alexa Down Syndrome Phenotype in a Child with Partial Trisomy of Chromosome 21 and Paternally Derived Translocation t (20p; 21q) | Open Access Journals
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Down Syndrome Phenotype in a Child with Partial Trisomy of Chromosome 21 and Paternally Derived Translocation t (20p; 21q)

Biaduń- Popławska Anna1, Jamsheer Aleksander2, Henkelman Małgorzata1, Tuziak Martyna3, Pietrzyk Aleksandra1, Piotrowski Krzysztof1*,Giżewska Maria1, Walczak Mieczysław1 and Zajączek Stanisław1
1Cytogenetic Unit, Department of Pathology, Pomeranian Medical University, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland
2Centre for Medical Genetics Genesis, Grudzieniec 4, 60-601 Poznań, Poland
3Clinic of Paediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland
Corresponding Author : Krzysztof Piotrowski,Cytogenetic Unit
Department of Pathology
Pomeranian Medical University
Powstanców Wielkopolskich 72
70-11 Szczecin, Poland
Tel: +48 91 466 11 87
E-mail: [email protected]
ReceivedMay 28, 2014; Accepted September 25, 2014; Published October 05,2014
Citation: Anna BP, Aleksander J, Malgorzata H, Martyna T, Aleksandra P, et al.(2014) Down Syndrome Phenotype in a Child with Partial Trisomy of Chromosome 21 and Paternally Derived Translocation t (20p; 21q). Gen Med (Los Angel) 2:149. doi: 10.4172/2327-5146.1000149
Copyright: 2014 Anna BP, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

We present a case of the partial trisomy of chromosome 21 encompassing Down Syndrome Critical Region (DSCR) accompanied by 20p13 deletion. Patient’s karyotype was determined as: 46, XY, der20t (20,21) (21qter- >21q22::20p13->21qter)pat. The boy presented nearly all typical features of Down syndrome but no specificsigns described in rare cases of patients with deletion 20p13. Microarray- CGH analysis has shown that trisomic segment contained DSCR whereas 20p deleted segment did not contain JAG1 gene. Clinical data of our patient was compared with the data available for other 48 patients carrying similar chromosomal microaberrations.

Keywords
Down syndrome critical region; Partial trisomy of chromosome 21; Down syndrome
Introduction
Down syndrome (DS) is the most frequent chromosomal cause of mental retardation. It usually results from the presence of additional copy of the entire chromosome 21 but in very few cases (~50 worldwide) can be caused only by the partial trisomy of chromosome 21, with a variable span of the duplicated fragment. Therefore, in the early 80’s of the twentieth century Epstein proposed that the clinical manifestation of DS may not only result from the pure chromosome 21 trisomy but also from the imbalances limited to a small fragment of the chromosome named Down Syndrome Critical Region (DSCR) [1]. DSCR was defined as responsible for: mental retardation, congenital heart anomalies of cushion type and some other minor (particularly facial) dysmorphic features. DSCR was mapped by two approaches, primarily by the “common minimal region of overlap” analysis of particularly rare cases and secondly by the analysis of the genetically engineered mice with trisomy of chromosome 16 corresponding to human trisomy of chromosome 21 [2].
Due to extremely rare incidence of patients with partial trisomy of chromosome 21 presenting full- blown DS phenotype we would like to present a boy with partial trisomy of chromosome 21 accompanied by small partial subtelomeric monosomy of chromosome 20, both resulting from the paternal balanced translocation t(20,21). Similar cases have not been reported in the literature so far [3-6].
Clinical Report
We present a two-month-old boy who was being diagnosed on the grounds of clinical features suggesting DS. He was born as the 4th pregnancy, 1st delivery. The previous three pregnancies were spontaneously lost at 8-9 weeks of gestation. The child was born by caesarean section in the 39th week of gestation due to foetal decelerations and oligohydroamnios and scored 8,9,10,10 points in Apgar score. His body weight was 2540 g, length 46 cm and head circumference 32 cm. All parameters were below the 3rd percentile. Parents: a 24-year-old mother and 29 year-old father were Caucasian and non-consanguineous. Since the father had been adopted in early childhood, paternal family history was not available.
The first clinical evaluation was performed at the time of birth revealing: typical DS facial features, hypotonia, FOA and tricuspid valve insufficiency, which arose suspicion of DS. At two months the child was admitted to hospital due to respiratory infection, hypothyroidism and dysmorphic features, which led to subsequent, more detailed examinations. Heart ultrasound scan revealed FOA and tricuspid valve insufficiency of the 1st degree without hemodynamic significance. Additionally, the child displayed hypotonia, strabismus and slight nystagmus. After the successful treatment of respiratory infection and introducing medications for hypothyroidism the child was evaluated by a specialist in clinical genetics. Standard karyotyping was performed, revealing additional unbalanced chromosomal material on short arm of chromosome 20. Upon genetic consultation the growth parameters were noted: body weight – 2730 g, length- 51 cm and typical Down syndrome gestalt was observed including: large fontanel, sparse hair, low posterior hairline, prominent forehead, microophtalmia, flat occiput, small nose with low nasal bridge, small low-set ears, epicanthal folds, telecanthus, small mouth with thin lips, retrognathia and high arched palate, along with a short neck. We also noticed preaxial polysyndactyly and abnormal dermatoglyphs on his left hand but without the presence of the simian crease. Bilateral sandal gaps, right inguinal hernia and bilateral hydrocele of testis have also been found. The complete description of dysmorphic features observed in our patient is shown in Tables 1 and 2.
Cytogenetic Analyses
As mentioned above, the karyotype of peripheral blood lymphocytes showed additional chromosomal material located on short arm of chromosome 20 (Figure 1a). Striking DS appearance pointed further investigation into the long arm of chromosome 21 [7]. FISH analysis with painting probe for chromosome 21 (MP Biomedical; PAINT21-R5) (Figure 2a) and specific probe for 21q22.13q22.2 (Vysis LSI21 SO) (Figure 2b) was performed. It allowed us to identify the discussed material to be of chromosome 21 origin. Another FISH test with subtelomeric probe for 20p ( Cytocel LPT 20 PG) (Figure 3) showed the deletion of the investigated part of this translocated chromosome. Patient karyotype was defined as 46,XY,der20t(20,21) (21qter->21q22::20p13->21qter).
Trisomy of the long arm of chromosome 21 was delineated by BACson- Beads™ (PerkinElmer) molecular karyotyping. Microarray analysis on NimbleGen CGX 12-plex chips (Roche) detected a terminal deletion of chromosome 20p band 20p13 (2.31- 233 Mb, coordinates according to HG18: 19264- 2325528) and concurrent trisomy of 21q22.11- 21q22.3 (14.22- 14.25 Mb, coordinates according to HG18: 32669557- 46915771) (Figure 6a-c) including DS critical region. Additionally, a second small duplication of chromosome 21q22.2-21q22.3 (6.03- 6.08 Mb, coordinates according to HG18: 40888112- 46915771) was found in region responsible for Holoprosencephaly 1 (not detected in our patient).
The karyotype of the patient’s mother was normal, i.e. 46, XX. However, the father’s karyotype revealed reciprocal translocation, which was described as (Figure 1b): 46,XY,t(20,21)(20pter:21q21) (21qter->21q22::20p13->20qter:21pter->21q22::20p13).
It was confirmed by identical FISH analysis as the one performed on his son (Figures 4a, 4b and 5). Finally, we compared main dysmorphic features observed in our proband with the ones observed in cases of subtelomeric monosomy of 20p (Table 1), as well as DSCR trisomy on 21q (Table 2) that were found in literature.
Discussion
We present a boy with typical dysmorphic features of DS, partial trisomy of chromosome 21 including DSCR and accompanying microdeletion of subtelomeric region of 20p. His chromosomal aberration appeared as a result of balanced paternal translocation t (20,21).
Clinical manifestation closely resembled the DS phenotype described in regular trisomy of chromosome 21. Conversely, our patient does not show any distinctive features that could be attributed only to subtelomeric deletion of 20p
Our proband carries partial trisomy of chromosome 21, which was defined by array- CGH method to involve the region of 21q22.11- 21q22.3 with a span of 14.22- 14.25 Mb with genomic position according to HG18: 32669557- 46915771. The identified aberration contains Down Syndrome Critical Region (DSCR), which comprises many genes, DYRK1A, DSCR3, DSCR4, DSCR8, DSCR9, DSCR10, KCNJ15 being the most important among them, yet excluding SOD1 gene.
An extensive review of literature revealed descriptions of 48 patients with partial trisomy of chromosome 21 that has been juxtaposed with our patient’s.
In this small cohort of patients with partial trisomy of chromosome 21: mental retardation, upslanting palpebral fissures, epicanthus, abnormal dermatoglyphs, flat nasal bridge and clinodactyly were repeatedly described. Not all of these features, however, were noted in our patient, i.e. clinodactyly and upslanting palpebral fissures. Also other frequent features of DS, such as brachycephaly, loose skin of the neck, simian crease were not observed. Evaluation of the clinical signs of 20p deletion happened to be more difficult. As to this day we have found description of only 3 patients with this aberration who have manifested diverse clinical features reported at different ages. They presented only a few common features, such as: large fontanels, ear abnormalities and mental retardation, which we have also seen in our patient. These symptoms seem to be nonspecific and not relating to any particular chromosomal localisation.
This leads us to conclusion that our patient clearly exhibits features typical of DS only, excluding polysyndactyly.
In 1986 C.J. Ebstein presumed that DS features are not the consequence of the full imbalance of all 300- 400 genes covering entire chromosome 21, instead they are caused by the additional copy of limited number of specific genes which constitute the so called DSCR [8,9]. To this day, the mentioned region has not been fully defined. Distal terminus of the long arm of chromosome 21 (21q22) has been assumed as a probable location as it contains all the genes which are considered sufficient for producing DS phenotype [10]. Since 2000 DSCR has been estimated within the range of 1,6 to 2,5 Mb [11-15]. However, it may also incorporate duplication of 4,3 to 5 Mb sequence between the bands 21q22.13- 22q22.2 which contains a new candidate gene RCAN1 that has been associated with cardiac anomalies frequently observed in DS [16] and MX1 in band 21q22.3 that lies near sequence D21S17.
DSCR comprises probably about 43 conserved genes and in previous investigations has been connected with main DS features, such as: craniofacial abnormalities, short stature, joint hypermobility, hypotonia, and mental retardation [3-6]. Throughout the years the list of DSCR genes has been modified.
Recently, a significant role has been attributed to genes involved in DSCR- NFATc (Nuclear Factor of activated T- cells), DSCR1, DYRK1A [3-6]. The ultimate and penultimate act synergistically to prevent nuclear occupancy on NFATc transcription factors, known regulators of vertebrate development. They are dosage sensitive and their overexpression is responsible for neurodevelopmental defects [17].
Crucial influence on the development of DS phenotype may have NFATc- complex of 4 gene regulatory factors. Decalcification in cytoplasm via the enzyme called calcineurin allows NFATc protein to enter nucleus and activate many target genes. DSCR1 and DYRK1A are known inhibitors of calcineurin. Their increased expression due to trisomic dosage effect may cause alterations in proper development of individual. All above mentioned genes are positioned in the area that was to found to be trisomic in our patient.
An important piece of data about DSCR has been obtained from the research carried on genetically engineered mice with trisomic chromosomal segment homologous with the human 21st chromosome [18].
The present knowledge regarding DSCR architecture is not comprehensive; thus, every new patient with a partial trisomy of chromosome 21 manifesting typical DS features is a valuable contribution to more precise description of DSCR [7].
Our patient presented main features of DS but some of those typical, frequent, like brachycephaly, loose skin of the neck, upslanting palpebral fissures or simian crease were absent. At the same time we observed preaxial polysyndactyly, which is neither as a classical feature of DS nor was found in 2 reported patients with subtelomeric deletion of 20p [19].
In DECIPHER database we found two patients with deletions of 20p of similar span. The first one, No 251338, had a deletion of band 20p13 with genomic size 1680634, which encompassed 15 known genes, such as: angiopoetin 4 and 6 different genes coding defensins, without a known role in human dysmorphy induction. His clinical description listed developmental delay, mental retardation obesity and brachydactyly. The second patient, No 261715, had a deletion in the same band with genomic size 812126 and nearly identical spectrum of specified genes. The following features have been included in his record: developmental delay, mental retardation, microcephaly, neuroradiological abnormalities, seizures, deeply set eyes and strabismus. Five patients with similar partial duplication of chromosome 21 were registered in the DECIPHER database, each showing different clinical symptoms. The most precise is the dysmorphological assessment of patient No 257536 with downslanting palpebral fissures, prominent ear helix, wide intermamillary distance, pectus excavatum, open mouth appearance as well as ASD, autism and intellectual disability. Clinical manifestation of patient No 2214 was matching with typical DS features, i.e.: epicanthal folds, hypertelorism, deeply set eyes, abnormal palmar creases, clinodactyly of the 5th finger. In that patient, however, the considered duplication was not the only finding, as concurrent deletion Xq25, with genomic size 666983, was identified.
The involved duplicated fragment of chromosome 21 holds 9 genes, 3 of which have been described as collagens and 1 of folate transporter.
Comprehensive analysis of the patient’s clinical findings juxtaposed to features observed in similar cases of atypical partial trisomy of chromosome 21 is shown in Table 2.
Most frequently partial trisomies of chromosome 21 result from parental balanced reciprocal translocation; however, in a few cases they have also appeared de novo [16,20,21]. A balanced translocation involving chromosomes 20 and 21 hasn’t been described so far, as we haven’t found any available medical literature on this matter. Cases of DS in patients with partial duplications of chromosome 21 with coexisting more complex aberrations, such as concurrent deletion in the mentioned chromosome has been reported. Since DSCR remains disputable until this day, every newly described patient may be a valuable contribution to further refinement of the map of this particular region.
Acknowledgements
This study makes use of data generated by the DECIPHER Consortium. A full list of centres that contributed to the generation of the data is available athttp:// decipher.sanger.ac.uk and via email from [email protected] The funding for the project was provided by the Wellcome Trust.
Web Resources
http://decipher.sanger.ac.uk/- DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth, H.V. et al (2009). Am.J.Hum.Genet 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)
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