Complex rearranged small supernumerary marker chromosomes (sSMC), three new cases; evidence for an underestimated entity?
© Trifonov et al; licensee BioMed Central Ltd. 2008
Received: 20 November 2007
Accepted: 15 April 2008
Published: 15 April 2008
Small supernumerary marker chromosomes (sSMC) are present ~2.6 × 106 human worldwide. sSMC are a heterogeneous group of derivative chromosomes concerning their clinical consequences as well as their chromosomal origin and shape. Besides the sSMC present in Emanuel syndrome, i.e. der(22)t(11;22)(q23;q11), only few so-called complex sSMC are reported.
Here we report three new cases of unique complex sSMC. One was a de novo case with a dic(13 or 21;22) and two were maternally derived: a der(18)t(8;18) and a der(13 or 21)t(13 or 21;18). Thus, in summary, now 22 cases of unique complex sSMC are available in the literature. However, this special kind of sSMC might be under-diagnosed among sSMC-carriers.
More comprehensive characterization of sSMC and approaches like reverse fluorescence in situ hybridization (FISH) or array based comparative genomic hybridization (array-CGH) might identify them to be more frequent than only ~0.9% among all sSMC.
Small supernumerary marker chromosomes (sSMC) are a major problem in cytogenetic diagnostics and genetic counseling. sSMC are structurally abnormal chromosomes that cannot be identified or characterized unambiguously by conventional banding cytogenetics alone, and are generally about the size of or smaller than a chromosome 20 in the same metaphase spread. Molecular cytogenetic techniques are necessary for comprehensive sSMC characterization . Cases with a de novo sSMC, particularly those that are prenatally ascertained, are not easy to correlate with a clinical outcome . It has been established that substantial parts of sSMC lead to four specific syndromes, i.e. Pallister-Killian [= i(12p)], isochromosome 18p [i(18p)], cat-eye [i(22p~q)], and Emanuel or derivative chromosome 22 [der(22)t(11;22)] syndromes . Moreover, for the remaining ones, recently a first step towards a genotype-phenotype correlation was reported . In general, the risk for an abnormal phenotype in prenatally ascertained de novo cases with sSMC is considered to be ~13% . This has been refined to 7% (for sSMC from chromosome 13, 14, 21 or 22) and 28% (for all non-acrocentric autosomes)  and has now been suggested to be 30% . Also generally speaking, sSMC transmitted by normal sSMC carriers to their progeny are not correlated with clinical problems , although exceptions have been described .
Cases with unique complex sSMC reported in the literature.
Case acc. to 
sSMC acc. to FISH
abnormal clinical outcome
der(13 or 21)t(13 or 21;18)(13 or 21pter->13 or 21q11::18p11.21->18pter)
der(13 or 21)t(13 or 21;18)(q11;p11.2)
dic(13 or 21;22)(13 or 21pter->13 or21q11::22q11.1~11.2->22q11.21~11.22::22q11.21~11.22->22pter)
dic(Y;15) presence of 2 alpha-cepY and cep15 signals; PCR prove of Yq11 euchromatic region (AZF1); absence of SRY region
sSMC from mother
47,XX,+mar [87%]/46,XX [13%]
dic(13 or 21;14)(q10;q10)
dic(13 or 21;15)(q10;q10)
der(13 or 21)t(13 or 21;18)(13 or 21pter->13 or 21q11::18p11.21->18pter)
Parental balanced translocation
der(18)t(18;21 or 22) mat der(18)t(18;21 or 22) pat
Results and discussion
Case A (= #13 in Tab. 1)
A 13 months old boy was studied cytogenetically because of failure to thrive and psychomotor development delay. The patient was the product of the fourth pregnancy of a non-consanguineous couple. At birth, the mother was 31 and the father 55 years old. The pregnancy was complicated by hyperemesis gravidarum treated with metoclopramid; additionally, there was a mild exposure to tobacco (3 cigarettes a day) and to alcohol (1 unit per month). Sonography was normal during whole pregnancy. The patient was born by normal vaginal delivery at 41 1/7 weeks of gestation with a birth weight of 2150 g (10th centile), a length of 52 cm (50th to 90th centile) and a head circumference of 34 cm (10th centile). Neonatal adaptation was good with an APGAR-score of 9/10/10 and no apparent congenital abnormalities were noticed. During the first year of live, the patient showed an increasing refusal to eat with insufficient growth (weight -3.6 SDS, length 2.4 SDS, head circumference 3.8 SDS at the age of 13 months). At 13 months, psychomotor development was markedly delayed with a Griffith General Intelligence Quotient of 63. The neurological examination revealed slight muscular hypotonia but otherwise no abnormalities. MRI of the brain was normal. Laboratory analyses were not suggestive for any metabolic disorder.
For family history: the mother was treated for attention-deficit/hyperactivity problems during her adolescence and her IQ was borderline. The father presented no medical problems. The patient's 6 year old brother was born with diaphragmatic hernia and is at present treated for attention-deficit disorder. The 4 years old brother showed a delayed speech development with first words at the age of 3 years but to date his linguistic performance was normal. A fourth child was lost in the 12th week of gestation due to unknown reasons. A neuropsychological development therapy was initiated.
Case B (= case #16 in Tab. 1)
A newborn male, born at 42 weeks of gestation by normal vaginal delivery, was product of the first pregnancy of a healthy and not consanguineous couple. At birth the mother was 23 years old and the father 38. During whole pregnancy an exposure to tobacco (3 cigarettes a day) was present. Sonography performed in 5th month of pregnancy revealed an artrial septal defect (ASD) and a club foot on the right side. Pregnancy was continued and birth weight was 2,760 g (3rd to 25th centile) with a length 49 cm (25th to 50th centile) and an occipito-frontal circumference (OFC) of 33 cm (25th centile). The prenatally observed findings were confirmed, but no other congenital defects reported. At present the child is two years old, and his development is normal without any delay. The parents are phenotypically normal, even though the mother seems to have a border line IQ.
Case C (= case #10 in Tab. 1)
A 14 month old female with significant developmental delay, cardiac anomalies, preauricular tags, dysmorphism, polyspenia, extrahepatic biliary atresia, intestinal malrotation and hearing loss in right ear was referred to cytogenetic analysis in connection with thrombocytopenia following liver transplant. Clinically a cat eye syndrome was suggested. Bone marrow showed complete replacement with chronic lymphocytic leukemia and marked reduction in erythroid precursors (pure red cell aplasia). Following bone marrow transplant the patient remained in remission. The parents were phenotypically normal.
Here we report three new cases of patients with unique complex sSMC. Two of the sSMC are maternally derived (cases A and B) and one is de novo (case C). The two maternally derived sSMC both lead to partial trisomies of the short arm of chromosome 18 and interestingly two similar cases are already reported in the literature [8, 9] (cases 2 and 3 in Tab. 1). Compared to cases with partial tetrasomy of the short arm of chromosome 18 (overview on 140 cases reported in the literature see ), those four cases with partial trisomy 18p present with surprisingly mild clinical signs and symptoms.
The third case reported here (Case C) is a child with a cat eye syndrome which is carrier of a dicentric sSMC leading to a partial tetrasomy of 22q11.21. However, it is the first cat eye syndrome associated sSMC with centromeres derived from two different chromosomes, i.e. 13 or 21 and 14 or 22, even though 132 cases are already reported . It is suggested that acrocentric derived dicentric inverted duplicated sSMC are formed due to an U-type exchange during meiosis . Thus, the most likely explanation for this unusual sSMC in case C is, that one of the original chromosomes 22 already had a polymorphic centromeric region with D13/21Z1 instead of D14/22Z1 sequences in its centromeric region. A similar polymorphic behavior for the sequence D15Z1 was recently reported to be present in 17.6% of the acrocentric chromosomes . An alike mode of formation could be suggested for cases 4, 6, 12, 14 and 15 of Tab. 1.
Among ~2500 reported sSMC cases studied for their chromosomal origin and subsequently reported, by now 22 cases with unique complex sSMC were detected . I.e. unique complex sSMC are to be expected in at least 0.9% of patients with an sSMC. However, the question is, if the percentage of this specific kind of sSMC is not underestimated. Unique complex sSMC are easy to be missed if, in case of acrocentric chromosome derived sSMC not all centromeric probes are applied, and/or if no flow sorting or microdissection followed by reverse FISH or array-CGH  is performed. Thus, for cases similar to cases 2, 3, 9, 10, 15 and 16 from table 1 one may suggest there is no euchromatin on the sSMC after its origin from an acrocentric chromosome was revealed by a centromeric probe. Or, as in case 13, if already a (relatively large) euchromatic imbalance was detected, which could explain the clinical symptoms of the specific patient, a very small part of another chromosomal origin is very unlikely to be detected. This can be problematic especially in prenatal diagnostics, but also concerning genotype-phenotype correlations of sSMC.
In conclusion, a really comprehensive characterization of all sSMC by different probes, probe sets and approaches could enhance the detection rate of unique complex sSMC. Unique complex sSMC are especially to be expected in cases with a 'heterochromatic sSMC', no uniparental disomy in connection with the sSMC and, nonetheless, clinical symptoms. Here a reverse FISH or array-CGH experiment of the sSMC should be performed and might show additional chromosomal imbalances.
Cytogenetics and molecular cytogenetics
Banding cytogenetics (GTG-banding and NOR-staining) was done on metaphase cells derived from peripheral blood of the three aforementioned patients and their parents according to standard procedures. 25 cells were analyses per case.
The sSMC were characterized in more detail by commercially available centromeric probes or centromere-specific multicolor fluorescence in situ hybridization (cenM-FISH) , subcentromere-near  (#13, #18, 21, #22) and commercially available subtelomeric FISH-probes (#8 and #18, Vysis) and/or home made partial chromosome painting probes for the long and the short arm of chromosome 18  plus the short arm of all acrocentric chromosomes (probe midi54 ). Additionally, the multicolor banding (MCB) probe set for chromosome 18  was applied in case A. In case C the probes RP11-172D7 and RP11-81B3 in 22q11.21 plus RP11-1058B20 in 22q11.22 were used to characterize the size of the cat eye syndrome specific tetrasomy. In case A and B also chromosome flow sorting  or glass needle based microdissection of the sSMC were done , respectively, followed by reverse FISH. All aforementioned molecular cytogenetic approaches are standard techniques of (multicolor) FISH and were repeatedly described before in detail.
Review of the literature
This work was supported by the DFG (436 RUS 17/135/03; 436 RUS 17/109/04, 436 RUS 17/22/06, WE 3617/2-1, LI820/11-1), the DAAD/British Council support (313-ARC-XX-lk) and the Boehringer Ingelheim Fonds.
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