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H.T.el-bassyouni eT al., TERMINAL 2 DELETION AND TRISOMY CHROMOSOME 15GENETIC COUNSELING, Vol. 25, No 2, 2014, pp 151-158

TERMINAL 2q DELETION AND PARTIAL TRISOMY CHROMOSOME 15q: A CLINICAL AND CYTOGENETIC

STUDYBY H.T. EL-BASSYOUNI 1, A.M.S. El-GERZAWY 2, A.M. MOHAMED 2, A.K.

KAMEL2, H.A. HUSSEIN 2, M.M. THOMAS 1 AND M. EL-RUBY 1

Summary: Terminal 2q deletion and partial trisomy chromosome 15q: a clinical and cytogenetic study: We report on a 5 years old female patient with a karyotype 46, XX, add (2), t(2;15) (q37;q22) associated with dysmorphic facial features, digital deformities, heart defect (mild mitral regurge) and severe mental retardation. This is the third reported case worldwide on the terminal 2q deletion and trisomy of chromosome 15q syndrome. The findings in this case and our literature review, delineates the pattern of malformations secondary to trisomy of 15q and deletion of 2q.

Key words: Trisomy chromosome 15q - Deletion 2q - Mental retardation - Facial dysmorphism.

INTRODUCTION

Trisomy of the distal part of chromosome 15q is an extremely rare chromosomal disorder, characterized by prenatal and postnatal over-growth, mental retardation, and craniofacial malformations (10, 19). Additional abnormalities include short neck and skeletal malforma-tions in the fingers and toes with scoliosis and cardiac defects may occur in some cases (2) and rarely renal anomalies in the form of renal agenesis, horseshoe kidney, and hydronephrosis were described (20). To date, about 41 patients with trisomy or tetrasomy for distal 15q have been reported (4). The range and severity of symptoms and physical findings vary from case to case, depending upon the length and loca-tion of the duplicated portion of chromosome 15q (9), most of the re-ported cases have resulted from unbalanced translocations or deletions involving chromosome 15 and another chromosome as well as other structural chromosomal abnormalities (17).Deletions of 2q, 12p, 13q, and 20p have been described in associa-tion with trisomy 15q (3, 5, 7, 13). To date, only two cases with par-tial duplication of 15q and deletion of 2q have been reported (7, 21). The 2q37 locus is one of the most commonly deleted subtelomeric regions, it is known as ‘2q37-deletion syndrome’; brachydactyly-men-

(1) Clinical Genetics Department, National Research Centre, Egypt.(2) Human Cytogenetics Department, National Research Centre, Egypt.

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tal retardation syndrome or Albright’s hereditary osteodystrophy-like syndrome (OMIM 600430) (14). Patients present with intellectual de-ficiency, facial dysmorphism and brachydactyly, associated with be-havioral problems, short stature, autism or autism spectrum disorders of varying severity and overweight or obesity (12). The study of dupli-cation or deficiency of chromosomes in affected individuals can offer insight into the delineation of segmental aneuploidy syndromes. In this study we report a case with unbalanced chromosomal rearrangement of distal 15q and terminal del of 2q37.

CLINICAL REPORT

A five-year-old female with delayed motor milestones of development was referred to the Department of Clinical Genetics, National Research Center, Egypt. She was the offspring of a healthy non-consanguineous 23 and 32-year-old mother and father, respectively. The pregnancy and delivery histories were unremarkable except for intrauterine growth retardation and low birth weight. The patient’s weight, height and head circumference were 13.3 Kg (- 1.88 SD), 110 cm (+0.3 SD) and 48.7 cm (- 1.6 SD) respectively. She had a plageocephalic skull and dys-morphic facies; long face, prominent metopic suture, arched eyebrows with sparse hair at the outer third, narrow palpebral fissure, epicanthal fold, broad and prominent nasal bridge, hypoplastic ala nasi, long flat philtrum, thin upper lips, posteriorly rotated low set ears with promi-nent columella and pointed chin (Fig.1 a, b). She had a skin appendage on the chest and low displaced hypoplastic nipples (Fig 1c, d). The hands were narrow and long with abnormal dermatoglyphics, hypo-plastic palmar crease, camptodactyly of 2nd, 3rd and 4th fingers, taper-ing fingers and soft tissue syndactyly between 2nd, 3rd, 4th & 5th fingers (Fig.1e, f). X-rays of the hand showed soft tissue syndactyly between 2nd, 3rd, 4th and 5th fingers (Fig. 1g). There were also camptodactly of 2nd and 3rd toes, overriding between 2nd, 3rd, 4th and 5th toes, lateral devi-ation of toes, flat feet and talipus equino vulgum corrected by a splint (Fig. 1h). Echocardiography revealed mild mitral regurge. Abdominal ultrasonography was normal. Mental assessment using portage pro-gram, revealed severe mental retardation. Chromosomal examination of the patient’s peripheral blood lympho-cytes using G- banding technique according to Seabright (18) and Ver-ma and Babu (22) were done, any structural or numerical anomalies were recorded and karyotyped according to the ISCN (6). Cytogenetic analysis of the proband revealed 46, XX, add (2) (q) as shown in fig-

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Figure 1: a, b) Clinical features of the patient: plageocephalic skull, long face, prominent metopic suture, arched eyebrows with sparse hair at the outer 1/3, narrow palpebral fissure, epicanthal fold, broad and prominent nasal bridge, hypoplastic ala nasi, long flat philtrum, thin upper lips, posteriorly rotated low set ears with prominent columella and pointed chin. c, d) a skin appendage on the middle upper chest and asymmetric hypoplastic nipples with lower position. e, f) The hands were narrow and long with abnormal dermatoglyphics, hypoplastic palmar crease, camptodactly of 2nd, 3rd and 4th fingers, tapering fingers. g) X-rays of the hand showing soft tissue syndactyly between 2nd, 3rd, 4th & 5th fingers. h) camptodactly of 2nd and 3rd toes, overriding between 2nd, 3rd, 4th & 5th toes, lateral deviation of toes, flat feet and foot splint to correct talipus equino vulgum.

Figure 2: Metaphase spread and karyotype of the proband revealed 46, XX, add (2) (q).

ure 2. Fluorescence in situ hybridization (FISH) was done according to Pinkel et al., (15) and manufacturer’s instructions. Using whole chromosome painting probe (WCP) for chromosome No. 2 (Vysis) (spectrum green) showed that the segment added to chromosome 2q belonged to another chromosome (Fig. 3). To identify the origin of the added part to chromosome (2) (q) a total subtelomere kit (Vysis) was used and demonstrated that the added part belonged to chromosome 15 (Fig. 4) (3 red and green signals represent the two normal subtelomere 15q and the third one represents the sub-telomere at the added segment. Also, using the total subtelomere kit showed deletion of chromosome (2) (q) subtelomere (one red signal) (Fig. 5).

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Figure 3: FISH using whole chromosome painting (WCP) for chromosome No.2 (spectrum green) showed that the added segment (arrow) belonged to another chromosome.

Figure 5: FISH using Total Subtelomere (mix No.2) showed intact subtelomere 2p (2 green signals), deleted one subtelomere 2q (one red signal) and intact subtelomere Xq (red and green signals).

Figure 4: Total Subtelomere Kit (Vysis) using mix No. 10 demonstrated that the added part belonged to chromosome No. 15 ( 2 green signals represented subtelomere of chromosome No.10p and 2 red signals represented subtelomere 10q ; 3 red and green signals represented the two normal subtelomere 15q (arrows) and the third one represented the subtelomere at the added segment (arrow head).

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Using whole chromosome painting (WCP) for chromosome 2 (spec-trum red) and (WCP) for chromosome No.15 (spectrum green) con-firmed that the added segment belonged to chromosome 15 (partial trisomy 15) (Fig. 6). To identify which part of chromosome 15 was duplicated and added to the long arm of chromosome 2, we used Vysis probe to identify locus specific identifier (LSI) for SNRPN (spectrum orange), located at 15q11-q13 and LSI for PML (spectrum green) lo-cated at 15q22 (Fig. 7) which demonstrates two normal chromosome 15 (each with the 2 signals; red and green) and the added, duplicated part of chromosome 2 showed only the green segment. This indicates that the break point is proximal to PML locus (15q22) but distal to SN-

Figure 6: whole chromosome painting (WCP) for chromosome No.2 (spectrum red) showed two normal signals and (WCP) for chromosome No.15 (spectrum green) showed 3 signals.

Figure 7: LSI showed two normal chromosome 15 (each with the 2 signals; red and green) and the added part to chromosome No. 2 demonstrated only the green segment.

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RPN locus (15q11-1-q13), so the karyotype is: 46, XX, add (2) (q37).ish der (2), t (2;15) (q37;q22) (WCP 2+, 2q tel-; WCP 15+ , SNRPN- , PML+, 15q tel +). Thus the proband had 2 normal chromosomes )15( and derived chromosome )2( with deletion of segment 2q37 and an extra segment of chromosome 15. The karyotype of the parents was normal.

DISCUSSION

Partial trisomy 15 is an extremely rare chromosomal aberration charac-terized mainly by mental retardation, distinctive facial dysmorphism, skeletal and congenital heart disease, renal anomalies and overgrowth (20). In our proband, the cytogenetic analysis revealed 46, XX, add (2) (q). FISH demonstrated der (2), t (2;15) (q37;q22) (WCP 2 +, 2q tel -; WCP 15 +, SNRPN -, PML +, 15q tel +), while the karyotype of the parents was normal. Trisomy of chromosome 15q has been reported to affect males approximately twice as often as females (11). Our patient, exhibited craniofacial malformations in accordance with the findings of Tatton-Brown et al. (20), and Poot et al. (16), who noted that pa-tients with trisomy of the distal chromosome 15q have a characteristic facial appearance in the form of a long thin face with a prominent chin and nose. Our patient had a history of intrauterine growth retar-dation and low birth weight, which contravenes with the findings of Browne et al. (2) and Kim et al. (9), who found that trisomy chromo-some 15q is characterized by prenatal and postnatal overgrowth. They further described mental retardation, craniofacial malformations, short neck, skeletal malformations and cardiac defects which are concordant with the findings in our patient. Insulin growth factor 1 receptor gene (IGFR1) is located on the distal terminal genes of 15q26 causing tall stature and overgrowth (20). The duplicated region of chromosome 15 in our proband did not include the distal 15q26 region, this could ex-plain the absence of overgrowth and tall stature. The same explanation could be the cause of absent renal anomalies in our patient.The range and severity of symptoms and physical findings vary from case to case, depending upon the length and location of the duplicated portion of chromosome 15q (8). Chen et al. (3), reported on a girl suf-fering from mental retardation and dysmorphic features, whose karyo-type revealed 46,XX,der(2)t(2;15)(q37.3;q24.3). The break points in our patient were proximal to PML locus (15q22) but distal to SNRPN locus (15q11.1-q13). The 2q37 locus is one of the most commonly deleted subtelomeric

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regions. Significant variability in clinical presentation exists, but al-most all patients have some degree of mental retardation and facial dysmorphism. Brachymetaphalangism has been reported in approxi-mately 50% and congenital heart anomalies are present in around 20% of patients with deletion 2q37 (1). The deleted region carries the candi-date genes for skeletal malformations (facial dysmorphism and camp-todactly) (12). In our study, the patient presented with the typical facial appearance of deletion 2q37 together with the most common clinical features of partial trisomy 15q. To date, only two cases with partial duplication of 15q and deletion of 2q have been reported (7, 21). Our case is the third report on par-tial duplication of distal 15q and deletion of the terminal 2q with a characteristic phenotype comprising mental retardation, craniofacial dysmorphism, skeletal malformations and cardiac defects. More re-ports about chromosomal rearrangements of chromosome 2 and 15 are recommended for the delineation of genotype- phenotype correlation.

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ADDRESS FOR CORRESPONDENCE: Hala T. El-Bassyouni Prof. of Clinical Genetics Clinical Genetics Department National Research Centre El-Tahreer Street, Dokki, Egypt E-mail: halabassyouni@yahoo.com