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Background: Females with Xp;Yq translocations manifest short stature and normal fertility, but rarely have follow-up. The study purpose was to define the phenotype of a family with t(X;Y)(p22.3;q11.2), determine long-term reproductive function, and compare to all reported female cases., Methods: Comprehensive clinical and molecular analyses were performed on the female proband, who had regular menses, normal endocrine function, and three pregnancies spanning seven years--a normal liveborn male and two with unbalanced translocations (liveborn female and stillborn male)., Results: The translocation truncated KAL1 and deleted 44 genes on der(X). Our report constitutes the longest follow-up of an X;Y translocation female. She had no evidence of Kallmann syndrome, gonadoblastoma, or cardiovascular disease. Detailed analysis of 50 published female cases indicated a uniform lack of follow-up and significant morbidity-intellectual disability (10%), facial dysmorphism (28%), eye abnormalities (14%), and skeletal defects (28%)., Conclusions: Our findings indicate normal ovarian function to date in a woman with an t(X;Y)(p22.3;q11.2). However, additional published studies in the literature suggest careful follow-up is necessary and contradict the generalization that females with Xp;Yq translocations are usually normal except for short stature.

Background: 46,XY sex reversal is a rare disorder and familial cases are even more rare. The purpose of the present study was to determine the molecular basis for a family with three affected siblings who had 46,XY sex reversal., Methods: DNA was extracted from three females with 46,XY sex reversal, two normal sisters, and both unaffected parents. All protein coding exons of the SRY and NR5A1 genes were subjected to PCR-based DNA sequencing. In addition, array comparative genomic hybridization was performed on DNA from all seven family members. A deletion was confirmed using quantitative polymerase chain reaction. Expression of SOX9 gene was quantified using reverse transcriptase polymerase chain reaction., Results: A 349kb heterozygous deletion located 353kb upstream of the SOX9 gene on the long arm of chromosome 17 was discovered in the father and three affected siblings, but not in the mother. The expression of SOX9 was significantly decreased in the affected siblings. Two of three affected sisters had gonadoblastomas., Conclusion: This is the first report of 46,XY sex reversal in three siblings who have a paternally inherited deletion upstream of SOX9 associated with reduced SOX9 mRNA expression., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To mobilize and make available for anastomosis the maximal amount of mucosa from the expanded upper vaginal tissue and avoid postoperative narrowing of the vagina., Design: Technique paper., Setting: Tertiary care medical center., Patient(s): Patients with a hematocolpos due to transverse vaginal septum., Intervention(s): Pull through of proximal distended vagina using an Olbert balloon catheter., Main Outcome Measure(s): To avoid midvaginal narrowing due to retraction of the suture line in the surgical management of transverse vaginal septum with hematocolpos., Result(s): High-pressure balloon expansion of the proximal hematocolpos optimizes the vaginal mucosa available for final anastomosis., Conclusion(s): The use of a high-pressure dilatation balloon permits high intraballoon pressures that facilitate the surgical management of transverse vaginal septum and limit postoperative narrowing of the vagina., (Copyright © 2010. Published by Elsevier Inc.)

Objective: To characterize the phenotypic spectrum of males with bilaterally descended testes and a 45,X/46,X,(r)Y karyotype., Design: Retrospective review of patient records; cytogenetic and molecular analysis., Setting: Tertiary medical center setting., Participant(s): Five males, two prepubertal and three postpubertal, with a 45,X/46,X(r)Y karyotype and bilaterally descended testes., Intervention(s): Linear growth evaluation, testicular endocrine and exocrine studies, cytogenetic and molecular analysis on each patient., Main Outcome Measure(s): Clinical phenotype versus genotype., Result(s): Both prepubertal males had short stature and low testosterone. All three adults had normal puberty and normal testosterone levels. Two of the adults (one with short stature and one with normal stature) had elevated gonadotropins and azoospermia. The third adult had normal stature, severe oligospermia, normal gonadotropins, and normal serum testosterone., Conclusion(s): The phenotypic spectrum of males with a 45,X/46,X(r)Y karyotype and bilaterally descended testes varies greatly from males with short stature and spermatogenic failure to males without short stature and less severely affected spermatogenesis. This broad spectrum of phenotypic findings needs to be taken into account when the clinical geneticist encounters a prenatal diagnosis of a 45,X/46,X(r)Y karyotype. This information will also be helpful for pediatric and reproductive endocrinologists in counseling males with bilaterally descended testes and a 45,X/46,X(r)Y karyotype.

We report on the follow-up of a set of monozygotic (MZ) twins who were concordant for peripheral blood karyotype 45,X/46,XY but discordant for phenotypic sex. One twin is a phenotypically normal male and the other twin has asymetrical gonadal dysgenesis. The female twin has the mos45,X/46,XY karyotype in all four tissues: left testis, right streak, vas deferens, and clitoral skin. The normal male twin has the normal 46,XY karyotype in all three tissues tested: foreskin, scrotal skin, and testis. Follow-up of the twins at age 21, revealed persistence of mos45,X/46,XY karyotype in peripheral blood into adult life. However, the male grew up with normal male stature, reaching an adult height of 182 cm. The female twin received low dose estrogen replacement with complete breast development at age 14 years. She reached an adult height of 156 cm. At 21 years of age the male twin had normal testicular endocrine function, but severe oligospermia. The long-term follow-up of this set of MZ twins indicate that the male twin has the mosaicism confined to peripheral blood and has the normal 46,XY male constitution. This was further confirmed by his normal male stature and normal testicular endocrine function. The 45X cell line is likely due to his receiving these cells passively from his twin sister via placental anastomoses in utero. The exposure to these 45,X cells during development may have had an impact on his spermatogenesis., (Copyright 2007 Wiley-Liss, Inc.)

Context: Kallmann syndrome (KS) consists of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia/hyposmia. Currently, the fibroblast growth factor receptor 1 (FGFR1) gene is the only known autosomal dominant cause of KS, which is also associated with synkinesia, midfacial defects, and dental agenesis., Objective: Mutations in FGFR1 typically demonstrate reduced penetrance, variable expressivity, and until recently have been exclusively identified in families with anosmia. The purpose of this study was to determine whether FGFR1 mutations were present in a unique family with autosomal dominant, fully penetrant, normosmic IHH., Design: The study is a review of detailed clinical findings, dynamic endocrine studies, and performance of a molecular analysis of the FGFR1 gene., Setting: The study was carried out in an academic medical center., Patients: All four affected individuals have complete IHH with full penetrance but no anosmia/hyposmia, and they have none of the FGFR1-associated anomalies. In addition, no other family member has anosmia. Inverventions: Interventions included detailed phenotype characterization including history, physical exam, smell testing, dynamic pituitary testing, brain imaging, and molecular analysis., Main Outcome Measures: Outcome was measured by the determination of the severity of IHH, olfactory function, and sequence of the FGFR1 gene., Results: The same heterozygous nonsense mutation, Arg622X, was present in all four affected members, but not in three unaffected members or 100 controls. The mutation is predicted to encode a truncated protein or result in nonsense-mediated decay., Conclusions: Our findings indicate that mutations in the FGFR1 gene can cause normosmic, fully penetrant, complete IHH with little or no variable expressivity, and without the other FGFR1-associated anomalies typically found in KS.

Objective: To evaluate patients with hyperprolactinemia for the presence of dopamine receptor D2 polymorphisms., Design: Case-control study., Setting: Academic research environment., Patient(s): Women and men with pathologic hyperprolactinemia and healthy controls., Intervention(s): DNA extraction of peripheral blood, polymerase chain reaction, single-strand conformation polymorphism, DNA sequencing, and restriction digest., Main Outcome Measure(s): Two polymorphisms in exon 7 of the dopamine receptor D2 (DRD2) gene. Polymorphism 1 involves nucleotide 3420 (C to T, 313 His), and polymorphism 2 involves nucleotide 3438 (C to T, 319 Pro)., Result(s): The frequency of DRD2 polymorphism 1 alleles was increased in subjects with hyperprolactinemia. Analysis of the DRD2 genotypes demonstrates an odds ratio of 6.77 (2.39, 19.14; 95% confidence interval) for the polymorphism 1 homozygous state in hyperprolactinemia., Conclusion(s): A genetic predisposition to hyperprolactinemia is suggested by an excess homozygosity for polymorphism 1 in exon 7 of the DRD2 gene. Previous studies of lactotrophs from prolactinomas have found normal DRD2 receptors but differing isoform density. Homozygosity of polymorphism 1 may influence the distribution of the DRD2 isoforms on the lactotroph. Other potential mechanisms include an association with a molecular defect in a postreceptor signaling mechanism, such as a somatic inactivating mutation in a G1 protein, which could result in autonomous function of the lactotroph. Mutations could also result in different receptor-G protein interactions, such as a Gs instead of Gi, and result in autonomous lactotroph function.

Objective: The purpose of this study was to determine the consistency of calling single nucleotide polymorphisms (SNPs) by custom genome resequencing microarrays compared with capillary DNA sequencing., Study Design: Amplified genomic DNA from 23 patients with hypogonadotropic hypogonadism was hybridized to microarrays containing 30 kilobases of sequence from 6 different candidate genes. Capillary DNA sequencing was performed in 10 patients., Results: For 10 patients with > or =90% of bases called, 49 SNPs in 5 of 6 genes were identified. Of the 490 bases, 75 were ambiguous (read as "N"), and 415 were able to be called an A, C, G, or T. Of 415 called, 401 (96.6%) sequences were confirmed by DNA sequencing. All homozygotes (285/285) were called identically, while sequence from 89.2% (116/130) of heterozygotes agreed by both methods. The level of agreement between microarray calls and capillary DNA sequencing demonstrated substantial accuracy., Conclusion: Custom genome resequencing microarrays are highly consistent with capillary sequencing in calling individual bases in genomic DNA from patients with human disease.

Due to the original study design the frequency distribution of the slide categories sent to each of the three expert pathologists was essentially bimodal. The intraclass correlation coefficient for the 1-14 continuous categories reveals excellent agreement (0.82), whereas the kappa statistic for the dichotomized outcomes (>2 day lag) is poor (0.54). The discrepancy between the intraclass correlation coefficient and kappa values seems to be due to the bimodal distribution of the slide ratings. Some impartial mechanism was needed to make an unbiased selection of the slides used for endometrial dating. Imprecision in endometrial dating is due primarily to the limitations of the instrument and not the observer. Maturation stage of the endometrium is not critical for predicting a successful pregnancy.