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

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

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. 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
Materials and Methods
screen the subtelomeric regions [6]. The test included 41 subtelomeric
probes (p-arms from the acrocentric chromosome end not included), and
Population all 41 chromosome ends were analyzed on one slide. At least four
metaphases were examined for each chromosome. Positive results were
All the participants had been referred to Scientific Institute “E. Medea” confirmed by a separate fluorescence in situ hybridization analysis using
(Bosisio Parini) for a neuropsychiatric disorder (mental retardation of the same probe as the one used in the Multi-T device.
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 Results
we selected all the patients with complete or partial callosal agenesis,
while excluding patients with callosal hypoplasia. Similarly, all the This study involved 1753 patients admitted to Scientific
patients with agenesis of the corpus callosum associated with cerebral
Institute “E. Medea” during the study period and for whom
cortex lesions secondary to perinatal injury were excluded.
All the participants received an assessment protocol including a a neuroradiologic examination was available. Sixty-three
detailed medical history, neurologic, pediatric, and ophthalmologic patients (3.5%)—39 males and 24 females with mean age
examinations as well as diagnostic testing (audiometric testing, electro- 2 years and 7 months (age range: 1-25 years)— displayed
encephalogram, electrocardiogram, and echocardiography, abdominal agenesis of the corpus callosum.
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- Agenesis of the Corpus Callosum and Central Nervous
colic acid levels; electromyography, motor and sensory nerve conduction
System Malformations
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
Thirty patients (47%) manifested complete agenesis and
and mental state were assessed by age-appropriate intelligence tests 33 patients (53%) partial agenesis. A slight prevalence of
(Griffiths Scale; Wechsler Preschool and Primary Scale of Intelligence; males was observed (36 males vs 27 females), with even
Wechsler Intelligence Scale for Children Revised; Wechsler Adult distribution between the two types (complete agenesis: 17
Intelligence Scale Revised). males and 13 females; partial agenesis: 19 males and 14
All neuroradiologic examinations were reviewed. A second magnetic
resonance imaging study was performed if the previous one was not females).
qualitatively satisfactory or when only a computed tomographic scan was Table 1 summarizes all the cases where complete
available. agenesis of the corpus callosum was associated with other
Agenesis was classified as complete or partial, and the association with central nervous system malformations. These 10 cases
central nervous system malformations was observed. In the presence of
exhibited mainly malformations of cortical development
non– central nervous system malformations, syndromic pictures were
distinguished from pictures of callosal agenesis due to chromosomal resulting from altered neuronal proliferation or migration
defects when malformations involving not only the central nervous processes (pachygyric or heterotopic areas, 4 cases) and
system were observed. 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 Cardiac abnormalities included the following: ventric-
present both singly or in association with supratentorial ular septal defect in 5 patients, atrial septum defect in 4
malformations. In the latter case (1 patient), only the patients, patent ductus arteriosus in 1 patient, and Ebstein
vermis was involved. In the remaining 20 patients with anomaly in 1 patient. Ocular pathologies included oculo-
complete callosal agenesis, the neuroradiologic examina- motor disorders (strabismus, nystagmus) in 4 patients,
tion did not reveal any other central nervous system chorioretinopathy in 2 patients, bilateral iris coloboma in 1
malformations. patient, and bilateral anophthalmia in 1 patient.
Fourteen (42%) of the 33 patients with partial agenesis Skeletal abnormalities comprised: hand malformations
manifested other central nervous system malformations (brachydactyly, absent proximal and distal phalanges,
(Table 2). These malformations (8 cases) mainly involved clinodactyly of the fifth fingers) in 10 patients; cervical
the posterior fossa with the brainstem (cerebellum, brain- spine anomalies (scoliosis, hyperkyphosis) in 2 patients;
stem, and ventricular system). Two cases presented also feet abnormalities (bilateral club foot, valgus foot, bilat-
with a malformation of the cerebral cortex (holoprosen- eral syndactyly of the second/third toes) in 6 patients.
cephaly and periventricular nodular heterotopia). In four Two patients presented with cryptorchidism. Only one
cases, the malformation associated with callosal agenesis patient manifested renal anomalies, namely asymptomatic
affected the development of the cerebral cortex (unilateral left hydronephrosis.
or bilateral frontal pachygyric areas), whereas in two cases Twenty-one (21) of 41 cases with agenesis of the corpus
it was associated with pituitary hypoplasia, hypothalamus callosum displayed a more complex malformation picture.
and optic nerve hypoplasia (septo-optic syndrome). This finding allowed us to establish associations between
agenesis of the corpus callosum and known syndromic
Agenesis of the Corpus Callosum and Non–Central pictures (Table 3).
Nervous System Malformations
Agenesis of the Corpus Callosum and Clinical
An involvement of organs and apparatus other than the Associations
central nervous system was present in 65% of the cases
(41/63). Cranio-facial abnormalities (65%), skeletal ab- Neuromotor skills were impaired in almost all cases
normalities (31%), cardiac pathologies (27%), ocular ab- (58/63, 92%). This impairment is severe in 32 patients as it
normalities (22%), genital (4%) and renal abnormalities interferes with independent motor skills: severe spastic or
(2%) were present to various degrees. Cranio-facial ab- spastic-dystonic tetraparesis (12 cases), cerebellar involve-
normalities involved: the skull conformation (macroceph- ment (8 cases), and severe generalized hypotonia (12 cases).
aly, trigonocephaly) in 14 patients; the ocular region In 24 cases the neuromotor damage was less severe as only
(hypertelorism, broad and depressed nasal bridge) in 18 mild hypotonia and clumsiness were observed. In two cases
patients; the palate (high arched palate and cleft palate) in where agenesis of the corpus callosum is associated with
11 patients; the oral region (cleft lip, macrostomia) in 9 Chiari malformation and myelomeningocele, a picture of
patients. 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 preterm infants or in cases of more or less severe perinatal
neurology unit for neuropsychiatric pathologies. In this sam- asphyxia. As the present study focused on malformations, all
ple, the incidence of agenesis of the corpus callosum was pictures of hypoplasia were excluded (see inclusion criteria in
3.5%, in line with findings documenting a prevalence of Methods).
2-3% in children with neuropsychiatric disability [4]. It is In the present sample, complete and partial agenesis
also important to note that many of the previously published represent 53% and 47% of the cases, respectively. This
studies attempted to demonstrate an association of agenesis finding is in contrast with studies by Taylor and David
of the corpus callosum with callosal hypoplasia. In our [8]—who reported a prevalence of complete agenesis
opinion, this second pattern is more frequently caused by an (71% vs 29%)—and Serur [9] who reported a prevalence
abnormal event during cortical development such as in 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- defects) could be the result of the same defect during
ture, appear to be not comparable to our own study owing embryonic development.
to different recruitment approaches (Taylor and David In 21 cases, these malformations were co-present in
used a checklist) and methods (Serur reviewed only specific syndromes. In nine syndromes, callosal agenesis
medical records). Furthermore, both studies relied exclu- was a constant anomaly (Aicardi syndrome—OMIM
sively (Serur) or mainly (Taylor and David) on computed 304050, FG syndrome—OMIM 305450, Sotos syn-
tomographic scans. drome—OMIM 117550, and acrocallosal syndrome—
Sex distribution indicated a prevalence of male patients OMIM 200990) [12-15]. In the remaining 12 syndromes
(62% vs 38%), thus confirming previous findings [8,9]. (De Morsier syndrome—OMIM 182230, Kabuki syn-
Cases of isolated agenesis (17%) were less frequent drome—OMIM 147920, Joubert syndrome—OMIM
than agenesis associated with other malformations. This is 213300, Opitz trigocephaly syndrome—OMIM 211750,
probably due both to the origin of our patient sample (a hemifacial microsomia—OMIM 164210), partial or total
pediatric neurology unit) and to the method used for absence of the corpus callosum is not a frequent malfor-
neuroradiologic investigation, magnetic resonance imag- mation. It rather has low rates of occurrence in the affected
ing instead of computed tomographic scan, the latter being populations [16-18], and the genetic defects underlying
less sensitive to minimal cerebral malformations. Indeed, these malformations may not be directly involved in
isolated agenesis may be clinically silent and pass unno- callosal agenesis. Because an accurate neuroradiologic
ticed, as demonstrated by the increasing high number of investigation of patients with syndromes characterized by
cases that are occasionally detected during pregnancy by complex malformations affecting non– central nervous
fetal ultrasound or during follow-up after birth and present system organs and systems is not made on a regular basis
no clinical disorder [10]. by pediatricians despite the consistent presence of mental
A comparison of our findings with those of Taylor and retardation (sometimes severe), it is not easy to estimate
David [8] indicates a higher rate of multiple non– central the real incidence of agenesis of the corpus callosum. In
nervous system malformations in our cohort of patients Seckel syndrome, for instance, detailed neuroradiologic
(65% vs 34%), which underlines the complexity of the investigations demonstrated that central nervous system
clinical picture of our sample. This result could also be due anomalies such as agenesis of the corpus callosum and
to the different methods and criteria used for patient malformations of cortical development are indeed frequent
screening and analysis, which combine a detailed clinic- [19].
diagnostic evaluation of many organs and apparatus. Chromosomal anomalies were present in 7 patients (11%),
In line with the literature, among the most frequent which confirms that agenesis of the corpus callosum can be
non– central nervous system anomalies we observed were associated with several consistent chromosomal rearrange-
cranio-facial abnormalities, namely macrocephaly, hyper- ments [1]. The best documented anomalies include
telorism, broad and depressed nasal bridge, and cleft del(4)(p16) or Wolf-Hirschhorn syndrome, del(6)(q23),
lip/palate [9,11]. Because callosal agenesis is a midline dup(8)(p21p23), dup(11)(q23qter),del(X)(p22), and trisomies
defect, the prevalence of other midline abnormalities 13 and 18 [1]. We also found two patients with
(hypertelorism, depressed nasal bridge, palate closure 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 (1) If associated with other cerebral malformations, no
these regions could be candidates for agenesis of the corpus difference in risk patterns was observed between
callosum gene searching [20-23]. In one case, a subtelomeric complete or partial agenesis: agenesis was present in
deletion was documented (at 13q13.32) which had never 34-42% of patients in both cases. In contrast, there
been observed before (Table 5, Case 58). A relevant region was a slight difference between complete or partial
for the association between cytogenetic abnormalities and agenesis depending on the type of central nervous
agenesis of the corpus callosum is del(1)(q44) [24]. Two of system malformation: partial callosal agenesis is
our patients presented with a deletion involving 1q: the first correlated with posterior fossa malformations to a
one carries a gross terminal deletion detected by karyotype greater extent, whereas complete callosal agenesis is
analysis, whereas the latter manifests a subtelomeric deletion more frequently associated with malformations of
1q. In accordance with this observation, it has been reported cortical development.
[25] that 8 of 11 patients with distal monosomy at 1q— (2) An association with a more complex picture of
who received a neuroradiologic evaluation—presented with multiple malformations was present in 65% of the
agenesis of the corpus callosum. This finding indicates cases. A detailed clinical evaluation and examination
that this malformation is quite frequently associated with dis- of organs and apparatus may allow one to identify a
tal monosomy 1q [25]. Other regions have been associ- known underlying syndrome or highlight features
ated with agenesis of the corpus callosum owing to the accounting for the complexity of the clinical picture.
presence of cytogenetic abnormalities, namely del(2)q(14) The frequent association of agenesis of the corpus
[26-29], dup(5)(p15,3p13,1) [30,31], dup(6)(p25) [32,33], callosum with craniofacial anomalies (e.g., macro-
dup(14)(q23q24) [34], del(15)(q13) [35], del(21)(q11q22.1) cephaly, hypertelorism, depressed nasal bridge, pal-
[36,37], and triploidy mosaicism [38]. These and many other ate defects) warrants the need for neuroradiologic
chromosomal regions may contain agenesis of the corpus investigations. In contrast, no frequent association
callosum genes. with cardiac, ocular, renal, or genital malformations
One of the patients in the present study displayed inv was observed.
dup(10p), which seems to be quite frequent as six other (3) There is no unique prognosis for patients with agen-
cases are reported in the literature displaying partial esis of the corpus callosum. It is associated with a
duplication of the short arm and deletion of the long arm broad range of clinical manifestations, oscillating
of chromosome 10. All these events seem to be secondary between the normal cognitive level and severe psy-
to maternal pericentric inversion in five cases and paternal chomotor delay. Other associated pathologies may
pericentric inversion in one case [39]. These patients recur frequently or remain silent throughout the
manifest the same clinical features as Patient 26 described patient’s life. This observation is relevant as increas-
in this study: minor facial anomalies, microcephaly, cleft ingly more often agenesis of the corpus callosum is
palate, and renal anomalies. However, not all the patients diagnosed prenatally, thus raising many issues of
reported in literature underwent neuroradiologic examina- genetic counseling.
tions. Thus, we could not establish whether agenesis of the
At present, while caution is needed when formulating a
corpus callosum is a frequent or sporadic event [39].
prognosis, it is important to collect data on a larger number
The study of subtelomeric rearrangements documented
of cases of different complexity to be able to draw more
a deletion in three patients, all of whom had a complex
precise conclusions.
clinical picture with severe mental retardation. In the
literature, approximately 4-7% of patients with idiopathic
moderate-severe mental retardation or clinically undefined The authors wish to express their gratitude to all the participating families
multiple malformations are carriers of chromosome aneu- for their cooperation and also wish to thank Professor Orsetta Zuffardi
ploidy in the subtelomeric regions, whereas the rate of from the Department of Human Genetics, University of Pavia for her
occurrence of these anomalies in individuals with mild helpful suggestions throughout the completion of the study and Dr.
Barbara Alberti for supervising the English translation.
mental retardation is less than 0.04% [40-44]. Subtelo-
This study was partially supported by research funding from the Italian
meric rearrangements in our patients amounted to 5%. Ministry of Health, grant RF/1997 and grant RC/2000.
These patients presented with severe mental retardation
and a complex picture of malformations, which indirectly
supports published data. Thus, in our opinion, molecular- References
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Bedeschi et al: Clinical and Genetic Aspects of Callosum Agenesis 193