American Journal of Medical Genetics 90:382–385 (2000)
Ring Chromosome 22 and Autism: Report and Review
Joanna E. MacLean,1 Ikuko E. Teshima,2 Peter Szatmari,3 and Małgorzata J.M. Nowaczyk1,4*
1
Department of Pathology and Molecular Medicine, McMaster University, and Hamilton Health Sciences
Corporation, Hamilton, Canada
2
Division of Clinical Genetics, Department of Pediatric Laboratory Medicine, Hospital for Sick Children and
University of Toronto, Toronto, Canada
3
Department of Psychiatry and Behavioral Neuroscience, McMaster University, and Hamilton Health Sciences
Corporation, Hamilton, Canada
4
Department of Pediatrics, McMaster University, and Hamilton Health Sciences Corporation, Hamilton, Canada
Ring chromosome 22 has been described in
over 50 cases. A characteristic phenotype
has not been fully delineated; however, long
face, thick eyebrows, 2–3 toe syndactyly,
mental retardation, adequate somatic
growth and the absence of major malforma-
tions are noted in many cases. An 11-year-
old boy with ring chromosome 22 and
46,XY,r(22)(p11.31-q13.31∼q13.33) karyotype
presented with global developmental delay,
autistic disorder, and dolichocephaly, ap-
parently low-set and large ears, midface hy-
poplasia, and 2–3 toe syndactyly. This is the
second report of a ring chromosome 22 with
autistic disorder. There appears to be an as-
sociation between abnormalities of chromo-
some 22, including r(22), and autistic disor-
der; however, this occurrence may be a re-
sult of the association of autistic disorder
with mental retardation rather than specifi-
cally due to r(22). The physical findings in
this case also suggest that ring chromosome
22 causes a subtle but distinct phenotype
which has previously been proposed. Am. J.
Med. Genet. 90:382–385, 2000
© 2000 Wiley-Liss, Inc.
KEY WORDS: ring chromosome 22; 2–3 toe
syndactyly; autism
INTRODUCTION
Ring chromosome 22 [r(22)] has been described in
over 50 cases [Lindenbaum et al., 1973; Hunter et al.,
1977; Palmer et al., 1977; Dallapiccola et al., 1977;
Funderburk et al., 1979; Fryns and Van den Berghe
*Corresponding author: Dr. M.J.M. Nowaczyk, McMaster Uni-
versity Medical Centre, Room 3N16, 1200 Main Street West,
Hamilton, Ontario, Canada, L8S 4J9.
E-mail: nowaczyk@hsc.ca
Received 12 July 1999; Accepted 2 November 1999
© 2000 Wiley-Liss, Inc.
1979; Stoll and Roth, 1983; Arinami et al., 1986; Gus-
tavson et al., 1986; Crusi and Engel, 1986; Lassen et
al., 1987; Watanabe and Yamanaka, 1988; Severien et
al., 1991; Petrella et al., 1993; Sovner et al., 1996; Ru-
bio, 1997; Assumpcăo, 1998; Duncan et al., 1987; Tom-
merup et al., 1992; Kehrer-Sawatzki et al., 1997; Taal-
man et al., 1987; Coulter-Mackie et al., 1995; Ritter et
al., 1990; Christodoulou et al., 1990; Joyce et al., 1996].
The most consistent phenotypic findings in this condi-
tion are mental retardation, delayed motor function-
ing, and the absence of major malformations, and in-
clude microcephaly [Lindenbaum et al., 1973; Hunter
et al., 1977; Funderburk et al., 1979; Fryns and Van
den Berghe, 1979; Stoll and Roth, 1983; Arinami et al.,
1986; Gustavson et al., 1986; Petrella et al., 1993; As-
sumpcăo, 1998], epicanthic folds [Lindenbaum et al.,
1973; Hunter et al., 1977; Lassen et al., 1987; Taalman
et al., 1987; Severien et al., 1991], full eyebrows
[Hunter et al., 1977; Funderburk et al., 1979; Arinami
et al., 1986; Petrella et al., 1993], large ears [Funder-
burk et al., 1979; Stoll and Roth, 1983; Arinami et al.,
1986; Watanabe and Yamanaka, 1988; Tommerup et
al., 1992; Petrella et al., 1993; Coulter-Mackie et al.,
1995], maxillary hypoplasia [Hunter et al., 1977;
Palmer et al., 1977; Funderburk et al., 1979; Stoll and
Roth, 1983], long eyelashes [Hunter et al., 1977, Fun-
derburk et al., 1979; Arinami et al., 1986; Severien et
al., 1991], 2–3 toe syndactyly [Hunter et al., 1977; Fun-
derburk et al., 1979; Taalman et al., 1987; Petrella et
al., 1993], hand abnormalities [Hunter et al., 1977;
Gustavson et al., 1986; Petrella et al., 1993], prominent
lips [Hunter et al., 1977; Funderburk et al., 1979; Stoll
and Roth, 1983], and ataxia [Hunter et al., 1977; Stoll
and Roth, 1983; Taalman et al., 1987]; however, four
reported cases showed no dysmorphology or mental re-
tardation [Stoll and Roth, 1983; Crusi and Engel,
1986]. There have been reports of r(22) in association
with multiple meningiomas [Arinami et al., 1986; Pe-
trella et al., 1993; Rubio, 1997], seminoma [Tommerup
et al., 1992], neurofibromatosis type 2 [Duncan et al.,
1987; Taalman et al., 1987; Tommerup et al., 1992;
Kehrer-Sawatzki et al., 1997], hypomelanosis of Ito
[Ritter et al., 1990], IgA deficiency [Taalman et al.,
1987], metachromatic leukodystrophy [Coulter-Mackie

et al., 1995], Opitz/BBB syndrome [Christodoulou et
al., 1990], and Williams-Breuren syndrome [Joyce et
al., 1996]. Autistic disorder has been reported in a case
of a 13-year-old male with r(22) who also had micro-
cephaly, long arms, and developmental delay [Assump-
căo, 1998]. We report on a second patient with r(22)
who carries a diagnosis of autistic disorder.
CLINICAL REPORT
The patient was delivered by cesarean section at
term because of failure to progress; pregnancy was un-
Ring Chromosome 22 383
Fig. 1. A: Anterior facial view of the patient showing bitemporal nar-
rowing and midface hypoplasia. B: Profile view of the head showing low-set
ears. C: Dorsal view of the feet showing near-complete cutaneous syndac-
tyly of second and third toes.
complicated. Birth weight was 3,720 g. Near-complete
syndactyly of the second and third toes was noted at
birth; there were no other gross anomalies.
At 6 months he was reported as being difficult to
engage in play, and reacted aversely to affection and
eye contact. He sat supported at 1 year and took his
first independent steps at 19 months. At the time of the
original genetic assessment, at 23 months, he had no
recognizable speech, communicating his needs by pro-
testing without pointing. His head circumference was
48 cm (10th–25th centiles), length was 87 cm (50th
384 MacLean et al.
centile), and weight was 12 kg (30th centile). He had an
r(22) in 50 of 50 cells. Parents had normal chromo-
somes. At 51⁄2 years he was diagnosed with autism
based on the DSM III-R diagnostic criteria. He had
significant repetitive behaviors such as turning door
knobs to the point of causing blisters on his hands,
picking up fibers from the carpet and placing them in
his mouth, rubbing his hands on cement walls and
chairs, and unusual mannerisms such as clenching and
flapping his hands, rocking, spinning, and bouncing.
He was referred for re-evaluation at 11 years. Psy-
chometric testing showed that he was functioning at an
18-month level. He had no verbal language and was not
yet toilet trained. His head circumference was 52 cm
(3rd centile), weight 35 kg (50th centile), and length
141.2 cm (25th centile). He had bitemporal narrowing,
an eccentric and elongated hair whorl with a low pos-
terior hairline, mild midface hypoplasia, and normal
oropharynx (Fig. 1A). Ears were normal in shape and
size (Fig. 1B). Neck, back, cardiovascular and respira-
tory systems, and abdominal findings were normal.
The genitalia were normal male, Tanner stage 1, with
lanugo hair over the scrotum. The hands were normal
with normal dermatoglyphics. There was complete cu-
taneous syndactyly of the second and third toes bilat-
erally (Fig. 1C). At that time he still had significant
impairments in social reciprocity. Psychiatric evalua-
tion of the patient at 12 years of age showed that he
met the DSM-IV diagnostic criteria for autistic disor-
der. His scores on the Autism Diagnostic Interview-
Revised (completed by P.S.) were 35 for social impair-
ment (cut-off ⳱ 10), 15 for no-verbal communication
(cut-off ⳱ 7), and 5 for repetitive and stereotyped be-
haviors (cut-off ⳱ 3) [Lord et al., 1994].
CYTOGENETIC ANALYSIS
Q-bands by fluorescence using quinacrine analysis
had been performed on peripheral blood obtained from
the patient at 2½ years using standard cytogenetic
techniques. The analysis identified an unbalanced
male karyotype with an r(22) in all 50 metaphases ex-
amined. At 11 years, further cytogenetic investigations
on peripheral blood included G-bands by trypsin using
Fig. 2. Left to right: Modified ideogram of chromosome 22 (original ideogram from Mitelman [1995]), chromosome 22 and single-ring 22 with GTG
banding, double-ring 22 with GTG banding, FISH image of chromosome 22 and single-ring 22 with signals indicated by one star for TUPLE1 and two stars
for ARSA. Arrows indicate positions of the centromeres.
Giemsa (GTG), C-bands by barium hydroxide using Gi-
emsa (CBG), and fluorescent in situ hybridization
(FISH). The probes were dual color and were as follows:
N25 (D22S75 within 22q11.2)/WI-941 (within 22q13)
from Oncor (Gaithersburg, MD), and TUPLE1 (within
22q11.2)/ARSA (arylsulfatase A within 22q13.31→qter
[Christodoulou et al., 1990]) from Vysis (Downers
Grove, IL). The karyotype was confirmed by GTG-
banding (Fig. 2), with a single centromere and two
light-staining stalks evident by CBG and solid staining
(not shown). FISH analysis indicated that the locus
represented by WI-941 was not deleted in the ring (not
shown) whereas the signal for the probe ARSA was
diminished in the ring in 9 of 19 metaphases. Thus, the
breakpoints of the ring were interpreted to be 22p13
and 22q13.31∼q13.33 [Joyce et al., 1996]. Ring insta-
bility was noted with a single ring in 33 metaphases, a
dicentric ring in one metaphase, and two rings in one
metaphase.
DISCUSSION
Although a distinct physical phenotype has not been
delineated in r(22), Hunter et al. [1977] concluded that
patients with r(22) commonly have microcephaly and
growth failure, hypotonia, epicanthic folds, full eye-
brows, malocclusion, cutaneous syndactyly between
the second and third toes, thick and fissured lips, mild
anomalies of the spine, ataxia or unsteady gait, and
seizures. Mental retardation and delayed motor devel-
opment are the most consistent findings in this chro-
mosomal aneuploidy. Our patient had a long skull, low-
set and large ears, midface hypoplasia, near-complete
cutaneous 2–3 toe syndactyly, and profound mental re-
tardation. In addition to the physical findings, our pa-
tient met the diagnostic criteria for autistic disorder, as
demonstrated by the scores on the formal psychiatric
evaluation. The exact incidence of r(22) is not known;
however, it has been observed in individuals with both
normal and subnormal intelligence [Dallapiccola et al.,
1977; Funderburk et al., 1979; Stoll and Roth, 1983].
Autism is defined on the basis of impairments in so-
cial reciprocity and communication, and a pattern of
repetitive and stereotyped behaviors. Genetic factors

have been shown to play an important role in the cause
of this disorder [Le Couteur et al., 1996; Szatmari et
al., 1996; Bailey et al., 1995] but, to date, no clear mode
of inheritance has been identified. Association between
structural or numerical abnormalities of chromosome
22 and autism have been reported in four cases: ring
(22) [Assumpcăo 1998], trisomy 22 [Turner and Jen-
nings, 1962], translocation between chromosome 22
and one of the “D” group chromosomes [Gillberg, 1998],
and translocation 20/22 [Carratalá et al., 1998]. Autis-
tic behaviors are also present in patients with muta-
tions of the adenylosuccinate lyase (ADSL) gene at
22q13.1 [Marie et al., 1999]. Our patient presents with
many PDD autistic-like characteristics. However, it is
conceivable that he has a primary diagnosis of devel-
opmental delay, with a secondary diagnosis of PDD fea-
tures. He has delays in social responsiveness in excess
of those that could be explained by developmental de-
lay alone.
The variable clinical presentations of r(22) in the
published cases may be explained by variable break-
points, tissue mosaicism, or by the contribution of the
“ring phenotype” (severe growth failure without a char-
acteristic pattern of malformations and with mental
retardation independent of which chromosome is in-
volved) as proposed by Kosztolányi [1987] to the overall
phenotype. There appears to be an association between
abnormalities of chromosome 22, including r(22), and
autistic disorder; however, this occurrence may be a
result of the association of autistic disorder with men-
tal retardation rather than specifically due to r(22).
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