Agenesis of the Corpus Callosum: Clinical and

Genetic Study in 63 Young Patients

Maria Francesca Bedeschi, MD*†, Maria Clara Bonaglia, PhD, Rita Grasso, MD*,
Alda Pellegri, MD‡, Rosaria Rita Garghentino, MD*, Maria Amalia Battaglia, MD‡,
Anna Maria Panarisi, MD*, Maja Di Rocco, MD*§, Umberto Balottin, MD!¶,
Nereo Bresolin, MD*#, Maria Teresa Bassi, PhD*, and Renato Borgatti, MD*

This study reports the clinical features of 63 patients
with agenesis of the corpus callosum who received
in-depth genetic, clinical, and laboratory testing with
the aim to contribute to a better description of the
large spectrum of associated malformations and to
assist clinicians in the diagnosis. Thirty patients man-
ifested complete agenesis and 33 patients displayed
partial agenesis. Other associated nervous system mal-
formations were detected in 14 patients with partial
agenesis of the corpus callosum (mostly correlated to
posterior fossa malformations) and in 10 patients with
complete agenesis (more frequently associated with
malformations of cortical development). Involvement
of organs and apparatus other than the nervous system
was present in 41 patients (ascribed to known syn-
dromes in 21 cases). Cytogenetically detectable chro-
mosomal abnormalities (7 patients) and subtelomeric
rearrangements (3 patients) were found. Neuromotor
skills were impaired in almost all cases (58/63). Mental
retardation of different severity was present in 52
cases, whereas 2 patients were borderline and 9 pa-
tients had normal intelligence quotient. This study
demonstrates that there is no unique prognosis for
agenesis of the corpus callosum as this condition is
associated with a broad range of clinical manifesta-
tions, oscillating between the limits of the norm and
severe psychomotor delay. © 2006 by Elsevier Inc.
All rights reserved.
Bedeschi MF, Bonaglia MC, Grasso R, Pellegri A, Gargh-
entino RR, Battaglia MA, Panarisi AM, Di Rocco M,
Balottin U, Bresolin N, Bassi MT, Borgatti R. Agenesis of
the corpus callosum: Clinical and genetic study in 63
young patients. Pediatr Neurol 2006;34:186-193.
Introduction
Agenesis of the corpus callosum is among the most
common brain malformations observed in humans [1]. Its
incidence varies as a function of both diagnostic tech-
niques and sample populations. In the general population
its estimated prevalence is 3-7 per 1000 [2,3], while in
children with developmental disabilities it is 2-3 per 100
[2,4].
Agenesis of the corpus callosum may occur as an
isolated malformation or as a component of more complex
malformation syndromes. It has been associated with
several consistent chromosomal rearrangements in more
than 20 autosomal and X-linked malformation syndromes
[1]. This extreme genetic heterogeneity may be due to the
embryologic processes underlying the formation of corpus
callosum. Indeed, several mechanisms might be responsi-
ble for callosal agenesis. However, the same genetic
defects responsible for callosal agenesis can determine
even more diffuse malformations of the central nervous
system or of other organs and apparatus. The severity of
the clinical picture can thus vary significantly. Genotype-
phenotype correlation studies can contribute to identifying
subpopulations with common features.
The present study describes the clinical characteristics
of 63 patients with agenesis of the corpus callosum who
received in-depth genetic, clinical, and laboratory testing
with the aim to contribute to a better description of the

From the *IRCCS “E Medea”, Bosisio Parini Lecco, Italy † Medical
Genetic Unit Istituti Clinici di Perfezionamento, Milano, Italy; ‡ IRCCS
“E Medea”, Conegliano Veneto Treviso, Italy; § IRCCS “G. Gaslini”,
Genova, Italy; !Child Neuropsychiatry Unit, University of Insubria,
Macchi Foundation Hospital, Varese, Italy; ¶Department of Child
Neuropsychiatry, University of Pavia, IRCCS Fondazione C. Mondino,
Pavia, Italy; #IRCCS Ospedale Maggiore Policlinico, “Centro Dino
Ferrari”, Department of Neurology, University of Milano, Italy.
Communications should be addressed to:
Dr. Borgatti; Divisione di Neuroriabilitazione 1; IRCCS “Eugenio
Medea”; La Nostra Famiglia; Via Don Luigi Monza, 20; 23842
Bosisio Parini (Lecco), Italy.
E-mail: borgatti@bp.lnf.it
Received January 26, 2005; accepted August 2, 2005.

186 PEDIATRIC NEUROLOGY Vol. 34 No. 3 © 2006 by Elsevier Inc. All rights reserved.
doi:10.1016/j.pediatrneurol.2005.08.008 ● 0887-8994/06/$—see front matter
Table 1. Complete agenesis of the corpus callosum associated with other CNS malformations

Patient Sex/Age Classification Supratentorial CNS Malformations Brainstem CNS Malformations

6 M, 17 yr ACCc Cerebellar vermis and hemisphere hypoplasia

(Dandy Walker variant)
7 F, 5 yr ACCc synd Frontoparietal pachygyria, left midline cysts
10 M, 17 yr ACCc synd Right frontoparietal cysts, left perisylvian schizencephaly
13 F, 7 yr ACCc Left temporo-parietal schizencephaly
17 F, 3 yr ACCc synd Bilateral temporo-parietal schizencephaly Cerebellar vermis agenesis, cerebellar
hemisphere hypoplasia
23 F, 13 yr ACCc synd Left nodular interhemispheric pachygyria
42 F, 1 yr ACCc Frontal lissencephaly
46 M, 5 yr ACCc synd Cerebellar vermis hypoplasia
47 F, 4 yr ACCc Hydrocephalus, interhemispheric cysts
58 F, 8 yr ACCc chrom Frontal operculi hypoplasia Cerebellar vermis hypoplasia

Abbreviations
ACCc ! Complete agenesis of the corpus callosum
chrom ! Associated with chromosomal rearrangements
CNS ! Central nervous system
synd ! Associated with syndrome

large spectrum of malformations associated with agenesis Cytogenetic Investigations

of the corpus callosum and to assist clinicians in clinical
diagnosis.
Materials and Methods
Population
All the participants had been referred to Scientific Institute “E. Medea”
(Bosisio Parini) for a neuropsychiatric disorder (mental retardation of
varying severity, learning disability, epilepsy) between March 1998 and
September 2001. For all of them, a neuroradiologic examination (com-
puted tomography or magnetic resonance) was available. From this pool
we selected all the patients with complete or partial callosal agenesis,
while excluding patients with callosal hypoplasia. Similarly, all the
patients with agenesis of the corpus callosum associated with cerebral
cortex lesions secondary to perinatal injury were excluded.
All the participants received an assessment protocol including a
detailed medical history, neurologic, pediatric, and ophthalmologic
examinations as well as diagnostic testing (audiometric testing, electro-
encephalogram, electrocardiogram, and echocardiography, abdominal
and renal echo), laboratory data (including plasmatic amino acids,
urinary organic acids, very long fatty acids, and serologic tests for
intrauterine infection). Other diagnostic tests (pyruvic, orotic, and pipe-
colic acid levels; electromyography, motor and sensory nerve conduction
velocities, auditory brainstem response, visual evoked potentials, elec-
troretinography, fundus oculi examination) were also performed accord-
ing to the results of the clinical evaluations. Psychomotor development
and mental state were assessed by age-appropriate intelligence tests
(Griffiths Scale; Wechsler Preschool and Primary Scale of Intelligence;
Wechsler Intelligence Scale for Children Revised; Wechsler Adult
Intelligence Scale Revised).
All neuroradiologic examinations were reviewed. A second magnetic
resonance imaging study was performed if the previous one was not
qualitatively satisfactory or when only a computed tomographic scan was
available.
Agenesis was classified as complete or partial, and the association with
central nervous system malformations was observed. In the presence of
non– central nervous system malformations, syndromic pictures were
distinguished from pictures of callosal agenesis due to chromosomal
defects when malformations involving not only the central nervous
system were observed.
Metaphase slides were prepared from lymphocyte cultures of periph-
eral blood. A chromosomal analysis was performed according to standard
high-resolution techniques using GTG banding [5]. The Chromoprobe
Multiprobe T System (Cytocell Ltd, Adderbury, England) was used to
screen the subtelomeric regions [6]. The test included 41 subtelomeric
probes (p-arms from the acrocentric chromosome end not included), and
all 41 chromosome ends were analyzed on one slide. At least four
metaphases were examined for each chromosome. Positive results were
confirmed by a separate fluorescence in situ hybridization analysis using
the same probe as the one used in the Multi-T device.
Results
This study involved 1753 patients admitted to Scientific
Institute “E. Medea” during the study period and for whom
a neuroradiologic examination was available. Sixty-three
patients (3.5%)—39 males and 24 females with mean age
2 years and 7 months (age range: 1-25 years)— displayed
agenesis of the corpus callosum.
Agenesis of the Corpus Callosum and Central Nervous
System Malformations
Thirty patients (47%) manifested complete agenesis and
33 patients (53%) partial agenesis. A slight prevalence of
males was observed (36 males vs 27 females), with even
distribution between the two types (complete agenesis: 17
males and 13 females; partial agenesis: 19 males and 14
females).
Table 1 summarizes all the cases where complete
agenesis of the corpus callosum was associated with other
central nervous system malformations. These 10 cases
exhibited mainly malformations of cortical development
resulting from altered neuronal proliferation or migration
processes (pachygyric or heterotopic areas, 4 cases) and
macroscopic alterations of cortical organization (schizen-

Bedeschi et al: Clinical and Genetic Aspects of Callosum Agenesis 187

Table 2. Partial agenesis of the corpus callosum associated with other CNS malformations

Patient Sex/Age Classification Supratentorial CNS Malformations Brainstem CNS Malformations

1 F, 18 yr ACCp Cranial meningocele, Chiari malformation type II

5 F, 15 yr ACCp chrom Cerebellar vermis agenesis, cerebellar hemisphere
hypoplasia (Dandy-Walker variant)
11 F, 11 yr ACCp synd Periventricular nodular heterotopia Pontine hypoplasia, intraventricular cysts, cerebellar
vermis agenesis
14 M, 15 yr ACCp chrom Right frontal-temporo pachygyria
16 M, 16 yr ACCp synd Cerebellar vermis hypoplasia
19 M, 11 yr ACCp synd Left frontal pachygyria
20 F, 8 yr ACCp synd Hypothalamic, pituitary, optic nerve hypoplasia
27 M, 10 yr ACCp Mega cisternamagna
31 F, 16 yr ACCp Lumbo-sacral meningocele, Chiari malformation
type II
33 M, 10 yr ACCp synd Septum pellucidum and hypothalamic hypoplasia
35 M, 15 yr ACCp synd Fronto-temporo pachygyria-polymicrogyria
41 M, 15 yr ACCp synd Pons, cerebellar vermis and hemisphere hypoplasia
50 F, 4 yr ACCp synd Lobar holoprosencephaly Cerebellar vermis hypoplasia
59 F, 2 yr ACCp Frontal polymicrogyria, white matter diffuse alteration

Abbreviations
ACCp ! Partial agenesis of the corpus callosum
chrom ! Associated with chromosomal rearrangements
synd ! Associated with syndrome

cephaly in 4 other cases). Cerebellar malformations were
present both singly or in association with supratentorial
malformations. In the latter case (1 patient), only the
vermis was involved. In the remaining 20 patients with
complete callosal agenesis, the neuroradiologic examina-
tion did not reveal any other central nervous system
malformations.
Fourteen (42%) of the 33 patients with partial agenesis
manifested other central nervous system malformations
(Table 2). These malformations (8 cases) mainly involved
the posterior fossa with the brainstem (cerebellum, brain-
stem, and ventricular system). Two cases presented also
with a malformation of the cerebral cortex (holoprosen-
cephaly and periventricular nodular heterotopia). In four
cases, the malformation associated with callosal agenesis
affected the development of the cerebral cortex (unilateral
or bilateral frontal pachygyric areas), whereas in two cases
it was associated with pituitary hypoplasia, hypothalamus
and optic nerve hypoplasia (septo-optic syndrome).
Agenesis of the Corpus Callosum and Non–Central
Nervous System Malformations
An involvement of organs and apparatus other than the
central nervous system was present in 65% of the cases
(41/63). Cranio-facial abnormalities (65%), skeletal ab-
normalities (31%), cardiac pathologies (27%), ocular ab-
normalities (22%), genital (4%) and renal abnormalities
(2%) were present to various degrees. Cranio-facial ab-
normalities involved: the skull conformation (macroceph-
aly, trigonocephaly) in 14 patients; the ocular region
(hypertelorism, broad and depressed nasal bridge) in 18
patients; the palate (high arched palate and cleft palate) in
11 patients; the oral region (cleft lip, macrostomia) in 9
patients.
Cardiac abnormalities included the following: ventric-
ular septal defect in 5 patients, atrial septum defect in 4
patients, patent ductus arteriosus in 1 patient, and Ebstein
anomaly in 1 patient. Ocular pathologies included oculo-
motor disorders (strabismus, nystagmus) in 4 patients,
chorioretinopathy in 2 patients, bilateral iris coloboma in 1
patient, and bilateral anophthalmia in 1 patient.
Skeletal abnormalities comprised: hand malformations
(brachydactyly, absent proximal and distal phalanges,
clinodactyly of the fifth fingers) in 10 patients; cervical
spine anomalies (scoliosis, hyperkyphosis) in 2 patients;
feet abnormalities (bilateral club foot, valgus foot, bilat-
eral syndactyly of the second/third toes) in 6 patients.
Two patients presented with cryptorchidism. Only one
patient manifested renal anomalies, namely asymptomatic
left hydronephrosis.
Twenty-one (21) of 41 cases with agenesis of the corpus
callosum displayed a more complex malformation picture.
This finding allowed us to establish associations between
agenesis of the corpus callosum and known syndromic
pictures (Table 3).
Agenesis of the Corpus Callosum and Clinical
Associations
Neuromotor skills were impaired in almost all cases
(58/63, 92%). This impairment is severe in 32 patients as it
interferes with independent motor skills: severe spastic or
spastic-dystonic tetraparesis (12 cases), cerebellar involve-
ment (8 cases), and severe generalized hypotonia (12 cases).
In 24 cases the neuromotor damage was less severe as only
mild hypotonia and clumsiness were observed. In two cases
where agenesis of the corpus callosum is associated with
Chiari malformation and myelomeningocele, a picture of
flaccid paraparesis prevailed. Among five patients with

188 PEDIATRIC NEUROLOGY Vol. 34 No. 3

Table 3. ACC patients associated with specific syndromes once. Generally epilepsy began in the first year of life (16
of 22; 72%) and, in these cases, West syndrome is the
Patient Sex/ Type of prevalent syndrome. In six patients seizures appeared later
Age ACC Diagnosis
but before the age of 8. Response to antiepileptic drugs
4 M 9 yr partial FG syndrome was different according to the associated presence or
7 F 5 yr complete Aicardi syndrome absence of cortical malformations: 12 cases (54%; in 5
8 M 7 yr partial Opitz trigonocephaly syndrome cases agenesis of the corpus callosum is associated with
11 M 11 yr partial Joubert syndrome
18 F 9 yr partial Kabuki syndrome other central nervous system malformations) achieved full
20 F 8 yr partial De Morsier syndrome seizure control and among them 3 patients are now
23 F 13 yr complete Aicardi syndrome therapy-free; 6 patients (three with associated central
24 F 2 yr complete Acrocallosal syndrome nervous system malformations) displayed a remarkable
33 M 10 yr partial De Morsier syndrome
35 M 15 yr partial Seckel syndrome evolution with seizures shifting from daily to monthly
37 M 5 yr partial Winter-Baraitser syndrome frequency. Finally, four patients (presenting with associ-
38 M 3 yr complete Sotos syndrome ated other central nervous system malformations) had
39 M 6 yr partial Malpuech syndrome
41 M 5 yr partial Facio-auriculo-vertebral
multiple seizures per day despite polytherapy and can be
syndrome considered drug-resistant patients.
43 M 6 yr complete FG syndrome
44 F 15 yr partial Sotos syndrome
49 M 6 yr complete Acrocallosal syndrome
Cytogenetic and Fluorescence In Situ Hybridization
50 F 4 yr partial Holoprosencephaly–ectrodactyly– Analysis
cleft lip association
54 M 27 yr complete Tuberous sclerosis Constitutional karyotype analysis revealed a chromo-
55 F 12 yr complete Sotos syndrome somal rearrangement in 7 patients (11%) (Table 4). De
61 M 3 yr complete Facio-auriculo-vertebral
syndrome novo deletions were documented in two patients. De novo
inverted duplications of chromosome 8p were detected in
Abbreviation two cases. A duplication of chromosome 10p was present
ACC ! Agenesis of the corpus callosum in one case, inherited from a pericentric chromosome 10
inversion. An unbalanced translocation inherited from a
balanced carrier mother was detected in one patient.
normal neuromotor skills, four patients presented with iso- Finally, agenesis of the corpus callosum was found in a
lated agenesis of the corpus callosum (complete in 3 cases) trisomy-21 patient.
and one patient exhibited agenesis of the corpus callosum A total of 56 patients were analyzed by fluorescence in
associated with other brain malformations. situ hybridization analysis using subtelomeric probes. In 3
Mental retardation of varying severity was evident in cases (5%) (Table 5), an aberration of the subtelomeric
83% of the cases (52/63) and was distributed as follows: region was detected. De novo deletions were present in
profound (16%), severe (42%), moderate (21%), and mild two patients, whereas an unbalanced translocation—inher-
(21%). Two patients were borderline and nine patients had ited from a balanced carrier parent—was observed in one
normal intelligence quotient. In three patients with normal patient. Table 4 and Table 5 summarize the results and the
intelligence quotient, agenesis of the corpus callosum was list of phenotypic characteristics of the patients with
associated with a brain malformation. Profound and severe macroscopic and cryptic subtelomeric rearrangement, re-
mental retardation was mainly associated with a more spectively.
complex picture of multiple malformations. In all the cases presenting callosal agenesis associated
In the sample, 22 patients (11 with complete agenesis) with chromosome and subtelomeric rearrangements, pro-
presented with epilepsy (35% of the entire sample). The found mental retardation, facial dysmorphisms, and major
incidence of epilepsy varies depending on whether agen- malformations were evident (see Tables 4 and 5). This
esis of the corpus callosum is associated with other central clinical picture was associated with partial agenesis in 7
nervous system malformations: it is low when agenesis is patients (21% of all cases with partial agenesis) and
the only brain malformation (10 of 39; 26%), whereas it is complete agenesis in 3 patients (10% of all cases with
higher when agenesis is associated with other central complete agenesis).
nervous system malformations (12 of 24; 50%). More
frequently, patients had partial seizures (13 of 22; 60%) Discussion
often with blurred consciousness and sometimes associ-
ated with erratic myoclonic jerks; generalized seizures Agenesis of the corpus callosum is one of the most
include infantile spasms, atypical absences, atonic, tonic, frequent cerebral malformations in humans. However, it is
and tonic-clonic seizures. In seven patients (31%; all cases difficult to define its exact incidence as the literature reports
with agenesis of the corpus callosum associated with other highly variable rates depending on the test methodology used
brain malformations), a convulsive (5 patients) or noncon- (autoptic examination, x-rays) [7]. The present study does not
vulsive (2 patients) status epilepticus was observed at least allow one to draw epidemiologic conclusions as the patients

Bedeschi et al: Clinical and Genetic Aspects of Callosum Agenesis 189

Table 4. Phenotypes associated with chromosomal rearrangements in patients with agenesis of the corpus callosum

CNS Extra CNS Facial Minor Chromosomal

Malformations Malformations Anomalies MR Rearrangement Familial/De Novo

5 F 5 yr ACCp, cerebellar Clinodactyly of fifth Microcephaly, round profound 46,XX, invdupdel(8) de novo
vermis fingers of hands face, depressed (:p12-p23.1::qter)
agenesis, nasal bridge,
cerebellar malocclusion of
hemisphere, teeth
hypoplasia
12 M 6 yr ACCc Café-au-lait patches on Microcephaly, mild profound 46,XY,inv(10) de novo
the right hip trigonocephaly, (q11.2-23.2),del(1)
upslanting (pter-q42:)
palpebral fissures,
broad nasal
bridge,
malocclusion of
teeth
14 M 5 yr ACCp, frontal Bilateral cryptorchidism, Hypertelorism, severe 46,XY,der(10)t(4;10) familial t(4,10)
temporal, right hypogenitalism, SS micrognathia, low (p15.2;p15) (p15.3-p15) mother
pachygyria set ears
26 M 7 yr ACCc Cleft palate, urethral Microcephaly, severe 46,XY,der(10)(pter-q26:: familial inv(10)
stenosis, clinodactyly prominent p11.2-pter) (p11.2q26) mother
of fifth fingers of forehead, wide
hands nasal bridge,
preauricular tags
36 M 8 yr ACCp Cleft hard palate, Microcephaly, high severe 46,XY,del(4) de novo
coloboma of iris nasal bridge, (p15.3)
hypertelorism,
short philtrum,
micrognathia, low
set ears
40 M 11 ACCp Ventricular septal Brachycephaly, flat moderate 47,XY,"21 de novo
yr defect, cryptorchidism face, up-slanting
palpebral fissures,
epicanthic folds,
low set ears,
microtia
56 M 6 yr ACCp Generalized obesity, tall Macrocephaly, severe 46,XY,invdup(8) de novo
stature, brachydactyly prominent (p23.1)
of hands, genu valgus forehead,
hypertelorism,
down-slanting
palpebral fissures,
epicanthic folds,
micrognathia, flat
philtrum

Abbreviations
ACC ! Agenesis of the corpus callosum
c ! Complete
CNS ! Central nervous system
MR ! Mental retardation
p ! Partial
SS ! Short stature

were selected from a pool of patients referred to a child
neurology unit for neuropsychiatric pathologies. In this sam-
ple, the incidence of agenesis of the corpus callosum was
3.5%, in line with findings documenting a prevalence of
2-3% in children with neuropsychiatric disability [4]. It is
also important to note that many of the previously published
studies attempted to demonstrate an association of agenesis
of the corpus callosum with callosal hypoplasia. In our
opinion, this second pattern is more frequently caused by an
abnormal event during cortical development such as in
preterm infants or in cases of more or less severe perinatal
asphyxia. As the present study focused on malformations, all
pictures of hypoplasia were excluded (see inclusion criteria in
Methods).
In the present sample, complete and partial agenesis
represent 53% and 47% of the cases, respectively. This
finding is in contrast with studies by Taylor and David
[8]—who reported a prevalence of complete agenesis
(71% vs 29%)—and Serur [9] who reported a prevalence
of partial agenesis (74% vs 26%). Both studies, which are

190 PEDIATRIC NEUROLOGY Vol. 34 No. 3

Table 5. Phenotypes associated with subtelomeric rearrangements in patients with agenesis of the corpus callosum

CNS Extra CNS Chromosomal

Malformations Malformations Facial Minor Anomalies MR Rearrangement Familial/De Novo

58 F 8 yr ACCc, frontal Atrial septal defect, Microcephaly, hypertelorism, severe 46,XX, Familial
opercoli strabismus down-slanting palpebral (del13)(q13).ish.der(13) t(6;13)(q27;q32)
hypoplasia, fissures, broad nasal t(6;13)(q27;q32) mother
cerebellar bridge, large mouth, upper
vermis, thin lip, micrognathia
hypoplasia
60 F 2 yr ACCp Ebstein anomaly Microcephaly, prominent profound 46,XX,ishdel(1)(p36.3) de novo
forehead, short palpebral
fissures, depressed nasal
bridge, bulbous nasal tip,
anteverted nares,
prominent ears
63 M 3 ACCc posterior Atrial septal defect Microcephaly, profound 46,XX,ish.del(1)(q44-qter) de novo
yr lipoma trigonocephaly, synophrys,
anteverted nares,
micrognathia, low set ears

Abbreviations as in Table 4

the only studies on large samples published in the litera-
ture, appear to be not comparable to our own study owing
to different recruitment approaches (Taylor and David
used a checklist) and methods (Serur reviewed only
medical records). Furthermore, both studies relied exclu-
sively (Serur) or mainly (Taylor and David) on computed
tomographic scans.
Sex distribution indicated a prevalence of male patients
(62% vs 38%), thus confirming previous findings [8,9].
Cases of isolated agenesis (17%) were less frequent
than agenesis associated with other malformations. This is
probably due both to the origin of our patient sample (a
pediatric neurology unit) and to the method used for
neuroradiologic investigation, magnetic resonance imag-
ing instead of computed tomographic scan, the latter being
less sensitive to minimal cerebral malformations. Indeed,
isolated agenesis may be clinically silent and pass unno-
ticed, as demonstrated by the increasing high number of
cases that are occasionally detected during pregnancy by
fetal ultrasound or during follow-up after birth and present
no clinical disorder [10].
A comparison of our findings with those of Taylor and
David [8] indicates a higher rate of multiple non– central
nervous system malformations in our cohort of patients
(65% vs 34%), which underlines the complexity of the
clinical picture of our sample. This result could also be due
to the different methods and criteria used for patient
screening and analysis, which combine a detailed clinic-
diagnostic evaluation of many organs and apparatus.
In line with the literature, among the most frequent
non– central nervous system anomalies we observed were
cranio-facial abnormalities, namely macrocephaly, hyper-
telorism, broad and depressed nasal bridge, and cleft
lip/palate [9,11]. Because callosal agenesis is a midline
defect, the prevalence of other midline abnormalities
(hypertelorism, depressed nasal bridge, palate closure
defects) could be the result of the same defect during
embryonic development.
In 21 cases, these malformations were co-present in
specific syndromes. In nine syndromes, callosal agenesis
was a constant anomaly (Aicardi syndrome—OMIM
304050, FG syndrome—OMIM 305450, Sotos syn-
drome—OMIM 117550, and acrocallosal syndrome—
OMIM 200990) [12-15]. In the remaining 12 syndromes
(De Morsier syndrome—OMIM 182230, Kabuki syn-
drome—OMIM 147920, Joubert syndrome—OMIM
213300, Opitz trigocephaly syndrome—OMIM 211750,
hemifacial microsomia—OMIM 164210), partial or total
absence of the corpus callosum is not a frequent malfor-
mation. It rather has low rates of occurrence in the affected
populations [16-18], and the genetic defects underlying
these malformations may not be directly involved in
callosal agenesis. Because an accurate neuroradiologic
investigation of patients with syndromes characterized by
complex malformations affecting non– central nervous
system organs and systems is not made on a regular basis
by pediatricians despite the consistent presence of mental
retardation (sometimes severe), it is not easy to estimate
the real incidence of agenesis of the corpus callosum. In
Seckel syndrome, for instance, detailed neuroradiologic
investigations demonstrated that central nervous system
anomalies such as agenesis of the corpus callosum and
malformations of cortical development are indeed frequent
[19].
Chromosomal anomalies were present in 7 patients (11%),
which confirms that agenesis of the corpus callosum can be
associated with several consistent chromosomal rearrange-
ments [1]. The best documented anomalies include
del(4)(p16) or Wolf-Hirschhorn syndrome, del(6)(q23),
dup(8)(p21p23), dup(11)(q23qter),del(X)(p22), and trisomies
13 and 18 [1]. We also found two patients with
invdup(8)(p21p23) and one patient with a pure terminal

Bedeschi et al: Clinical and Genetic Aspects of Callosum Agenesis 191

del(4)(p15,3). This finding supported the hypothesis that
these regions could be candidates for agenesis of the corpus
callosum gene searching [20-23]. In one case, a subtelomeric
deletion was documented (at 13q13.32) which had never
been observed before (Table 5, Case 58). A relevant region
for the association between cytogenetic abnormalities and
agenesis of the corpus callosum is del(1)(q44) [24]. Two of
our patients presented with a deletion involving 1q: the first
one carries a gross terminal deletion detected by karyotype
analysis, whereas the latter manifests a subtelomeric deletion
1q. In accordance with this observation, it has been reported
[25] that 8 of 11 patients with distal monosomy at 1q—
who received a neuroradiologic evaluation—presented with
agenesis of the corpus callosum. This finding indicates
that this malformation is quite frequently associated with dis-
tal monosomy 1q [25]. Other regions have been associ-
ated with agenesis of the corpus callosum owing to the
presence of cytogenetic abnormalities, namely del(2)q(14)
[26-29], dup(5)(p15,3p13,1) [30,31], dup(6)(p25) [32,33],
dup(14)(q23q24) [34], del(15)(q13) [35], del(21)(q11q22.1)
[36,37], and triploidy mosaicism [38]. These and many other
chromosomal regions may contain agenesis of the corpus
callosum genes.
One of the patients in the present study displayed inv
dup(10p), which seems to be quite frequent as six other
cases are reported in the literature displaying partial
duplication of the short arm and deletion of the long arm
of chromosome 10. All these events seem to be secondary
to maternal pericentric inversion in five cases and paternal
pericentric inversion in one case [39]. These patients
manifest the same clinical features as Patient 26 described
in this study: minor facial anomalies, microcephaly, cleft
palate, and renal anomalies. However, not all the patients
reported in literature underwent neuroradiologic examina-
tions. Thus, we could not establish whether agenesis of the
corpus callosum is a frequent or sporadic event [39].
The study of subtelomeric rearrangements documented
a deletion in three patients, all of whom had a complex
clinical picture with severe mental retardation. In the
literature, approximately 4-7% of patients with idiopathic
moderate-severe mental retardation or clinically undefined
multiple malformations are carriers of chromosome aneu-
ploidy in the subtelomeric regions, whereas the rate of
occurrence of these anomalies in individuals with mild
mental retardation is less than 0.04% [40-44]. Subtelo-
meric rearrangements in our patients amounted to 5%.
These patients presented with severe mental retardation
and a complex picture of malformations, which indirectly
supports published data. Thus, in our opinion, molecular-
cytogenetic analysis of subtelomeric regions is not re-
quired in the presence of callosal agenesis only. On the
contrary, if agenesis of the corpus callosum is associated
with multiple malformations or severe mental retardation,
it does require detailed molecular and cytogenetic inves-
tigations.
In conclusion, the present study allows some general
comments:
192 PEDIATRIC NEUROLOGY Vol. 34 No. 3
(1) If associated with other cerebral malformations, no
difference in risk patterns was observed between
complete or partial agenesis: agenesis was present in
34-42% of patients in both cases. In contrast, there
was a slight difference between complete or partial
agenesis depending on the type of central nervous
system malformation: partial callosal agenesis is
correlated with posterior fossa malformations to a
greater extent, whereas complete callosal agenesis is
more frequently associated with malformations of
cortical development.
(2) An association with a more complex picture of
multiple malformations was present in 65% of the
cases. A detailed clinical evaluation and examination
of organs and apparatus may allow one to identify a
known underlying syndrome or highlight features
accounting for the complexity of the clinical picture.
The frequent association of agenesis of the corpus
callosum with craniofacial anomalies (e.g., macro-
cephaly, hypertelorism, depressed nasal bridge, pal-
ate defects) warrants the need for neuroradiologic
investigations. In contrast, no frequent association
with cardiac, ocular, renal, or genital malformations
was observed.
(3) There is no unique prognosis for patients with agen-
esis of the corpus callosum. It is associated with a
broad range of clinical manifestations, oscillating
between the normal cognitive level and severe psy-
chomotor delay. Other associated pathologies may
recur frequently or remain silent throughout the
patient’s life. This observation is relevant as increas-
ingly more often agenesis of the corpus callosum is
diagnosed prenatally, thus raising many issues of
genetic counseling.
At present, while caution is needed when formulating a
prognosis, it is important to collect data on a larger number
of cases of different complexity to be able to draw more
precise conclusions.
The authors wish to express their gratitude to all the participating families
for their cooperation and also wish to thank Professor Orsetta Zuffardi
from the Department of Human Genetics, University of Pavia for her
helpful suggestions throughout the completion of the study and Dr.
Barbara Alberti for supervising the English translation.
This study was partially supported by research funding from the Italian
Ministry of Health, grant RF/1997 and grant RC/2000.
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