P34.14: Brachmann‐de Lange syndrome: antenatal diagnosis in two consecutive pregnancies due to rare gonadal mosaicism of NIPBL gene mutation

Abstract

We report on a 35-year old gravida, who was referred to our ultrasound unit for targeted ultrasound examination. She had an uneventful prior delivery and a previous spontaneous abortion. Both parents were healthy and phenotypically normal. The mother had a history of antihypertensive drug treatment and suffered from moderate obesity. The first trimester scan appeared to be normal. However, biochemical testing revealed an elevated risk for trisomy 13/18. After genetic counseling the patients decided to undergo invasive karyotyping. The amniocentesis revealed a normal female karyotype. A follow-up scan at 18 gestational weeks showed a distal micromelia of both forearms, abnormal profile and microretrognathia. Thus, an underlying syndromal genetic disorder was assumed, such as Brachmann-de Lange syndrome (BdL) potentially affecting mental health in later infancy. After comprehensive genetic and pediatric counseling the parents opted for termination of the pregnancy. Molecular genetic investigation finally established the diagnosis of a BdL syndrome with a heterozygous nonsense-mutation in exon 29 of the NIPBL-gene. No such mutation was found in both parents. Due to the possibility of a rare gonadal mosaicism in one of the parents detailed prenatal scans in the next pregnancy were advocated. Surprisingly, detailed anatomical survey during the subseqent pregnancy showed similar limb reduction deformities of both forearms and an abnormal profile of the fetus at 14 weeks. A chorionic villous sampling was done for karyotyping and mutational analysis in the NIPBL-gene. This fetus again showed a normal female karyotype but the identical genetic alteration. In fact, a parental gonadal mosaicism was causative for recurrent BdL syndrome. The pregnancy was terminated on parental request. Psychological and genetical counseling was offered to the parents. The recurrence risk for BdL syndrome is verifiably elevated. The parents are still double-minded regarding a further pregnancy.