primaria/metabolismo , Receptores de HFE/agonistas , Receptores de HFE/química , Receptores de HFE/metabolismo , Treonina/genéticaRESUMEN
La función ovárica depende de la expresión de múltiples genes, por lo que las anomalías del cromosoma X y los autosomas revisten gran importancia en la etiología de la insuficiencia ovárica primaria (IOP). Las translocaciones de autosomas en mujeres con IOP son muy raras y solo se han detectado tres casos: dos translocaciones entre los cromosomas 2 y 15 en dos mujeres con cariotipo 46, XX, t (2, 15) (q32.3, q13.3)2; una translocación entre los cromosomas 13 y 14 en una mujer con cariotipo 45, XX, t (13; 14)3; por lo que nuestro caso sería el cuarto reporte de mujeres con translocaciones de autosomas e IOP.
Ovarian function depends on the expression of multiple genes, so Xchromosome abnormalities and autosomes are of great importance in the etiology of primary ovarian insufficiency (IOP). Autosomal translocations in women with IOP are very rare and only three cases have been detected: two translocations between chromosomes 2 and 15 in two women with karyotype 46, XX, t (2, 15) (q32.3, q13.3)2; a translocation between chromosomes 13 and 14 in a woman with karyotype 45, XX, t (13; 14)3 , so our case would be the fourth report of women with autosomal translocations and IOP.
Asunto(s)
Humanos , Femenino , Adulto , Aberraciones Cromosómicas , Insuficiencia Ovárica Primaria/genética , Amenorrea/genética , Translocación Genética , CariotipoRESUMEN
BACKGROUND: Hypergonadotropic hypogonadism (HH) is a genetically heterogeneous disorder that usually presents with amenorrhea, atrophic ovaries, and low estrogen. Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progression, was recently implicated as a cause of HH. We identified a NUP107 genetic variant in a nonconsanguineous family with two sisters affected with primary amenorrhea and HH, and generated a mouse model that carried the human variant. METHODS: We performed a high-resolution X-chromosome microarray and whole exome sequencing on parents and two sisters with HH to identify pathogenic variants. We generated a mouse model of candidate NUP107 variant using CRISPR/Cas9. RESULTS: Whole exome sequencing identified a novel and rare missense variant in the NUP107 gene (c.1063C>T, p.R355C) in both sisters with HH. In order to determine functional significance of this variant, we used CRISPR/Cas9 to introduce the human variant into the mouse genome. Mice with the homolog of the R355C variant, as well as the nine base pairs deletion in Nup107 had female subfertility. CONCLUSIONS: Our findings indicate that NUP107 R355C variant falls in the category of variant of unknown significance as the cause of HH and infertility.
Asunto(s)
Mutación Missense , Proteínas de Complejo Poro Nuclear/genética , Insuficiencia Ovárica Primaria/genética , Adulto , Amenorrea/genética , Animales , Secuencia de Bases , Consanguinidad , Modelos Animales de Enfermedad , Femenino , Humanos , Hipogonadismo/genética , Masculino , Menopausia Prematura/genética , Ratones , Proteínas de Complejo Poro Nuclear/metabolismo , Linaje , Polimorfismo de Nucleótido Simple , Secuenciación del ExomaRESUMEN
BACKGROUND/AIMS: Splicing CYP19 gene variants causing aromatase deficiency in 46,XX disorder of sexual development (DSD) patients have been reported in a few cases. A misbalance between normal and aberrant splicing variants was proposed to explain spontaneous pubertal breast development but an incomplete sex maturation progress. The aim of this study was to functionally characterize a novel CYP19A1 intronic homozygote mutation (IVS9+5G>A) in a 46,XX DSD girl presenting spontaneous breast development and primary amenorrhea, and to evaluate similar splicing variant expression in normal steroidogenic tissues. METHODS: Genomic DNA analysis, splicing prediction programs, splicing assays, and in vitro protein expression and enzyme activity analyses were carried out. CYP19A1 mRNA expression in human steroidogenic tissues was also studied. RESULTS: A novel IVS9+5G>A homozygote mutation was found. In silico analysis predicts the disappearance of the splicing donor site in intron 9, confirmed by patient peripheral leukocyte cP450arom and in vitro studies. Protein analysis showed a shorter and inactive protein. The intron 9 transcript variant was also found in human steroidogenic tissues. CONCLUSIONS: The mutation IVS9+5G>A generates a splicing variant that includes intron 9 which is also present in normal human steroidogenic tissues, suggesting that a misbalance between normal and aberrant splicing variants might occur in target tissues, explaining the clinical phenotype in the affected patient.
Asunto(s)
Amenorrea/genética , Aromatasa/deficiencia , Adolescente , Glándulas Suprarrenales/metabolismo , Amenorrea/metabolismo , Animales , Aromatasa/genética , Aromatasa/metabolismo , Células COS , Línea Celular , Chlorocebus aethiops , Femenino , Humanos , Masculino , Ratones , Mutación , Fenotipo , Placenta/metabolismo , Embarazo , Empalme de Proteína , Testículo/metabolismoRESUMEN
OBJECTIVE: To map the X-chromosome and autosome breakpoints in women with balanced X-autosome translocations and primary amenorrhea, searching candidate genomic loci for female infertility. DESIGN: Retrospective and case-control study. SETTING: University-based research laboratory. PATIENT(S): Three women with balanced X-autosome translocation and primary amenorrhea. INTERVENTION(S): Conventional cytogenetic methods, genomic array, array painting, fluorescence in situ hybridization, and quantitative reverse transcription-polymerase chain reaction. MAIN OUTCOME MEASURE(S): Karyotype, copy number variation, breakpoint mapping, and gene expression levels. RESULT(S): All patients presented with breakpoints in the Xq13q21 region. In two patients, the X-chromosome breakpoint disrupted coding sequences (KIAA2022 and ZDHHC15 genes). Although both gene disruptions caused absence of transcription in peripheral blood, there is no evidence that supports the involvement of these genes with ovarian function. The ZDHHC15 gene belongs to a conserved syntenic region that encompasses the FGF16 gene, which plays a role in female germ line development. The break in the FGF16 syntenic block may have disrupted the interaction between the FGF16 promoter and its cis-regulatory element. In the third patient, although both breakpoints are intergenic, a gene that plays a role in the DAX1 pathway (FHL2 gene) flanks distally the autosome breakpoint. The FHL2 gene may be subject to position effect due to the attachment of an autosome segment in Xq21 region. CONCLUSION(S): The etiology of primary amenorrhea in balanced X-autosome translocation patients may underlie more complex mechanisms than interruption of specific X-linked candidate genes, such as position effect. The fine mapping of the rearrangement breakpoints may be a tool for identifying genetic pathogenic mechanisms for primary amenorrhea.
Asunto(s)
Amenorrea/genética , Cromosomas Humanos X , Translocación Genética , Amenorrea/diagnóstico , Amenorrea/fisiopatología , Puntos de Rotura del Cromosoma , Pintura Cromosómica , Hibridación Genómica Comparativa , Proteínas de Unión al ADN/genética , Femenino , Fertilidad/genética , Factores de Crecimiento de Fibroblastos/genética , Regulación de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Hibridación Fluorescente in Situ , Proteínas con Homeodominio LIM/genética , Proteínas Musculares/genética , Proteínas del Tejido Nervioso/genética , Fenotipo , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo , Factores de Transcripción/genéticaRESUMEN
Despite the increasing understanding of female reproduction, the molecular diagnosis of primary ovarian insufficiency (POI) is seldom obtained. The RNA-binding protein NANOS3 poses as an interesting candidate gene for POI since members of the Nanos family have an evolutionarily conserved function in germ cell development and maintenance by repressing apoptosis. We performed mutational analysis of NANOS3 in a cohort of 85 Brazilian women with familial or isolated POI, presenting with primary or secondary amenorrhea, and in ethnically-matched control women. A homozygous p.Glu120Lys mutation in NANOS3 was identified in two sisters with primary amenorrhea. The substituted amino acid is located within the second C2HC motif in the conserved zinc finger domain of NANOS3 and in silico molecular modelling suggests destabilization of protein-RNA interaction. In vitro analyses of apoptosis through flow cytometry and confocal microscopy show that NANOS3 capacity to prevent apoptosis was impaired by this mutation. The identification of an inactivating missense mutation in NANOS3 suggests a mechanism for POI involving increased primordial germ cells (PGCs) apoptosis during embryonic cell migration and highlights the importance of NANOS proteins in human ovarian biology.
Asunto(s)
Homocigoto , Mutación , Insuficiencia Ovárica Primaria/genética , Proteínas de Unión al ARN/genética , Adolescente , Adulto , Amenorrea/genética , Animales , Apoptosis , Brasil , Células COS , Estudios de Casos y Controles , Chlorocebus aethiops , Femenino , Citometría de Flujo , Humanos , Microscopía Confocal , Unión Proteica , ARN/química , Adulto Joven , Dedos de ZincRESUMEN
We tested the hypothesis that mutations in NR5A1 and PIN1 cause disorders in gonadotropin-gonadal system development and function, throught direct DNA sequencing of the coding sequence and splice-sites of NR5A1 and PIN1 in 50 subjects with sporadic idiopathic hypogonadotropic hypogonadism. These patients were recruited from the Pediatrics section of Tongji Hospital, Tongji Medical College, in Wuhan, China. None of the affected subjects had clinical signs of adrenal insufficiency. The NR5A1 and PIN1 mutations were found in 7 of the 50 cases. These 7 individuals presented severely low serum concentrations of testosterone or of estradiol and gonadotropin. Adrenal insufficiency was not diagnosed in any of these patients. Consequently, NR5A1 and PIN1 mutations should be considered in idiopathic hypogonadotropic hypogonadism patients with normal karyotypes and without adrenal insufficiency.
Asunto(s)
Dineínas Citoplasmáticas/genética , Hipogonadismo/genética , Factor Esteroidogénico 1/genética , Adolescente , Insuficiencia Suprarrenal/genética , Amenorrea/genética , Secuencia de Aminoácidos , Secuencia de Bases , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Mutación Missense , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
Introducción: el síndrome de resistencia completa a los andrógenos, feminización testicular o síndrome de Morris, puede presentarse en uno de cada 20 000 a 64 000 recién nacidos varones. Objetivo: presentar un caso con genotipo masculino y fenotipo femenino dado por desarrollo mamario, con genitales externos femeninos con hipoplasia de los labios mayores y menores y la vagina muy corta que termina en un fondo de saco ciego. Métodos: se valora en la consulta a una paciente adolescente de 19 años de edad con amenorrea primaria y contacto sexual insatisfactorio (imposibilidad de penetración). Resultados: se comprueba al examen vagina rudimentaria de unos dos centímetros y escaso desarrollo de genitales externos. En los exámenes complementarios se comprueban cifras de testosterona y LH aumentadas, así como el estradiol disminuido y un cariotipo 46 XY por lo que se sospecha síndrome de Morris y se planifica intervención quirúrgica combinada en un tiempo (vaginal y abdominal) donde se realiza anexectomía total derecha por video laparoscopia y reconstrucción de vagina por técnica de Williams. Posoperatorio satisfactorio y seguimiento ulterior por consulta donde se comprueba vagina funcional y estabilidad emocional de la paciente. Conclusiones: el estudio anatomo-patológico comprueba la existencia de ovario y testículo en la muestra quirúrgica lo que confirma el diagnóstico de síndrome de Morris o de resistencia completa a los andrógenos(AU)
Introduction:the syndrome of complete androgen resistance, testicular feminization or Morris syndrome may occur in one in 20 000 to 64 000 of male newborns. Objective: to present a case with male genotype and female phenotype given by breast development, female external genitalia with hypoplasia of the labia and very short vagina ending in a blind pouch Methods: a 19 year- old female patient is assisted in consultation due primary amenorrhea and unsatisfactory sexual contact (impossibility of penetration). Results: at examination, we found a rudimentary vagina of about two inches and underdeveloped external genitalia. The exams confirmed increased LH and testosterone levels and decreased estradiol. It is also found a 46 XY karyotype, so Morris syndrome is suspected. Combined surgery is planned for the vagina and abdomen. Total videolaparoscopy right adnexectomy and vaginal reconstruction by technique of Williams are performed. We had satisfactory postoperative and subsequent follow-up consultation where functional vagina and emotional stability of the patient were checked. Conclusions: the pathological study verifies the existence of ovary and testis in the surgical specimen confirming the diagnosis of Morris syndrome or complete androgen resistance(AU)
Asunto(s)
Humanos , Masculino , Femenino , Adolescente , Síndrome de Resistencia Androgénica/patología , Síndrome de Resistencia Androgénica/cirugía , Vagina/anomalías , Amenorrea/genética , Informes de CasosRESUMEN
Introducción: el síndrome de resistencia completa a los andrógenos, feminización testicular o síndrome de Morris, puede presentarse en uno de cada 20 000 a 64 000 recién nacidos varones. Objetivo: presentar un caso con genotipo masculino y fenotipo femenino dado por desarrollo mamario, con genitales externos femeninos con hipoplasia de los labios mayores y menores y la vagina muy corta que termina en un fondo de saco ciego. Métodos: se valora en la consulta a una paciente adolescente de 19 años de edad con amenorrea primaria y contacto sexual insatisfactorio (imposibilidad de penetración). Resultados: se comprueba al examen vagina rudimentaria de unos dos centímetros y escaso desarrollo de genitales externos. En los exámenes complementarios se comprueban cifras de testosterona y LH aumentadas, así como el estradiol disminuido y un cariotipo 46 XY por lo que se sospecha síndrome de Morris y se planifica intervención quirúrgica combinada en un tiempo (vaginal y abdominal) donde se realiza anexectomía total derecha por video laparoscopia y reconstrucción de vagina por técnica de Williams. Posoperatorio satisfactorio y seguimiento ulterior por consulta donde se comprueba vagina funcional y estabilidad emocional de la paciente. Conclusiones: el estudio anatomo-patológico comprueba la existencia de ovario y testículo en la muestra quirúrgica lo que confirma el diagnóstico de síndrome de Morris o de resistencia completa a los andrógenos
Introduction:the syndrome of complete androgen resistance, testicular feminization or Morris syndrome may occur in one in 20 000 to 64 000 of male newborns. Objective: to present a case with male genotype and female phenotype given by breast development, female external genitalia with hypoplasia of the labia and very short vagina ending in a blind pouch Methods: a 19 year- old female patient is assisted in consultation due primary amenorrhea and unsatisfactory sexual contact (impossibility of penetration). Results: at examination, we found a rudimentary vagina of about two inches and underdeveloped external genitalia. The exams confirmed increased LH and testosterone levels and decreased estradiol. It is also found a 46 XY karyotype, so Morris syndrome is suspected. Combined surgery is planned for the vagina and abdomen. Total videolaparoscopy right adnexectomy and vaginal reconstruction by technique of Williams are performed. We had satisfactory postoperative and subsequent follow-up consultation where functional vagina and emotional stability of the patient were checked. Conclusions: the pathological study verifies the existence of ovary and testis in the surgical specimen confirming the diagnosis of Morris syndrome or complete androgen resistance
Asunto(s)
Humanos , Masculino , Femenino , Adolescente , Síndrome de Resistencia Androgénica , Vagina/anomalías , Amenorrea/genética , Informes de CasosRESUMEN
A rare cause of congental adrenal hyperplasia is 17α-hydroxylase deficiency. It results in sexual infantilism, primary amenorrhea in females, pseudohermaphroditism in males, hypertension, and hypokalemia. We studied two female siblings from a rural community in Mexico. The cause of consultation was primary amenorrhea. The proband had low levels of estrogen, progesterone and cortisol. Deoxycorticosterone and corticosterone levels were elevated. The proband was homozygous for a transversion of cytosine to thymine at exon 4 (CGAâTGA), causing a premature stop codon at position 239 (R239X). Analysis of family members showed the presence of this heterozygous mutation in the mother, father and one healthy sibling. In summary, we describe a Mexican family with 17α-hydroxylase deficiency due to R239X mutation.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Amenorrea/genética , Mutación , Esteroide 17-alfa-Hidroxilasa/genética , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/fisiopatología , Adulto , Amenorrea/complicaciones , Amenorrea/fisiopatología , Arginina/genética , Codón sin Sentido , Femenino , HumanosRESUMEN
Women harbouring inactivating mutations in luteinizing hormone (LH) beta subunit (LHB) or LH receptor (LHCGR) genes have similar clinical manifestations characterized by female external genitalia, spontaneous breast and pubic hair development at puberty, and normal or late menarche followed by oligo-amenorrhea and infertility. Oestradiol and progesterone levels are normal for the early to midfollicular phase, but do not reach ovulatory or luteal phase levels, confirming lack of ovulation. Notably, serum LH levels are low in patients with LHB mutations and high in those with LHCGR mutations, whereas follicle-stimulating hormone levels are normal or only slightly increased. Pelvic ultrasound has demonstrated a small or normal uterus and normal or enlarged ovaries with cysts. Women with LHB mutations may be treated with hCG (human chorionic gonadotropin) or LH, whereas those with mutations in LHCGR are resistant. Lhb and Lhcgr knockout female mice are close phenocopies of the respective human mutations, and confirm that early follicular development, low levels of oestrogen production and theca cell development are independent of LH action, which is necessary for ovulation. Although inactivating mutations in LHB and LHCGR are rare in comparison to other genetic and non-genetic causes of hypogonadism, they should be considered in the differential diagnosis of oligo-amenorrhea and infertility.
Asunto(s)
Amenorrea/genética , Infertilidad Femenina/genética , Hormona Luteinizante de Subunidad beta/genética , Mutación , Receptores de HL/genética , Amenorrea/sangre , Amenorrea/tratamiento farmacológico , Amenorrea/patología , Animales , Gonadotropina Coriónica/uso terapéutico , Femenino , Terapia de Reemplazo de Hormonas , Humanos , Infertilidad Femenina/sangre , Infertilidad Femenina/tratamiento farmacológico , Infertilidad Femenina/patología , Hormona Luteinizante de Subunidad beta/uso terapéutico , Ciclo Menstrual/sangre , Ciclo Menstrual/efectos de los fármacos , Ciclo Menstrual/genética , Ratones , Ratones Noqueados , Receptores de HL/metabolismoRESUMEN
PURPOSE: to correlate the clinical manifestations of patients with amenorrhea and X chromosome abnormalities. METHODS: a retrospective analysis of the clinical and laboratorial findings of patients with amenorrhea and abnormalities of X chromosome, attended between January 1975 and November 2007 was performed. Their anthropometric measures were evaluated through standard growth tables, and, when present, minor and major anomalies were noted. The chromosomal study was performed through the GTG banded karyotype. RESULTS: from the total of 141 patients with amenorrhea, 16% presented numerical and 13% structural abnormalities of X chromosome. From these patients with X chromosome abnormalities (n=41), 35 had a complete clinical description. All presented hypergonadotrophic hypogonadism. Primary amenorrhea was observed in 24 patients, 91.7% of them with a Turner syndrome phenotype. Despite a case with Xq22-q28 deletion, all patients with this phenotype presented alterations involving Xp (one case with an additional cell lineage 46,XY). The two remaining patients with only primary amenorrhea had proximal deletions of Xq. Among the 11 patients with secondary amenorrhea, 54.5% presented a Turner phenotype (all with isolated or mosaic X chromosome monosomy). Patients with phenotype of isolated ovarian failure had only Xq deletions and X trisomy. CONCLUSIONS: the cytogenetic analysis must always be performed in women with ovarian failure of unknown cause, even in the absence of clinical dysmorphic features. This analysis is also extremely relevant in syndromic patients, because it can either confirm the diagnosis or identify patients in risk, like the cases involving a 46,XY lineage.
Asunto(s)
Amenorrea/genética , Cromosomas Humanos X , Aberraciones Cromosómicas Sexuales , Adolescente , Adulto , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: to verify the prevalence and clinical characteristics of patients with primary amenorrhea and XY karyotype, evaluated in our Service, aiming at identifying findings which could help their recognition. METHODS: from January 1975 to November 2007, 104 patients with amenorrhea were evaluated. All the cases were analyzed by the karyotype by GTG bands. Among them, 21 (20.2%) presented a XY 46 constitution. Nevertheless, two of them were excluded from the study, because of incomplete data in their patient's chart. Most of the 19 patients who formed the sample had been referred to us by the gynecology clinics (63.2%). Their ages varied from 16 to 41 years old (an average of 22.1). Data were collected about their family and previous history, physical examination and results of complementary exams and the information was taken into consideration to determine the diagnosis. RESULTS: the predominant diagnosis was resistance to androgens syndrome (n=12; 63.2%); five patients (25.3%) presented XY pure gonadal dysgenesis (XY PGD), one (5.3%) 17 alpha-hydroxylase deficiency, and one (5.3%), 5 alpha-reductase deficiency. Clinical findings frequently found in these patients included abnormal development of secondary sexual characters (n=19), uterine agenesia with a blind vagina (n=14), family history of amenorrhea (n=8), and palpable gonads in the inguinal canal (n=5). Two of them presented a history of inguinal hernia. Systemic arterial hypertension was only diagnosed in the patient with 17 alpha-hydroxylase deficiency, and gonadal malignization, in the one with XY PGD. CONCLUSIONS: the rate of patients with XY karyotype (20%) was higher than the one described in the literature (3 to 11%). It is believed that this fact is related to the way patients are usually referred to our service. Some findings from the clinical history and from the physical examination should be evaluated as a routine in individuals with primary amenorrhea. This way, there would be a more precocious detection of XY 46 patients, and a better clinical management of them, as a consequence.
Asunto(s)
Amenorrea/genética , Aberraciones Cromosómicas Sexuales , Adolescente , Adulto , Amenorrea/diagnóstico , Amenorrea/epidemiología , Femenino , Humanos , Cariotipificación , Linaje , Prevalencia , Factores de Riesgo , Adulto JovenRESUMEN
OBJETIVO: correlacionar as manifestações clínicas de pacientes com amenorréia e anormalidades do cromossomo X. MÉTODOS: realizou-se uma análise retrospectiva dos achados clínicos e laboratoriais das pacientes com amenorréia e anormalidades do cromossomo X, atendidas entre janeiro de 1975 e novembro de 2007. Suas medidas antropométricas foram avaliadas através de tabelas de crescimento padrão, sendo que, quando presentes, dismorfias menores e maiores foram anotadas. O estudo dos cromossomos foi realizado através do cariótipo com bandamento GTG. RESULTADOS: do total de 141 pacientes com amenorréia, 16 por cento apresentavam anormalidades numéricas e 13 por cento estruturais do cromossomo X. Destas pacientes com anormalidade do X (n=41), 35 possuíam descrição clínica completa. Todas elas apresentavam hipogonadismo hipergonadotrófico. Amenorréia primária foi observada em 24 pacientes, das quais 91,7 por cento com fenótipo de síndrome de Turner. Com exceção de um caso com deleção Xq22-q28, todas as demais pacientes com este fenótipo apresentavam alterações envolvendo Xp (uma com uma linhagem 46,XY associada). Os dois casos restantes com apenas amenorréia primária possuíam deleções proximais de Xq. Entre as 11 pacientes com amenorréia secundária, 54,5 por cento apresentavam fenótipo de Turner (todas com monossomia do X isolada ou em mosaico). Entre aquelas com fenótipo de falência ovariana isolada observaram-se somente deleções Xq e trissomia do X. CONCLUSÕES: a análise cromossômica deve sempre ser realizada em mulheres com falência ovariana de causa não conhecida, mesmo na ausência de achados dismórficos. Esta também é de extrema importância em pacientes sindrômicas, pois, além de confirmar o diagnóstico, é capaz de identificar pacientes em risco, como nos casos com uma linhagem 46,XY.
PURPOSE: to correlate the clinical manifestations of patients with amenorrhea and X chromosome abnormalities. METHODS: a retrospective analysis of the clinical and laboratorial findings of patients with amenorrhea and abnormalities of X chromosome, attended between January 1975 and November 2007 was performed. Their anthropometric measures were evaluated through standard growth tables, and, when present, minor and major anomalies were noted. The chromosomal study was performed through the GTG banded karyotype. RESULTS: from the total of 141 patients with amenorrhea, 16 percent presented numerical and 13 percent structural abnormalities of X chromosome. From these patients with X chromosome abnormalities (n=41), 35 had a complete clinical description. All presented hypergonadotrophic hypogonadism. Primary amenorrhea was observed in 24 patients, 91.7 percent of them with a Turner syndrome phenotype. Despite a case with Xq22-q28 deletion, all patients with this phenotype presented alterations involving Xp (one case with an additional cell lineage 46,XY). The two remaining patients with only primary amenorrhea had proximal deletions of Xq. Among the 11 patients with secondary amenorrhea, 54.5 percent presented a Turner phenotype (all with isolated or mosaic X chromosome monosomy). Patients with phenotype of isolated ovarian failure had only Xq deletions and X trisomy. CONCLUSIONS: the cytogenetic analysis must always be performed in women with ovarian failure of unknown cause, even in the absence of clinical dysmorphic features. This analysis is also extremely relevant in syndromic patients, because it can either confirm the diagnosis or identify patients in risk, like the cases involving a 46,XY lineage.
Asunto(s)
Humanos , Femenino , Adolescente , Adulto , Amenorrea/genética , Cromosomas Humanos X , Cariotipificación , Síndrome de Turner , Técnicas y Procedimientos DiagnósticosRESUMEN
Primary amenorrhoea refers to the absence of menarche by the age of 16-18 years in the presence of secondary sexual characteristics, and occurs in 1-3% of women of reproductive age. To study the prevalence of chromosomal abnormalities and the different options available for clinical management of women in Mexico with primary amenorrhoea, a cross-sectional study was conducted in 187 women with primary amenorrhoea referred from Department of Reproductive Medicine of Morones Prieto Hospital, IMSS in Monterrey, Mexico during 1995-2003. Peripheral blood lymphocytes were cultured for chromosomal studies by the standard methods. Numerical or structural abnormalities of the sex chromosome were found in 78 women (41.71%). These women were classified into four categories: X-chromosome aneuploidies (22.99%: 12.83% pure line and 10.16% mosaicism association with a 45, X cell line); presence of chromosome Y (10.70%); structural anomalies of the X chromosome (4.28%); and marker chromosomes (3.74%). In conclusion, the prevalence of chromosomal abnormalities in Mexican women with primary amenorrhoea is within the range (24-46%) reported in world literature. Chromosomal analysis is absolutely necessary for appropriate clinical management of these patients.
Asunto(s)
Amenorrea/genética , Aberraciones Cromosómicas , Amenorrea/epidemiología , Estudios Transversales , Femenino , Pruebas Genéticas , Humanos , Cariotipificación , México , PrevalenciaAsunto(s)
Humanos , Masculino , Femenino , Aborto Espontáneo/genética , Aborto Habitual/genética , Amenorrea/genética , Infertilidad Femenina/genética , Infertilidad Masculina/genética , Amenorrea/etiología , Anomalías Congénitas , Infertilidad , Infertilidad Femenina/complicaciones , Infertilidad Masculina/complicaciones , Técnicas Reproductivas/efectos adversosRESUMEN
OBJECTIVE: To report the clinical, hormonal, and molecular features of a female adolescent with selective FSH deficiency. In addition, a complete review of previous cases is provided, focusing on hormonal aspects. DESIGN: Clinical study. SETTING: University hospital. PATIENT(S): A 16-year-old girl with primary amenorrhea and poor breast development due to isolated FSH deficiency. INTERVENTION(S): Blood drawing before and after GnRH stimulation and pelvic ultrasound examination. MAIN OUTCOME MEASURE(S): Gonadotropin and E(2) measurements and sequencing of the FSH beta-subunit gene. RESULT(S): The patient was referred for primary amenorrhea and partial breast development (Tanner III). Her basal and GnRH-stimulated LH levels were elevated (31 IU/L and 98 IU/L, respectively), whereas her FSH levels were undetectable (<1 IU/L) in both conditions. Estradiol levels were low (<13 pg/mL). Automatic sequencing showed a nucleotide substitution of C for A in exon 3, resulting in a homozygous nonsense mutation in amino acid position 76 (Tyr76X) of the FSH beta-subunit. CONCLUSION(S): The Tyr76X mutation of the FSH beta-subunit was associated with a partial phenotype of FSH deficiency. To date, only four loss-of-function mutations of the FSH beta-subunit have been described in eight patients with undetectable serum FSH and high serum LH levels. Therefore, this unusual hormonal profile strongly suggests a defect in the FSH beta-subunit in both sexes.
Asunto(s)
Hormona Folículo Estimulante de Subunidad beta/deficiencia , Hormona Folículo Estimulante de Subunidad beta/genética , Infertilidad Femenina/genética , Infertilidad Masculina/genética , Adolescente , Adulto , Amenorrea/sangre , Amenorrea/genética , Sustitución de Aminoácidos , Femenino , Hormona Folículo Estimulante de Subunidad beta/sangre , Humanos , Infertilidad Femenina/sangre , Infertilidad Masculina/sangre , Masculino , FenotipoRESUMEN
An 18-year-old woman was evaluated because of primary amenorrhea and hypogonadism. Chromosome analysis from peripheral blood lymphocytes revealed a nonmosaic 46,X,+mar constitution. The marker was shown to be a rearranged Y chromosome consisting of an inverted duplication of the long arm: rea(Y)(qter-q11::q11-qter). Deletion mapping analysis with Y-specific STS showed that the marker lacked Yp and Y-centromeric (DYZ3) sequences, but it was positive for Yq sequences tested. Fluorescence in situ hybridization analysis with Y and X chromosome centromeric and pancentromeric probes showed no hybridization signals. The marker chromosome is present in 100% of the cells; therefore, it is mitotically stable despite the absence of DYZ3 centromeric sequence. Hybridization with CENP-A and CENP-C specific antibodies localized a neocentromere close to the breakpoint.
Asunto(s)
Centrómero/genética , Cromosomas Humanos Y/genética , Aberraciones Cromosómicas Sexuales , Adolescente , Amenorrea/genética , Bandeo Cromosómico , Femenino , Humanos , Hipogonadismo/genética , Hibridación Fluorescente in Situ , ProhibitinasRESUMEN
The luteinizing hormone receptor (LHR) plays a critical role in reproductive physiology in both males and females. Naturally occurring mutations in this receptor can cause genetically transmitted disorders by producing either gain or loss of receptor function. The clinical phenotype of the heterozygous activating mutations of the LHR gene has been exclusively described in males, who present familial or sporadic pseudoprecocious puberty. Affected boys were usually fertile at an adult age. In contrast, homozygous inactivating mutations of the LHR gene can cause a distinct spectrum of phenotypes. Severe inactivating mutations of the LHR have been recognized as the cause of Leydig cell hypoplasia, a rare form of male pseudohermaphroditism, in genetic males and as a novel cause of amenorrhea and infertility in genetic females. In addition, inactivating mutations that partially inactivate LH signaling can cause micropenis, sometimes accompanied by hypospadias and cryptorchidism. Both males and females with homozygous inactivating mutations of the LHR gene have suppression of fertility, which can represent the chief complaint of these patients.