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Diprosopus: Systematic Review and Report of Two Cases
Mar
ıa Paz Bidondo*
1,2
, Boris Groisman
1
, Agostina Tardivo
1
, Fabi
an Tomasoni
1,3
,
Ver
onica Tejeiro
1,3
,In
es Camacho
1,4
, Mariana Vilas
1
, Rosa Liascovich
1
, and Pablo Barbero
1
Background: Diprosopus is a subtype of symmetric conjoined twins with one
head, facial duplication and a single trunk. Diprosopus is a very rare
congenital anomaly. Methods: This is a systematic review of published cases
and the presentation of two new cases born in Argentina. We estimated the
prevalence of conjoined twins and diprosopus using data from the National
Network of Congenital Anomalies of Argentina (RENAC). Results: The
prevalence of conjoined twins in RENAC was 19 per 1,000,000 births (95%
confidence interval, 12–29). Diprosopus prevalence was 2 per 1,000,000
births (95% confidence interval, 0.2–6.8). In the systematic review, we
identified 31 diprosopus cases. The facial structures more frequently
duplicated were nose and eyes. Most frequent associated anomalies were:
anencephaly, duplication of cerebral hemispheres, craniorachischisis, oral
clefts, spinal abnormalities, congenital heart defects, diaphragmatic hernia,
thoracic and/or abdominal visceral laterality anomalies. One of the RENAC
cases and three cases from the literature had another discordant
nonmalformed twin. Conclusion: The conjoined twins prevalence was similar
to other studies. The prevalence of diprosopus was higher. The etiology is still
unknown. The presence of visceral laterality anomalies may indicate the link
between diprosopus and the alteration or duplication of the primitive node in
the perigastrulation period (12–15 days postfertilization). Pregnancies of more
than two embryos may be a risk factor for diprosopus. Given the low
prevalence of this defect, it would be useful to perform studies involving
several surveillance systems and international consortiums.
Birth Defects Research (Part A) 00:000–000, 2016.
V
C2016 Wiley Periodicals, Inc.
Key words: diprosopus-craniofacial duplication-conjoined twins-very rare con-
genital anomalies-neural tube defects-heterotaxy
Introduction
Multiple pregnancies (MP) carry a higher risk on maternal
and perinatal health, and its prevalence has increased
because of assisted reproduction techniques. In Argentina,
MP represent 2% of total births (DEIS, 2014). MP can be
classified according to their zygosity in dizygotic gesta-
tions (twins originating from two oocytes fertilized by two
different spermatozoa) or monozygotic (twins originating
from one oocyte fertilized by one spermatozoon). The lat-
ter represents approximately one-third of spontaneous MP.
Depending on when monozygotic twinning occurs, the
fetuses may or may not share the placenta and/or amniot-
ic sac, thus giving three forms of presentation: dichorionic
diamniotic, monochorionic diamniotic, and monochorionic
monoamniotic. Conjoined twins share parts of the
body and vital organs. This type of anomaly occurs in
monoamniotic monochorionic twin pregnancies resulting
from a disturbance during early embryonic development
(approximately 12–15 days postconception). Conjoined
twins can be classified according to different criteria
(Spencer 2000a, 2000b): shared structure (i.e., cephalo-
pagus, shared head; thoracopagus, shared thorax; etc.);
joining area (dorsal, ventral, lateral) and if they have or
not an equivalent body surface (symmetrical / asymmet-
rical). For an accurate description, the duplicated struc-
tures are numbered (i.e., di-tri-tetra). The International
Clearinghouse for Birth Defects Surveillance and Research
estimated the prevalence at birth of conjoined twins at
1.47 per 100,000 births (CI 95%: 1.32–1.62) (Mutchinick
et al., 2011).
“Diprosopus” (from Greek: di-two; prosopon-face) is
the duplication of facial structures in a single head. Dipro-
sopus is considered a subtype of conjoined twins: symmet-
rical, monocephalic, and with a single trunk. This entity
has a very low frequency. The pathogenesis of this anoma-
ly is still unknown.
This study aims to delineate the features of diprosopus
through a systematic review of published cases, to present
two new cases, and to calculate the prevalence in Argentina.
Materials and Methods
SYSTEMATIC REVIEW OF CASE REPORTS
We carried out a systematic review of case reports pub-
lished until June 30, 2015. We used as a methodological
framework for this review: the “Preferred reporting items
for systematic review and meta-analysis protocols
(PRISMA-P)” checklist (Shamseer et al., 2015) (Fig. 1).
We searched in MEDLINE by means of PubMed; SciELO;
LILACS; restricting the search to human cases. We consid-
ered scientific papers available in English and Spanish. We
1
National Network of Congenital Anomalies of Argentina (RENAC), National
Center for Genetic Medicine (CNGM), National Administration of Labs and
Health Institutes (ANLIS), Buenos Aires, Argentina
2
Department of Cellular Biology, Histology, Embryology and Genetics.
Medicine College, University of Buenos Aires (UBA), Buenos Aires, Argentina
3
Neonatology Service in the Evita Pueblo Hospital, Buenos Aires, Argentina
4
Neonatology Service in the 25 de Mayo Hospital, Catamarca, Argentina
Supported by National Center for Genetic Medicine (CNGM) and the National
Program of Rare Diseases and Congenital Anomalies, National Ministry of
Health. It was supported by Grants: Agencia Nacional de Promoci
on Cient
ıfica
y Tecnol
ogica, Buenos Aires, Argentina (PICTO 2011-0147), Becas Salud
Investiga 2011, 2012, 2013; Fondos concursables ANLIS 2015 (FOCANLIS).
*Correspondence to: Mar
ıa Paz Bidondo, Av. Las Heras 2670, Ciudad
Aut
onoma de Buenos Aires, Argentina, PO: C1425ASP. E-mail: mariapazbi-
dondo@gmail.com
Published online 0 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Doi: 10.1002/bdra.23549
V
C2016 Wiley Periodicals, Inc.
used the keywords “Diprosopus”, “Diprosopia”, “Craniofacial
duplication”, “Duplicaci
on craniofacial”. Search was done on
1 July 2015. The publications were assessed independently
by two authors of this study (M.P.B. and P.B.). In cases in
which there was disagreement, a third author (B.G.) was
consulted. The abstracted data were: (a) Publication infor-
mation: first author, year. (b) Cases information: pregnancy
outcome, sex, weight, gestational age; twinning maternal
age, sonographic prenatal diagnosis, karyotype, consanguini-
ty, facial structures affected, and associated anomalies
(Appendices A and B).
For this study, we defined “Diprosopus” as the duplica-
tion of at least two full facial organs, or two structures
from two different organs (eyes, ears, nose, oral cavity) in
an individual with one head and one trunk (Fig. 2). We
excluded cases of partial duplication, i.e., those who have
only a duplication of a single organ or part of an organ
from the face in an individual with one head and one
trunk (i.e., duplication of nose).
Inclusion criteria were that the publication had at least
one reported case with an image of the head and the
observed phenotype met the case definition.
FIGURE 1. Diagram of the process of data collection and selection of the studies included in the systematic revision (using PRISMA flow chart; Shamseer et al.,
2015; Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P: elaboration and explanation).
FIGURE 2. Examples of different types of facial duplication in diprosopus cases. The pictures represent the duplication of at least two full facial organs, or two
structures from two different organs (eyes, ears, nose, oral cavity) in an individual with one head. (A) Partial duplication of nose and complete mouth duplication.
(B) Complete duplication of nose and mouth. (C) Complete duplication of nose, oral cavity and an extra orbit. (D) Tetraophthalmos, two noses; and partial mouth
duplication. (E) Tetraophthalmos, two noses, two oral cavities and an extra ear in the middle of the facial region.
2 DIPROSOPUS REVIEW AND REPORT OF CASES
PREVALENCE OF DIPROSOPUS IN ARGENTINA, AND THE REPORT OF
TWO NEW CASES
We used data from the National Network of Congenital
Anomalies of Argentina (in Spanish “Red Nacional de Anom-
al
ıas Cong
enitas”, RENAC) from November 1
st
, 2009 to Janu-
ary 31, 2015. The RENAC is a hospital based surveillance
system of congenital anomalies working in 182 maternity
hospitals distributed in the 24 jurisdictions of Argentina. It
covers around 300,000 births per year, 42% of annual births
in the country. The pregnancy outcomes included are live
births and stillbirths weighing 500 grams or more, with
major structural congenital anomalies detected from birth
until hospital discharge. Neonatologists from each hospital
send monthly reports to the RENAC coordination. The reports
include a description of the affected cases and a core set of
variables. The reporting neonatologists can send photographs
and/or results of additional studies that contribute to the
diagnostic accuracy. The reports are sent through an on-line
forum. This methodology allows review and discussion of
cases (Groisman et al., 2013). We analyzed cases reported
and coded as conjoined twins (ICD-10 code: Q89.4), and spe-
cifically those fitting the case definition of diprosopus. The
diagnosis of Diprosopus was made through clinical descrip-
tion and photographs of full body and face. Prevalence was
calculated as the proportion between the number of cases
and the total number of newborns, expressed per 1,000,000
births. The 95% confidence intervals were estimated accord-
ing to the Poisson distribution for rare events.
Results
SYSTEMATIC REVIEW OF CASE REPORTS
The systematic review identified 324 publications, 33 pub-
lications met the inclusion criteria and 291 were excluded.
Three full texts were not available, so 30 publications
were included in our review, with 31 patients reported
with Diprosopus (Fig. 1).
Fifteen cases were born alive, 5 were stillbirths and 9
had prenatal diagnosis followed by elective termination of
pregnancy for fetal anomaly (ETOPFA). In two cases the
pregnancy outcome was not described. The median mater-
nal age was 24 years. The male to female ratio was 0.7.
Excluding cases of ETOPFA, the median gestational age
was 34.5 weeks. In 3 of 31 cases, there was an extra twin
fetus without diprosopus (Appendix A). Two had a dichor-
ionic placentation and one had diamniotic monochorionic
placentation. Sex was discordant in one case (Rai et al.,
1998); one had ambiguous genitalia (D’Armiento et al.,
2010); in the third case, there was no information about
the sex of the twin without diprosopus (al Muti Zaitoun
et al., 1999). In the same report, coarctation of the aorta
was found in the twin without diprosopus.
Facial structures more frequently duplicated were nose
and eyes; nine patients had oral clefts. Thirty cases had
different central nervous system (CNS) anomalies such as
anencephaly, duplicated hemispheres and rachischisis. At
thoracic–abdominal level, reported cases presented dia-
phragmatic hernia and conotruncal heart defects; there
were anomalies in the right–left laterality viscera, includ-
ing situs inversus totalis, transposition of the great arter-
ies, dextrocardia, anomalies in lung lobation, intestinal
malrotation, asplenia or polysplenia, among others (Table
1 and Appendix B). Twelve patients had karyotype per-
formed, with normal results in all of them. One patient
also underwent CGH-microarray, showing an imbalance. In
two cases, consanguinity was reported (Appendix A).
PREVALENCE OF DIPROSOPUS IN ARGENTINA, AND THE REPORT OF
TWO NEW CASES
From November 1st, 2009 to January 31st, 2015, 20 cases
of conjoined twins were reported from a total of 1,052,088
examined newborns in the RENAC, resulting in a prevalence
of 19 per 1,000,000 births (95% confidence interval [CI],
11.6–29.4). Diprosopus was detected in two cases involving
10% of all conjoined twins. Prevalence of diprosopus was
1.9 per 1,000,000 births (95% CI, 0.2–6.8).
Case 1 was a female stillbirth. Maternal age was 29
years old and paternal age was 28 years old. The parents
were a nonconsanguineous couple. They had a previous 5-
year-old healthy son. Gestational age was 36 weeks;
weight was 1600 grams. Clinical features were anencepha-
ly, craniofacial duplication and diaphragmatic hernia. It
was a dichorionic diamniotic twin pregnancy. The first
twin was a healthy female live newborn weighing 2,200
grams. There were no exposures to teratogenic agents dur-
ing pregnancy. Prenatal ultrasound at 17 weeks of gesta-
tion showed a fetus with exencephaly, left diaphragmatic
hernia, heart with four chambers displaced by the intesti-
nal loops, the presence of kidneys, undamaged spine, and
normal amniotic fluid volume. The facial anomaly was
detected prenatally. The other fetus was normal. Neither
prenatal/postnatal karyotype nor necropsy was per-
formed. The external examination showed anencephaly;
tetraophthalmos (two very close eyeballs were placed at
the midline, and the remaining two eyes were laterally
located); two lateral noses; two lateral oral cavities and
unilateral cleft lip and palate of the left oral cavity; two
dysplastic lateralized ears; and a structure that seemed
like a remnant of a pinna located in the midline of the
cephalic pole. The structures of the trunk and upper and
lower limbs were not affected. External genitalia were
female (Figs. 3 and 4; Appendices A and B).
Case 2 was a female newborn. Gestational age was 28
weeks; weight was 740 grams. The patient had prenatal
diagnosis of anencephaly. There were no exposures to tera-
togens during pregnancy. At birth, the patient had anenceph-
aly, craniofacial duplication consisting of tetraophtalmos
(four eyeballs in three orbits, with two eyeballs occupying a
single orbit); two noses, two oral cavities and unilateral cleft
lip. The structures of the trunk and upper and lower limbs
showed no abnormalities. The external genitalia were
BIRTH DEFECTS RESEARCH (PART A) 00:00–00 (2016) 3
female. The patient died at birth. Neither karyotype nor nec-
ropsy could be performed. Maternal age was 34 with five
previous healthy children. The parents were a nonconsan-
guineous couple (Figures 5 and 6; Appendices A and B).
Discussion
PREVALENCE
The prevalence of conjoined twins in RENAC was similar to
that observed in other investigations. A multicenter study
(Mutchinick et al., 2011) from 21 epidemiological
surveillance programs with more than 26 million births
showed a total conjoined twins prevalence of 1.5 per
100,000 births (95% CI, 1.3–1.6) and for the South-
American region, the prevalence was 2.4 per 100,000 births
(95% CI, 1.9–2.9). This study included 11 cases of diproso-
pus, involving 3% of conjoined twins. It is noteworthy that
nine of them occurred in Latin American countries over 5.5
million births evaluated in the region. This may indicate a
greater prevalence of diprosopus in Latin America. The over-
all frequency of diprosopus in this study was lower than that
observed in the RENAC. However, given the low frequency of
this anomaly, the prevalence of diprosopus estimated in our
study could be artifactually elevated.
Some authors have defined very rare defects as those
with prevalence lower than 1 in 30,000 births (Castilla
and Mastroiacovo, 2011). Knowledge of epidemiological
features of very rare defects is important because an
increase in frequency could indicate the introduction of
new teratogens as a well-known example of this was the
epidemic of phocomelia caused after the market introduc-
tion of thalidomide. In relation of conjoined twins, an
investigation detected an increase of prevalence in Polissia,
a region close to Chernobyl. The authors hypothesized a
relationship between disruptions during early blastogene-
sis and exposure to ionizing radiation (Wertelecki, 2010).
TABLE 1. Specific Congenital Anomalies in the Systematic Diprosopus Review
Specific congenital anomalies
No. of cases
affected/total
specified cases % of affection*
CNS
Duplication of hemispheres
Craniorachischisis
Anencephaly
Rachischisis
14/31 45.2%
10/31 32.3%
4/31 13.0%
2/31 6.5%
Oral Cleft 9/30 30.0%
Cardiovascular
CHD: Laterality defect (TGA/ Dextrocardia/Double right outlet)
CHD: Septal defect
9/17 53.0%
7/17 41.2%
Diaphragmatic hernia 8/10 80.0%
Other localization
Other laterality defects (i.e.: in lung lobulation, gastrointestinal rotation, spleen defects)
Ambiguous genitalia
Gastroschisis
Omphalocele
Thumb duplication
7/19 37.0%
1/31 3.2%
1/31 3.2%
1/31 3.2%
1/31 3.2%
% of affection*, taking into account the total number of cases with the specification.
CHD, congenital heart disease; CNS, central nervous system; TGA, transposition of great arteries.
FIGURE 3. Diprosopus: Case 1 RENAC. Anencephaly; facial duplication;
female genitalia; normal trunk and limbs.
4 DIPROSOPUS REVIEW AND REPORT OF CASES
MAIN FEATURES AND POSSIBLE RISK FACTORS
In this systematic review of case reports, we excluded
cases with partial facial duplication, because it is not clear
whether it is a subtype of conjoined twins, a focal duplica-
tion or the result of interference with other structure,
such as a teratoma (Baar, 1982; Costa et al., 2014). Cases
reported to RENAC were female, which is consistent with
the observed female predominance in Diprosopus and con-
joined twins (Mutchinik et al., 2011). This female predomi-
nance could be related to the presence of a conditioning
gene on the X chromosome still unknown. Gene expression
could result in a high lethality in male embryos following
an X-linked dominant pattern, such as incontinentia pig-
menti (Le Roux et al., 1996). RENAC cases had maternal
age under 35 years. In reviewed cases, maternal age did
not show a tendency to extreme ages. Diprosopus is asso-
ciated with a high neonatal lethality, mostly due to severe
neural tube defects (anencephaly, rachischisis). In the
reviewed literature, there were only two cases that sur-
vived the neonatal period. Both patients showed duplica-
tion of cerebral lobes (Kudo and Toda, 1970; Hahnel et al.,
2003).
Prenatal sonographic findings during the first and sec-
ond trimesters included heterogeneous features such as:
variable range of duplication of craniofacial structures;
CNS and spine anomalies, diaphragmatic hernia, heart dis-
ease and/or polyhydramnios. In some prenatally detected
cases, tomography and / or nuclear magnetic resonance
(NMR) helped define facial, CNS and other internal anoma-
lies (Dhaifalah et al., 2008; Maruotti et al., 2009; Laor
et al., 2012; Thornton, 2014). In RENAC case 1 (Figs. 3
and 4), exencephaly was detected prenatally, and
anencephaly was diagnosed postnatally. This situation
could be explained by the sequence of conversion of exen-
cephaly in anencephaly (Wood and Smith, 1984). Two
cases reviewed had parental consanguinity (Amr and Ham-
mouri, 1995; Suryawanshi et al., 2013). That might suggest
a genetic factor with an autosomal recessive pattern of
expression. However, both patients were from India and
Saudi Arabia, countries with a high proportion of consan-
guineous couples. Recurrence among siblings was not
reported.
In the cases reviewed, no chromosomal abnormalities
were identified in the karyotype. In one case, a CGH micro-
array study showed a complex genomic imbalance (Thorn-
ton et al., 2014). In this report, the study showed two
duplicated areas: Xp22.31p22.2 and 13q12.11; and a dele-
tion of 4q34.3. The duplications were also observed in the
patient’s mother; therefore, the 4q34.3 deletion may be
associated with diprosopus. However, the study was not
performed in the patient’s father and it is not possible to
determine if the deletion was pathogenic.
Diprosopus includes a monozygotic twinning event (it is
a subtype of conjoined twins); a third twin without disopro-
pus could be a risk factor. It is important to consider that
there is a 48% of monozygotic twinning in triplets, and a
higher frequency of conjoined twins in triplets (Baldwin,
1999; Guilherme et al., 2009). In this study 4 of the 33
cases had another twin without this defect; this happened in
case 1 from RENAC and cases 8, 18, and 20 from the review
(Rai et al., 1998; al Mutti Zaitoun, 1999; Maruotti, 2009). In
these reports, placentation and sex concordance between
twins was described, but without an analysis of polymorphic
genetic markers for the accurate identification of the twin-
ning type. Discordant sex was observed in case 20, which is
the only one that could be interpreted as dizygotic (Rai
et al., 1998). The case 18 had biamniotic monochorionic pla-
centation, which could be an indicator of monozygotic twin-
ning. However, in that case the thinning of the chorionic
plate and some mild vascular changes were also observed,
without being able to rule out an etiological mechanism
related to oxygen deficiency (al Muti Zaitoun, 1999).
PATHOGENESIS AND PROPOSED HYPOTHESIS
Conjoined twinning is a primary congenital anomaly, fol-
lowed by other secondary anomalies (malformations and /or
disruptions). These disorders occur most likely in epiblast
cells during the perigastrular period (12–15 days postfertili-
zation in humans). There are two alternative models to
explain conjoined twins pathogenesis: the fusion of two
monozygotic embryos that were separated in previous
stages; and the fission (splitting) of a single embryo (Spencer
2000a, 2000b; Kaufman, 2004). Given the impossibility of
using an experimental model in humans, some authors have
postulated different pathogenic mechanisms of diprosopus
based on the analysis of the phenotype and associated
anomalies of the affected and its relationship with concepts
FIGURE 4. Diprosopus: Case 1 RENAC. Cephalic pole. Anencephaly, tetraoph-
thalmos, rudimentary and dysplastic ear in the midline, unilateral cleft lip and
palate in the two oral cavities. A: left profile B: right profile.
BIRTH DEFECTS RESEARCH (PART A) 00:00–00 (2016) 5
of developmental biology emerged from experimental
models.
First, Spencer (2000a, 2000b) classified and analyzed
1200 cases of conjoined twins. In the case of Diprosopus
the author interpreted the initial abnormality as the early
fusion of two monozygotic embryonic discs at the ventral
and lateral levels. Secondary to this fusion, there might be
an aplasia and divergence of tissues from the midline. This
would explain the presence of CNS anomalies arising from
the forebrain, the duplication of facial structures and cer-
vical and thoracic vertebrae duplication as well as cardiac
and diaphragmatic anomalies (Table 2).
Second, Carles and colleagues (1995) considered histo-
pathological findings of two cases with Diprosopus and
defined the condition as a neurocristopathy with excess of
neural crest cells formation in a single embryonic disc.
These authors postulated that this excess would be sec-
ondary to the formation of two nothocords in a single
embryo, which produces two neural induction plates, and
an extra edge-neural crest medially located between the
two plates. These altered structures could explain the
presence of anencephaly, duplication of facial structures,
conotroncal heart disease and spinal disorders (Table 2).
Third, we propose that diprosopus occurs in a single
embryo but before the formation of the notochord, by the
presence of two early primitive nodes instead of one. This
hypothesis arises from the presence in many cases of
anomalies of visceral laterality-heterotaxy. The sequence of
events could be the following: The initial alteration would
be a doubling of the early primitive node and secondarily, a
group of specific congenital anomalies occurs in response
to the nodal alteration (Table 2). In the human epiblast, the
early primitive node begins to develop at the end of the
second week of gestation. It has multiple roles during the
gastrulation process such as being a signal emission center
that induces the neural plate. It participates in the left–right
axis establishment through the node ciliary cells, which
have a nonrandom preferential movement that generates
different cell behavior in the left and in the right embryo
position. The node derivated structures also are involved in
the specification of various structures of the head (Foley
and Stern, 2001; Boettger et al., 2001).
In diprosopus cases the craniofacial duplications and
the brain alteration (anencephaly or brain hemispheres
duplication) are related with alterations in the node and
its derivated signals during anterior neural induction pro-
cess and the craniofacial development. If there is a node
duplication, there will be a duplicated ciliary flow. This
causes the reception of signals (from both right and left
identity) in the midline area of the embryo. Consequently,
it generates a random assignation of laterality in the trunk
causing the heterotaxia event (Burn and Hill, 2009; Hiro-
kawa et al., 2009). We agree with Carles et al., in that the
alteration of the neural induction could generate extra
neural crest cells, which can explain the presence of facial
anomalies and cono-truncal heart defects. We add to this
hypothesis that the alteration of neural induction could be
the result of an initial event in the early primitive node.
STRENGTH AND WEAKNESSES
RENAC is a surveillance system with high coverage which
makes it possible to detect this rare birth defect. RENAC
operation allows the attachment of photos, which are essen-
tial for diagnosing this condition. One weakness is that in
RENAC cases, karyotype and necropsy were not performed.
Therefore, we do not have any data on the presence of
FIGURE 5. Diprosopus: Case 2 RENAC. Anencephaly; facial duplication;
female genitalia; normal trunk and limbs.
FIGURE 6. Diprosopus: Case 2 RENAC. Cephalic pole. Anencephaly, tetraoph-
thalmos: four eyeballs in three orbits, two noses, and two oral cavities with
unilateral cleft lip.
6 DIPROSOPUS REVIEW AND REPORT OF CASES
TABLE 2. Diprosopus: Mechanisms, Proposed Sequence of Events, and Its Link with the Associated Congenital Anomalies
Spencer’s Hypothesis
Congenital anomalies - Duplication of organs (brain hemispheres, facial structures, cervical spine)
- Malformations without duplications (congenital heart defects, diaphragmatic hernia;
respiratory and digestive tract anomalies)
Embryological mechanisms
and defects
Early ventrolateral fusion of monozygotic twins and reorganization of merged tissues (structures in the midline) Struc-
tures with aplasia and structures that diverge from the midline.
Schemes
Types of fusion of monozygotic twins: A) Rostral fusion B) Caudal fusion c) Ventrolateral fusion (the Diprosopus case is
indicated).
Picture adapted from Figure 3 in Spencer R, 2000. Theoretical and analytical embryology of conjoined twins: part I:
embryogenesis. Clin Anat.; 13(1): page 43.
Carles’ Hypothesis
Congenital anomalies - Anencephaly
- Facial anomalies; conotroncal cardiac defects
- Anomalies in vertebrae
- Diaphragmatic defects
Embryological mechanisms
and defects
Fission in a monozygotic gestation that produces the presence of two notochords. The two notochords in consequence
generate the duplication of the cephalic neural plate, the presence of an extra medial cranial neural crest, and alter-
ations in paraxial mesoderm
Schemes
Diprosopia as a result of the duplication of the notocohord, neural plate and excessive component of neural crest.
Picture adapted from Figure 10 in Carles D., et al.; 1995. Diprosopia revisited in light of the recognized role of the neural
crest cell in facial development. J Craniofacial Genet Dev Biol; 15:page 95
TABLE 2. Continued
Our Hypothesis
Congenital anomalies - Neural tube defects (anencephaly, hemispheres duplication, rachischisis)
- Facial anomalies (duplication in different structures with or without oral clefts)
- Conotroncal heart defects
- Vertebral anomalies
- Laterality defects (Dextrocardia, TGV; intestinal malrotation, spleen defect, alteration in lung lobulation)
Embryological mechanisms
and defects
Duplication of the early primitive node and secondarily, a group of specific congenital anomalies occurs in response to
the nodal alteration:
a) Alteration in node signaling for anterior neural induction correlated with: Duplication and / or alteration in the for-
mation of the neural plate; presence of an extra cephalic neural crest (facial and conotroncal alterations)
b) Alteration of node derivate structures (floor plate; precordal mesoderm; notochord and pharyngeal endoderm)
correlated with: Duplication and / or alteration in the formation of the neural plate; facial anomalies; vertebral anomalies
and diaphragmatic defects.
c) Alteration in ciliary node flow correlated with: Laterality anomalies in the visceral thoracic and abdominal organs.
Schemes
Epiblast structures in a normal human embryo
CNC: Cephalic neural crest. D: dorsal. V: Ventral
Epiblast structures in a Diprosopus human embryo
CNC: Cephalic neural crest. D: dorsal. V: Ventral
Note: The white arrow indicates the area in the midline of the embryo that receives signals from both right and left iden-
tity. This causes random determination of laterality at the level of the trunk (heterotaxia).
additional internal congenital anomalies. Most of the cases
from the literature did not have cytogenetic studies.
CONCLUSIONS
To our knowledge patients with diprosopus reported to
RENAC are the first cases described in Argentina. In the sys-
tematic review we included 31 cases with diprosopus.
Diprosopus prevalence in our study was 1.9 per 1,000,000
births and they represented 10% of conjoined twins. This
proportion is higher than observed in other epidemiological
studies. However, because only two cases were detected, we
need larger studies to confirm these results. It seems that
diprosopus may be associated with triple twin pregnancies.
Given the low prevalence of the defect, it is recommended
to have a monitoring system for congenital anomalies with
high coverage and /or to perform studies involving several
surveillance systems and international consortiums.
The etiology of diprosopus is still unknown, but associ-
ated congenital anomalies support some of the mechanisms
that may be involved. The laterality anomalies were not
previously described as a main associated anomaly in this
entity; it is one of the reasons to raise the hypothesis of the
early primitive node duplication. This hypothesis could pro-
vide an initial step for further research as it establishes a
period of time (perigastrulation) for the occurrence and the
structures involved (node and its derivates).
Acknowledgment
Authors declare no conflict of interest.
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10 DIPROSOPUS REVIEW AND REPORT OF CASES
Appendix A. Diprosopus Cases (RENAC and Systematic Review)
ID –author – year- country
Pregnancy
outcome Sex Weight (g)
Gestational
age (weeks) Twinning
Maternal
age
Sonographic
Prenatal
diagnosis Karyotype Consanguinity
1 RENAC 2015 ARGENTINA SB F 1600 36 Yes 29 YES NO NO
2 RENAC 2015 ARGENTINA LB F 740 28 NO 34 YES NO NO
3 THORNTON 2014 USA LB M 2440 36 NO 29 YES 46,XY
a
NO
4 PACHAJOA 2014 BRAZIL Elective TOP F NA 28 NO 37 YES 46,XX NA
5 SURYAWANSHI 2013 INDIA LB M NA NA NO NA NA NA YES
6 LAOR 2012 USA LB F 3400 32 NO 24 YES NA NO
7 ULKER 2012 ITALY Elective TOP F NA NA NO 22 YES NA NO
8DARMIENTO
b
2010 ITALY LB I 1800 37 YES 26 YES NA NO
MARUOTTI 2009
9 CHOH 2010 INDIA LB M 3200 NA NO NA NO NA NO
10 FERNANDES 2010 BRAZIL LB F 1700 30 NO 13 YES 46,XX NO
11 KASTEMBAUM 2009 USA LB M 3524 38 NO 21 YES 46,XY NO
12 DHAIFALAH 2008 CZECH Elective TOP M 450 23 NO 33 YES NA NA
13 EKINCI 2005 TURKEY SB F 130 28 NO 18 NA 46,XX NO
14 BUBUL 2004 FRANCE Elective TOP F NA 15 NO 34 YES 46,XX NO
15 KOSEOGLU 2003 TURKEY LB F NA NA NO NA NA NA NA
16 HAHNEL 2003 GERMANY LB NA NA NA NO NA NA NA NA
17 RODRIGUEZ MORALES 2002 PUERTO RICO Elective TOP M 1850 39 NO 23 YES NA NA
18 AL MUTI ZAITOUN 1999 UK SB M 1260 33 YES 16 NA 46,XY NO
19 ANGTUACO 1999 USA LB M NA 30 NO 20 YES NO NA
20 RAI 1998 UK LB M 1852 28 YES NA YES 46,XY NO
21 OOSTRA 1998 HOLLAND NA F NA NA NO NA NO NO NA
22 OOSTRA 1998 HOLLAND NA F NA NA NO NA NO NO NA
23 AMR 1995 SAUDI A. SB M 1260 30 NO 28 NA NO YES
24 FONTANAROSA 1992 ITALY Elective TOP M NA 14 NO 30 YES NO NO
25 PAVONE 1987 ITALY LB F 1210 28 NO 24 NA 46,XX NO
BIRTH DEFECTS RESEARCH (PART A) 00:00–00 (2016) 11
Appendix A. Continued
ID –author – year- country
Pregnancy
outcome Sex Weight (g)
Gestational
age (weeks) Twinning
Maternal
age
Sonographic
Prenatal
diagnosis Karyotype Consanguinity
26 PAVONE 1987 ITALY LB F 2450 NA NO 24 NA 46,XX NO
27 OKAZAKI 1987 PHILIPPINES SB F NA 31 NO 31 YES NO NA
28 STRAUSS 1987 ISRAEL Elective TOP F NA NA NO 27 YES NA NA
29 RYDNERT 1985 SWEDEN Elective TOP NA NA 20 NO NA YES NO NO
30 MOERMAN 1983 BELGIUM Elective TOP F NA 29 NO 21 YES 46,XX NO
31 JASCHEVATZKY 1980 ISRAEL SB NA 4200 38 NO 24 NO NO NO
32 KUDO 1970 JAPAN LB F 2980 NA NO 33 NO 46,XX NO
33 BRODER 1935 USA LB F 2500 NA NO NA NO NO NA
Pregnancy outcome: LB, livebirth; SB, stillbirth; Elective TOP, termination of pregnancy. SEX: M, Male; F, female; I, Indeterminate.
a
CGH array, Del4q34;DupXp22.31p22.2;Dup13q12.11.
b
Maruotti 2009 and D‘Armiento 2010 are two different publications of the same case.
NA, not available data.
Appendix B. Diprosopus cases (RENAC and systematic review)
ID –author - year
Facial structures
CNS/NTD
Other malformations
Ears Eyes Nose Mouth Oral clefts DH Heart Others
1 RENAC 2015 2 11 PIT 4; 3 ORBITS 2 2 BILATERAL Y
UNILATERAL
ANENCEPHALY YES NA NA
2 RENAC 2015 2 4; 3 ORBITS 2 2 UNILATERAL ANENCEPHALY NA NA NA
3 THORNTON 2014 2 11 PIT 4 2 2 NO DUPLICATION OF
HEMISPHERES Y
RAQUISQUISIS
YES TF ACCESORY SPLEEN,
ECTOPIC KIDNEYS,
INTESTINAL
MALROTATION
4 PACHAJOA 2014 4; 2 MEDIAL
LOCATION
5; 4
ORBITS
2 2 BILATERAL RACHISCHISIS NA ASD NA
5 SURYAWANSHI 2013 2 3 2 2 NO DUPLICATION OF
HEMISPHERES
NA NA NA
12 DIPROSOPUS REVIEW AND REPORT OF CASES
Appendix B. Continued
ID –author - year
Facial structures
CNS/NTD
Other malformations
Ears Eyes Nose Mouth Oral clefts DH Heart Others
6 LAOR 2012 NA 4; 3 ORBITS 2 2 BILATERAL DUPLICATION OF
HEMISPHERES
NA TF TRACHEOESOPHAGEAL
FISTULA AND ABSENT
SPLEEN
7 ULKER 2012 4; 2 MEDIAL
LOCATION
4 2 2 NO CRANEORACHISCHISIS NA TGA, VSD NA
8 MARUOTTI
b
2009 2 4; 4 ORBITS 2 2 NO CRANEORACHISCHISIS NA TGA AMBIGUOUS GENITALIA,
ABSENT PANCREAS,
TALIPES
9 CHOH 2010 2 4; 3 ORBITS 2 11PIT 2 NO DUPLICATION OF
HEMISPHERES
NA NA NA
10 FERNANDES 2010 2 4 2 11 PIT 2 NO OTRO YES DEXTROCARDIA, HYPO-
PLASTIC LEFT VENTRICLE
NO
11 KASTEMBAUM 2009 2 2 11PIT 1 11PROBOSCIS 2 UNILATERAL DUPLICATION OF HEMI-
SPHERES AND
ALTERATIONS OF
NEURONAL
MIGRATION
NO TGA and DUPLICTION OF
CARDIAC CHAMBERS
INTESTINAL
MALROTATION
12 DHAIFALAH 2008 2 3 2 2 NO NO NA NA DUPLICATED THUMB,
PULMONARY
HYPOPLASIA
13 EKINCI 2005 2 4 2 2 NO CRANEORACH ISCHISIS S YES DEXTROCARDIA SITUS INVERSUS
TOTALIS
14 BUBUL 2004 NA 4 2 2 BILATERAL DUPLICATION OF
HEMISPHERES Y
RACHISCHISIS
NA NA VERTEBRAL
DUPLICATION
15 KOSEOGLU 2003 NA 4 2 2 NA DUPLICATION OF
HEMISPHERES
NA NA NA
16 HAHNEL 2003 2 2 11PIT 2 1 NO DUPLICATION OF
HEMISPHERES
NA VSD NA
BIRTH DEFECTS RESEARCH (PART A) 00:00–00 (2016) 13
Appendix B. Continued
ID –author - year
Facial structures
CNS/NTD
Other malformations
Ears Eyes Nose Mouth Oral clefts DH Heart Others
17 RODRIGUEZ MORALES 2002 NA 4; 3 ORBITS 2 2 NO CRANEORACHISCHISIS NA TGA TRACHEOLARINGEAL
AND PULMONARY
DUPLICATION
18 AL MUTI ZAITOUN 1999 2 2 11PIT 2 2 BILATERAL CRANEORACHISCHISIS YES VSD UNILATERAL RENAL
AGENESIS; VERTEBRAL
DUPLICATION
19 ANGTUACO 1999 2 4; 3 ORBITS 2 11 PIT 2 NO DUPLICATION OF
HEMISPHERES
YES NA NA
20 RAI 1998 NA 4 2 2 NO DUPLICATION OF
HEMISPHERES
NA NA NA
21 OOSTRA 1998 2 4; 3 ORBITS 2 2 UNILATERAL CRANEORACHISCHISIS NA NA NA
22 OOSTRA 1998 2 4; 3 ORBITS 2 2 NO DUPLICATION OF
HEMISPHERES
NA NA NA
23 AMR 1995 3 4 2 2 BILATERAL CRANEORACHISCHISIS NA NA VERTEBRAL DUPLICA-
TION, OMPHALOCELE
24 FONTANAROSA 1992 2 4 2 2 NO CRANEORACHISCHISIS NA NA GASTROSCHISIS
25 PAVONE 1987 211 PIT 4; 3 ORBITS 2 2 NO CRANEORACHISCHISIS YES VSD NO
26 PAVONE 1987 211 PIT 3 2 2 BILATERAL ANENCEPHALY NA NA ANGIOMA IN LOWER
LIMB
27 OKAZAKI 1987 2 4; 3 ORBITS 2 2 NO DUPLICATION OF
HEMISPHERES
NA DEXTROCARDIA NO
28 STRAUSS 1987 2 11 PIT 4 2 2 NO DUPLICATION OF
HEMISPHERES Y
RACHISCHISIS
YES NA NA
29 RYDNERT 1985 2 4 2 2 NO CRANEORACHISCHISIS NO NO NO
30 MOERMAN 1983 2 4 11 PIT 2 2 NO ANENCENPHALY NA TGA , AVC, DUCTUS DUPLCATED SPLEEN
AND PANCREAS; INTES-
TINAL MALROTATION
31 JASCHEVATZKY 1980 NA NA 2 11 PIT 2 BILATERAL ANENCEPHALY NA NA NA
14 DIPROSOPUS REVIEW AND REPORT OF CASES
Appendix B. Continued
ID –author - year
Facial structures
CNS/NTD
Other malformations
Ears Eyes Nose Mouth Oral clefts DH Heart Others
32 KUDO 1970 2 4; 3 ORBITS 2 11 PIT 2 NO DUPLICATION OF
HEMISPHERES
NA DOUBLE OUTLET OF
RIGHT VENTRICLE; VSD;
ASD; COA
DUPLICATED
MESENTERY
33 BRODER 1935 2 2 2 2 NO ANENCEPHALY 1
LUMBOSACRAL
MYELOMENINGOCELE
YES NO DUPLICATED LOBES OF
RIGHT LUNG
NR, non reported; NTD, neural tube defects; DH, diaphragmatic hernia; TF, tetralogy of Fallot; ASD, atrial septal defect. TGA. transposition of great arteries; VSD, ventricular septal defect;
AVC, atrio-ventricular canal; COA; coarctation de aorta. (b): Maruotti 2009 and D‘Armiento 2010 are two different publications of the same case.
BIRTH DEFECTS RESEARCH (PART A) 00:00–00 (2016) 15
