The genetics of recurrent hydatidiform moles: new insights and lessons from a comprehensive analysis of 113 patients.

Hydatidiform mole is an aberrant human pregnancy characterized by early embryonic arrest and excessive trophoblastic proliferation. Recurrent hydatidiform moles are defined by the occurrence of at least two hydatidiform moles in the same patient. Fifty to eighty percent of patients with recurrent hydatidiform moles have biallelic pathogenic variants in NLRP7 or KHDC3L. However, in the remaining patients, the genotypic types of the moles are unknown. We characterized 80 new hydatidiform mole tissues, 57 of which were from patients with no mutations in the known genes, and we reviewed the genotypes of a total of 123 molar tissues. We also reviewed mutation analysis in 113 patients with recurrent hydatidiform moles. While all hydatidiform moles from patients with biallelic NLRP7 or KHDC3L mutations are diploid biparental, we demonstrate that those from patients without mutations are highly heterogeneous and only a small minority of them are diploid biparental (8%). The other mechanisms that were found to recur in patients without mutations are diploid androgenetic monospermic (24%) and triploid dispermic (32%); the remaining hydatidiform moles were misdiagnosed as moles due to errors in the analyses and/or their unusual mechanisms. We compared three parameters of genetic susceptibility in patients with and without mutations and show that patients without mutations are mostly from non-familial cases, have fewer reproductive losses, and more live births. Our data demonstrate that patients with recurrent hydatidiform moles and no mutations in the known genes are, in general, different from those with mutations; they have a milder genetic susceptibility and/or a multifactorial etiology underlying their recurrent hydatidiform moles. Categorizing these patients according to the genotypic types of their recurrent hydatidiform moles may facilitate the identification of novel genes for this entity.

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes.

PURPOSE: Genomic rearrangements of chromosome 22q11.2, including the microdeletion associated with DiGeorge/velocardiofacial syndrome, are mediated by nonallelic homologous recombination between region-specific low-copy repeats. To date, only a small number of patients with 22q11.2 microduplication have been identified. METHODS: We report the identification by array-comparative genomic hybridization of 14 individuals from eight families who harbor microduplications within the 22q11.2 region. RESULTS: We have now observed a variety of microduplications, including the typical common approximately 3-Mb microduplication, approximately 1.5-Mb nested duplication, and smaller microduplications within and distal to the DiGeorge/velocardiofacial syndrome region, consistent with nonallelic homologous recombination using distinct low-copy repeats in the 22q11.2 DiGeorge/velocardiofacial syndrome region. These microduplications likely represent the predicted reciprocal rearrangements to the microdeletions characterized in the 22q11.2 region. The phenotypes seen in these individuals are generally mild and highly variable; familial transmission is frequently observed. CONCLUSIONS: These findings highlight the unbiased ability of array-comparative genomic hybridization to identify genomic imbalances and further define the molecular etiology and clinical phenotypes seen in microduplication 22q11.2 syndrome. Our findings also further support that the 22q11.2 region is highly dynamic with frequent rearrangements using alternative low-copy repeats as recombination substrates.

Severe intrauterine growth restriction associated with the development of a submucosal leiomyoma during pregnancy: a case report.

BACKGROUND: Small, intramural leiomyomas are not generally considered a risk factor for poor reproductive outcomes. CASE: A patient with a 6-mm intramural leiomyoma and a normal uterine cavity by hysteroscopic evaluation who conceived after in vitro fertilization developed severe early-onset intrauterine growth restriction (IUGR), leading to pregnancy termination at 23.4 weeks' gestation. At 6 weeks postpartum, a 1.7-cm, intracavitary leiomyoma was detected on ultrasound evaluation and removed by hysteroscopic resection. The patient conceived in a subsequent in vitro fertilization cycle and gave birth to monozygotic twins with appropriate weights at 34 weeks of gestation. In the absence of other identifiable etiologies of the IUGR, it is plausible that the small, intramural leiomyoma enlarged and migrated into the cavity, causing abnormal placentation and leading to fetal growth restriction in the first pregnancy. CONCLUSION: Uterine cavity reevaluation is recommended in the investigation of IUGR before a woman attempts further pregnancies.

Prothrombin gene variants in non-Caucasians with fetal loss and intrauterine growth retardation.

Thrombotic predisposition may affect pregnancy outcome, but in non-Caucasians the contributing genetic factors are poorly characterized. Two recently identified prothrombin gene mutations (20209C>T and 20221C>T) have been observed in non-Caucasian patients with thrombosis. The mutations are located near the commonly identified variant 20210G>A and have not been reported in Caucasian patients. The authors report a novel connection with pregnancy complications. The identification of sequence variants other than 20210G>A in the 3'-untranslated region of the prothrombin gene suggests that additional nucleotide substitutions may contribute to the development of thrombotic events and adverse pregnancy outcomes, especially in less well-characterized populations.

Postpartum uterine arteriovenous fistula.

BACKGROUND: Uterine arteriovenous communications are uncommon lesions that may be associated with life-threatening postpartum and postinstrumentation hemorrhage. CASE: A primigravida presented with infected retained products of conception. Excessive hemorrhage of unclear etiology occurred at dilation and curettage. After a second episode of bleeding, the patient received a diagnosis of uterine arteriovenous fistula. CONCLUSION: Uterine arteriovenous communications should be included in the differential diagnosis in patients with excessive postpartum or postinstrumentation bleeding. Color and spectral flow Doppler can aid diagnosis and clinical management.