Recurrent First-trimester Cystic Hygroma with Normal Chromosomes Identified in Two Cases with a Recessive Genetic Syndrome

Abstract

First-trimester cystic hygroma (CH) was a frequent finding in a general obstetric screening program for fetal aneuploidy. Chromosomal abnormalities can be diagnosed in most cases with CH, especially common trisomies and Turner syndrome. For first-trimester CH with a normal array result, management choices are limited except for waiting for serial ultrasounds to detect structural anomalies. We report two cases with a recurrent diagnosis of fetal first-trimester CH in two subsequent pregnancies. In both cases, detailed anatomic surveys in the second trimester showed structural anomalies. After excluding chromosomal abnormalities, trio-exome sequencing (ES) revealed two pathogenic variants, P3H1:c.1032T >A and c.1927_1930delinsGCTT in Case 1, and two pathogenic variants, KIAA1109:c.5788del and c. 3055C >T in Case 2. These findings were associated with two recessive genetic syndromes, osteogenesis imperfecta type VIII and Alkuraya-Kucinskas syndrome, in the two cases, respectively. Our study showed that the recurrence of fetal CH with a normal karyotype strongly indicates the existence of an autosomal recessive type of genetic disorder. For such cases, health providers should be alerted to this possibility, and early application of ES should be considered before the presentation of fetal structural anomalies which are usually present in second-trimester anatomic scans.