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.

The arterial system in pre-eclampsia and chronic hypertension with superimposed pre-eclampsia.

OBJECTIVES: To determine if the normal gestational changes in mechanical properties of the arterial system are altered in pre-eclampsia. DESIGN: Prospective controlled observational study. SETTING: University urban tertiary medical centre. POPULATION: Eleven pre-eclamptics and 10 chronic hypertensives with superimposed pre-eclampsia were compared with 14 normotensive gravidas experiencing preterm labour, all receiving MgSO(4). Two additional control groups were studied as well: (A) nine normal pregnant women receiving neither magnesium nor epidural, for baseline comparisons; and (B) eight normotensive gravidas receiving epidural anaesthesia. METHODS: Two-dimensional targeted M-mode echocardiograms and continuous wave Doppler velocity were used to obtain instantaneous pressure and flow data. Total vascular resistance (TVR) quantified the steady component of systemic arterial load; pulsatile arterial load was characterised by global arterial compliance (AC), aortic input impedance spectrum (Z(1)) and characteristic impedance (Z(0)). MAIN OUTCOME MEASURES: TVR, AC, Z(1), Z(0). RESULTS: Controls, pre-eclamptics and chronic hypertensives with superimposed pre-eclampsia, respectively: TVR index 1328 [299], 1973 [609]*, 2428 [562]*(,#) dyn second cm(-5) m(2); AC area index 1.69 [0.46], 1.19 [0.46]*, 0.93 [0.38]* mL mmHg(-1) m(-2); Z(0) index 253.2 [61.3], 327.0 [135.1], 307.5 [130.9] dyn second cm(-5) m(2); and Z(1) index 184.2 [56.5], 283.6 [81.6]*, 357.1 [119.5]* dyn second cm(-5) m(2) (*P < 0.05 vs control;(#)P < 0.05 vs pre-eclampsia). Normal gravidas (in secondary controls group A) had decreased mean systolic and diastolic blood pressures, and increased AC and cardiac indices, compared with women receiving magnesium tocolysis, verifying the need for these primary controls. No differences were noted between normotensive gravidas receiving epidural anaesthesia (secondary controls group B) and the non-anesthetised controls (group A), eliminating epidural as a confounder. CONCLUSIONS: The normal gestational changes in systemic arterial mechanical properties are significantly altered in pre-eclampsia and these alterations are more marked with superimposed hypertensive disease.