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Objective: To report the occurrence of a spontaneous pregnancy in a patient who was homozygous for the Q106R mutation in the GnRH receptor (GnRHR) gene. Design: Case report. Setting: Reproductive endocrinology unit of an academic medical center. Patient(s): A 27-year-old woman who initially presented with partial idiopathic hypogonadotropic hypogonadism and who achieved a spontaneous pregnancy 3 months after oral contraceptive pill (OCP) withdrawal. Intervention(s): Blood sampling for hormonal and genetic investigations, transvaginal ultrasound. Main Outcome Measure(s): LH, FSH, E 2 , and βhCG serum levels. Ultrasound examination of the uterine cavity. Result(s): Three months after OCP withdrawal, the patient was amenorrheic. However, the βhCG serum level was 149 IU/L. Transvaginal ultrasound 2 weeks later revealed the presence of one intrauterine sac containing two embryos with cardiac activity. At 9 weeks of gestation, no cardiac activity was found. A curettage was then performed, and the pathological examination indicated the presence of chorionic villi. Conclusion(s): OCP withdrawal might have induced a transient situation with optimal endogenous pulsatile GnRH secretion, thus overriding the GnRH resistance induced by the partially inactivating Q106R GnRHR gene mutation and allowing ovulation to occur.

Variability in the expression of monogenic lipid disorders may be observed in patients carrying the same DNA mutation, suggesting possible genetic or environmental interactions. Our objective was to investigate the genotype-phenotype relationships in two unrelated French patients with an aggravated expression of a dominantly inherited hypercholesterolemia. In probands, segregation analysis complemented by DNA sequencing identified heterozygous defective alleles and mutations on two nonallelic loci for two monogenic lipid disorders: familial hypercholesterolemia at the low density lipoprotein (LDL) receptor locus and familial defective apolipoprotein B-100 at the locus encoding its ligand, apolipoprotein B-100. The LDL-receptor missense mutations had been reported in French Canadians. The apolipoprotein B mutation was the Arg3500Gln founder mutation in Northern Europe. Probands had an unusual phenotype of aggravated hypercholesterolemia that was complicated with premature coronary arterial disease, although remaining responsive to lipid-lowering drugs. This phenotype was distinct from that observed in their heterozygous relatives and distinct from those observed in FH or FDB homozygotes. These cases refer to a new class of patients with digenic lipid disorders, defined by specific clinical features that result from the combined effects of two independent loci. Moreover, the observed phenotype of aggravated hypercholesterolemia gives further evidence that receptor and ligand play distinct roles in regulating LDL metabolism. Although uncommon, these cases give insight into the molecular mechanisms that underly the clinical variability of inherited hypercholesterolemia.

Using DNA sequencing of the coding and exon flanking regions of the low density lipoprotein receptor (LDLR) gene we identified an Alw26 I site in exon 10 by a transition G142A. The alleles are represented by one uncut fragment (A1=108bp) or two fragments (A2=82bp and 26 pb). Two other fragments (72bp and 16bp) were systematically found within the amplified product. The alleles were detected in 157 unrelated French Caucasians with A1 frequency = 0.58 and A2=0.42. The observed heterozygoty was 44.5%. Homozygous familial hypercholesterolemie (FH) has a severe clinical picture leading to death during childhood. Because it is very informative, the present polymorphism was very useful as genetic marker for clinical diagnois and counseling as we described in linkage analysis at the LDLR locus for prenatal diagnosis in a fetus who could inherit two LDLR mutant alleles from FH heterozygote parents.