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Minor dysmorphism in a child with inherited ring chromosome 18

El-Gerzawy, Asaada; Raouf, Ehab Abdelb; Meguid, Nagwa Abdelb

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doi: 10.1097/01.MJX.0000430656.89800.53
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Structural abnormalities that involve chromosome 18 are relatively high 1,2; the most frequent of these abnormalities are deletions and ring chromosome formation. The classic mode of ring formation is breakage in both arms of the affected chromosome with fusion of the breakpoints and loss of the distal fragments; this rearrangement therefore results in partial monosomies for the distal short and long arms. Sometimes, ring chromosomes develop because of nonfunctioning telomeres with adhesion of both ends with no loss of chromosomal material 3.

The severity of the clinical features of ring chromosome carriers depends on the extent of the deleted chromosomal segments, the 18p and 18q deletion syndromes 3,4. Ring (18) syndrome is characterized by severe mental and growth deficiency, microcephaly, brain and ocular malformations, hypotonia, microacrodactyly, and other skeletal abnormalities in different frequencies. Facial dysmorphisms include midface dysplasia, epicanthal folds, hypertelorism, down-turned corners of the mouth, micrognathia, low-set and dysplastic ears, and webbing of the neck. The majority of patients show a clinical picture similar to that of the 18q syndrome 3,5 and because of the terminal deletion of the p arm, the clinical symptoms of 18p- syndrome can also be observed 4,6, with no difference in the severity of the phenotypes between patients with paternally and maternally derived deletions.

It has been postulated that all carriers of a ring autosome show a phenotype with short stature as a consistent criterion for ‘ring syndrome’, irrespective of which autosome is involved 7,8; generally, severe growth failure is seen more often in patients with larger rings than among patients with smaller ones, because of the probability of the higher frequency of sister chromatid exchanges in the former 7. The association of ring chromosome (18) and other clinical features has also been documented, with immunological problems 9 or with Klippel–Trenaunay syndrome 10, and with abnormal white mater myelination 11.

There is a difficulty in establishing a genotype–phenotype correlation in a ring carrier. It is necessary to determine primary deletions associated with ring chromosome formation and also secondary loss or gain of material that may occur because of the instability of ring chromosomes; therefore, this can cause a dilemma in prenatal diagnosis 12. In another study 13, using tiling resolution chromosome 18 array comparative genomic hybridization (aCGH) to determine the exact breakpoints in patients with chromosome 18q deletions, the authors could refine the critical regions for microcephaly (18q21.33), short stature (18q12.1–q12.3, 18q21.1–q21.33, and 18q22.3–q23), white matter disorders and delayed myelination (18q22.3–q23), growth hormone insufficiency (18q22.3–q23), and congenital aural atresia (18q22.3). In addition, the overall level of mental retardation appeared to be mild in patients with deletions distal to 18q21.33 and severe in patients with deletions proximal to 18q21.31. The critical region for the ‘typical’ 18q phenotype is a 4.3 Mb located within the 18q22.3–q23 region.

Ring chromosomes are uncommon cytogenetic findings; they almost always arise de novo; it can be speculated that rings of chromosomes 18 mainly derive from a postzygotic mitotic error; this observation is in agreement with the de-novo formation of the majority of ring chromosomes 3. However, in another study 1, they observed the meiotic origin of two ring chromosomes 18 in a girl with developmental delay.

Rings often appear as mosaics (ring 18 is missed in one cell line) because of loss of the ring during cell division, because of sister chromatid exchange within a ring in mitotic crossing-over events, which generates aneuploid cells with increased mortality 14,15, and, in some cases, loss of the ring, double-sized rings, or multiple copies of the ring have been observed as a consequence of the structural instability of the ring during cell division 1,2. Sodré et al.16 found no clear-cut correlation between ring size and ring instability; furthermore, mosaicism involving both structural and numerical chromosome anomalies in a single individual is rare 17,18.

Clinical report

We report on a mother and her daughter; the mother had a history of oligomenorrhea and received hormonal replacement therapy. At 30 years of age (husband aged 34), she became pregnant, with an uneventful course; a cesarean section was elected because of fetal face presentation. A female infant grew normally until the age of 6 years, when she was clinically presented to the Department of Children with Special Needs, the National Research Center, because of a parental complaint of hyperactivity and occasional episodes of loss of concentration simulating atypical absence seizure.

Examination indicated a minor and nonspecific pattern of dysmorphism including upward slanting of the eyes with bilateral epicanthic folds. Similar to her mother, she has a prominent philtrum with Cupid’s bow of the upper lip. She also has Rt., incomplete Simian creases, and Lt., complete one, together with a wide gap between the first and the second toes. The mother had bilateral epicanthic folds, short stature, and below-average mentality.

The patient was mildly growth retarded; measures of height, head circumference, and body weight were − 2.9, −2.9, and −2.8 SD, respectively. The mother was also short (−2.9 SD), with below-average mentality. The cognitive ability of the child was assessed using the Wechsler Intelligence Scale for Children, which showed a lower performance than verbal skills with a total score of 93 (low average). Electroencephalography (EEG) indicated a generalized epileptogenic discharge; however, a brain MRI did not show any abnormality. Family history indicated that two different male cousins (from the mother’s side) were mentally retarded, with abnormal severe psychological behavior.

Cytogenetic studies and results

Chromosomal analysis for the family was carried out using the G-banding technique according to the described method 19,20 and high-resolution banding according to the method of Yunis et al.21. A total of 50 metaphases were analyzed for each case; structural or numerical anomalies were recorded and karyotyped according to the ISCN (2009) 22.

Cytogenetic analysis of the proband indicated 46,XX, r(18)(65%)/46,XX, double size r(18)(35%) Fig. 1 and analysis for the mother showed karyotype 46,XX, r(18) in all cells Fig. 2. The father showed the normal male karyotype 46,XY.

Fig. 1
Fig. 1:
Karyotype of the proband showing double-size r(18) (arrow).
Fig. 2
Fig. 2:
Karyotype of the mother showing 46,XX, r(18) (arrow).

Fluorescent in-situ hybridization (FISH) was carried out using whole chromosome paint 18 probe (Q-Bio-gene, MP Biomedicals, Irvine, California, USA) (spectrum red). Total telomere Kit (Vysis, Abbot Laboratories, Illinois, USA) Mix. No.11 [tel.11p (spectrum green), tel. 11q (spectrum orange) and tel. 18p (spectrum green and orange)] and Mix. No.12 [tel.12p (spectrum green), tel. 12q (spectrum orange), and tel. 18q (spectrum green and orange)] were applied as these two mixes include the 18p and 18q subtelomeres. Slides were prepared from 3 : 1 methanol: acetic acid-fixed cells, pretreated with 2×SSC at 37°C for 30 min, dehydrated for 2 min. in 70, 90, and 100% ethanol, respectively. Denaturation of the slides in 70% formamide at 73±1°C for 5 min was performed, followed by dehydration in cold ethanol 70, 90, and 100%. Denaturation of 10 µl of the probe (3 µl in case of tel. mix 11 and mix 12) was performed in a water bath at 74±1°C for 5 min, covered and sealed with rubber cement, and incubated at 37°C overnight. Slides were washed in 0.4×SSC in 73°C for 2 min, followed by (2×SSC/NB-40) for 1 min, and finally in 2×SSC for 2 min at room temperature, counterstaining of cells was carried out using 10 µl DAPI. Slides were examined at ×100 magnification and photographed using an Olympus (BX51, Tokyo, Japan) fluorescent microscope.

FISH was performed using the whole chromosome paint 18 probe (Q-Bio-gene) (spectrum red) of the proband Fig. 3 and the mother, and it was found that the ring was derived from chromosome 18 material with no other complex chromosome rearrangement. Total telomere (Vysis) Mix. 11 of the proband Fig. 4 and the mother showed subtelomeric 18p deletion in the ring chromosome and in Mix. 12 showed subtelomeric 18q deletion in the ring chromosome of both the proband Fig. 5 and the mother.

Fig. 3
Fig. 3:
Fluorescent in-situ hybridization of the proband using the whole chromosome paint probe for chromosome 18 (Q-Bio-gene) (spectrum red) showing chromosomes 18 and r(18).
Fig. 4
Fig. 4:
Total telomere (Vysis) Mix. 11 [tel.11p (spectrum green), tel. 11q (spectrum orange), and tel. 18p (spectrum green and orange)] showed an intact subtelomere in normal chromosome 18 and subtelomeric deletion of 18p of the ring chromosome of the proband.
Fig. 5
Fig. 5:
Total telomere (Vysis) Mix. 12 [tel.12p (spectrum green), tel. 12q (spectrum orange), and tel. 18q (spectrum green and orange)] showed an intact subtelomere in normal chromosome 18 and subtelomeric deletion of 18q of the ring chromosome of the proband and the presence of a single centromere 18 in the ring (spectrum aqua).


A 6-year-old female child was presented to the Department of Children with Special Needs, the National Research Center, because of a parental complaint of hyperactivity and occasional episodes of loss of concentration simulating atypical absence seizure. She showed a minor and nonspecific pattern of dysmorphism and was mildly growth retarded; height, head circumference, and body weight were below −2.5 SD and EEG indicated a generalized epileptogenic discharge whereas brain MRI did not indicate any abnormality.

The patient was showing two major components of the ‘ring syndrome’: growth retardation and seizures. However, she had low average mentality whereas in most reported cases of r(18), the full spectrum of mental insufficiency, mild, moderate, and severe, is observed 9,23,24. As the patient showed a minor and nonspecific pattern of dysmorphism, the parents were mainly concerned about hyperactivity, poor concentration, and memory leading to learning disability. Although the EEG of the proband indicated a generalized epileptogenic discharge, her parents did not notice any symptoms suggestive of seizures; this is in accordance with the observation (9) that although 18p and 18q deletion syndromes are associated with epileptic disorders, in mosaic r(18) patients, seizures are rare. Koç et al.23 reported on a boy with diffuse EEG slow activity with the presence of seizures, but a description of clinical epileptic presentation was not remarkable. In another study 25, they reported on a mildly retarded girl with a 1.6 Mb deletion of 18p11.32 who had two episodes of febrile convulsions with normal EEG results. This observed phenotypic variability in patients with ring chromosomes 18 depends primarily on the extent of the deleted chromosome 18p and 18q segments and the genes involved 26. The phenotypic characteristics of our case match some of those features that are usually associated with patients with a ring chromosome 18; such features include those observed in cases with terminal deletions of both short and long arms of chromosome 18 1.

Cytogenetic analysis of the patient indicated mosaic 46,XX, r(18)/46,XX, double-size r(18); the mother showed karyotype 46,XX, r(18) in all cells whereas the father showed the normal male karyotype 46,XY. FISH showed deletion of both 18p and 18q subtelomeres for both the patient and her mother in their ring chromosome. Although ring chromosomes are uncommon cytogenetic findings, they have been reported for almost all human chromosomes including chromosome 18 27. Rings often appear as mosaics, leading to different karyotype forms as loss of the ring (cases with small rings often show a subclone without the ring chromosome) 8,28, double-sized rings, dicentric ring, or multiple copies of the ring have been observed 1,2,23.

The cytogenetic analysis for the patient indicated the presence of double-size ring 18 in about 35% of the studied cells compared with the mother, who had no size enlargement in the ring chromosome; this may explain the more severe phenotypic manifestations present in the patient, which is in agreement with other reports 1,2,23. However, Strathdee et al.29found no correlation between ring size, parental origin, and severity of the resulting phenotype; also, both the patient and her mother showed 46,XX, ring 18 without loss of the ring chromosome, which was not observed in other studies 14,15. There was no loss of the ring chromosome in the proband, although she had a mosaic cell line with a double-size ring chromosome, which is in agreement with another study 16 in which no correlation was found between ring size and ring instability; furthermore, this mosaic cell line was present as a structural anomaly of the ring chromosome without numerical affection (aneuploid, multiple rings or supernumerary marker), which is in agreement with other studies 17,18, as they observed that mosaicism involving both structural and numerical chromosome anomalies in a single individual is rare. The ring chromosome 18 in our study showed only one centromere as mentioned previously in other studies 9,15 and is different from the study with dicentric ring 18 23,30.

This family represents a rare case, where the mother with ring chromosome 18 transmitted the chromosomal aberration to her daughter, resulting in a mosaic cell line with a double-size ring, and resulted in minor dysmorphism compared with other studies 3,9,15. The double-size ring 18 is expected to have clinical features of partial trisomy 18 but the low percent of the mosaic cell line may have had a minor effect.

The variability of the cell lines observed and in the structure of the ring chromosomes found highlights the importance of analyzing a large number of cells and of using various cytogenetic techniques. The use of aCGH is of great value in the establishment of the presence of either loss or gain of chromosomal material in the ring structure, because it will help to elucidate the role played by that material in determining the phenotypes, facilitating the search for candidate genes in those regions; however, recent studies have suggested that aCGH cannot detect low mosaicism in peripheral blood cells 30,31.

No title available.


Conflicts of interest

There are no conflicts of interest.


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