Triploidy and Fetal Holoprosencephaly

Holoprosencephaly (HPE) is a developmental abnormality characterized by congenital malformations of the forebrain and mid-face. There are variable types of HPE, ranging from severe alobar HPE with cyclopia, ethmocephaly, cebocephaly, or HPE-PMA, to microforms with microcephaly, corpus callosum agenesis/dysgenesis, mental retardation, ocular hypotelorism, or a single maxillary central incisor. Chromosomal aberrations, Mendelian mutations, and teratogens are known causes of HPE. HPE is associated with chromosomal abnormalities such as trisomy 13, trisomy 18, triploidy, del(2p), dup(3p), del(7q), del(13q), del(18p), and del(21q). Prenatal diagnosis of HPE may be associated with triploidy. However, the actual frequency of triploidy associated with fetal HPE has not been well studied. During the period January 1987-August 2006,73 consecutive cases of fetal HPE presenting between 13 and 39 gestational weeks (mean: 23 weeks) were cytogenetically analyzed at the Department of Obstetrics and Gynecology, Mackay Memorial Hospital, faipei, Taiwan. Of the 73 cases with karyotyping, 41 cases (56.2 %) had numerical chromosomal abnormalities including 23 cases with trisomy 13, four cases with trisomy 18, five cases with triploidy, nine cases with structural chromosomal abnormalities such as distal 7q deletion, distal 3p duplication, distal 18p deletion and interstitial deletion of 14q, and 32 cases (43.8 %) had normal karyotypes. Triploidy represented 6.9 % (5/73) in fetal HPE detected in the second and third trimesters. The perinatal findings of five cases of triploidy with HPE are presented in Table I. All cases were diagnosed and terminated in the early second trimester. The mean maternal age was 29.6 ± 4.7 (mean ± SD) years, and the mean gestational age at prenatal diagnosis was 14.2 ± 1.3 (mean ± SD) weeks. None of the five cases had undergone assisted reproductive technology. Among these cases, there were one case of HPE-premaxillary agenesis (PMA) and four cases of cyclopia. The male to female sex ratio was 2:3. All cases resulted from errors in maternal meiosis II. Asymmetric intrauterine growth restriction (IUGR), oligohydramnios and relative macrocephaly were the most common associated sonographic abnormalities in addition to HPE. All cases were not associated with cystic placenta or partial hydatidiform mole. This study documents the frequency of triploidy in HPE detected in the second and third trimesters. The present study shows that triploidy in fetal HPE is predominantly maternal in origin as the result of an error in the second meiotic division and is not related to maternal age. Triploidy can be classified into two phenotypes based on the parental origin of the extra haploid set of chromosomes (7,8,10-12). Digynic triploidy is characterized by marked asymmetric IUGR, a small placenta without partial mole and a variety of congenital malformations that may affect almost every organ system. Diandric triploidy is characterized by normal fetal growth or mild degree of symmetric growth restriction, normal or partial molar placenta and a range of malformations similar to those of digynic triploidy. In the fetal period, cases with digynic triploidy are far more commonly observed than those with diandric triploidy. Fetal biometry and maternal serum screening have been shown to be useful for the first-trimester screening for fetal triploidy. Severe asymmetric IUGR is the most common presentation of digynic triploidy. Diandric triploidy is characterized by extremely high levels of free β-hCG and elevated nuchal translucency (NT), and digynic triploidy is characterized by very low levels of PAPP-A and free β-hCG with normal NT (9,11,16,18). All of our triploidies with HPE were digynic. However, triploidies with HPE may occasionally be diandric (2). Several reports of recurrent triploidy of maternal origin suggested an underlying genetic predisposition to errors in oogenesis (1,3,14). The frequency of HPE in prenatally diagnosed triploidy varies with gestational age at diagnosis. …