Frontonasal dysplasia, callosal agenesis, basal encephalocele, and eye anomalies syndrome with a partial 21q22.3 deletion.
ABSTRACT We describe a girl with a phenotype characterized by frontonasal dysplasia, callosal agenesis, basal encephalocele, and eye anomalies who presents a 46,XX,r(21) karyotype. Array-comparative genomic hybridization using the Afflymetrix 100K DNA oligoarray set showed an interstitial deletion 21q22.3 of approximately 219 kb. Conventional karyotype of both parents was normal, and it was not possible to perform the molecular studies. In this report we raise the hypothesis that the deleted genes located at 21q22.3 could account to the phenotype.
Frontonasal Dysplasia, Callosal Agenesis, Basal
Encephalocele, and Eye Anomalies Syndrome With
a Partial 21q22.3 Deletion
Maria Leine Guion-Almeida,1* Antonio Richieri-Costa,1Fernanda Sarquis Jehee,2
Maria Rita Santos Passos-Bueno,2and Roseli Maria Zechi-Ceide1
1Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies (HRAC), University of S~ ao Paulo, Bauru, SP, Brazil
2Human Genome Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of S~ ao Paulo,
S~ ao Paulo, SP, Brazil
Manuscript Received: 10 August 2011; Manuscript Accepted: 30 January 2012
lies who presents a 46,XX,r(21) karyotype. Array-comparative
ray set showed an interstitial deletion 21q22.3 of approximately
it was not possible to perform the molecular studies. In this
report we raise the hypothesis that the deleted genes located at
Key words: frontonasal dysplasia; CNS midline anomalies; basal
encephalocele; 21q22.3 deletion
Frontonasal dysplasia (FND) is a genetically heterogeneous group
and Gorlin, 1988]. The involvement of other additional fields have
been resulted in a growing number of different syndromes
described within the spectrum of the FND and, some of these
syndromes support a known genetic pattern of inheritance while
others have been reported as unique or recurrent pattern syn-
dromes [revised by Wu et al., 2007]. One of the syndromes within
this spectrum comprises the syndrome of midline facial defects,
basal encephaloceles, callosal agenesis, and eye anomalies, recog-
sample of patients (case 6) with similar phenotype [Richieri-Costa
and Guion-Almeida, 2004].
A girl (Fig. 1A–C) was referred to our Hospital at the age of
6 months for assessment and management of median cleft lip.
She was the first child and the mother had a previous pregnancy
which resulted in a miscarriage of unknown cause and two
other normal girls. The parents were non-consanguineous and
phenotypically normal. The pregnancy was unremarkable with
outer canthal distance of 8.1cm (97th centile). She had prominent
frontal, hypertelorism, left palpebral ptosis, broad nasal root, and
incomplete median cleft lip with median alveolar notch. Upper
and lower limbs were normal. The follow up showed weight and
height below the normal ranges and normal neuropsychological
development but with mild learning disabilities. Ophthalmic
was normal. Endocrinological evaluation detected GH and TSH
deficiency. Cranial CT and MRI scans demonstrated a large
sphenoethmoidal encephalocele extending in direction to the
nasopharinx with part of the anterior frontal lobe projecting
through it; mild enlargement of the lateral ventricles; callosal
Grant sponsor: CNPq; Grant numbers: 301789/2009-6, 302712/2010-0.
Maria Leine Guion-Almeida, PhD, HRAC-USP, Rua Silvio Marchione
3-20, CEP 17012-900, Bauru, SP, Brazil. E-mail: email@example.com
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 24 May 2012
How to Cite this Article:
Guion-Almeida ML, Richieri-Costa A, Jehee
FS, Passos-Bueno MRS, Zechi-Ceide RM.
basal encephalocele, and eye anomalies
syndrome with a partial 21q22.3 deletion.
Am J Med Genet Part A 158A:1676–1679.
? 2012 Wiley Periodicals, Inc.
agenesis; anterior pituitary gland, stalk, optic chiasm, and anterior
commissure were not visualized. Migrational defects or abnormal
gyral pattern were not observed (Fig. 2A,B).
andTGIFgenes were normal. Array-comparative genomic hybrid-
ization (aCGH) using the Afflymetrix 100K SNP array detected
an interstitial deletion of 219kb, spanning from position
46.625.055 to 46.884.297pb (build 37.2) and encompassing eight
RefSeq annotated genes (three protein coding genes; three
non-protein coding RNA, and two hypothetical genes) (http://
www.ncbi.nlm.nih.gov/mapview) at 21q22.3. The karyotypes of
the parents were normal and the deletion testing was not
The girl here described presented with midline craniofacial defect,
comprising a midline cleft lip, hypertelorism, sphenoethmoidal
a de novo chromosome 21 ring. According to literature data
1998]. Sakoda et al.  first suggested that the association of
palate, later termed Sakoda complex by Tada and Nakamura
, is a distinct clinical entity. Clinical delineation of this
condition was performed by Richieri-Costa and Guion-Almeida
clinically homogeneous and phenotypically defined as FND, cal-
and ocular anomalies (palpebral ptosis, orbital asymmetry, stra-
bismus, and optic disc anomalies). According to these authors,
facial and ocular anomalies are variable. In relation to the etiology,
the authors have done some conjectures about TGIF gene as
causative of this condition. Later, Ribeiro-Bicudo et al. 
screened for mutation the TGIF gene in six individuals with this
combination of signs and no mutations were found. They also
investigated the ALX3 and ALX4 genes in these individuals and
FIG. 1. Facial aspects of the patient at age 6 months (A) and at age 12 years (B,C).
FIG. 2. A,B: Brain MRI of the patient showing a large sphenoethmoidal encephalocele and corpus callosum agenesis.
GUION-ALMEIDA ET AL.
similarly no changes were found. So far, the etiology of the FND,
callosal agenesis, basal encephalocele, and ocular anomalies syn-
the chromosome 21 ring in patient, we performed an aCGH that
detected a 21q22.3 interstitial microdeletion of about 219kb. The
phenotype of the patients with ring chromosome 21 can be highly
involvement, and intellectual disability [Bertini et al., 2008; Spec-
chio et al., 2011; Arslan et al., 2011]. This variability of the
phenotype has been explained by the instability of the ring chro-
size and structure of the ring [Ahzad et al., 2010; Specchio et al.,
2011]. In our case, the aCGH detected a 219kb interstitial deletion
most terminal region of the chromosome 21 (21q22.2–q22.3) has
been reported and related to phenotype ranging from mild, with
minor dysmorphic features and mild intellectual disability, to
uterine growth retardation, microcephaly, seizures, corpus cal-
losum abnormalities, eyes anomalies, micrognathia, dysplasic
ears, intellectual disability, and speech problems [Oegema et al.,
2010; Roberson et al., 2011). Corpus callosum anomalies are
present in our case who also presented with mild facial phenotype.
According to DECIPHER database (the DECIPHER consortium,
http://decipher.sanger.ac.uk/), three deletions and three duplica-
tions have been found encompassing the deleted region of our
patient. Apparently normal phenotype was referred in cases pre-
senting two of these three deletions.
In relation to genes encompassing the region deleted in our
patient, three of them are coding proteins genes: ADARB1,
POFUT2, and COL18A1 gene. The COL18A1 gene encodes the
alpha chain of type XVIII collagen, a multiplexin extracelular
matrix protein that contains multiple triple-helix domain
(collagenous domains) interrupted by non-collagenous domains.
Homozygous or compound heterozygous null mutations in
COL18A1 cause a rare condition namely Knobloch syndrome,
which is characterized by high myopia, vitreoretinal degeneration
with retinal detachment, macular abnormalities, occipital ence-
phalocele, epilepsy, ataxia, septum pellucidum agenesis, neuronal
migration defect, and cerebellar malformation [Sertie et al., 2000;
Suzuki et al., 2002; Pais? an-Ruiz et al., 2009]. The phenotype of our
patient is not consistent with Knobloch syndrome. According to
DECIPHER database there is no evidence of haploinsufficiency of
COL18A1 gene causing disease and, deletions of this gene were
reported in apparently normal individuals in the Database of
Genomic Variants (http://projects.tcag.ca). Thus, it is likely that
COL18A1 gene deletion is not associated to the phenotype in our
for pre-mRNA editing of the glutamate receptor subunit B by
site-specific deamination of adenosines. This gene has two tran-
many human adult and fetal tissues. ADARB1 gene has not been
associated with human disease but the homozygous mice to Adar2
gene (OMIM 610249) is an O-fucosyltransferase that use throm-
bospodin (THBS; MIM 188060) type 1 repeats as substrates. This
gene also has not been associated with human disease however, in
Caenorhabditis elegans, the changed expression of the ortholog of
POFUT2 gene (Pad2) display severe body malformation and
abnormal neuronal development [Menzel et al., 2004]. Research
in Database of Genomic Variants (http://projects.tcag.ca) showed
in normal controls. Thus, it is not clear if theses genes could be
influencing the phenotype in our patient.
In conclusion, it is possible that the 21q22.3 deletion can be
related to the phenotype of our case and, investigation of the genes
within this region could be helpful to clarify the etiology of the
FND, callosal agenesis, basal encephalocele, and ocular anomalies
our patient, since the parents’ DNA samples were not available for
The authors are indebted for CNPq (Grants: 301789/2009-6
[MLG-A] and 302712/2010-0 [AR-C]) supports.
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