Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: Searching for population variations

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DOI: 10.1002/bdra.20479 · Source: PubMed
Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median maxillary central incisor. Information on the epidemiology of HPE is limited, both because few population-based studies have been reported, and because small studies must observe a greater number of years in order to accumulate sufficient numbers of births for a reliable estimate. We collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International Clearinghouse for Birth Defects Surveillance and Research. This study is based on more than 7 million births in various areas from North and South America, Europe, and Australia. A total of 963 HPE cases were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heterogeneous, possible causes of variations among populations were analyzed: random variation, under-reporting and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases and real differences among populations. The data do not suggest large differences in total prevalence of HPE among the studied populations that would be useful to generate etiological hypotheses.


Frequency of Holoprosencephaly in the International
Clearinghouse Birth Defects Surveillance Systems:
Searching for Population Variations
Emanuele Leoncini,
Giovanni Baranello,
da M. Orioli,
ran Annere
Marian Bakker,
Fabrizio Bianchi,
Carol Bower,
Mark A. Canfield,
Eduardo E. Castilla,
Guido Cocchi,
Adolfo Correa,
Catherine De Vigan,
Berenice Doray,
Marcia L. Feldkamp,
Miriam Gatt,
Lorentz M. Irgens,
R. Brian Lowry,
Alice Maraschini,
Robert Mc Donnell,
Margery Morgan,
Osvaldo Mutchinick,
Simone Poetzsch,
Merilyn Riley,
Annukka Ritvanen,
Elisabeth Robert Gnansia,
Gioacchino Scarano,
Antonin Sipek,
Romano Tenconi,
and Pierpaolo Mastroiacovo
Centre of the International Clearinghouse for Birth Defects Surveillance and Research, Roma, Italy
Istituto di Neuropsichiatria Infantile, Universita
Cattolica Sacro Cuore, Roma, Italy
ECLAMC at Dept. Gene
tica, Universidade Federal do Rio de Janeiro, Brazil
Department of Clinical Genetics, Uppsala University, Uppsala and Swedish Births Defects Registry, Stockholm, Sweden
EUROCAT Northern Netherlands, Department of Genetics, University Medical Centre Groningen,
University of Groningen, Groningen, Netherlands
Sezione di Epidemiologia e Biostatistica, Istituto di Fisiologia Clinica del CNR, Pisa, Italy
Western Australian Birth Defects Registry (WABDR), Women and Newborn Health Service, Subiaco, Western Australia
Texas Birth Defects Epidemiology & Surveillance Branch, Austin, Texas
Istituto Clinico di Pediatria Preventiva e Neonatologia, Universita
di Bologna, Bologna, Italy
Metropolitan Atlanta Congenital Defects Program, National Center on Birth Defects and Developmental Disabilities,
Centers for Disease Control and Prevention, Atlanta, Georgia
Registre des malformations conge
nitales de Paris, INSERM U 149, Recherches e
en sante
rinatale et sante
des femmes, Villejuif, France
Service de Ge
tique Me
dicale, Hopital de Hautepierre, Strasbourg, France
Department of Pediatrics, Division of Medical Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah
Malta Congenital Anomalies Registry, Department of Health Information and Research, Guardamangia, Malta
Medical Birth Registry of Norway, Department of Public Health and Primary Care,
University of Bergen and the Norwegian Institute of Public Health, Bergen, Norway
Alberta Congenital Anomalies Surveillance System, Alberta Health & Wellness, Calgary, Alberta, Canada
Population Health Directorate, HSE, Dr. Steevens Hospital, Dublin, Ireland
Congenital Anomaly Register and Information Service (CARIS), Singleton Hospital, Swansea, Wales, United Kingdom
RYVEMCE, Department of Genetics, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City, Mexico
Malformation Monitoring Saxony-Anhalt, Faculty of Medicine, Otto-von-Guericke University, Magdeburg, Germany
Victorian Birth Defects Register, Perinatal Data Collection Unit, Department of Human Services, Victoria, Australia
National Research and Development Centre for Welfare and Health (STAKES), Helsinki, Finland
REMERA, Registre des Malformations en Rho
ne Alpes, Faculte
Laennec, Lyon, France
Birth Defects Campania Registry, Medical Genetics Dept., General Hospital ‘‘G. Rummo’’ Benevento, Italy
Department of Population Teratology, Institute for Care of Mother and Child, Prague, Czech Republic
Dipartimento di Pediatria, Genetica Clinica ed Epidemiologica, Universita
di Padova, Padova, Italy
Received 25 February 2008; Revised 10 April 2008; Accepted 12 April 2008
BACKGROUND: Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incom-
plete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly
and single median maxillary central incisor. Information on the epidemiology of HPE is limited, both
because few population-based studies have been reported, and because small studies must observe a greater
number of years in order to accumulate sufficient numbers of births for a reliable estimate.
collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International
Grant sponsor: Centers for Disease Control and Prevention, National Center
on Birth Defects and Developmental Disabilities; Grant number: U50/
*Correspondence to: Pierpaolo Mastroiacovo, Centre of the International
Clearinghouse for Birth Defects Surveillance and Research, Roma, Italy.
Published online 19 June 2008 in Wiley InterScience (www.interscience.
DOI: 10.1002/bdra.20479
Birth Defects Research (Part A): Clinical and Molecular Teratology 82:585–591 (2008)
Ó 2008 Wiley-Liss, Inc. Birth Defects Research (Part A) 82:585–591 (2008)
Clearinghouse for Birth Defects Surveillance and Research. This study is based on more than 7 million births
in various areas from North and South America, Europe, and Australia. RESULTS: A total of 963 HPE cases
were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heteroge-
neous, possible causes of variations among populations were analyzed: random variation, under-reporting
and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases
and real differences among populations.
CONCLUSIONS: The data do not suggest large differences in
total prevalence of HPE among the studied populations that would be useful to generate etiological
hypotheses. Birth Defects Research (Part A) 82:585–591, 2008. Ó 2008 Wiley-Li ss, Inc.
Key words: holoprosencephaly; epidemiology; pre valence; brain malformations; ICBDSR
Holoprosencephaly (HPE) is a developmental field
defect of the brain that results from a primary defect in
induction and patterning of the forebrain during the first
4 weeks of embryogenesis (Golden, 1999; Cohen, 2006;
Dubourg et al., 2007). The exact processes involved in the
pathogenesis of HPE, however, still remain unknown.
This defect results in incomplete separation of the cere-
bral hemispheres and has traditionally been classified
into three types: alobar, semilobar, and lobar, with alobar
being the most severe. Alobar, despite its severity, may
be associated with facial anomalies (e.g., cyclopia, ethmo-
cephaly, cebocephaly, premaxillary agenesis), with a mild
hypotelorism, or no anomalies at all (De Myer et al.,
1964). Included in the HPE spectrum with less severe
phenotypes are arhinencephaly, characterized by the ab-
sence of the olfactory tracts and bulbs, and other less
severe phenotypes, such as single median maxillary cen-
tral incisor or choanal stenosis, and the most mild sub-
type, called middle interhemispheric variant (De Myer
et al., 1964; Dubourg et al., 2007).
Etiologically, HPE is a heterogeneous condition, with
known genetic and environmental factors influencing
early brain development (Cohen, 2006). Chromosomal
abnormalities account for nearly one-third of HPE cases,
trisomy 13 being the most common (Bullen et al., 2001;
Dubourg et al., 2007). Isolated HPE cases, recognized as
familial or presumably due to a single gene, represent a
small proportion and have heterogeneous phenotypes.
Multiple genes have been implicated, including Sonic
hedgehog, ZIC 2, SIX 3, and TIGF (Cohen, 2003). A few
cases have been attributed to nongenetic factors, mainly
maternal diabetes (Croen et al., 2000). Approximately
65% of HPE cases remain unexplained, suggesting the
involvement of many other genes or environmental risk
factors (Dubourg et al., 2007).
Information on the epidemiology of HPE is limited. The
reported frequency of HPE in the available population-
based studies ranges from 0.51 to 2.62 per 10,000 (Saunders
et al., 1984; Croen et al., 1996; Rasmussen et al., 1996;
Whiteford and Tolmie, 1996; Olsen et al., 1997; Forrester
and Merz, 2000; Bullen et al., 2001; Ong et al., 2007). The
relative rarity of HPE makes it challenging to estimate the
prevalence. Small population-based studies must include
births over many years in order to collect sufficient num-
bers for reliable estimates. Studies covering long time
spans may be affected by changes over time in factors
determining the occurrence of the defect and its diagnosis.
Furthermore, in recent years the use of prenatal diagnosis
and termination of pregnancies (ToPs) compel us to con-
sider cases of terminated pregnancy as an indispensable
source of information to evaluate the frequency of this
defect. The aims of the present study are: (1) to evaluate
the frequency of HPE in the most recent years in a large
number of registries of birth defects; (2) to evaluate the
proportion of terminated pregnancies among all cases; and
(3) to identify possible differences among the studied pop-
We used data collected by birth defects surveillance
systems that are Members of the International Clearing-
house for Birth Defects Surveillance and Research
(ICBDSR). The data, sent year by year by the surveillance
systems to the ICBDSR Center to prepare the annual
report, were reviewed and validated with the authors
according to the following definition of HPE: ‘‘A congen-
ital malformation of the brain, characterized by various
degrees of incomplete lobation of the brain hemispheres.
Olfactory nerve tract may be absent’’ (ICBDSR, 2005).
Among the 46 ICBDSR Members we have selected for
this study those that regularly sent data annually in the
last 5 years (2000–2004) and routinely registered live-
births, stillbirths, and ToPs (ToPs not permitted in Ire-
land Dublin, Malta, Mexico RYVEMCE-Mexican Registry
and Epidemiological Surveillance of External Congenital
Malformations, South America ECLAMC-Latin-American
Collaborative Study of Congenital Malformations) and
confirmed or corrected data for this article. We have
excluded England and Wales because an under-registra-
tion of birth defects has been detected (Boyd et al., 2005),
and Hungary because only the registered isolated cases
are regularly provided, excluding cases with multiple
defects and syndromes.
The main characteristics of each surveillance system
are given in Table 1. With two exceptions (Mexico
RYVEMCE and South America ECLAMC), all of them
are population-based surveillance systems. The specific
methods used by these surveillance systems to identify,
code, and report birth defects are available from the an-
nual report of the ICBDSR (ICBDSR, 2005) and in the
main papers of some surveillance systems (Bower, 1995;
Castilla and Orioli, 2004; De Vigan et al., 2005; Feldkamp
et al., 2005; Irgens, 2000; Ka
n, 2005; Lowry et al., 1989;
STAKES, 2007). In general, diagnosis of HPE has been
Birth Defects Research (Part A) 82:585–591 (2008)
confirmed by clinical examination, autopsy, ultrasound,
and/or MRI.
We computed the ‘‘total prevalence’’ per 10,000 births
for each surveillance system and for eight groups of
registries to evaluate possible population similarities and
variations: North America (Canada and USA, four sur-
veillance systems), Latin America (Mexico and South
America, two surveillance systems), Nordic Countries
(Northern Netherlands, Norway, Sweden, and Finland,
four surveillance systems), Central Europe (Czech Repub-
lic and Germany Saxony-Anhalt, two surveillance sys-
tems), British Isles (Ireland Dublin and Wales, two sur-
veillance systems), France (three surveillance systems),
Italy (four surveillance systems), and Australia (two sur-
veillance systems). Malta was excluded, having zero
The numerator was the total number of cases of HPE
occurring in stillbirths, livebirths, and ToPs with HPE,
and the denominator was the total number of births (live-
births plus stillbirths). Spontaneous abortions (e.g., mis-
carriages less than 20 weeks gestation) were excluded
from prevalence estimates. We calculated 95% CI around
the prevalence for each register and overall using
the Poisson distribution. Statistical heterogeneity was
assessed using Q statistic and visually with the Galbraith
plot using STATA version 10.0 software. p value less
than 10% was considered significant for statistical hetero-
geneity. The Spearman’s rank correlation coefficient (r
was used to compute correlation between HPE rates and
proportion of ToPs according to the following interpreta-
tion of r: r ranging from zero to about .20 may be
regarded as indicating no or negligible correlation, from
about .20 to .40 may be regarded as indicating a low
degree of correlation, from about .40 to .60 may be
regarded as indicating a moderate degree of correlation,
from about .60 to .80 may be regarded as indicating a
marked degree of correlation, from about .80 to 1.00 may
be regarded as indicating high correlation (Franzblau,
Of the 24 ICBDSR Surveillance Systems, 963 HPE cases
were registered among a total of 7.35 million births,
yielding an overall prevalence of 1.31 per 10,000 births
(95% CI: 1.23–1.40) (Table 2 and Fig. 1).
Total prevalence rates varied from 0.63 (USA Atlanta)
to 2.50 (France Strasbourg) per 10,000. The wide hetero-
Table 1
Participating Surveillance Systems and Their Main Methodological Characteristics
Surveillance systems Coverage
Type of
Termination of
Maximum age for
or registration
Australia Victoria RP A 1 P, MS P 15 years
Canada Alberta RP A 1 P, MS P 1 year
Czech Republic RP A 1 P, MS P 15 years
Finland RP P, MS P 1 year
France Central East RP A 1 P, MS P 1 year
France Paris RP A, MS P Hospital
France Strasbourg RP P, SS P 2 years
Germany Saxony Anhalt RP A 1 P, MS P 1 year
Ireland Dublin RP P, MS NP 5 years
Italy Campania PP P, MS P 1 week
Italy Emilia Romagna PP P, SS P 1 week
Italy North East PP P, MS P 1 week
Italy Tuscany RP P, SS P 1 year
Malta RP A, MS NP 1 year
Mexico RYVEMCE H P, SS NP 72 hours
Northern Netherlands RP A 1 P, MS P 15 years
Norway RP P, MS P 1 year
South America ECLAMC H P, SS NP 3 days
Sweden RP P, MS P 1 year
USA Atlanta RP A, MS P 6 years
USA Texas PP A, MS P 1 year
USA Utah RP A 1 P, MS P 2 years
Wales RP A 1 P, MS P 1 year
Western Australia RP P, MS P 6 years
RP 5 ‘‘based on resident population’’ when it includes only subjects born to mothers with the residency during gestation in the area
covered by the registry, wherever the delivery took place, and it excludes all the subjects born to nonresident mothers that delivered in
the area covered by the registry. PP 5 ‘‘based on present population’’ when it includes all subjects born to mothers that delivered in the
area covered by the registry, wherever they had residency during gestation. A PP registry makes effort to exclude non resident mothers
but does not makes any effort to include resident mothers who delivered out of the covered area.
H 5 ‘‘hospital based’’ when it includes only a proportion -even near to 99% and not a random sample–of all subjects delivered in one
or more hospitals of the area covered by the registry without taking in to account the mother’s residency.
Type of ascertainment: SS 5 single source, e.g., from the maternity hospital. MS 5 multiple sources, e.g., from maternity hospitals,
childrens hospital, specialized services. A 5 the registry’s coordinating centre staff actively seek’s the relevant information reviewing
patient’s clinical records. P 5 the health care providers provide the information to the registry’s staff.
Termination of pregnancy: P 5 permitted by country’s legislation. NP 5 not permitted.
Birth Defects Research (Part A) 82:585–591 (2008)
geneity was due to statistically significantly lower rates
seen in USA Atlanta, Norway, and Czech Republic, while
statistically significantly higher rates were seen in South
America ECLAMC, France Paris, and France Strasbourg.
Excluding the surveillance systems with statistically
higher or lower rates the resulting estimate was 1.27 per
America, Latin America, Nordic Countries, British Isles,
Central Europe, France, Italy, and Australia), similar and
not heterogeneous rates were seen only in Italy and Aus-
tralia, with a overall rate per 10,000 of 1.09 (95% CI: 0.88–
1.34) and 1.78 (95% CI: 1.40–2.22) respectively. In all the
other areas or countries heterogeneous rates were observed.
Considering the 20 surveillance systems where ToPs
are permitted and regularly registered, the overall total
prevalence rate was 1.23 (95% CI: 1.14–1.32). In these sur-
veillance systems a proportion of 50.3% of ToPs was reg-
The frequency of ToPs varied among these surveillance
systems: 11.1% in Northern Netherlands to 100.0% in
France Strasbourg. The frequency of ToPs was higher in
European surveillance systems (range from 11.1 to
100.0%, median 5 70.5%) than in North American (range
from 12.6 to 60.6%, median 5 25.6%). A very moderate
degree of correlation (r
5 0.46; p 5 .04) between HPE
prevalence rates and proportion of ToPs was observed.
We report an overall HPE prevalence of 1.31 per
10,000 births based on more than 7 million births from
five continents. This HPE prevalence provides the best
estimate from the ICBDSR during the time period 2000–
2004 and includes all cases of births (e.g., livebirths and
stillbirths) and ToPs. Based on previous studies, the
observed estimates are similar to the data collected in
the Eurocat network (Eurocat website, 2007), West Mid-
lands (Ong et al., 2007) recent study in Whites, North of
England study, and in the California population study,
but higher than in the Metropolitan Atlanta study and
the West of Scotland study (Whiteford and Tolmie,
1996) (Table 4).
A source of variation among previous studies as well
as in the various areas of the present study may be the
frequency of ToPs and, most important, the week of ges-
tation when the diagnosis has been made and conse-
quently the ToP performed. In fact, the diagnosis may be
possible as early as 10 weeks gestation (Pilu et al., 1986)
and prevalence of HPE among early spontaneous abor-
tions (<10 weeks) has been reported to be over 30–40
times higher (41 cases per 10,000 gestations) than that of
pregnancies that progress beyond 20 weeks (Matsunaga
and Shiota, 1977). This suggests a marked natural loss of
fetuses with HPE. We can speculate that the more fre-
quent the prenatal diagnosis and earlier the diagnosis is
made, the more likely HPE will be identified and the
pregnancy terminated, while in the absence of prenatal
diagnosis, the pregnancy may have been lost spontane-
ously before 20 weeks gestation. As reported in previous
studies (Bullen et al., 2001; Ong et al., 2007), approxi-
mately 50% of HPE cases were associated with chromo-
somal abnormalities. It is likely that in countries where
very early prenatal diagnosis is more common, there is a
Table 2
Number of Total Births and Frequency of Holoprosencephaly (HPE) among 24 Surveillance
System Members of the ICBDSR (2000–2004)
Surveillance system Total births
Total cases
of HPE
(x 10,000 births) 95% CI
Malta 19,803 0 0.00 0.00 1.86
USA Atlanta 255,901 16 0.63 0.36 1.02
Norway 290,301 23 0.79 0.50 1.19
Czech Republic 467,116 39 0.83 0.59 1.14
Northern Netherlands 100,552 9 0.90 0.41 1.70
Italy North East 291,762 29 0.99 0.67 1.43
Sweden 479,555 50 1.04 0.77 1.37
Italy Campania 283,377 31 1.09 0.74 1.55
Italy Tuscany 136,241 15 1.10 0.62 1.82
USA Texas 1,870,366 223 1.19 1.04 1.36
France Central East 533,361 65 1.22 0.94 1.55
Ireland Dublin 113,437 14 1.23 0.67 2.07
Italy Emilia Romagna 129,766 17 1.31 0.76 2.10
USA Utah 246,111 33 1.34 0.92 1.88
Finland 283,887 40 1.41 1.01 1.92
Germany Saxony Anhalt 89,025 13 1.46 0.78 2.50
Mexico RYVEMCE 129,044 21 1.63 1.01 2.49
Australia Victoria 313,876 54 1.72 1.29 2.24
Wales 156,423 27 1.73 1.14 2.51
Canada Alberta 193,241 34 1.76 1.22 2.46
Western Australia 125,169 24 1.92 1.23 2.85
South America ECLAMC* 639,419 136 2.13 1.78 2.52
France Paris 132,582 33 2.49 1.71 3.50
France Strasbourg 68,028 17 2.50 1.46 4.00
Total 7,348,343 963 1.31 1.23 1.40
*Study period 2001–2003.
Birth Defects Research (Part A) 82:585–591 (2008)
subsequent higher identification of chromosomal abnor-
malities, many of which end in early loss and hence are
not included in the total prevalence rate.
Other reasons for total prevalence rate of heterogeneity
found among surveillance systems were evaluated. Ran-
dom variation of prevalence rates among periods of years
was evaluated and we found that among the 24 surveil-
lance systems, Norway and USA Atlanta had a decreas-
ing rate over the study period. Under-reporting bias may
be present, particularly for ToPs or for HPE in termi-
nated pregnancies. This may be the case in Czech Repub-
lic and Northern Netherlands where cases of HPE among
ToPs could be missed because necropsy is not routinely
performed in all centers when chromosomal abnormal-
ities have been documented. Another source of under-
reporting is the late diagnosis after the neonatal period,
especially of milder cases: in some surveillance systems a
late diagnosis is made in outpatient settings, which are
not always associated with hospitals and have no obliga-
tion to report and include such cases into congenital mal-
formation statistics (e.g., Norway). On the contrary, late
diagnoses are registered in those surveillance systems
where the age limit for registering cases is 6 or more
years (e.g., Australian surveillance systems) and a multi-
ple source of ascertainment is more efficient. The issue of
over-reporting due to referral bias may be present in the
hospital-based programs (e.g., South America ECLAMC
and Mexico RYVEMCE). Differences in prenatal diagno-
sis and ToPs in some surveillance systems (e.g., in France
Paris and France Strasbourg the use of prenatal diagnosis
Figure 1. Frequency of holoprosencephaly (HPE) among 24 surveillance system members of the ICBDSR (2000–2004).
Birth Defects Research (Part A) 82:585–591 (2008)
Table 3
Proportion of ToPs among All Cases of Holoprosencephaly (HPE) among 20 Surveillance
System Members of the ICBDSR (2000–2004)
Surveillance system Births ToPs Total % of ToPs 95% CI
Northern Netherlands 8 1 9 11.1% 0.3% 48.2%
USA Texas 195 28 223 12.6% 8.5% 17.6%
USA Atlanta 13 3 16 18.8% 4.0% 45.6%
Canada Alberta 23 11 34 32.4% 17.4% 50.5%
Australia Victoria 35 19 54 35.2% 22.7% 49.4%
Czech Republic 19 20 39 51.3% 34.8% 67.6%
Norway 10 13 23 56.5% 34.5% 76.8%
Italy Emilia Romagna 7 10 17 58.8% 32.9% 81.6%
USA Utah 13 20 33 60.6% 42.1% 77.1%
Finland 14 26 40 65.0% 48.3% 79.4%
Sweden 17 33 50 66.0% 51.2% 78.8%
Italy Campania 10 21 31 67.7% 48.6% 83.3%
Western Australia 7 17 24 70.8% 48.9% 87.4%
Italy Tuscany 4 11 15 73.3% 44.9% 92.2%
France Paris 5 28 33 84.8% 68.1% 94.9%
Italy North East 4 25 29 86.2% 68.3% 96.1%
France Central East 7 58 65 89.2% 79.1% 95.6%
Germany Saxony Anhalt 1 12 13 92.3% 64.0% 99.8%
Wales 2 25 27 92.6% 75.7% 99.1%
France Strasbourg 0 17 17 100.0% 80.5% 100.0%
Total 394 398 792 50.3% 46.7% 53.8%
ToPs not permitted in Ireland Dublin, Malta, Mexico RYVEMCE, and South America ECLAMC.
Table 4
Prevalence of Holoprosencephaly (HPE) in Previous Studies
Year of
of study Country
(x 10,000
births CI 95%
Mitani and
1968 ng Japan, hospital
ng 0.97 ng ng ng
and Chung
1974 ng US, hospital based ng 0.19 ng ng ng
Roach et al. 1975 1970 Indiana, US ng 0.63 ng ng ng
Saunders et al. 1984 1976–1978 Bristol, Weston HD,
ng 0.69 ng ng ng
Saunders et al. 1984 1979–1982 Bristol, Weston HD,
6 1.92 31,225 0.70–4.18 ng
Urioste et al. 1988 1976–1986 Spain, Hospital
ng 0.56 ng ng ng
Mastroiacovo et al. 1992 1978–1989 Italy, Hospital
106 0.77 1,377,793 0.63–0.93 ng
Croen et al. 1996 1983–1988 California, US 121 1.17 1,035,386 0.97–1.40 17.4%
Rasmussen et al. 1996 1982–1986 Atlanta, US 63 0.86 734,272 0.66–1.10 4.8%
Whiteford and
1996 1975–1994 Scotland, UK 50 0.72 694,950 0.53–0.95 ng
Olsen et al. 1997 1984–1989 New York, US 82 0.51 1,614,166 0.40–0.63 ng
Forrester and Merz 2000 1986–1997 Hawaii, US 25 1.09 ng ng 24.0%
Bullen et al. 2001 1985–1998 Northern Region,
64 1.20 531,686 0.93–1.54 59.4%
Ong et al. 2007 1995–2004 West Midlands,
78 1.48 526,056 1.17–1.85 73.9% (
Ong et al. 2007 1995–2004 West Midlands,
UK-Non White
33 2.62 125,818 1.81–3.68
Orioli and Castilla 2007 1967–2000 South America (
) 342 0.82 4,157,224 0.74–0.91 ({)
Eurocat (*) 2007 2000–2004 Europe 521 1.34 3,883,789 1.23–1.46 75.3%
ToPs 5 termination of pregnancies.
ng 5 not given.
*Eurocat data published on the website, only full members.
Proportion given for all ethnic groups. Two spontaneous abortions not included.
No variation among 11 South American Countries. ToPs not permetted.
Birth Defects Research (Part A) 82:585–591 (2008)
is widespread at an earlier gestational age) may also con-
tribute to the heterogeneity we found.
The last source of heterogeneity may be due to the
presence of real differences among populations. Ong
et al. (2007) found that in Western USA a variation
existed between White and non-White ethnic groups,
mainly in those of Pakistani origin.
The hypothesis that in the present study real differen-
ces exist among populations could be considered, but the
alternative methodological explanations seem to be more
reasonable. For example, the different rates observed in
Italy and Australia can be better explained with greater
correlation and reporting of HPE in terminated pregnan-
cies with a chromosomal anomaly and the inclusion of
HPE diagnosed after the neonatal period in the two Aus-
tralian surveillance systems.
It is difficult to speculate, even in a large study like
this, on what could be the best estimate of the real total
prevalence of HPE. Methodological characteristics of the
surveillance systems do not correlate with the rates and
are not helpful. The three estimates given here: (a) by all
registries; (b) only by the surveillance systems with a not
heterogeneous rate; and (c) by the population-based sur-
veillance systems with ToP permitted, respectively of
1.31, 1.27, and 1.23 per 10,000 births, give a very narrow
range of where the best estimate can be located.
The most reasonable conclusion from this study, as
well as from all the published ones, is that there is no
evidence of real large differences in total prevalence rates
of HPE among populations that would be useful to gen-
erate etiological hypotheses. Small differences cannot be
excluded but are very difficult to demonstrate.
The Program Directors of each surveillance system
acknowledge their staff for the work done.
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Boyd PA, Armstrong B, Dolk H, et al. 2005. Congenital anomaly surveil-
lance in England-ascertainment deficiencies in the national system.
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Bullen PJ, Rankin JM, Robson SC. 2001. Investigation of the epidemiology
and prenatal diagnosis of holoprosencephaly in the North of Eng-
land. Am J Obstet Gynecol 184:1256–1262.
Castilla EE, Orioli IM. 2004. ECLAMC: the Latin-American collaborative
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Birth Defects Research (Part A) 82:585–591 (2008)
    • "Holoprosencephaly (HPE) is the most prevalent human forebrain malformation, and one of the most common of all developmental abnormalities, with an estimated prevalence of 1 in 250 conceptuses (Leoncini et al., 2008, Orioli and Castilla, 2010, Matsunaga and Shiota, 1977). HPE is defined by incomplete midline division of the embryonic forebrain and frequently co-occurs with facial abnormalities, including hypotelorism, ophthalmologic anomalies, midfacial hypoplasia, and orofacial clefts (Costa and Ribeiro, 2010, Cohen, 2006, Pineda-Alvarez et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Holoprosencephaly (HPE) is a common and severe human developmental abnormality marked by malformations of the forebrain and face. While several genetic mutations have been linked to HPE, phenotypic outcomes range dramatically and most cases cannot be attributed to a specific cause. Gene-environment interaction has been invoked as a premise to explain the etiological complexity of HPE but identification of interacting factors has been extremely limited. Here, we demonstrate that mutations in Gli2, which encodes a Hedgehog pathway transcription factor, can cause or predispose to HPE depending upon gene dosage. On the C57BL/6J background, homozygous GLI2 loss of function results in the characteristic brain and facial features of severe human HPE, including midfacial hypoplasia, hypotelorism, and medial forebrain deficiency with loss of ventral neurospecification. While normally indistinguishable from wildtype littermates, we demonstrate that mice with single-allele Gli2 mutations exhibit increased penetrance and severity of HPE in response to low-dose teratogen exposure. This genetic predisposition is associated with a Gli2 dosage-dependent attenuation of Hedgehog ligand responsiveness at the cellular level. In addition to revealing a causative role for GLI2 in HPE genesis, these studies demonstrate a mechanism by which normally silent genetic and environmental factors can interact to produce severe outcomes. Together, these findings provide a framework for understanding the extreme phenotypic variability observed in human mutation carriers, and a paradigm for reducing the incidence of this morbid birth defect.
    Article · Sep 2016
    • "For each treatment group the number of litters and fetuses examined, mean litter size and crown-rump length, and the incidence of edema, forelimb ectrodactyly, and kinked tail defects are presented in S1 Table.doi:10.1371/journal.pone.0120517.g005 [27, 28]. OFCs represent the second most prevalent human birth defect, affecting 1–2/1,000 newborns [1] . "
    [Show abstract] [Hide abstract] ABSTRACT: The Hedgehog (Hh) signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE), clefts of the lip with or without cleft palate (CL/P), and clefts of the secondary palate only (CPO). Here, we examined patterns of dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD) 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist-induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in "non-syndromic" orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug.
    Full-text · Article · Mar 2015
    • "International differences in the prevalence of EA across different geographical regions may also be attributable to differences in case identification methods, case definition, and case ascertainment. Best estimates of prevalence of major birth defects, based on international data, are important to serve as a reference point for the evaluation of individual, regional, or national surveillance programs and to identify geographical regions of higher or lower than expected prevalence (Leoncini et al., 2008; Cocchi et al., 2010). Investigation of geographical differences may also provide an insight into the underlying etiology of EA. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The prevalence of esophageal atresia (EA) has been shown to vary across different geographical settings. Investigation of geographical differences may provide an insight into the underlying etiology of EA. Methods: The study population comprised infants diagnosed with EA during 1998 to 2007 from 18 of the 46 birth defects surveillance programs, members of the International Clearinghouse for Birth Defects Surveillance and Research. Total prevalence per 10,000 births for EA was defined as the total number of cases in live births, stillbirths, and elective termination of pregnancy for fetal anomaly (ETOPFA) divided by the total number of all births in the population. Results: Among the participating programs, a total of 2943 cases of EA were diagnosed with an average prevalence of 2.44 (95% confidence interval [CI], 2.35-2.53) per 10,000 births, ranging between 1.77 and 3.68 per 10,000 births. Of all infants diagnosed with EA, 2761 (93.8%) were live births, 82 (2.8%) stillbirths, 89 (3.0%) ETOPFA, and 11 (0.4%) had unknown outcomes. The majority of cases (2020, 68.6%), had a reported EA with fistula, 749 (25.5%) were without fistula, and 174 (5.9%) were registered with an unspecified code. Conclusions: On average, EA affected 1 in 4099 births (95% CI, 1 in 3954-4251 births) with prevalence varying across different geographical settings, but relatively consistent over time and comparable between surveillance programs. Findings suggest that differences in the prevalence observed among programs are likely to be attributable to variability in population ethnic compositions or issues in reporting or registration procedures of EA, rather than a real risk occurrence difference. Birth Defects Research (Part A), 2012.
    Full-text · Article · Nov 2012
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