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Analysis of banding patterns in a case of ring chromosome 21.

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American Journal of Medical Genetics 10323-331 (1981)
Analysis of Banding Patterns in a Case of
Ring Chromosome 21
Claude-Lise Richer, Naomi Fitch, Sharon Sitahal, Manuela Murer-Orlando,
and Pierre Jean
Departement d'Anatomie, Universite de Montreal (C.-L.R., M.M.-O., P.J.) and
Departement de Pathologie et Centre de Recherche Pediatrique, H6pital
Sainte-Justine(C.-L.R.), and Lady Davis lnstitute for Medical Research of
the Sir Mortimer 6.Davis Jewish General Hospital (N.F., S.S.); Montrbal,
Quebec, Canada
An infant with psychomotor retardation, hypertonia, microphthalmia,
buphthalmos, cleft palate, nail dysplasia, and hypospadias had the karyotype
46,XY,r(21)/45,XY,-21. Cytogenetic analysis of prophase and prometaphase
chromosomes showed the breakpoints of chromosome 21 were at p12 and
q22.2.
Key words: chromosome 21, ring-21, deletion-21
INTRODUCTION
Ring chromosome 21 is a rare anomaly. Only 16 patients [ l - 171 have been
reported with a ring 21 identified by banding techniques. Four of these patients
[3, 6, 11, 141 had double rings and stigmata of Down syndrome. The other 12 patients, and our case, had a single ring, and most patiens had the 21q- syndrome
(G-deletion, syndrome I) [16]. The breakpoints of a ring 21 are often difficult to
identify because of the small size of the chromosome in metaphase plates. Using
the new techniques that enable study of extended chromosomes in prophase and
prometaphase [181, and identification of the nucleolus organizer regions [191, we
were able to determine the breakpoints of the ring 21 of our patient.
REPORT OF PATIENT
A male infant was born to Greek parents after a 41-week uncomplicated
pregnancy. The father was 31 years old, the mother 19. The gravida 3, para 1
mother had had a spontaneous miscarriage of a 3-month-old fetus when she was
16 years old. A 17-month-old daughter was healthy.
Received for publication November 21, 1980; revision received June 8, 1981.
Address reprint requests to Dr. Claude-Lise Richer, Dtpartement d'Anatomie, Universite de Montrtal
C.P. 6128, Succursale A, Montrtal, Qutbec, Canada H3C 357.
0148-7299/81/1004-0323$03.00 0 1981 Alan R. Liss. Inc.
324
Richer et al
Delivery was spontaneous with an Apgar of 4. The weight was 2,775 g,
length 48 cm, occipitofrontal head circumference (OFC) 32.8 cm, inner canthal
distance 2 cm, outer canthal distance 6 cm, ear length 3.5 cm, chest circumference
31.5 cm. The infant was markedly hypertonic, with scissoring of the lower limbs
(Fig. lc).
The occiput was prominent and the ears were dysplastic (Fig. la, b). The
right ear protruded from the head at almost a right angle. The forehead was hirsute and there was a flattened nasal bridge (Fig. 1). A coloboma was present on
each upper eyelid. There were no eyelashes on the lower lids. Both eyes were
microphthalmic. The cornea of the right eye was opaque, and there was
buphthalmos of the left eye with a cloudy perforated cornea. The infant had
macrostomia, thin lips, cleft soft palate, micrognathia, excess skin on the
posterior neck, a I/VI systolic murmur, a shawl scrotum and first-degree
hypospadias. The 4th finger overlapped the 3rd, and there was ulnar deviation of
all fingers (Fig. Id). The 3rd toe was narrower than the other toes and all fingerand toenails were hypoplastic.
At birth the fontanelles were normal in size. The Moro and deep tendon
reflexes were normal. At 1 month, sclerosis of the sagittal suture suggesting
craniosynostosis was noted on radiographs. At 3 months, the anterior fontanelle
was almost closed; there was limited responsiveness to tactile stimuli and a partial
Moro reflex. Facial movements were symmetrical. Tone was increased, particular
in the lower limbs. The only structural defects found in a CAT scan were small
ventricles.
Fig. 1 . The patient at birth. a) Note microphthalmia and dysplastic ears. b) Note micrognathia and
prominent occiput. c) Note scissoring of the lower limbs. d) Note dysplastic nails.
Ring Chromosome 21
325
At 1 month the red blood cell count was 3.2 million, Hgb 11.2, Hct 34.2,
MCV 104, MCH 35.5, MCHC 32.7. At 2 months the RBC was 3.7 million, Hgb
12.1, Hct 35.7, MCV 98, MCH 32.5, MCHC 34.4. At 5 months the RBC was 4.1
million, Hgb 12.1, Hct 36, KCV 88, MCH 28.5, MCHC 33.5. The white blood
cell count was normal at all times. The platelet count was in the normal range.
At 3 months the infant weighed 3430 g; his length was 51 cm, and OFC 37
cm. Psychomotor development was delayed. At 4 months the weight was 3,780 g,
OFC 38 cm, and length 54 cm. At 5 months he underwent surgery for correction
of sagittal craniosynostosis. At this time he was still hypertonic, unable to sit up,
or support his head.
Cytogenetic Studies
Chromosome preparations were made from cultures of peripheral blood
lymphocytes. GTG-banding [20], QFQ-banding [21], RHG-banding [22], C-banding 1231, and NOR staining [19] were done on metaphase plates. Prophase and
prometaphase chromosomes were obtained using our modification of the
amethopterin synchronization technique [ 181. These cells were R-banded.
The infant’s karyotype was 46,XY,r(21)/45,XY,-21. Approximately 6% of
cells were monosomic for chromosome 21. Both parents had normal
chromosomes.
One hundred forty cells were studied in the prophase-prometaphase stages.
A ring was present in 138 cells (Fig. 2), a rod-shaped, deleted acrocentric chromo-
Fig. 2. R-banded prometaphase karyotype. Note ring 21
326
Richer et al
some was present in the other 2 cells. C-banding revealed one C-band-positive
region in the ring. The breakpoints were identified by R-banding and NOR
staining as p12 and q22.2 (Fig. 3). The ring has therefore been formed from
fusion of the satellite stalks to band q22.1. The presence of the satellite stalks explains why, at this region of the ring, the chromatin appears thinner and stains
less intensely (Fig. 5 ) .
Eighty-five cells were studied at metaphase; 13 were monosomic for chromosome 21. In eight cells a ring was found; in three a double ring was present; and in
five there was a metacentric chromosome 21. In the remaining 56 the deleted
chromosome appeared as rod-shaped acrocentric. It is possible that some of these
rod-shaped chromosomes are small rings seen in various perspectives. However,
because these chromosomes look like the one illustrated in Figure 4, we think that
most of these chromosomes are acrocentric rods. This interpretation is
strengthened by the appearance of chromosomes stained to show the nucleolus
organizer region (Fig. 4). This region appears to be at one end of the chromosome
as contrasted to the chromosome illustrated in Figure 3 where the NOR region is
clearly incorporated into the ring.
Fig. 3. Prometaphase chromosomes, normal 21 (a), and ring 21 (b). The same ring 21 is illustrated as
stained with Giemsa (unbanded) and then for NOR, showing that the thin segment of the ring is the
stalk (nucleolus organizer region).
Ring Chromosome 21
327
Fig. 4. Metaphase chromosomes illustrating the appearance of the deleted rod-shaped acrocentric21
chromosomes (b). Normal 21 (a).
Fig. 5. Idiogram of normal and ring chromosome 21 with photographs of prometaphase chromosomes
R- and Q-banded.
328
Richer et al
DISCUSS10N
Ten patients have been described with single ring chromosome 21 [ l , 5 ,
7-10, 12, 13, 15-17]. (No clinical information is available on two other cases [2,
41 .) The infants have a unique facial appearance that is well exemplified by our
patient. The manifestations of these patients constitute a distinct syndrome, which
is summarized in Tables I and 11. Other less frequent abnormalities include convulsions, an abnormal ECG, apparently low-set ears, preauricular appendix,
epicanthic folds, long eyelashes, microphthalmia, cataracts, hypotelorism, choanal
stenosis, narrow philtrum, bifid uvula, pectus excavatum, muscle hypertrophy,
coarctation of the aorta, tetralogy of Fallot, osteoporosis, retarded bone age,
lateralization of the femoral capital epiphyses, inguinal hernia, micropenis,
hypoplastic scrotum, cryptorchidism, syndactyly of toes 2 and 3,
thrombocytopenia, and bone marrow eosinophilia.
Other infants with an apparent ring G chromosome were described before
banding techniques were available, which, on the basis of the clinical appearance,
can probably be classified as r(21) [24-291. One of these patients had corneal
opacities in both eyes and a cataract in one eye; at autopsy, small optic nerves and
chiasma were noted. Another infant had blepharochalasis and a persistent
pupillary membrane. Table I11 compares our patient to infants with monosomy 21
[30-351 and long-arm deletions [36-381.
The chromosome analysis of our patient, who has the typical appearance of
infants with r(21), shows that the missing genes responsible for the phenotype are
located in bands q22.2 and q22.3. Similar breakpoints were observed in a ring 21
described by Cantu et a1 [2], and in the patient of Ieshima [6].
It is interesting that the Down syndrome can be produced by trisomy of
21q22 [39].
TABLE I. Cases of r(21)
Crandall [5] Kucerova [7] Maeda [9] Palmer [12]
Karyotype
Sex
Birth weight
Age
Ht Voile
Wt Voile
Hypertonia
Psychomotor retardation
Prominent occiput
Microcephaly
Protuberant, large ears
Antimongoloid slant
Broad, prominent nasal bridge
Cleft palate
Micrognathia
Hypospadias
Death
r(21)
M
2353
01)
F
2340
3
25
+
+
+
-
+
+
-
r(21)
M
2400
18 mo
<3
3
-
+
+
+
+
+
+
+
-
-
r(21)r(21)
F F
r(21)
20d38 y
3
2Y
+
+
+
+
+
M
+
+
-
+
-
Warren
[16, 171
+
18 mo
12 d -
-
Ring Chromosome 21
329
TABLE 11. Cases of r/21 Mosaics
Armendares Larget-Piet
[1,2, 91
[81
Karyotype
Sex
Birth weight
Age
Ht Voile
Wt Voile
Hypertonia
Psychomotor retardation
Prominent occiput
Microcephaly
Protuberant, large ears
Antimongoloid slant
Broad, prominent nasal bridge
Cleft palate
Micrognathia
Hypospadias
Death
r(21)/-21
M
2260
3% yr
<3
<3
+
+
+
+
+
+
+
+
-
r(21)/-21
M
2335
newborn
Richmond
[13]
r(21)/-21/N
F
2098
3 yr
+
+
+
+
+
+
Shibata [IS]
Our case
r(21)/-21
F
3190
7 mo
50
3
r(21)/-21
M
2775
newborn
< 10
< 10
+
slight
-
+
+
+
-
-
-
-
+
=F
14 days
-
-
+
+
+
+
+
slight
+
+
+
+
-
TABLE 111. Manifestations of Monosomy 21 and 21q Deletions
Monosomy
21 [30-351
Number of cases
Sex
Growth retardation
Psychomotor retardation
Hypertonia
Microcephaly
Blepharochalasia/
blep harophimosis
Anophthalmia/microphthalmia
Antimongoloid slant
Broad, prominent nasal bridge
Broad nose
Macrostomia
Cleft palate, uvula
Micrognathia
Low-set ears
Large ears
Malposition of fingers
Flexion deformities
Abnormal nails
Cryptorchidism
Hypospadias
aMosaic.
bNo information for two cases.
del(21q)
q l l [36]"
q22 [37, 381"
6
4 F;2M
6
5
5
4/4b
1
1
5
3
2
3
3
6
4
2
2
4
2
2/2
2/2
Our case
M
+
+
+
+
+
+
+
+
+
2
1
1
2
2
2
1
2
1
2
2
2
1
+
+
slight
+
+
+
+
+
+
+
+
-
+
330
Richer et a1
The complications involved in ring chromosome mitosis are well known [40,
411. Chromosome loss is common and may explain some phenotypic abnormalities. Double rings, dicentric rings, metacentric, and rod-shaped chromosomes
[42-451 are consequences of the ring chromosome structural instability.
ACKNOWLEDGMENTS
We are indebted to Elise Menard and Anne Guenette for technical assistance. This study was supported in part by the Fondation Justine-LacosteBeaubien, and in part by the Women’s Auxilliary, Sir Mortimer B. Davis Jewish
General Hospital.
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Edited by John M. Opitz
ADDENDUM
Since this paper was submitted, karyotype analysis was done on the patient’s
fibroblasts by Dr. M. Vekemans, at the Montreal Children’s Hospital. The
chromosome anomalies described for the blood leucocytes were also present in the
fibroblasts.
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