RING AUTOSOMES: SOME UNEXPECTED FINDINGS
Caba L1,*, Rusu C1,2, Plăiaşu V3, Gug G4,5, Grămescu M1, Bujoran C2,
Ochiană D3, Voloşciuc M2, Popescu R1, Braha E1,2, Pânzaru M1,2,
Butnariu L1,2, Sireteanu A1, Covic M1, Gorduza EV1
*Corresponding Author: Dr. Lavinia Caba, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, Department
of Medical Genetics, 16 Universitatii str., Iasi, 700115, Romania; Tel.: +40724962671; Email: lavinia_zanet@yahoo.com
page: 35
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DISCUSSION
We synthesized the results of conventional banding
cytogenetic analyses using these criteria: number
of chromosomes of each cell, presence of one monocentric
ring chromosome, absence of ring chromosome
and presence of some derivative chromosomes
resulting from mitotic instability of the ring (two
monocentric rings, dicentric ring), normal diploid
cell (Table 2).
Ring chromosome is an unbalanced abnormality.
According to the number of rings there are two
situations. In the first situation, one chromosome
is replaced by the ring and this generates deletion/
monosomy of implicated genes. In the second situation,
a supernumerary ring is present and it generates
a duplication/trisomy of that part of the chromosome
implicated in ring formation in association with partial
monosomy [8]. For this reason the phenotype of
the patient depends on the presence of secondary
chromosome lines and the percentage of mosaicism.
Also, a rare situation was described when one normal
chromosome was replaced by two rings derived from
the same chromosome. The first case was reported
by Miller et al. [23] in 2003.
A condition similar to the second situation was
identified for case 1. In this case, 91 cells were examined
and three cell lines were found. The resolution
of the karyotype was approximately 400 bands per
haploid set. Eighty cells (88.0%) had a ring chromosome
with apparent breakpoints in the short arm at
band 5p14 and in the long arm at band 5q35. Eight
cells (8.8%) had the entire chromosome 5 missing,
and three cells (3.29%) had two 5 ring chromosomes
and a normal 5 chromosome in the same cell. In case
1, lack of normal diploid line was an argument for
meiotic origin. It is very likely that the most frequent
line (for those with one ring) is the first one and the
others are the expression of mitotic instability of the
ring. The monosomic line could be the result of an anaphase lag in mitosis of cell with ring chromosome
5. But the most likely mechanism is the chromatid
non disjunction that explains the formation of secondary
cellular lines: with monosomy 5 and with two
ring chromosome 5.
The patient’s phenotype was suggestive for Cridu-
Chat syndrome. Because three different cellular
lines were identified for this case, we compared the
clinical signs specific for each of them if they appeared
as singular abnormalities and clinical features
observed for our patient (Table 3). The patient
presented mild facial asymmetry and a unilateral ear
abnormality (malformed, small, low set right ear).
These features represent minimal diagnostic criteria
for oculo-auriculo-vertebral spectrum (OAVS).
The main feature that suggested the diagnosis was
microtia. Isolated microtia is considered the mildest
form of OAVS [25]. Tasse et al. [26] proposed the
following diagnosis criteria: hemifacial microsomia
with preauricular tags or microtia (with or without
preauricular skin tags). Marked facial asymmetry
is present in only 20.0% of cases, but the overall
frequency is about 65.0%. It becomes more apparent
by the age of 4. Our patient was examined at the
age of 3 and we expect the facial asymmetry to be
emphasized in the future. The association between
5p monosomy and OAVS has been described before
and some authors suggested there are some genes on
5p implicated in OAVS pathogeny [27-30].
Heart defects have been reported in OAVS in
5.0-58.0% cases in different studies. Digilio et al.
[31] communicated a frequency for VSD and PDA
(these defects were also present in our patient) of
6/87, respectively of 1/87, but in that study, the patients
with documented chromosomal abnormalities
were excluded. These types of heart defects also appear
in Cri-du-Chat syndrome and they have been
frequently associated with deletions of the distal part
of 5q and in rings with 5q35-5qter deletions [32].
Lorentz et al. [33] made a classification of cases
with ring chromosome 13. They identified four categories
of chromosomal anomalies named A-D, each
of them having specific deletion: A was a mosaic
partial monosomy 13q, B was non mosaic rearrangements
such as rings or deletions that lead to a net
deletion for distal 13q, C was mosaicism for a distal
13q deletion and complete mono-somy 13 and D was
complex chromosome rearrangements that result in
mosaicism for partial duplications and partial deletions
of chromosome 13 [33]. Previously, we showed
that our case belongs to group C [34]. The presence
of a dicentric ring chromosome 13 in the karyotype
of our patient can be explained by a sister chromatid
exchange of the monocentric ring after replication.
In our case, we consider that dicentric ring chromosome
13 has a Tai Chi configuration (an inverted mirror
image of the two halves of the double-sized ring
chromosome 13) in correlation with the mechanism
proposed by Hoo et al. [35].
For cases 1 and 2, the presence of a monosomic
line as a part of a “dynamic mosaicism” partially
influences the phenotype, especially growth (both
patients have growth retardation). Kosztolányi [5]
postulate that the ring behavior and the structure are
responsible for growth failure.
For case 3, the GTG-banded karyotype showed
two cell lines, both with 18 ring chromosome. The
less frequent line (7/50 metaphases) has a marker
chromosome unidentified by conventional banding
cytogenetic analysis or FISH. The marker chromosome
looks like an inverted duplicated chromosome
of an acrocentric but it was not checked by nuclear
organizing region (NOR) banding. Over 70.0% of
small marker chromosomes are de novo (like our case)
and over 70.0% of the overall cases are derived from
acrocentric chromosomes. The phenotype was normal
in 74.0% of individuals with a de novo small
supernumerary marker chromosome (sSMC). On the
other hand, the frequency of marker chromosomes
among different clinical situations varies from 7.0
to 28.0% and the incidence of marker chromosomes
in mentally retarded patients is only 0.288%. Other
phenomena that limited the phenotypic importance of
marker chromosomes were the decrease of percentage
of cells with marker chromosomes during lifetime.
Thus, in our case, it is hard to say if some features
such as mental retardation, were the result of a deleted
region on chromosome 18 or was influenced by the
presence of a marker chromosome [36]. Fluorescence
in situ hybridization analysis with telomeric probes
for both arms of chromosome 18 demonstrated the
presence of a telomeric region just for the normal
chromosome and absence for the ring chromosome.
For cases 4 and 5, the GTG-banded karyotype
revealed a homogeneous abnormality: 18 ring
chromosome. In case 4, by using Aquarius®Whole
Chromosome Painting Probes (Cytocell Technologies
Ltd.) for chromosome 18, the origin of the ring FISH probes were used for both arms of chromosome
18 and demonstrated the lack of telomere regions
for the ring formation. Based on this analysis,
a minimum of 220 kb on terminal 18p and 290 kb
on terminal 18q, were deleted in case 4.
The phenotype in ring 18 syndrome has some
main elements: developmental delay/mental retardation,
typical facial features, major abnormalities
and immunological problems [37]. The phenotype
in all three cases had specific features, especially
for 18q- syndrome, less for 18p- syndrome. Cleft
lip (case 3), narrow or atretic ear canals and hearing
loss (cases 3 and 4), foot deformities (cases 3 and 4)
are typical signs of 18q- syndrome. Other features
such as cardiac abnormalities (ventricular septal defect
and patent ductus arteriosus in case 5) or renal
defects (horseshoe kidney in case 4) can be present
in both 18p- and 18q- syndromes. Stankiewicz et
al. [6] suggested there were two types of 18 ring
chromosomes according to the breakpoints. The first
category has the breakpoints at the cen-tromere or
nearby and loses the short arm, and the second one
has one breakpoint on the long arm and has only a
deletion of distal 18q. Our cases with 18 ring chromosome
belonged to the second category. In 2007,
Feenstra et al. [38] updated the phenotypic map for
chromosome 18q deletions. The authors identified
some (various) critical regions for cardinal signs in
18q deletions (Table 4) and some of the clinical features
of our cases are in accordance with these areas.
The lack of a normal diploid line suggested that the
18 ring chromosome is formed in meiosis.
Ring chromosome 21 was reported to be de novo
or inherited. The phenotypes were different: almost
normal in familial cases and characterized by mental
retardation or developmental delay, short stature,
microcephaly, epican-thus, short neck and small ears.
According to loss of material or extra material from
chromosome 21, three types of 21 ring chromosome
were discribed. Clinically, type I is associated with
normal development, no malformations, in some cases
short stature, infertility, and slightly delayed puberty in
boys. The breakpoint is near the end of the q arm with
minimal loss of genetic material [39]. The second type
has different features synthesized by de Grouchy and Turleau [40]: hypertonia, proeminent occiput, protruding
forehead, down-slanting palpebral fissures, large
ears and others such as ocular anomalies, micrognathia,
cleft lip or palate, heart defects, inguinal hernias, hypospadias,
undescended testes, learning difficulties,
defects in the immune system. These features were associated
with the loss of region 21q22.3 or parts of this
region in the mechanism of ring formation [40]. The
third type of 21 ring chromosome shares features with
Down’s syndrome because these patients have three
copies of chromosome 21. It has been suggested as a
possible mechanism two breaks on different arms of a
21q isochromosome, followed by fusion in a circular
configuration [39]. Considering these features, we concluded
that our case belonged to the second category.
In conclusion, ring chromosomes are rare abnormalities,
most of the time of de novo origin, presenting
a different phenotype according to the loss of genetic
material and genetic instability. The karyotype represents
the main analysis for detection of ring chromosomes,
but other molecular techniques are necessary
for complete characterization. Also, parental investigation
is required for proper genetic counseling.
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