Disgenesia gonadal pura 46 XX, una causa infrecuente de hipogonadismo: presentación de un caso / Pure gonadal dysgenesis 46 XX, an ucommon cause of hypogonadism: case presentation

El término disgenesia gonadal pura hace referencia a mujeres fenotípicas con infantilismo sexual, amenorrea primaria, hábito eunucoide y un cariotipo 46, XX o 46, XY sin anomalías cromosómicas. Puede asociarse a complicaciones como osteoporosis y síndrome metabólico, elevando el riesgo cardiovascular. Se presenta una paciente femenina de 16 años y 8 meses de edad que acude a consulta de endocrinología por presentar amenorrea primaria.

The term pure gonadal dysgenesis refers to phenotypic women with sexual infantilism, primary amenorrhea an d the eunucoid habit and a 46, XX or 46, XY karyotype without chromosomal abnormalities. It can be associated with complications such as osteoporosis and metabolic syndrome, increasing cardiovascular risk. We present a female patient of 16 years and 8 months of age who attended endocrinology clinic for presenting primary amenorrea.

Trastorno del desarrollo sexual testicular 46, XX en evaluación de la fertilidad masculina. Presentación de caso / Disorder in the sexual testicular 46, XX in evaluation of the male fertility. Presentation of a case

El trastorno del desarrollo sexual testicular 46,XX es una causa infrecuente de infertilidad masculina. Con el objetivo de reportar un caso diagnosticado en la consulta de genética clínica del Centro Provincial de Genética Médica de Mayabeque, se presenta paciente fenotípicamente masculino que acude por infertilidad primaria con azoospermia y atrofia testicular (AU)

Preserved fertility in a patient with a 46,XY disorder of sex development due to a new heterozygous mutation in the NR5A1/SF-1 gene: evidence of 46,XY and 46,XX gonadal dysgenesis phenotype variability in multiple members of an affected kindred.

In humans, steroidogenic factor 1 (NR5A1/SF-1) mutations have been reported to cause gonadal dysgenesis, with or without adrenal failure, in both 46,XY and 46,XX individuals. We have previously reported extreme within-family variability in affected 46,XY patients. Even though low ovarian reserve with preserved fertility has been reported in females harboring NR5A1 gene mutations, fertility has only been observed in one reported case in affected 46,XY individuals. A kindred with multiple affected members presenting gonadal dysgenesis was studied. Four 46,XY individuals presented severe hypospadias at birth, one of them associated with micropenis and cryptorchidism. The other 3 developed spontaneous male puberty, and 1 has fathered 5 children. Four 46,XX patients presented premature ovarian failure (one of them was not available for the study) or high follicle-stimulating hormone levels. Mutational analysis of the NR5A1 gene revealed a novel heterozygous mutation, c.938G→A, predicted to cause a p.Arg313Hys amino acid change. A highly conserved amino acid of the ligand-binding domain of the mature protein is affected, predicting abnormal protein function. We confirm that preserved fertility can be observed in patients with a 46,XY disorder of sex development due to heterozygous mutations in the NR5A1 gene.

46,XX DSD and Antley-Bixler syndrome due to novel mutations in the cytochrome P450 oxidoreductase gene.

Deficiency of the enzyme P450 oxidoreductase is a rare form of congenital adrenal hyperplasia with characteristics of combined and partial impairments in steroidogenic enzyme activities, as P450 oxidoreductase transfers electrons to CYP21A2, CYP17A1, and CYP19A1. It results in disorders of sex development and skeletal malformations similar to Antley-Bixley syndrome. We report the case of a 9-year-old girl who was born with virilized genitalia (Prader stage V), absence of palpable gonads, 46,XX karyotype, and hypergonadotropic hypogonadism. During the first year of life, ovarian cyst, partial adrenal insufficiency, and osteoarticular changes, such as mild craniosynostosis, carpal and tarsal synostosis, and limited forearm pronosupination were observed. Her mother presented severe virilization during pregnancy. The molecular analysis of P450 oxidoreductase gene revealed compound heterozygosis for the nonsense p.Arg223*, and the novel missense p.Met408Lys, inherited from the father and the mother, respectively.

Laparoscopic surgery in 46,XX disorder of sex development: hysterosalpingectomy with gonadectomy.

PURPOSE: We present the outcomes of one of the largest series specifically of laparoscopic hysterosalpingectomy with bilateral gonadectomy in 46,XX patients with congenital adrenal hyperplasia raised as a male. PATIENTS AND METHODS: From June 2005 to March 2008, five patients raised as male were treated at our institution using laparoscopic surgery. 46,XX disorder of sex development was diagnosed in all the patients because of congenital adrenal hyperplasia. Hysterosalpingectomy with bilateral gonadectomy was performed completely laparoscopically in all five patients. RESULTS: All procedures were completed with minimal blood loss. The duration of the surgeries was 70-125 minutes. There were no complications during surgery or conversion to open surgery. The hospital stay ranged from 1 to 2 days, except in one patient who presented urinary retention and was discharged from the hospital a week after the surgery. CONCLUSIONS: Laparoscopic surgery can be safely used as part of the diagnosis and treatment of 46,XX disorder of sex development. Laparoscopy can be useful in the diagnosis as well as surgical management of Müllerian structures as well as intraabdominal gonads contrary to social sex.

Male infertility related to an aberrant karyotype, 46,XY,9ph,9qh+.

OBJECTIVE: To report a man with primary infertility and variant karyotype. DESIGN: Case report. SETTING: Private practice. PATIENT(S): A 37-year-old man with 4 years of primary infertility due to oligoasthenozoospermia. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): G- and C-banding. Polymerase chain reaction for SRY, DBY, RBMY, DAZ, AMELX, and AMELY. RESULT(S): G-band analysis of the proband revealed a 46,XY,9ph,9qh+ karyotype. C-banding confirmed increase in the heterochromatin in one chromosome 9 and inversion in the other. CONCLUSION(S): The morphologic difference between the homologous chromosomes 9 may have been responsible for an error in crossing-over, leading to aberrant spermatozoa and consequently to infertility.

Gene analysis in patients with premature ovarian failure or gonadal dysgenesis: a preliminary study.

OBJECTIVE: The aim of this study was to evaluate the presence of mutations in the coding region of the QM gene and fragile X in patients with premature ovarian failure and gonadal dysgenesis. METHODS: After approval by the local Ethics Committee, blood samples, in EDTA, of 100 normally ovulating women, 23 with premature ovarian failure (POF) and 14 with gonadal dysgenesis 46XX, aged less than 40 years, were screened for mutation in the QM gene coding region. All patients with POF have 46, XX karyotype and serum levels of follicle-stimulating hormone (FSH) over 30 mIU/mL. In addition, all samples from patients with premature ovarian failure underwent analysis for fragile X. RESULTS: The QM gene located at a hotspot region (Xq28) showed five points of mutations in a patient with premature ovarian failure. Four of them were able to change the amino acid sequence of the protein. None of our patients were diagnosed as having pre or mutant X fragile syndrome. CONCLUSION: Our study suggests that Xq28 (QM gene) may be involved in ovary failure. However, further studies are needed to confirm this hypothesis.

Predictive value of anatomical findings and karyotype analysis in the diagnosis of patients with disorders of sexual development.

We assessed the predictive value of anatomical findings and karyotype for establishing a diagnostic orientation in patients with disorders of sex development (DSD). We performed a retrospective chart analysis of 228 patients, grouped into 4 categories: 46,XX DSD, non-dysgenetic testicular DSD, dysgenetic testicular DSD and ovotesticular DSD. Degree of virilisation, presence of vagina, presence of palpable gonads, size of gonads and a plain karyotype was available for all cases. 46,XX DSD due to congenital adrenal hyperplasia counted for 59.2% of the cases, non-dysgenetic testicular DSD for 13.6%, dysgenetic testicular DSD for 21.5% and ovotesticular DSD for 5.7%. Excluding congenital adrenal hyperplasia (CAH), a karyotype with at least one 46,XX cell line had a high diagnostic efficiency for ovotesticular DSD. In these patients, anatomical findings were not as useful to predict the gonadal phenotype. The existence of a 45,X cell line predicted with very high efficiency dysgenetic testicular DSD. Genital palpation was only partially helpful to predict the existence of testicular tissue. Non-dysgenetic testicular DSD could be ruled out with high efficiency in patients with an abnormal karyotype. Anatomical findings were helpful in 46,XY patients: palpated masses predicted non-dysgenetic testes with high accuracy. In all cases assessment of gonadal volume was less useful.

A rare case of gonadal agenesis with paramesonephric derivatives in a patient with a normal female karyotype.

OBJECTIVE: To report a rare case of gonadal agenesis with rudimentary paramesonephric ducts derivatives in a female with a 46,XX normal karyotype. DESIGN: Case study. SETTING: National Institute of Health. PATIENT(S): An 18-year-old female with primary amenorrhea and lack of secondary sexual development. INTERVENTION(S): Clinical, gynecological, endocrine, and genetic evaluation. Laboratory studies conducted included measurement of pituitary, ovary, and thyroid hormones; analyses of G-banded chromosomes in peripheral blood and fibroblast cultures; search for genomic Y-chromosome DNA by fluorescence in situ hybridization and molecular biology techniques; X-ray, ultrasonography, echocardiographic and laparoscopic studies for the assessment of bone age, and genitourinary and other associated malformations. MAIN OUTCOME MEASURE(S): Clinical, hormonal, anatomical, and genetic characteristics of the patient. RESULT(S): The studies performed confirmed a prepubertal female with hypergonadotrophic hypogonadism, bilateral gonadal agenesis, a rudimentary uterus and fallopian tubes, a normal vagina, kidney, and urinary tract structures, and a 46,XX normal karyotype. The search for centromeric Y-chromosome DNA and SRY and ZFY genes was negative. CONCLUSION(S): A primary deficiency confined to the gonadal blastema and the nearby coelomic epithelium is proposed as an alternative embryologic mechanism to explain the occurrence of this singular sexual developmental defect.

Factors associated with the reduction of bone density in patients with gonadal dysgenesis.

OBJECTIVE: To correlate bone mineral density (BMD) in women with primary hypoestrogenism caused by 46,XX pure gonadal dysgenesis or Turner's syndrome with age, age at estrogen therapy initiation, length of estrogen use, and body mass index (BMI). DESIGN: Cross-sectional study. SETTING: Academic tertiary-care hospital. PATIENT(S): Thirty-eight women, aged 16 to 35 years (mean, 24.6 years), affected by these genetic disorders. INTERVENTION(S): Measurement of lumbar spine and femoral neck BMD using double x-ray absorptiometry. The results were correlated with the control variables by using Pearson's coefficient of correlation. Variables associated with BMD were evaluated by multiple linear regression analysis. MAIN OUTCOME MEASURE(S): Bone mineral density. RESULT(S): Bone mineral density of the lumbar spine showed that 90% of the women presented osteopenia or osteoporosis. The femoral neck was affected in 55% of these women. The length of estrogen therapy and the BMI showed a positive association with BMD at the lumbar spine and femoral neck, respectively. CONCLUSION(S): Women affected by pure gonadal dysgenesis or Turner's syndrome presented a marked decrease in BMD of the lumbar spine and femoral neck. Medical attention for their diagnosis and early hormone replacement therapy are advised.

46,XX sex reversal.

In humans, sexual differentiation is directed by SRY, a master regulatory gene located at the Y chromosome. This gene initiates the male pathway or represses the female pathway by regulating the transcription of downstream genes; however, the precise mechanisms by which SRY acts are largely unknown. Moreover, several genes have recently been implicated in the development of the bipotential gonad even before SRY is expressed. In some individuals, the normal process of sexual differentiation is altered and a sex reversal disorder is observed. These subjects present the chromosomes of one sex but the physical attributes of the other. Over the past years, considerable progress has been achieved in the molecular characterization of these disorders by using a combination of strategies including cell biology, animal models, and by studying patients with these pathologic entities.