The cumulative success of ovulation induction therapy with gonadotrophins in therapy-naïve anovulatory women: An observational study.

BACKGROUND: The use of gonadotrophins as a first-line treatment for anovulatory infertility has been limited by a perception of a risk of multi-fetal gestation and ovarian hyperstimulation syndrome (OHSS). However, it has recently been recognised as an acceptable first-line treatment if appropriate monitoring is performed. AIMS: To determine the cumulative live birth rate, incidence of multiple gestation, cycle cancellation rate and incidence of OHSS for therapy-naïve anovulatory women undergoing ovulation induction with gonadotrophins. MATERIALS AND METHODS: A prospective observational study of 258 patients undergoing ovulation induction with a 'low-dose step-up' protocol was performed over a three-year period across two fertility centres (40% of patients were currently or recently prescribed metformin). RESULTS: Twenty-six percent of patients required concurrent use of luteinising hormone. The cumulative pregnancy and live birth rates were 22.5% and 18.2%, 40.3% and 34.5%, 47.7% and 41.1% after completion of the first, second and third cycles of stimulation, respectively, with a median duration of stimulation of 15 days. No patients developed OHSS and 10.5% of cycles were cancelled due to an excessive or no follicular response. The multiple pregnancy rate was 2%. The cumulative pregnancy rate was reduced for women over 35 years of age (23.8 vs 55.3%, P = 0.006) and for women with a body mass index greater than 25 kg/m2 (40.6 vs 56.7%, P = 0.027). CONCLUSIONS: This study demonstrated that ovulation induction with gonadotrophin therapy, in the context of appropriate monitoring, is a safe and effective treatment for young therapy-naïve patients with anovulatory infertility.

Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes.

We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.

Independent post-zygotic breaks of a dicentric chromosome result in mosaicism for an inverted duplication deletion 9p and terminal deletion 9p.

Mosaicism with two cell lines having different rearrangements of the same chromosome is rare. Only a few cases of mosaicism have been described in association with chromosomal inverted duplication deletion (inv dup del) rearrangements. A well-established mechanism of formation of inv dup del rearrangements involves a dicentric intermediate, which undergoes breakage during cell division, generating cells with either an inv dup del or a simple deletion. A patient with developmental delay and dysmorphic features was found to carry two cell lines with rearrangements of 9p: an inv dup del 9p and a terminal deletion 9p. Microarray and FISH analysis showed that these cell lines do not constitute the reciprocal products of a single dicentric breakage event. We propose that independent post-zygotic breaks of a dicentric chromosome as a likely mechanism leading to the generation of the observed cell lines. The post-zygotic origin of the inv dup del rearrangements and the associated mosaicism can be a more frequent phenomenon than currently appreciated. Therefore, genotype-phenotype correlations in the inv dup del rearrangements need to take into account the possible presence of other abnormal cell lines during early development.

Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols.

OBJECTIVE: To ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in British Columbia between August 2002 and July 2007 to determine the incidence of this condition, the clinical and laboratory findings, and the risk of a contiguous gene deletion syndrome. METHODS: We reviewed the medical records of these patients to obtain detailed information about the maternal serum screening results, family history, investigations performed, and outcome of the pregnancy. RESULTS: Thirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimal estimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this condition was isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STS deficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 out of 12 (8.3%). CONCLUSION: The clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STS deficiency indicates that this is a common condition and in cases with no family history, the risk of contiguous gene deletion syndrome is significant, and warrants additional molecular genetic investigations of the mother and/or fetus.