Case report

Congenital asymmetric crying facies and agenesis of corpus callosum

Konstantinos A. Voudrisa,*, Angeliki Skardoutsoub, Eleni A. Vagiakouc

aDepartment of Neurology, ‘P & A Kyriakou’ Children’s Hospital, Thivon & Levadeias Street, 115 27 Athens, GreecebSecond Department of Paediatrics-University of Athens, ‘P & A Kyriakou’ Children’s Hospital, Thivon & Levadeias Street, 115 27 Athens, Greece

cDepartment of Microbiology, ‘G. Gennimatas’ General Hospital, Athens, Greece

Received 18 April 2002; received in revised form 29 August 2002; accepted 6 September 2002

Abstract

Although association of congenital asymmetric crying facies (CACF) with major congenital anomalies of central nervous system (CNS)

has been described, brain magnetic resonance imaging (MRI) studies have not been reported. Two children who had CACF associated with

agenesis of corpus callosum (ACC) diagnosed by MRI are described. Neurofibromatosis type 1 (NF-1) was diagnosed in one case. Both

patients had developmental delay. To the best of our knowledge, only one previous case with CACF associated with ACC has been reported,

but our cases are the first cases reported with the characteristic findings of ACC on MRI. Although cafe-au-lait spots have been described in

previous cases, the coexistence of CACF and NF-1 has not previously been reported. Although these associations may be coincidental,

clinicians should be aware of the potential link between these entities. Furthermore, these findings emphasize the importance of MRI studies

for detecting brain anomalies in cases with CACF and suspected CNS involvement.

q 2002 Elsevier Science B.V. All rights reserved.

Keywords: Congenital asymmetric crying facies; Depressor anguli oris muscle; Agenesis of corpus callosum; Neurofibromatosis type 1; Magnetic resonance

imaging

1. Introduction

Congenital asymmetric crying facies (CACF) is a minor

congenital anomaly characterized by a failure of one corner

of the mouth to move downward and outward with a cry or

grimace, while forehead wrinkling, nasolabial fold depth,

and eye closure remain intact on both sides [1]. In this

clinical presentation, only the lower lip is involved and

palpable thinning of the lateral portion of the lower lip is

usually present on the affected side. Associations of this

minor facial defect with major congenital anomalies have

been reported, most commonly in the cardiovascular system

and less frequently involving the genitourinary, skeletal,

and/or respiratory system, and, rarely, the central nervous

system (CNS) [2–4]. Two children who had CACF asso-

ciated with agenesis of corpus callosum (ACC) are

described. To our knowledge, there is only one previous

reported patient with CACF and ACC [3]; however, our

cases are the first cases reported with CACF associated

with ACC detected on brain magnetic resonance imaging

(MRI).

2. Case reports

2.1. Case 1

A 10-month-old girl was referred to our hospital for

evaluation of facial asymmetry. This defect had been noted

by her parents since birth, only on crying or smiling, and no

improvement was seen in subsequent months. She is the third

child in the family and was born at term by vaginal delivery.

No maternal use of medication or antepartum illness was

reported. Outlet forceps were not applied, and no neonatal

complications were recognized. There was no parental

consanguinity and family history was non-contributory.

She had a mild developmental delay; she was able to hold

her head at 5 months, and could not sit at the time of exam-

ination. The physical and neurological examinations was

unremarkable except for a failure of right corner of the

mouth to move downward and outward with a cry or grimace,

while forehead wrinkling, nasolabial fold depth, and eye

closure remained intact on both sides. Palpable thinning of

the right lower lip near its right margin was also noted.

Brain & Development 25 (2003) 133–136

0387-7604/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved.

doi:10.1016/S0387-7604(02)00165-1

www.elsevier.com/locate/braindev

* Corresponding author. Tel.: 13-010-6211354/7793000; fax: 13-010-

7774383.

E-mail address: kvoudris@otenet.gr (K.A. Voudris).

Abbreviations: CACF, congenital asymmetric crying facies; ACC, agenesis

of corpus callosum; CC, corpus callosum; MRI, magnetic resonance

imaging; NF-1, neurofibromatosis type 1; CNS, central nervous system

Laboratory investigations, such as full blood count,

routine blood chemistry and urinalysis were normal. Facial

electromyography showed the intactness of the facial nerve

on the affected side. Ultrasonographic examination of the

abdomen, brain-stem auditory evoked potentials, and a

complete cardiac evaluation were normal. The patient had

a normal karyotype and the electroencephalogram was

within normal limits. Brain MRI revealed ACC, with a

poorly formed rostrum, widely separated and parallel bodies

of the lateral ventricles, and dilatation of the trigones. The

sagittal plane scan of the medial surface of the cerebral

hemispheres showed sulci and gyri having an abnormal

pattern, radiating toward the missing corpus callosum

(CC) into the 3rd ventricle (Fig. 1).

The patient underwent follow-up in the out-patient clinic,

and at present, 3 years after the initial investigation, she has

language delay with persisted facial asymmetry on crying or

smiling, which is less obvious than on earlier examinations.

2.2. Case 2

A 9-year-old boy had a facial weakness on the left side

from birth. The patient underwent periodical examinations

in our outpatient clinic from the age of 4 years, and his facial

defect presented some improvement in the subsequent years

of life. He is the second child of the family and the product

of a full-term uncomplicated gestation, labor, and delivery.

No maternal use of medication or antepartum illness was

reported. Past medical history indicates some delay achiev-

ing the milestones, while family history was unremarkable

for similar facial defect. On examination, when he smiled or

cried, the right corner of the mouth drew right and down-

ward, while the left moved slightly. Extra-ocular move-

ments, eyelid closure, nasolabial fold depths, and forehead

elevation were intact and symmetric. Furthermore, the

patient had had mild mental retardation, learning disabil-

ities, several cafe-au-lait spots, axillary and inguinal freck-

ling and involvement of the iris by pigmented hamartomas

(Lisch nodules). Because of these findings, neurofibromato-

sis type 1 (NF-1) was diagnosed.

Laboratory investigations, such as full blood count,

routine blood chemistry and urinalysis were normal. Elec-

trical testing confirmed the intactness of the facial nerve.

The ultrasonographic examination of the abdomen, brain-

stem auditory evoked potentials, karyotype, and complete

cardiac evaluation were normal. Brain MRI revealed partial

ACC with a poorly formed genu and a small part of the body

of the CC, widely separated and parallel bodies of the lateral

ventricles, dilatation of the trigones and occipital horns,

upward, crescentic lateral ventricles, and upward extension

of cavity of third ventricle. The sagittal plane scan of the

medial surface of the cerebral hemispheres showed sulci and

gyri having an abnormal pattern, radiating toward the miss-

ing CC (Fig. 2).

3. Discussion

CACF is a relatively common minor anomaly, which is

K.A. Voudris et al. / Brain & Development 25 (2003) 133–136134

Fig. 1. (a) Midsagittal brain T1-weighted MRI of the first case showing

ACC, with a poorly formed rostrum, and radiating sulci and gyri. (b) Axial

brain T2-weighted MRI of the first case showing dilatation of the trigones.

Fig. 2. Midsagittal brain T1-weighted MRI of the second case showing

partial ACC, with a poorly formed genu and a small part of the body of

CC, and radiating sulci and gyri.

easily recognizable clinically. Supported by electromyogra-

phical investigations, congenital hypoplasia or absence of

the depressor anguli oris muscle has been assumed as the

main reason for this facial defect [5]. However, no patholo-

gical documentation for this is available and other investi-

gators showed that this muscle was present in some cases

with CACF [6,7]. The etiology of CACF is still unexplained

and probably multifactorial. Intrauterine viral infection,

chromosomal aberrations, hereditary factors, birth-trauma

to the marginal mandibular branch, and/or a defect located

at the brainstem level have been considered to be involved

in the pathogenesis of this facial defect [7]. In our patients,

history, examination, and laboratory investigations gave no

clue to the etiology of CACF.

The interest in the CACF has grown in recent years

because of its association with congenital abnormalities.

Incidence for these associated malformations varies from

4.9 to 75% [3,4]. The difference in incidence of associated

congenital anomalies in the previous studies may result

from the different methods of case finding or from the fail-

ure to search for hidden anomalies, such as CNS malforma-

tions. Anomalies of the CNS have been described in 10% of

cases [3]. These anomalies may easily overlooked unless

specifically sought after. To our knowledge, brain MRI find-

ings in patients with CACF have not previously been

published in the literature. Psychomotor retardation appears

to be uncommon in these patients, and only a few cases have

been described in the literature [3]. These manifestations

may be also overlooked unless active and long follow-up

is pursued. In the present report, both our patients had devel-

opmental delay and mild mental retardation.

On patients with CACF, ACC has been previously

reported only once, but details about the clinical manifesta-

tions and the neuroimaging findings of the case have not

been described [3]. The CC originates at the upper part of

the lamina terminalis from the lamina reuniens. Chemotac-

tic factors induce the developing axons of the cerebral hemi-

spheres to cross the midline forming the CC. ACC is among

the commonest developmental anomalies of the brain and

the clinical picture of patients with this malformation may

include developmental delay, psychomotor retardation,

seizures, and neurological abnormalities; however, isolated

developmental defects of CC can be asymptomatic [8].

ACC may be complete or partial and diagnosis of this

brain malformation is established by characteristic changes

seen on MRI. CC develops between the 8th and 20th weeks

of gestation; disturbed embryogenesis during this period can

lead to its complete or partial absence and the extent of

dysgenesis of CC depends on the stage at which the insult

has occurred. As development begins in the front and

progresses caudally, a partial defect usually involves the

posterior segment of CC. Deficiency in the posterior part

of CC results in extension of the 3rd ventricle between the

lateral ventricles and compensatory dilation of the ventricu-

lar atria (so-called colpocephaly), as it was observed in our

cases.

Etiopathogenesis of ACC is not homogenous, reflecting

in each case the relative importance of genetic and exogen-

ous factors and this malformation can be part of chromoso-

mal syndromes or accompany some inborn errors of

metabolism. In our cases, the etiology of the association

of CACF and ACC is unknown; however, the coexistence

of ACC, which usually occurs during early embryogenesis,

indicates that the facial defect might also occurred during

this period of embryonic life. It was postulated by Cayler

that CACF may be due to a subclinical viral infection occur-

ring in the mother during the first trimester of pregnancy [2].

During early embryogenesis, the hyoid arch, from which the

facial structures are derived, is in close proximity to the

other embryonic tissues and factors operating at this stage

of embryonic life could involve their formation, causing

extensive congenital anomalies. However, in the present

and most other studies, no noxious influences during preg-

nancy were identified.

The CACF may be familial in some cases and a genetic

background may be involved. Autosomal dominant inheri-

tance has been suggested in some families with CACF and

the chromosome 22q11 microdeletions and some other rare

chromosomal abnormalities have been associated with this

facial defect [9]. In this report, NF-1 was diagnosed in the

second patient and although cafe-au-lait spots without other

features of NF-1 have been described in previous cases [3],

the association of CACF with NF-1 has not previously been

reported. The gene of NF-1 is located in the pericentric

region of the long arm of chromosome 17 (17q11.2).

Although NF-1 has been rarely reported in conjunction

with ACC [10], no previous descriptions in the literature

of CACF with chromosome 17 aberrations have been

described. The description of further similar cases will

help to more clearly define the possible relationship between

CACF and chromosome 17 aberrations.

In conclusion, the findings of ACC in our cases may be

due to our thorough search for such anomalies. Children

with CACF should be examined for CNS involvement and

MRI studies should be considered in demonstrating brain

malformations. Long-term follow-up is also necessary, as

psychomotor retardation may occur in such patients.

However, these conditions could co-occur by chance and

further studies are required to delineate the incidence of

these associated anomalies.

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