Holoprosencephaly

Embryo

In 2004, a large embryonic study of HPE from Japan was published. Embryos were diagnosed with HPE if they had characteristic craniofacial features, such as closely apposed or fused eyes, proboscis, and abnormally narrow heads. They found 201 HPE cases among 44,000 human embryos ranging from Carnegie stages 13 to 23, which corresponds approximately to 6 to 10 completed weeks based on last menstrual period. The prevalence of severe HPE in this embryonic population was 50 : 10,000. The actual prevalence is probably higher because mild forms of HPE could have escaped detection, particularly in the early stages of craniofacial development. This Japanese study did not classify the types of HPE according to brain anomalies, and karyotype was unknown.

Fetus

Many US reports describe the diagnosis of fetal HPE. A few fetal studies allow some epidemiologic conclusions. Kagan reported 57,119 pregnancies at 11 to 13 weeks' gestation, in which 44 cases of alobar HPE were detected, a prevalence of alobar HPE of 7.7 : 10,000. Of the 44 cases, 29 (66%) were aneuploid. Two likely reasons account for the high prevalence in this study: (1) early pregnancy losses in HPE fetuses, especially among fetuses associated with presumptive lethal chromosome defects, would not appear in series ascertained at birth, and (2) this may have been a selected population.

Blaas et al. reported 17 fetuses from a referral population and 13 fetuses from a nonselected population of 119,411 deliveries (greater than or equal to 16 weeks' gestation). The mean age of detection of the cases was 21 ± 3 weeks' gestation. After reviewing records at all hospitals with departments of obstetrics, pediatrics, and pathology within the catchment area, two further HPE cases (one alobar and one semilobar) were identified that had not been diagnosed before delivery and resulted in death shortly after birth. Cases with lobar HPE were not identified. The prevalence of HPE in the nonselected fetal population was 1.26 : 10,000. Chromosome aberrations were present in 37% (11 of 30) of the whole study group. The brain anomalies consisted of 18 lobar HPE (60%), 5 semilobar HPE (17%), 4 lobar HPE (13%), and 3 anencephalic HPE (10%; see later).

A study from Taiwan was based on HPE cases that were detected by US among cases referred for fetal karyotyping (Chen C, personal communication). A high prevalence of 6 : 10,000 could be the result of selection bias of pregnancies at risk for abnormal chromosomes. Only alobar HPE types were diagnosed, and 34 (58%) had abnormal chromosomes.

A perinatal study from California (121 HPE diagnoses in 1,035,386 live births and fetal death deliveries, registered from greater than or equal to 20 weeks' gestational age to 1 year after delivery) reported a prevalence of 1.2 : 10,000. The investigators found 56 alobar (46%), 24 semilobar (20%), and 11 lobar (9%) HPE cases, and 30 specimens (25%) had undetermined HPE type.

International Studies

Large international studies including termination of pregnancies, stillbirths, and live births have found relatively high prevalences of HPE. The prevalence of HPE cases ascertained was 2.16 : 10,000 in a hospital-based population of 179 cases from South America (during 2000 to 2003). In the International Clearinghouse Birth Defects Surveillance Registry, the prevalence was 1.31 : 10,000, based on 963 HPE cases from 2000 to 2004. A similar prevalence of 1.33 : 10,000 was observed in the EUROCAT registry in 2010, which included 827 cases of arrhinencephalia or HPE in approximately 6,218,000 deliveries occurring from 2000 to 2008.

HPE study populations differ depending on the age of the specimens, the time of the detection of HPE, the number of cases, identified subgroups (e.g., chromosomal, nonchromosomal, not karyotyped), and the type of population (selected or nonselected). Substantial variations also exist in the identified cerebral defects and accompanying facial anomalies that generate differences in the ascertainment and categorizing of HPE cases. The discrepancy between embryonic and early fetal populations versus perinatal populations indicates a high loss rate of fetuses with HPE early in the first trimester. In addition, it is probable that some HPE cases are not recognized perinatally and not registered. Newborns with HPE and normal faces and infants with mild cerebral HPE types are especially prone to being missed. The inclusion of diagnoses until age 1 year in the postnatal study in California probably explains the relatively high prevalence and large share of mild HPE types. HPE features in conditions such as anencephaly and agnathia can also be overlooked or ignored in some studies.

Embryology

A common denominator for the large variety of the HPE spectrum is a defective induction of the prosencephalic neuroepithelium, including neural crest population by the prechordal plate during embryonic development, which may lead to HPE with its variable facial and cerebral appearances. The mesendodermal prechordal plate is usually detectable in human embryos at Carnegie stages 7 and 8 rostral to the notochordal process in contact with the floor of the neural groove. At stages 9 and 10, the plate is related to neuromere D1, which consists of thick neural ectoderm and comprises the optic primordium. In humans, the critical time period for teratogenic induction of HPE is in “the [embryologic] 3rd to early 4th week” of human development, which corresponds approximately to Carnegie stages 9 and 10, or 4 weeks, 6 days to 5 weeks, 2 to 3 days, based on the last menstrual period.

Environmental Influences

Maternal factors such as diabetes have been associated with HPE. According to a study from 1983, the approximate risk to infants of diabetic mothers is 1% to 2%, which is a 200-fold greater risk than the general population. The pathogenetic factors and their effects could be summarized as the result of any interference with the glycolytic pathway leading to a decreased rate of glycolysis and conversion of glucose to pyruvate.

Animal studies have revealed that numerous teratogens may be involved in the development of HPE. In a review of teratogenesis of HPE, Cohen and Shiota summarized that various factors may be involved in the development of HPE, such as maternal alcohol consumption during early pregnancy, the influence of isotretinoin and etretinate on neural crest cells, mutated genes, and teratogens involving the Sonic Hedgehog (SHH) signaling pathway including perturbations in cholesterol homeostasis, which is an important part of this pathway. Two known causes of HPE in humans, fetal alcohol exposure and maternal diabetes, are both associated with elevated levels of reactive oxygen species. The possible involvement of oxidative stress in the pathogenesis of HPE was shown by treating pregnant mice with antioxidants (vitamins C and E) to reduce oxidative stress. They partly prevented ethanol-induced apoptosis in the prechordal mesendoderm and HPE malformations. This study may have important implications to the pathogenetic mechanisms and gene-environmental interaction in the genesis of HPE.

Abnormal Karyotype

The most frequently identified etiology of HPE is an abnormality of chromosome numbers. These abnormalities include trisomy 13, trisomy 18, and triploidy, although several other aberrations have been reported. Such chromosome aberrations are almost universally fatal in gestation or in infancy. Trisomy 13 accounts for 75% of HPE cases caused by chromosomal anomalies (including cryptic rearrangements). Triploidy accounts for 20% of HPE cases. Trisomy 18 is less commonly seen in conjunction with HPE and accounts for 1% to 2% of the cases. HPE has also been reported in patients with trisomies other than trisomies 13 and 18. Overall, the recurrence risk of HPE secondary to cytogenetic anomalies is approximately 1%.

Previous research on the genetic etiology of HPE showed at least 12 HPE candidate loci on 11 chromosomes, designated HPE 1 through 12. Advances in cytogenetic techniques have enabled higher resolution and improved descriptions of chromosome aberrations in cases with HPE and have identified at least 14 genes where heterozygous mutations cause HPE, and even suggest that in some families several genetic events are necessary to cause HPE.