Comparison of mutation findings in ZIC2 between microform and classical holoprosencephaly in a Brazilian cohort.

BACKGROUND: Holoprosencephaly is the most frequent congenital malformation of the forebrain in humans. It is anatomically classified by the relative degree of abnormal formation and separation of the developing central nervous system. Mutations of ZIC2 are the second most common heterozygous variations detected in holoprosencephaly (HPE) patients. Mutations in most known HPE genes typically result in variable phenotypes that rage from classic alobar HPE to microforms represented by hypotelorism, solitary central maxillary incisor (SCMI), and cleft lip/palate, among others. Patients with HPE owing to ZIC2 mutations have recently been described by a distinct phenotype compared with mutations in other HPE causative genes. METHODS: We report the comparison of ZIC2 molecular findings by Sanger bidirectional DNA sequencing and ad hoc genotyping in a cohort of 105 Brazilian patients within the clinical spectrum of HPE, including classic and microform groups. RESULTS: We detected a total of five variants in the ZIC2 gene: a common histidine tract expansion c.716_718dup (p.His239dup), a rare c.1377_1391del_homozygous (p.Ala466_470del, or Ala 15 to 10 contraction), a novel intronic c.1239+18G>A variant, a novel frameshift c.1215dupC (p.Ser406Glnfs*11), and a c.1401_1406dup (p.Ala469_470dup, or alanine tract expansion to 17 residues). CONCLUSIONS: From these patients, only the latter two mutations found in classic HPE are likely to be medically significant. In contrast, variants detected in the microform group are not likely to be pathogenic. We show conclusively that the histidine tract expansion is a polymorphic alteration that demonstrates considerable differences in allele frequencies across different ethnic groups. Therefore, careful population studies of rare variants can improve genotype-phenotype correlations. Birth Defects Research (Part A) 2012.

Holoprosencefalia: a propósito de un caso clínico / Holoprosencephaly: a report of a case

La holoprosencefalia es la malformación prosencefálica más frecuente; su etiología es heterogénea y en ocasiones se asocia alteraciones genéticas e infecciones virales. Se presenta el caso de una paciente de 27 años de edad, IIG, IP, 1 Aborto, con embarazo de 27 semanas + 4 días, amenaza de parto pretérmino, holoprosencefalia y antecentes de herpes genital durante el primer trimestre.

Holoprosencephaly is the more frequent prosencephalic malformation. The etiology is heterogeneous an d some times is associated with genetic alterations and uterine viral infections. We present a pregnant 27 old year patient with 27 weeks and 4 days, preterm labor and genital herpes infection on the first trimester.

Risk factors for non-syndromic holoprosencephaly in the National Birth Defects Prevention Study.

Holoprosencephaly (HPE) is a complex structural brain anomaly that results from incomplete cleavage of the forebrain. The prevalence of HPE at birth is low, and risk factors have been difficult to identify. Using data from a large multi-state population-based case-control study, we examined risk factors for non-syndromic HPE. Data from maternal telephone interviews were available for 74 infants with HPE and 5871 controls born between 1997 and 2004. Several characteristics and exposures were examined, including pregnancy history, medical history, maternal diet and use of nutritional supplements, medications, tobacco, alcohol, and illegal substances. We used chi(2)-tests and logistic regression (excluding women with pre-existing diabetes) to examine associations with HPE. Except for diet (year before pregnancy) and sexually transmitted infections (STIs) (throughout pregnancy), most exposures were examined for the time period from the month before to the third month of pregnancy. HPE was found to be associated with pre-existing diabetes (chi(2) = 6.0; P = 0.01), aspirin use [adjusted odds ratio (aOR) = 3.4; 95% confidence interval (CI) 1.6-6.9], lower education level (aOR = 2.5; 95%CI 1.1-5.6), and use of assisted reproductive technologies (ART) (crude OR = 4.2; 95%CI 1.3-13.7). Consistent maternal folic acid use appeared to be protective (aOR = 0.4; 95%CI 0.2-1.0), but the association was of borderline statistical significance. While some of these findings support previous observations, other potential risk factors identified warrant further study.

Epidemiology of holoprosencephaly: Prevalence and risk factors.

The wide variation in cerebral and facial phenotypes and the recognized etiologic heterogeneity of holoprosencephaly (HPE) contribute to the observed inter-study heterogeneity. High lethality during the early stages of embryonic and fetal development makes HPE detection age dependent. By reviewing 21 HPE epidemiologic articles, the observed prevalence rate differences can be largely explained by the pregnancy outcome status of the studied cohort: livebirth, stillbirth, and terminations of pregnancy (TOPs): lower than 1 per 10,000 when live and still births were included, higher when TOPs were included, and between 40 and 50 per 10,000 in two classical Japanese studies on aborted embryos. The increasing secular trend observed in some studies probably resulted from an increasing use of prenatal sonography. Ethnic variations in birth prevalence rates (BPRs) could occur in HPE, but the available data are not very convincing. Higher BPRs were generally observed in the less favored minorities (Blacks, Hispanics, Pakistanis), suggesting a bias caused by a lower prenatal detection rate of HPE, and consequently less TOPs. Severe ear defects, as well as microstomia, were part of the spectrum of HPE. Non-craniofacial anomalies, more frequently associated with HPE than expected, were genital anomalies (24%), postaxial polydactyly (8%), vertebral defects (5%), limb reduction defects (4%), and transposition of great arteries (4%). The variable female predominance, found in different HPE studies, could also depend on the proportion of early conceptions in each study sample, as males are more likely to be lost through spontaneous abortions.

Clinical epidemiologic study of holoprosencephaly in South America.

ECLAMC: Latin American Study of Congenital Malformations examined 4,157,224 births (1967-2000), detecting 370 newborns with suspected holoprosencephaly (HPE): 182 (49.2%) had only craniofacial defects; 99 (26.8%) had defects in other systems; (15.1%) had chromosomal anomalies; 5 (1.4%) had recognized syndromes; and 28 (7.6%) had isolated median cleft lip. The latter group was excluded from subsequent analyses because of epidemiological differences from the other groups. The birth prevalence rate (BPR) of isolated HPE was homogeneous among the 11 sampled countries, increasing from 0.5/10,000 births to 1/10,000 births between 1967 and 2000, suggesting improved ascertainment, mainly after 1996. Microtia, cleft lip/palate, and microstomia were preferentially associated with HPE, but cleft palate only was not. Maternal diabetes was more prevalent in HPE than in controls when adding the isolated and associated groups (OR: 3.5; 95% CI: 0.9-16.2). Maternal flu was more prevalent in isolated HPE (OR: 3.6; 0.9-16.6) and in isolated plus associated HPE (OR: 2.8; 1.0-7.9) than in controls. A second series of better documented HPE cases, 179 in number (2.2/10,000), ascertained from 827,968 births occurring from 2000 to 2003, was used for phenotypic definition of cerebral and facial anomalies. In 83 of 174 HPE cases with specified cerebral defects, 40% were alobar, 43% were semilobar, and 17% were lobar. All cases of cyclopia, ethmocephaly, and cebocephaly were of the alobar or semilobar types. Female excess occurred in the total sample, but not within the subgroups themselves because of their small sample sizes. Neither alobar HPE nor cyclopia was associated with female predilection. Among the 174 HPE cases, 39% had neither oral clefting nor a severe dysmorphic face. Of facial phenotypes, 26% had cyclopia, ethmocephaly, or cebocephaly; 25% had premaxillary agenesis; and 10% had cleft lip and palate or cleft palate only. Cyclopia was not associated with oral clefts; 6 of 8 cases of ethmocephaly had cleft palate; 6 of 20 cases of cebocephaly had oral clefts; 4 of 20 cases had premaxillary agenesis; and 2 of 20 cases had cleft palate.

An epidemiological study of holoprosencephaly from a regional congenital anomaly register: 1995-2004.

BACKGROUND: Adequate contemporary information to counsel patients with a prenatal diagnosis of holoprosencephaly is lacking. We addressed this using data from the West Midlands Congenital Anomaly Register (WMCAR), a population-based malformation register, during a time where technological improvements have been stable and anomaly screening is well established. METHODS: Cases were defined using the ICD 10 code for holoprosencephaly. Cases of livebirths, stillbirths and termination at all gestations were included in the study. The diagnosis was verified by a pathology or definitive radiological report with cross validation from the regional pathology, clinical genetics, cytogenetics and fetal medicine databases. RESULTS: There were 113 cases reported of holoprosencephaly for the years 1995-2004. This represents a prevalence of 1.7 per 10,000 births and terminations, with no change in prevalence over time. There was a decreased risk of holoprosencephaly in the white population [white vs. nonwhite; RR 0.53(0.36-0.79)]. Karyotypical abnormality was noted in 46% of cases where the karyotype was known. Trisomy 13 was the most common chromosomal abnormality. Correct allocation of a diagnosis of holoprosencephaly by ultrasound occurred in 77% of cases, with another 12% having a severe intracranial abnormality but was not reported as holoprosencephaly. In 4%, a prenatal diagnosis of holoprosencephaly was not made. Termination of pregnancy was performed in 80% of all cases. CONCLUSION: Holoprosencephaly is a morbid condition associated with significant secondary etiologies.

Holoprosencephaly: epidemiologic and clinical characteristics of a California population.

Holoprosencephaly is a brain defect resulting from incomplete cleavage of the embryonic forebrain. It involves forebrain and facial malformations that can range from mild to severe. The epidemiology of holoprosencephaly is largely unknown. Published prevalence estimates have been derived from clinic-based case series, and suggested risk factors for holoprosencephaly have been identified in case reports, without confirmation from systematically conducted population-based studies. Using data from a population-based birth defects registry in California, we describe the epidemiologic and clinical characteristics of cytogenetically and phenotypically distinct types of holoprosencephaly. A total of 121 cases was identified among a cohort of 1,035,386 live births and fetal deaths. The prevalence of holoprosencephaly was 1.2 per 10,000 births (95% confidence interval 1.0-1.4 per 10,000). Of all cases, 41% (50/121) had a chromosomal abnormality, most commonly Trisomy 13. Among the 71 cytogenetically apparently normal cases, 18 had recognizable syndromes and the remaining 53 were of unknown cause. Among the cytogenetically abnormal cases, females had a greater risk than males (odds ratio = 2.3,95% confidence interval [1.2, 4.4]). Among the cytogenetically normal cases, increased risks were observed among Hispanic whites (OR = 1.8 [0.9, 3.6]) and cases whose mother was born in Mexico (OR = 2.2 [1.0, 4.5]). Approximately 46% of all cases had alobar holoprosencephaly, the most severe form of the forebrain malformation. The facial phenotype did not strongly predict the severity of the brain defect; however, severity was inversely correlated with length of survival. This study is the first to present findings based on such a large population-based series of infants/fetuses affected by holoprosencephaly, and demonstrates the importance of investigating the component subgroups of this rare phenotype.