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Clinical epidemiologic study of holoprosencephaly in South America.

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ß 2007 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 143A:3088 – 3099 (2007)
Clinical Epidemiologic Study of Holoprosencephaly
in South America
Iêda M. Orioli1* and Eduardo E. Castilla2,3
1
Estudo Colaborativo Latino Americano de Malformações Congênitas: ECLAMC at Departamento de Genética,
Curso de Pós-Graduação em Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
2
ECLAMC at Departamento de Genética, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
3
ECLAMC at Cemic, Buenos Aires, Argentina
Received 20 March 2007; Accepted 31 August 2007
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.
ß 2007 Wiley-Liss, Inc.
Key words: cyclopia; ethmocephaly; cebocephaly; premaxillary agenesis; cleft lip and palate; isolated cleft palate;
isolated median cleft lip; alobar; semilobar; lobar; matenal
diabetes; maternal flu; cohort analysis; case–control analysis;
syndromes; associated anomalies; chromosomal anomalies;
birth prevalence rate (BPR); maternal flu; risk factors;
gender; ECLAMC
How to cite this article: Orioli IM, Castilla EE. 2007. Clinical epidemiologic study of holoprosencephaly
in South America. Am J Med Genet Part A 143A:3088–3099.
INTRODUCTION
Holoprosencephaly (HPE) is a developmental
field defect of impaired midline ‘‘cleavage’’ of the
embryonic forebrain. The term ‘‘cleavage,’’ although
commonly used, is a misnomer because there are no
cleavages in brain development. In alobar HPE,
the prosencephalon fails to ‘‘cleave’’ sagittally into
cerebral hemispheres (actually fails to bud), fails to
‘‘cleave’’ transversely into telencephalon and diencephalon (actually an arbitrary designation given to
Grant sponsor: CNPq/MS/DECIT; Grant number: 40.3444/2004-7;
Grant sponsor: CNPq/MS/DECIT; Grant number: 40.1467/2004-0; Grant
sponsor: CNPq; Grant number: 30.8885/2006-6; Grant sponsor: FAPERJ;
Grant number: E-26/151.999/2004, Brazil; Grant sponsor: PAPES da
Fundação Oswaldo Cruz, Brazil; Grant sponsor: Agencia Nacional de
Promoción Cientı́fica y Tecnológica, CONICET, Argentina.
*Correspondence to: Iêda M. Orioli, Departamento de Genética,
Universidade Federal do Rio de Janeiro, Caixa Postal 68.011, 21944-970,
Rio de Janeiro, Brazil. E-mail: orioli@centroin.com.br
DOI 10.1002/ajmg.a.32104
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3089
HOLOPROSENCEPHALY IN SOUTH AMERICA
regions), and fails to ‘‘cleave’’ horizontally into
olfactory tracts and bulbs (actually fails to bud).
Although the classic definition of HPE is unambiguous, problems are encountered at the less severe
end of the phenotypic spectrum [Cohen, 2001].
In a classic article DeMyer et al. [1964] discussed
a graded series of facial anomalies that occur
with HPE: cyclopia, ethmocephaly, cebocephaly,
median cleft lip, and less severe anomalies. The
‘‘face predicts the brain’’ approximately 80% of
the time. The other 20% of the time, the facial
features are non-diagnostic [Roach et al., 1975;
DeMyer, 1977; Cohen, 1989b]. Although median
cleft lip may occur with HPE, this facial phenotype
may be seen without HPE; the head circumference
is within two standard deviations of the mean, and
normotelorism is commonly encountered. A number of minor anomalies have been found with HPE
[see Cohen, 2006 for references].
HPE is etiologically heterogeneous and pathogenetically variable. Identifiable causes account for
about 15–20% of all cases. These are monogenic,
chromosomal, and teratogenic. Monogenic inheritance of non-syndromic HPE includes most commonly autososomal dominant transmission with wide
expressivity and incomplete penetrance [Benke
and Cohen, 1983; Cohen, 1989a, 2006], and less
commonly autosomal recessive transmission [Cohen
and Gorlin, 1969; Cohen et al., 1971] and X-linked
transmission [Morse et al., 1987; Hockey et al., 1988].
To date, nine genes are known that have mutations for
HPE: SHH, PTCH, GLI2, DHCR7, ZIC2, TDGF1, TGIF,
FAST1, and SIX3. Because various pathways are
linked to the sonic hedgehog-signaling network, the
mutations are interrelated. SHH, PTCH, and GLI2 are
within the network itself. DHCR7 involves 7-dehydrocholesterol reductase in cholesterol biosynthesis
and about 4% of DHCR7 mutations for Smith-LemliOpitz syndrome have HPE. ZIC2 and GLI2 are related;
Gli proteins are translocated to cell nuclei by coexpressed Zic proteins. TDGF1, TGIF, and FAST1
involve Nodal/TGFb signaling. Only SIX3 has not
been linked to any of these interrelated pathways to
date [Cohen, 2003, 2006; Dubourg et al., 2007].
Cohen listed a large number of monogenic
syndromes with HPE [2006]. Several chromosomal
syndromes with HPE are also know, trisomy
13 syndrome being the most common of these.
Chromosomal anomalies have been reported in 24%
[Olsen et al., 1997] to 40% [Croen et al., 1996] of HPE
cases. Of teratogenic syndromes with HPE, diabetic
embryopathy is the most frequently cited, although
retinoic acid embryopathy and fetal alcohol syndrome have also been reported with HPE [Cohen and
Shiota, 2002; Cohen, 2006].
Epidemiological studies could provide new clues
for understanding the causes of HPE.
We identified cases of HPE from ECLAMC: Estudio
Colaborativo Latino Americano de Malformaciones
Congénitas database [Castilla and Orioli, 2004],
described their phenotypic characteristics, and
searched for risk factors.
METHODS AND MATERIALS
ECLAMC
Data are derived from ECLAMC: Estudio Colaborativo Latinoamericano de Malformaciones Congénitas
(Latin American Collaborative Study of Congenital
Malformations) [Castilla and Orioli, 2004]. ECLAMC is a
hospital-based registry which examines births in all
South American countries (excluding the three Guyanas), and Costa Rica.
ECLAMC procedures have been published elsewhere [Castilla and Orioli, 2004]. In short, consecutive livebirths and stillbirths were examined in all
participating hospitals, and every mother of a
malformed baby was interviewed by the pediatrician
who used a form, which was identical to the one used
for the next non-malformed newborn of the same sex
in the same hospital.
Mothers of cases and controls were interviewed
postpartum to gather information for 50 risk factors,
including environmental exposures, history of other
congenital defects in the family, and parental
consanguinity. The number of sibs, maternal halfsibs, parents, and grandparents were known for all
cases and controls. Stillbirths were defined as a
weight of 500 g or more (22–23 weeks of gestation);
recording began in 1982.
CASE SELECTION AND DEFINITION
Series A
Case definitions were based on verbal descriptions
given by the reporting pediatrician at birth or within
the first week of life. In the ECLAMC database, we
specified HPE as a cerebral malformation alone or
together with hydrocephalus or microcephaly. Since
neuroimaging examinations were not carried out in
all suspected cases, we searched the database for
cases specified only as cyclopia or only as median
cleft of the upper lip. All cases in the group median
cleft of the upper lip did not have neuroimaging. We
found a total of 370 cases among 4,157,224 livebirths
and stillbirths from 1967 to 2000.
Series B
To improve the study of HPE subtypes (alobar,
semilobar, and lobar), we selected HPE cases born
within the ECLAMC hospital network after 1999
when anatomical descriptions improved substantially due to operational changes. Then all 179 (2.16/
10,000) HPE cases registered after clinical examination of 827,968 births between 2000 and 2003
were selected, and these were designated as Series
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3090
ORIOLI AND CASTILLA
B. Suitable clinical information was not available for
five cases, which were discarded leaving 174 HPE
cases. Thirty-nine cases born in 2000 overlapped
with Series A (1967–2000).
ANALYSIS
Quality of HPE Diagnosis in the
ECLAMC Database
We divided the 370 cases in five groups: chromosomal anomalies (chromosomal HPE), non-chromosomal syndromes (syndromic HPE) with only
craniofacial defects (isolated HPE), cases with
defects also in other organs (associated HPE), and
cases with isolated median cleft lip (median cleft lip).
Since the non-chromosomal syndromes group had
only five cases, it was not considered further. Some
epidemiological variables were compared among
the four groups: gender, perinatal mortality, twinning, birth weight, gestational age, and maternal age.
Further clinical and epidemiological analyses were
done in the isolated HPE and/or in the isolated plus
associated HPE groups from 1982 to 2000.
Birth Prevalence Variation in
Time and Space
The birth prevalence and case–control comparisons of isolated HPE were established from 1982 to
2000 for each country. The secular trend was tested
by Poisson maximum-likelihood regression of the
number of HPE cases on years.
Risk Factors Using a Cohort Approach
Hospital health system (public or private), hospital
altitude above the sea level (under or 2,000 m),
birth weight (under or 2,500 g), maternal age (19,
20–29, 30 years), birth order (1, 2–3, 4), newborn
gender (male or female), and birth vitality (live or
dead) were analyzed by comparing the frequency of
isolated HPE cases within the total births of each
category by 95% confidence intervals.
Risk Factors Using a
Case–Control Approach
All other variables were compared between cases
and controls matched by gender, locality, and
moment of birth. The case–control analysis used
the intra-pair comparison with the McNemar test.
Further adjusting among the variables possibly
involved in the causality of HPE was carried out
by a step-wise conditional logistic regression for
matched case–control groups. Excluded were variables of phenotypic definition (birth weight >2,500 g,
intrauterine growth retardation, and prematurity).
Also excluded were perinatal variables (non-cephalic presentation and non-vaginal delivery).
Defects Not Randomly Associated
With the HPE Spectrum
To determine if HPE was significantly associated
with other non-craniofacial defects in our sample of
HPE cases, we compared the number of cases with a
given dyad (defined as a pair of anomalies with or
without other associated anomalies) with the number expected by chance association within the total
set of 9,236 non-syndromic malformed infants from
1982 to 2000, when both livebirths and stillbirths
were available. There were 258 cases with isolated
plus associated HPE during this period. This method
of measuring the strength of the association between
two given anomalies was described by Källen [1987].
Observed/expected differences were assessed by
the Z-test, and the limit of significance was set at 1%.
We also tested the strength of the association of the
‘‘HPE diagnosis’’ with each of the craniofacial
anomalies. Although median facial anomalies were
used as diagnostic criteria for case selection, this
analysis was carried out to find if some of the
craniofacial anomalies were not in excess among
HPE cases.
RESULTS
HPE Diagnosis
From 1967 to 2000, ECLAMC registered 370 cases
with facial anomalies suggestive of HPE: 182 had
only craniofacial anomalies; 99 had non-craniofacial
anomalies; 56 had chromosomal anomalies; 5 had a
recognizable syndrome at birth; and 28 had only
median cleft lip (Table I). The frequency of median
cleft lip, hydrocephalus, and cyclopia (malformation
codes used to search for additional cases in the
database) is shown in Table I. In the isolated group,
half or more cases had median cleft lip, hydrocephalus, and cyclopia.
To evaluate overlapping of the four groups
(syndromic group with only five cases ignored), we
compared the distribution of gender, perinatal
mortality, twinning, birth weight, gestational age,
and maternal age in years. The median cleft lip group
differed from the other groups by having a strong
male sex ratio, low perinatal mortality rate, and
normal birth weight, gestational age, and maternal
age (Table II). We do not consider this last group as
having probable HPE.
The associated HPE and the isolated HPE groups
had a lower maternal age mean than the chromosomal HPE group. From a practical standpoint, the
isolated and associated anomalies groups could be
considered the same (Table II).
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3091
HOLOPROSENCEPHALY IN SOUTH AMERICA
TABLE I. Classification of 370 Cases with Faces Suggestive of Holoprosencephaly (HPE) from 1967–2000
Median cleft lip
Groups
a
Isolated HPE (n ¼ 182)
Isolated median cleft lipb (n ¼ 28)
Associated HPEc (n ¼ 99)
Chromosomal anomalies (n ¼ 56)
Syndromes (n ¼ 5)
Total (n ¼ 370)
Hydrocephalus
Cyclopia
N
%
N
%
N
%
44
28
13
28
1
114
24.2
100.0
13.1
50.0
20.0
30.8
58
—
22
9
2
91
31.9
—
22.2
16.1
40.0
24.6
61
—
42
20
0
123
33.5
—
42.4
35.7
0.0
33.2
a
HPE and anomalies from the HPE sequence.
Without neuroimaging examination.
c
HPE and anomalies not usual in the HPE sequence.
b
Syndromes Identified at Birth
Prevalence
The five syndromes diagnosed in the first week of life
in the 1967–2000 case series were (a) pseudotrisomy
13, (b) thanatophoric dysplasia, type II, (c) Aicardi
syndrome, (d) Genoa craniosynostosis-HPE syndrome,
and (e) Meckel syndrome. There were 47 cases of
trisomy 13, 6 cases of trisomy 18, one case of triploidy
(69,XXX), and 2 with more complex karyotypes in
the chromosomal anomalies group: 46,XX, del13q
and 46,XY,-7,þt(7;18)(7q32;18q21). Thirty HPE cases,
among 338 with specified data, had one or more
relatives with congenital malformations: recurrence of
HPE in 8 families (2%), occurrence of other anomalies
of the central nervous system in 14 families (hydrocephalus, microcephaly, and cephalocele), and occurrence of oral clefts in 8 families. We did not assess other
types of anomalies in 63 families.
Excluding the isolated median cleft lip cases, we
found an HPE birth prevalence rate (BPR) of 0.82/
10,000 births (53% isolated, 29% associated, 16%
chromosomal, and 1% monogenic). We evaluated
the BPR by country (Table III) and by year of birth
(Fig. 1) only for the isolated group. The BPR did not
differ among countries. The BPR doubled the usual
BPR after 1996 (Fig. 1).
Risk Factors in Cohort Analysis
We compared the BPR of isolated HPE among
several demographic hospital subsets: altitude above
sea level, birth weight, maternal age, birth order, sex,
livebirths, and stillbirths. The HPE BPR was higher
with birthweights <2,500 g (65/383,751; rate: 1.69,
TABLE II. Comparison of Isolated HPE, Isolated Median Cleft Lip, Associated HPE, and Chromosomal Anomaly HPE for Several Variables in the
1967–2000 Case Series
Variables
Gender
Male
Female
Intersex
Totala
Perinatal mortality
Alive
Dead
Not discharged yet
Totala
Twinning
Yes
No
Totala
Birth weight
Totala
Mean
95% CI
Gestational age in days
Totala
Mean
95% CI
Maternal age in years
Totala
Mean
95% CI
a
Isolated HPE, N (%)
Median cleft lip, N (%)
Associated HPE, N (%)
Chromosomal HPE, N (%)
75 (41.2)
106 (58.2)
1 (0.5)
182 (100.0)
18 (64.3)
10 (35.7)
0 (0.0)
28 (100.0)
44 (44.4)
46 (46.5)
9 (9.1)
99 (100.0)
20 (35.7)
32 (57.1)
4 (7.1)
56 (100.0)
73 (41.5)
85 (48.3)
18 (10.2)
169 (100.0)
24 (88.9)
3 (11.1)
0 (0.0)
27 (100.0)
11 (11.2)
83 (84.7)
4 (4.1)
98 (100.0)
2 (3.6)
52 (92.9)
2 (3.6)
56 (100.0)
4 (2.2)
177 (97.8)
181 (100.0)
0 (0.0)
28 (100.0)
28 (100.0)
4 (4.0)
95 (96.0)
99 (100.0)
1 (1.9)
52 (98.1)
53 (100.0)
180
2,717.667
2,577.91–2,857.42
28
2,965.00
2,682.55–3,247.45
98
1,938.99
1,758.92–2,119.06
56
1,967.57
1,795.05–2,140.094
112
262.03
254.32–269.73
15
274.73
265.97–283.48
57
253.35
242.26–264.43
34
256.68
244.04–269.32
179
26.44
25.47–27.41
27
25.22
23.03–27.41
98
27.05
25.63–28.47
56
30.21
28.31–32.12
Total: Numbers vary among variables due to cases with missing data.
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3092
ORIOLI AND CASTILLA
TABLE III. Birth Prevalence of Isolated HPE in 11 Countries (ECLAMC, 1982–2000) by Increasing HPE
Birth Prevalence Rate per 10,000 (BPR)
Births
Country
Costa Rica
Paraguay
Colombia
Ecuador
Uruguay
Peru
Venezuela
Argentina
Bolivia
Chile
Brazil
Total
HPE cases
N
N
BPR
95% CI
38,003
101,997
68,089
61,684
204,669
72,864
294,197
1,245,835
94,051
353,065
833,281
3,367,735
1
3
2
2
7
3
12
53
4
19
61
164
0.26
0.29
0.29
0.32
0.34
0.41
0.41
0.42
0.42
0.54
0.73
0.49
— to 1.05
— to 0.78
— to 0.88
— to 0.97
0.05 to 0.68
— to 0.82
0.17 to 0.68
0.30 to 0.55
0 to 0.96
0.28 to 0.82
0.54 to 0.94
0.41 to 0.56
95% CI: 1.30–2.16), than with birthweights >2,500 g
(101/2,931,237; rate: 0.34, 95% CI: 0.26–0.43). It was
higher with stillbirths (22/58,385; rate: 3.77; 95% CI:
2.40–5.65) than with livebirths (145/3,292,580; rate:
0.44; 95% CI: 0.35–0.53). The HPE BPR was higher in
females (97/1,635,010; rate: 0.59; 95% CI: 0.48–0.72)
than in males (70/1,715,955; rate: 0.41; 95% CI: 0.32–
0.51), although not statistically significant. (The
complete table is available by request to the authors).
Risk Factors in Case–Control Analysis
In comparing isolated HPE cases with their
paired controls, birthweights were lower in HPE
cases, mainly due intrauterine growth retardation
(Table IV). For HPE cases, there were few primigravidas among mothers and an excess of noncephalic presentations and non-vaginal deliveries
(Table IV).
Since first trimester exposure factors did not differ
between isolated HPE cases and controls (Table IV),
we compared isolated HPE, associated HPE, and
isolated plus associated HPE groups with their paired
controls for selected maternal diseases and therapeutic drug use (Table V).
Maternal diabetic exposure was significantly higher
in HPE than in controls with respect to the isolated
plus associated group (OR: 3.5; 95% CI: 0.9–16.2)
(Table V). Insulin use during the first trimester was
higher in HPE, but since there was no exposure among
controls, the OR was not calculated (Table V). Flu
exposure was significantly higher for HPE in the
isolated and isolated plus associated groups than in
their paired controls (Table V). Vaginal bleeding and
sex hormone use during the first trimester were higher
in the isolated plus associated HPE group than in the
controls (Table V). For vaginal bleeding, the strength
of association seemed higher in the associated HPE
group. Anemia, iron supplementation, and aspirin/
salicylate use during the first trimester did not differ
among the HPE groups and their controls (Table V).
Associated Craniofacial Malformations in HPE
We tested the strength of the association between
each craniofacial anomaly and the diagnosis of HPE
to identify craniofacial anomalies not preferentially
associated with the diagnosis (Table VI). Not all
craniofacial anomalies were significantly associated
with HPE diagnosis. For example, microtia with
atresia of the external auditory canal seemed to be
part of the HPE spectrum, but less severe ear
anomalies such as low-set ears or preauricular tags
were not significantly associated with HPE. Unilateral-, bilateral-, and median cleft lip with or without
cleft palate were part of the HPE spectrum, but cleft
palate was only randomly associated with HPE.
Anencephaly, cephalocele, and spina bifida were not
more frequently associated with HPE than by chance
alone (Table VII). Agnathia is a very rare defect with
only two cases from 1982 to 2000. One case was
associated with HPE. Microstomia was associated in
excess with HPE (Table VII).
Associated Non-Craniofacial
Malformations in HPE
FIG. 1. Secular trend of birth prevalence per 10,000 births of isolated
holoprosencephaly (ECLAMC 1982–2000). [Color figure can be viewed in the
online issue, which is available at www.interscience.wiley.com.]
Excluding malformations represented by a single
case, there were only five types of non-craniofacial
defects associated with HPE. Twenty four cases had
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3093
HOLOPROSENCEPHALY IN SOUTH AMERICA
TABLE IV. Isolated Holoprosencephaly Cases (HPE) Compared With Matched Controls by Intra-Pair Method, ECLAMC 1982–2000
Types of pairs
Risk factor
þþ
þ
þ
DP
OR
95% Confidence
intervals
w2
Maternal age <20
Maternal age 35
Paternal age <20
Paternal age 40
Low maternal education
Low paternal education
Low paternal occupation
Low socioeconomic level
High socioeconomic level
Black ancestry
Native ancestry
Parental consanguinity
Primigravida
Multigravida 4
FT chronic illness
FT acute illness
FT physical agents
FT drugs
FT vaginal bleeding
Previous gestational loss
Birth weight <2,500
IUGR
Prematurity
Macrosomia
Non-cephalic presentation
Non-vaginal delivery
Twinning
4
3
0
5
19
12
20
10
9
10
68
0
11
9
3
9
1
28
0
6
7
0
5
0
2
23
0
11
15
7
8
13
18
16
11
14
8
13
4
16
29
10
18
5
15
13
12
38
14
16
4
19
41
3
17
11
7
9
18
15
25
13
12
7
10
1
36
17
8
18
5
10
9
11
8
0
8
2
2
19
2
88
91
100
92
67
59
47
66
65
89
23
108
57
65
95
70
107
63
93
29
67
67
52
75
94
37
115
28
26
14
17
31
33
41
24
26
15
23
5
52
46
18
36
10
25
22
23
46
14
24
6
21
60
5
0.65
1.36
1.00
0.89
0.72
1.20
0.64
0.85
1.17
1.14
1.30
4.00
0.44
1.71
1.25
1.00
1.00
1.50
1.44
1.09
4.75
—
2.00
2.00
9.50
2.16
1.5
0.30–1.38
0.63–2.97
0.35–2.85
0.34–2.30
0.35–1.47
0.60–2.38
0.34–1.20
0.38–1.89
0.54–2.52
0.41–3.15
0.57–2.96
0.45–35.79
0.25–0.80
0.94–3.10
0.49–3.17
0.52–1.92
0.52–1.92
0.67–3.34
0.62–3.38
0.48–2.47
2.22–10.18
0.00 to —
0.86–4.67
0.37–10.92
2.21–40.79
1.25–3.72
0.25–8.98
1.29
0.62
0.00
0.06
0.81
0.27
1.98
0.17
0.15
0.07
0.39
1.80
7.69
3.13
0.22
0.00
0.00
1.00
0.73
0.04
19.57
14.00
2.67
0.67
13.76
8.07
0.20
P
*
*
*
*
*
Types of pairs: þþ, both case and control affected; þ, case affected and control unaffected; þ, case unaffected and control affected; , both unaffected.
DP, discordant pairs; OR, odds ratio; FT: first trimester of pregnancy; IUGR: intrauterine growth retardation.
*P-value less than 0.001.
genital anomalies (micropenis, vaginal atresia, and
anomalies of the female internal genitalia); eight
cases had tetramelic postaxial polydactyly; five cases
had vertebral defects, including agenesis; four cases
had transposition of great vessels, and four cases had
upper and lower limb amelia or intercalary limb
reduction defect.
Cerebral and Facial Defects in HPE (Series B)
We analyzed the distribution of HPE cerebral subtypes (alobar, semilobar, lobar), facial phenotypes
(cyclopia, ethmocephaly, cebocephaly, premaxillary
agenesis, bilateral or unilateral cleft lip and palate,
cleft palate, absent facial cleft), and both of them by
gender.
Cerebral imaging was absent in 20 of 174 HPE
cases; 4 of them had cyclopia, 1 had ethmocephaly,
and 5 had cebocephaly, resulting in a certain
diagnosis in 94% of cases. Only 19 of 85 cases with
unspecified HPE sub-type had absent cerebral
imaging or pathological examination.
The distribution of gender by cerebral or facial
defect was significantly deviated towards females in
the total sample (Table VIII). Only 83 of 174 HPE
cases had a specified cerebral anomaly (40% alobar,
43% semilobar, and 17% lobar) (Table IX).
Cyclopia, ethmocephaly, and cebocephaly were
always of alobar or semilobar types; one case with
cyclopia, and one case with cebocephaly had semilobar HPE, and the lobar type was more common
among cases without orofacial clefts. Among 174
HPE cases, 39% had neither orofacial clefting nor
severe facial dysmorphism: 26% had cyclopia,
ethmocephaly, or cebocephaly; 25% had premaxillary agenesis; and 10% had cleft lip-palate or cleft
palate only (Table IX). Although facial and cerebral
anomalies were not mutually exclusive, cyclopia had
no orofacial clefting; 6 of 8 ethmocephaly cases had
cleft palate; most cebocephaly cases had no oral
clefting (14/20), but some had premaxillary agenesis
(4/20) and cleft palate (2/20).
Syndromes Identified at Birth (Series B)
Despite the small overlap between the two series,
syndromic HPE cases identified at birth in Series B
were not, by chance, included in Series A.
Chromosomal defects were identified in 17 of
174 cases: 10 with trisomy 13 and one case of each
of the following: trisomy 18; 46,XY,t(2;8)(p13;p23);
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3094
ORIOLI AND CASTILLA
TABLE V. Odds Ratios (OR) and 95% Confidence Intervals (CI) for Isolated, Associated, and Isolated Plus Associated HPE Related to Selected
Maternal Illness and the Use of Medication During the First Trimester of Pregnancy
Isolated group
Exposure
HPE
Diabetes
No
172
Yes
6
Insulin
No
175
Yes
3
Anemia
No
176
Yes
1
Iron supplement
No
162
Yes
16
Flu
No
166
Yes
11
Aspirin/salicylates
No
52
Yes
13
Vaginal bleeding
No
96
Yes
19
Sex hormones
No
170
Yes
8
Associated group
Isolated plus associated group
Controls
OR (95% CI)
HPE
Controls
OR (95% CI)
HPE
Controls
OR (95% CI)
163
3
1.0a
1.9 (0.4–9.7)
92
5
92
0
1.0a
—
264
11
255
3
1.0a
3.5 (0.9–16.2)
166
0
1.0a
—
95
1
92
0
1.0a
—
270
4
258
0
1.0a
—
164
2
1.0a
0.5 (0.02–6.6)
94
2
91
1
1.0a
1.9 (0.1–54.9)
270
3
255
3
1.0a
0.9 (0.1–5.9)
147
19
1.0a
0.8 (0.4–1.6)
77
19
76
16
1.0a
1.2 (0.5–2.6)
239
35
223
35
1.0a
0.9 (0.6–1.6)
163
3
1.0a
3.6 (0.9–16.6)
87
9
89
3
1.0a
3.1 (0.7–14.8)
253
20
212
6
1.0a
2.8 (1.0–7.9)
48
18
1.0a
0.7 (0.3–1.6)
34
6
30
13
1.0a
0.4 (0.1–1.3)
86
19
78
31
1.0a
0.6 (0.3–1.1)
93
11
1.0a
1.7 (0.7–4.0)
46
12
51
3
1.0a
4.4 (1.1–21.2)
142
31
144
14
1.0a
2.2 (1.1–4.6)
165
1
1.0a
7.8 (1.0–167.3)
90
6
87
5
1.0a
1.2 (0.3–4.6)
260
14
252
6
1.0a
3.7 (1.3–11.0)
a
Category of reference.
46,XX,7q-; 46,XX,r(13)/46,XX,dup r(13)/47,XX,r
(13)þr?; 46,XX(8)/47,XXþmar(1); 46,XX, add 11
(q:25); 46,XX,11pþ.
One case of each of the following syndromes was
detected among the 174 HPE cases: Genoa craniosynostosis-HPE syndrome; thanatophoric dysplasia,
type II; Meckel syndrome; and agnathia-HPE. Except
for the latter diagnosis, the other three were also
found in Series A cases.
Seventeen HPE cases had one or more relatives with
the following congenital anomalies: recurrence of HPE
in four families, occurrence of other anomalies of the
central nervous system in nine families (anencephaly,
hydrocephalus, microcephaly, and schizencephaly),
and occurrence of orofacial clefting, or anomalies of
the feet in four families. In two of these four families,
the diagnosis was questionable. One propositus had
complex cerebral anomalies, including HPE and
schizencephaly, and had a sister with porencephaly
and hydrocephalus. Another propositus had HPE of
unspecified type, ocular hypotelorism, median cleft lip
and palate, nasal hypoplasia, pedal preaxial polydactyly, and ectrodactyly; the mother had malformed
feet, a maternal uncle had clubfoot, a sister had EEC
syndrome, and a brother died 10 hours after birth.
DISCUSSION
Birth Prevalence Rate (BPR)
There are several published epidemiologic studies
of HPE with a variable range of BPRs. The results of
such studies are difficult to compare because of
differences in methodology. Our BPR of 0.82 per
10,000 livebirths and stillbirths in South America did
not differ significantly from other population estimates: 1.01 [Saunders et al., 1984], 1.20 [Croen et al.,
1996], 0.72 [Whiteford and Tolmie, 1996], 0.77
[Mastroiacovo et al., 1992], and 0.86 [Rasmussen
et al., 1996]. However, studies of livebirths, stillbirths,
and pregnancy terminations (TOP, termination of
pregnancy) had variable BPRs: 0.59 [Croen et al.,
2000], 1.20 [Bullen et al., 2001], 6.06 [Chen et al.,
2005], and 1.7 [Ong et al., 2007]. Källén et al. [1992]
found only 0.1, but they registered only cyclopia.
When only livebirths are considered, BPRs were
quite variable: 0.69–1.92 [Saunders et al., 1984], 0.62
[Roach et al., 1975], 0.56 [Urioste et al., 1988], and 0.48
[Olsen et al., 1997]. Earlier BPRs were also different
from ours: 0.19 [Myrianthopoulos and Chung, 1974].
The highest reported rate was 41.2 per 10,000 TOPs
[Matsunaga and Shiota, 1977], but they studied only
very early abortuses in which the HPE rate is known
to be dramatically increased.
The observed increase in the secular trend
probably resulted from an increased rate of prenatal
ultrasound examinations, which resulted from legislation against voluntary interruption of pregnancy in
most South American populations. However, several
authors have described unexplained concentrations
in the yearly frequency of HPE [reviewed by Cohen,
1989a]. Since the distribution of HPE cases in a
fixed period of time has a Poisson distribution,
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3095
HOLOPROSENCEPHALY IN SOUTH AMERICA
TABLE VI. Strength of the Association Between Non-Syndromic HPE,* and Craniofacial Anomalies by Decreasing Values of Observed/Expected
(O/E) Ratios**
ECLAMC
code
75921
74813
74816
74927
74811
74917
52406
75607
74814
7481
7492
7491/2
74585
7447420
7491
7431
7450
74420
7452E
74800
75731
7400
75601
74430
7560
74817
74901
7430
74902
7490
7452
7452G
52401
7452F
7451
74583
Specific defect
Observed
Expected
Z
P
O/E
Cyclopia
Proboscis
Single naris
Median cleft lip with cleft palate
Arhinia
Median cleft lip without cleft palate
Agnathia
Macrocephaly
Nasal hypoplasia
All nasal defects
All cleft lip with cleft palate
All cleft lip with or without cleft palate
Microstomia
All ocular defects except cyclopia
Hydrocephalus
All cleft lip without cleft palate
Microcephaly
Microtia with external auditory canal atresia
Glaucoma
Microtia NFS
Choanal atresia
Aplasia cutis vertex
Anencephaly
Ocular hypertelorism
Cataracts
Cranial defects
Deformed nose
Incomplete cleft palate
Cephalocele
Complete cleft palate
All cleft palate
Ear anomaly
Low-set ears
Mild micrognathia
Ear deformity
Preauricular tag
Unusual face
95
25
19
45
8
10
1
1
17
73
59
72
7
31
81
13
35
21
3
4
2
2
7
5
1
11
3
4
3
2
6
12
6
4
2
3
2
1.03
0.34
0.45
1.15
0.28
0.36
0.06
0.06
1.03
7.49
14.27
18.05
1.79
7.96
23.07
3.77
10.17
8.86
1.82
2.79
1.59
1.65
6.54
5.14
1.26
14.39
4.53
6.42
5.06
3.94
12.51
32.04
17.40
18.91
10.00
23.94
16.98
92.43
42.60
27.75
40.98
14.61
15.99
3.99
3.99
15.71
23.94
11.84
12.70
3.90
8.17
12.06
4.75
7.79
4.08
0.88
0.72
0.32
0.27
0.18
0.06
0.23
0.89
0.72
0.96
0.91
0.98
1.84
3.54
2.73
3.43
2.53
4.28
3.64
þþþ
þþþ
þþþ
þþþ
þþþ
þþþ
þþþ
þþþ
þþþ
þþþ
þþþ
þþþ
þþ
þþþ
þþþ
þþþ
þþþ
þþ
þþþ
þþ
þþþ
þþ
þþþ
þþþ
91.91
74.58
42.51
39.29
28.64
27.54
17.90
17.90
16.45
9.75
4.13
3.99
3.92
3.89
3.51
3.45
3.44
2.37
1.65
1.43
1.26
1.21
1.07
0.97
0.80
0.76
0.66
0.62
0.59
0.51
0.48
0.37
0.34
0.21
0.20
0.13
0.12
*258 isolated plus associated HPE cases from 1982 to 2000 period.
**Expected values derived from 9,236 babies with multiple malformations (ECLAMC, 1982–2000).
Z ¼ (ObservedExpected)/Expected2.
NFS, not further specified.
P values: , >0.05; þ, <0.05; þþ, <0.01; þþþ, <0.001.
the apparent cluster in time can only be a common occurrence in the distribution of rare events.
Recently, ECLAMC dealt with an impressive cluster of
sirenomelia and HPE in the city of Cali, Colombia
without identifying any causal factor [Saldarriaga
et al., 2007]. Earlier, this association was studied by
Källen et al. [1992].
HPE does not to appear to vary in BPR among
populations; this is suggested by even values among
ECLAMC hospitals and ECLAMC network sub-sets by
countries, which are known to vary in genetic and
environmental make-up [Lopez-Camelo and Orioli,
1996].
Median Cleft Lip
Cohen [2001] indicated that median cleft lip with
normal head circumference seldom reflects under-
lying HPE (a ‘‘normal’’ or enlarged head circumference with HPE can occur with accompanying
hydrocephalus). Generally, median cleft lip with
normal head circumference does have a better
prognosis than if associated with a microcephaly,
although developmental delay can be found some
cases. Accordingly, isolated median cleft lip in our
series did not behave as HPE, but had epidemiological data similar to that of oral clefts with a male
preponderance, prenatal mortality in 11%, and
normal birthweight.
Gender
HPE was more common among females in our
sample (M:F sex ratio ¼ 0.74 at birth). Female excess
was statistically significant for the total sample, but
not for sub-categories because of their small sample
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3096
ORIOLI AND CASTILLA
TABLE VII. Association Between Non-Syndromic HPE,* and Non-Craniofacial Anomalies in Decreasing Value of Observed/Expected (O/E)
Ratios**
ECLAMC
Code
75114
7552M
75610/9
7554A
75266
75404
75250
7561A
746TG
75503
7528A
75141
75724
75803
746TC
75802
746TA
746SE
75332
7554H
7552N
746IZ
75100
75900
7552O
7550 (POS)
746AL
75481
55112
7553D
75169
75922
75556
75681
7552H
75553
77190
75501
75262
75200
7532
7531
746TP
7548/9
75264
7486
7521
74750
7561
746SA
74861
7550(PRE)
55115
746SI
7561H
746SV
75701
7552D
74655000
7551
7417555
7552_4
7512
75502
Specific defect
Observed
Expected
Z
P
O/E
Atresia of ileum
Intercalary upper limb reduction
Vertebral defect
Upper and lower amelia
Vaginal atresia
Irreducible talipes cavus
Uterus, fallopian tubes and ovarian anomalies
Vertebral agenesis
Transposition of great vessels
Upper and lower limb postaxial polydactyly
Micropenis
Malrotation of intestine
Constrictive skin scar
Splenomegaly
Common arterial trunk
Polysplenia
Aortic anomaly
Other septal cardiac anomalies
Horseshoe kidney
Brachydactyly
Severe upper limb preaxial reduction
Left heart hypoplasia
Meckel diverticulum
Situs inversus
Mild upper limb preaxial reduction
Postaxial polydactyly
Endocardial cushion defect
Rockerbottom feet
Omphalocele
Lower limb digit reduction
Liver defect
Sirenomelia
Overlapping fingers
Diaphragmatic defect
Upper limb brachydactyly
Upper limb camptodactyly
Short umbilical cord
Manual postaxial polydactyly
Hypoplastic external female genitalia
Ambiguous genitalia
Hydronephrosis
Polycystic kidneys
Pulmonary anomaly
Talipes NFS
Anteriorly placed anus
Lung anomaly
Cryptorchidism
Single umbilical artery
Vertebral defect
Atrial septal defect
Lung hypoplasia
Preaxial polydactyly
Gastroschisis
Dextrocardia
Hemivertebrae
Ventricular septal defect
Hydrops
Upper limb digit reduction
Heart defect
Inguinal hernia
Syndactyly
Spina bifida
Upper limb defect
Limb reduction
Imperforate anus
Lower limb postaxial polydactyly
1
2
2
2
1
1
6
3
4
8
17
3
1
1
1
2
1
2
2
1
4
2
1
1
3
17
1
4
10
1
1
1
3
6
1
3
1
8
1
8
6
5
1
5
1
5
12
7
7
3
4
2
1
1
2
5
2
1
22
1
6
5
11
16
8
1
0.03
0.14
0.28
0.31
0.17
0.17
1.62
0.81
1.12
2.43
5.73
1.26
0.42
0.42
0.45
0.89
0.47
1.01
1.01
0.50
2.29
1.26
0.70
0.73
2.32
14.02
0.84
3.38
8.46
0.87
0.89
0.89
2.71
5.56
0.95
3.02
1.03
9.05
1.15
10.08
8.07
6.73
1.45
7.35
1.48
7.65
18.88
11.09
11.09
4.78
6.68
3.49
1.84
1.84
3.80
9.89
3.99
2.04
45.98
2.10
13.02
10.89
24.14
35.50
17.77
2.54
5.82
4.98
2.30
3.03
2.03
2.03
3.44
2.43
2.73
3.57
4.71
1.55
0.90
0.90
0.83
1.17
0.76
0.99
0.99
0.70
1.13
0.66
0.36
0.32
0.45
0.79
0.18
0.34
0.53
0.14
0.11
0.11
0.18
0.19
0.05
0.01
0.03
0.35
0.14
0.66
0.73
0.67
0.38
0.87
0.39
0.96
1.58
1.23
1.23
0.81
1.04
0.80
0.62
0.62
0.92
1.55
1.00
0.73
3.54
0.76
1.94
1.79
2.67
3.27
2.32
0.97
þþþ
þþþ
þ
þþþ
þ
þ
þþþ
þþ
þþ
þþ
þþþ
þþþ
þþ
þþþ
þ
35.80
14.32
7.16
6.45
5.97
5.97
3.70
3.70
3.58
3.29
2.97
2.39
2.39
2.39
2.24
2.24
2.11
1.99
1.99
1.99
1.75
1.59
1.43
1.38
1.29
1.21
1.19
1.18
1.18
1.15
1.12
1.12
1.11
1.08
1.05
0.99
0.97
0.88
0.87
0.79
0.74
0.74
0.69
0.68
0.68
0.65
0.64
0.63
0.63
0.63
0.60
0.57
0.54
0.54
0.53
0.51
0.50
0.49
0.48
0.48
0.46
0.46
0.46
0.45
0.45
0.39
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3097
HOLOPROSENCEPHALY IN SOUTH AMERICA
TABLE VII. (Continued)
ECLAMC
Code
55111
746O
75552
75723
75120
75682
75741
75551
75564
75571
7558
7541
7530
7522
22701
75713
Specific defect
Umbilical hernia
Other specified heart defects
Single palmar crease
Pilonidal defect
Imperforate anus NFS{
Abdominal muscular wall defect
Nail hypoplasia
Fifth finger camptodactyly
Hip dislocation
Overlapping toes
Arthrogryposis
Talipes equinovarus
Renal agenesis
Hypospadias
Flat vascular nevus
Brown pigmented nevus
Observed
Expected
Z
P
O/E
1
1
3
3
1
1
1
1
1
1
2
4
1
1
1
1
2.74
2.77
8.69
8.69
3.04
3.24
3.60
4.25
4.36
5.11
11.09
26.93
7.46
9.86
15.28
17.12
1.05
1.06
1.93
1.93
1.17
1.24
1.37
1.58
1.61
1.82
2.73
4.42
2.36
2.82
3.65
3.90
þþ
þþþ
þþ
þþ
þþþ
þþþ
0.37
0.36
0.35
0.35
0.33
0.31
0.28
0.24
0.23
0.20
0.18
0.15
0.13
0.10
0.07
0.06
*258 isolated plus associated HPE cases from 1982 to 2000 period.
**Expected values derived from 9,236 babies with multiple malformations (ECLAMC 1982–2000).
{
NFS, not further specified.
Z ¼ (ObservedExpected)/Expected2.
P values: , >0.05; þ, <0.05; þþ, <0.01; þþþ, <0.001.
sizes. We identified a 2:1 female predilection in
alobar HPE in contrast to Roach et al. [1975], who
reported a 3:1 ratio in Indiana.
Chromosomal Anomalies
Studies of chromosomal anomalies in HPE (particularly trisomy 13) have ranged from 25% [Mastroiacovo et al., 1992] to 58% [Chen et al., 2005]. These are
well above our rate of 15%. It is difficult to identify all
trisomy 13 cases with HPE because perinatal mortality is high and, frequently, it is not possible to draw
cell samples and/or culture cells successfully, particularly in South American hospitals.
However, HPE with unidentified trisomy 13 in our
study did not appear to contribute significantly to the
associated HPE group, since mean maternal age in
this group was similar to that of isolated HPE and
significantly lower than that of chromosomal HPE.
The frequency of HPE among cases with trisomy 13
registered in ECLAMC was 42% in the more recent
Series B. It is not appropriate to use this rate to
calculate the expected number of HPE cases with
trisomy 13 for Series A because diagnosis of HPE
showed a significant increase after 1996.
Risk Factors
For some variables we had data from the total
examined newborn population in the 1982–2000
period, and cohort analysis was carried out to
identify or confirm risk factors for HPE. There were
more HPE cases among birthweight <2,500 g and
among stillbirths. The case–control comparisons
showed that low birthweight arise mainly from
IUGR. We also identified a lack of primigravidas
among mothers of HPE cases, and an excess of noncephalic presentations. A Californian population
case–control analysis in non-syndromic HPE was
reported by Croen et al. [1996], but they used
primigravidas as the category of reference, and did
not analyze other variables. Croen et al. [2000]
described increased HPE risk for maternal alcohol
consumption, cigarette smoking, combined alcohol
and cigarette smoking, insulin-dependent diabetes,
medication for repiratory illness, and salicylatecontaining medication. Cohen and Shiota [2002]
extensively reviewed etiologic factors in HPE,
including ethyl alcohol, diabetic embryopathy,
retinoic acid, and several anecdotal suggestions of
teratogenic factors for HPE, including viruses, and
salicylates. In our case–control analysis, we confirmed the risk of maternal insulin-dependent
diabetes and flu. Vaginal bleeding and the use of
exogenous sex hormones could be risk factors or a
consequence of the defect. Maternal anemia, iron
supplementation, and salicylates were not risk
factors for HPE in our study.
Associated Defects
We confirmed that severe ear defects with atresia of
the auditory canal were part of HPE spectrum
[Mastroiacovo et al., 1992] as well as microstomia.
Among the six defects found less frequently than
expected with the HPE spectrum, four were mild ear
defects.
Matsunaga and Shiota [1977] described the presence of CNS defects, cleft lip, branchial arch
anomalies, polydactyly, and limb anomalies in HPE
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
3098
ORIOLI AND CASTILLA
TABLE VIII. Types of Cerebral and Facial Defects and Gender in 174 HPE Cases (ECLAMC 2000–2003)
Gendera
Defect
Cerebral
Alobar
Semilobar
Lobar
NFSd
Total
Facial
Cyclopia
Ethmocephaly
Cebocephaly
Premaxillary agenesis
Uni/Bilat. CLPe
Cleft palate
No facial cleft
Totala
Male
Female
Intersex
Total
N (p)b
N (p)b
N (p)b
N (p)b
%
M/Fc
11 (0.33)
16 (0.44)
6 (0.43)
37 (0.41)
70 (0.40)
18 (0.55)
19 (0.53)
7 (0.50)
50 (0.55)
94 (0.50)
4 (0.12)
1 (0.03)
1 (0.07)
4 (0.04)
10 (0.06)
33 (1.00)
36 (1.00)
14 (1.00)
91 (1.00)
174(1.00)
18.97
20.69
8.04
52.30
100.00
0.61
0.84
0.86
0.74
0.74
8 (0.47)
3 (0.38)
5 (0.25)
15 (0.36)
4 (0.33)
3 (0.50)
31(0.45)
70 (0.40)
7 (0.41)
4 (0.50)
13 (0.65)
24 (0.57)
7(0.58)
3 (0.50)
36 (0.52)
94 (0.67)
2 (0.12)
1 (0.13)
2 (0.10)
3 (0.07)
1 (0.08)
0 (0.00)
1 (0.01)
10 (0.06)
17 (1.00)
8 (1.00)
20 (1.00)
42 (1.00)
12 (1.00)
6 (1.00)
69 (1.00)
174(1.00)
9.77
4.60
11.49
24.14
6.90
3.44
39.66
100.00
1.1
0.75
0.38
0.63
0.57
0.86
0.86
0.74
a
There were five males (2L, 1SL, 2NFS), seven females (2A, 2SL, 3NFS), and five intersex among the cases with proved chromosomal anomaly.
N (p), number (proportion).
M/F, male index: only the total sample differ significantly (P < 0.05) from the expect female proportion in this population (0.49).
d
NFS, not further specified (including two cases with complex defects).
e
Uni/bilateral cleft lip and palate.
b
c
embryos. Cohen [1989b] reviewed the association of
anencephaly, spina bifida, and polydactyly. We
confirmed the association, but with tetramelic postaxial polydactly, and we could not decide between
an excess of trisomy 13 or an excess of unidentified
syndromes with tetramelic polydactyly, such as
pseudotrisomy 13, Meckel syndrome, hydrolethalus
syndrome, Pallister–Hall syndrome, and Smith–
Lemli–Opitz syndrome. The association with anencephaly, and spina bifida was not found in our
study.
Other findings with HPE including genital anomalies, vertebral defects, and transposition of the great
vessels have not been mentioned previously except
for genital anomalies, which have been recorded
with some frequency because of the abnormal
hypothalamic-pituitary axis in HPE; genital anomalies previously recorded have included agenesis or
hypoplastic ovaries, agenesis or hypoplastic testes,
micropenis, and abnormalities of the clitoris [Cohen,
1989b].
The BPR in Series B is higher (2.2/10,000) than that
found in Series A (0.82/10,000) and reflects the
increased secular trend observed since 1996. Only
Chen et al. [2005] found a higher BPR (6.06/10,000) in
livebirths, stillbirths, and pregnancy terminations.
HPE is more common in females [reviewed by
Cohen, 1989b]. Similarly, we found a 0.74 male:female sex ratio at birth. We identified a 2:1 female
predilection in alobar HPE, in contrast to Roach et al.
[1975] who found a 3:1 sex ratio. Female excess was
statistically significant in the total sample, but not in
TABLE IX. Types of Cerebral and Facial Defects in 174 HPE Cases (ECLAMC 2000–2003)
Cerebral defect
Facial defecta
Cyclopia
Ethmocephaly
Cebocephaly
Premaxillary agenesis
Uni/Bilat. CLPd
Cleft palate
No facial cleft
Total
Alobar
Semilobar
Lobar
NFSb
Total
N (p)c
N (p)c
N (p)c
N (p)c
N (p)c
0 (0.00)
0 (0.00)
0 (0.00)
2 (0.14)
2 (0.14)
1 (0.07)
9 (0.64)
14 (1.00)
14 (0.15)
5 (0.05)
14 (0.15)
27 (0.30)
8 (0.09)
2 (0.02)
21 (0.23)
91 (1.00)
17 (0.10)
8 (0.05)
20 (0.11)
43 (0.25)
12 (0.07)
6 (0.03)
68 (0.39)
174 (1.00)
2 (0.06)
3 (0.09)
5 (0.15)
9 (0.27)
1 (0.03)
0 (0.00)
13 (0.39)
33 (1.00)
1
0
1
5
1
3
25
36
(0.03)
(0.00)
(0.03)
(0.14)
(0.03)
(0.08)
(0.69)
(1.00)
a
There were two ethmocephaly (A, NS), one cebocephaly (A), eight premaxillary agenesis (1A, 3SL, 4NFS), one cleft lip and palate (SL), and 5 cases with no facial clefts
(2A, 1SL, 1L, 1NFS), among the cases with proved chromosomal anomaly.
b
Not further specified (including two cases with complex defects).
c
N (p), number (proportion).
d
Uni/bilateral cleft lip and palate.
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
HOLOPROSENCEPHALY IN SOUTH AMERICA
each of the subcategorie, probably because of the
small sample size of each.
The frequency of HPE among cases with 13 trisomy
registered in ECLAMC was 42%, somewhat higher
than the rate of 25% described by Mastroiacovo et al.
[1992] in Italy.
In general, alobar HPE is considered the more
common HPE type, and is generally found with the
most severe facial HPE phenotypes [Cohen, 1989a].
However, we found approximately the same proportion of alobar (40%), and semilobar (43%) types,
with examples of semilobar HPE in one case with
cyclopia and in one case with cebocephaly. Semilobar HPE in cyclopia and cebocephaly has also been
reported by Croen et al. [1996] in a Californian
population.
Cases with cebocephaly can have premaxillary
agenesis, bilateral or unilateral cleft lip and palate,
cleft palate only, or no oral cleft. When facial defects
were correlated with cerebral defects in specific
cases, some interesting facts appeared: cyclopia did
not exhibit any kind of oral cleft; cleft palate was
frequent in ethmocephaly; and most cases with
cebocephaly did not have facial clefting. Even
though some studies described each case [Whiteford
and Tolmie, 1996; Chen et al., 2005] they did not have
enough cases or enough detailed description to
confirm or reject our results.
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