Journal of Genetic Disorders & Genetic Reports ISSN: 2327-5790

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Case Report, J Genet Disor Genet Rep Vol: 5 Issue: 3

Inherited Unbalanced Chromosome from Parent with Balanced Translocation: A Case Report and Review of Literature

Kumari P1*, Mishra VV1 and Tewari S2
1Department of Obstetrics and Gynecology, Institute of Kidney Diseases and Research Center, Dr. HL Trivedi Institute of Transplantation Sciences (IKDRCITS), Civil Hospital Campus, Asarwa, Ahmedabad, India
2Scientific Pathology, Agra, India
Corresponding author : Kumari Pritti
Department of Obstetrics and Gynecology, Institute of Kidney Diseases and Research Center, Dr. HL Trivedi Institute of Transplantation Sciences (IKDRC-ITS), Civil Hospital Campus, Asarwa, hmedabad, India
Tel: +91 79 226871111
E-mail: [email protected]
Received: May 12, 2016 Accepted: June 29, 2016 Published: June 30, 2016
Citation: Kumari P, Mishra VV, Tewari S (2016) Inherited Unbalanced Chromosome from Parent with Balanced Translocation: A Case Report and Review of Literature. J Genet Disor Genet Rep 5:3. doi:10.4172/2327-5790.1000138

Abstract

Reciprocal translocations are common, and the translocation heterozygote (carrier) may have a risk to have a child who would be mentally and physically abnormal due to a segmental aneusomy. The carriers of balanced translocation mostly do not have recognizable phenotypic expression, however, they can produce unbalanced chromosome, which is transmitted to next generation through fertilization of gametes carrying the derivative chromosome. We describe a 4-year-old boy with partial 10q trisomy and distal 13qmonosomy. The patient presented with delayed milestones, dysmorphic face, congenital heart defect, renal and skeletal anomalies. The conventional cytogenetic analysis showed a 46,XY, add(13q) karyotype. The child inherited the unbalanced chromosome from mother who was a carrier of balanced reciprocal translocation,t(10;13)(p24.2;q33.1). The phenotype observed in our patient resulted from the combination of those defects described in the isolated dup(10q) and distal del(13q) syndromes but predominantly resembles the children with distal trisomy 10q syndrome. Our finding are in concordance with the literature and supports the importance of critical regions like 10q24 and 13q32 for the phenotypic expression of distal 10q trisomy syndrome and distal 13q trisomy syndrome respectively.

Keywords: Balanced reciprocal translocation; Distal trisomy 10q; Distal trisomy 13q

Keywords

Balanced reciprocal translocation; Distal trisomy 10q; Distal trisomy 13q

Introduction

A not uncommon problem encountered in the genetic clinic is that of the unbalanced chromosomal rearrangement, which has been discovered in the process of investigation of a child with dysmorphic facial feature and also features of psychomotor retardation. Structural rearrangements can be balanced, with the correct amount of genetic material in a cell, or unbalanced, with a deletion and /or duplication of genetic material. In duplications, there is 150% of the normal amount of this chromosomal segment; and in the deletion, 50% of the normal amount. Differing lengths of deleted or duplicated segments enable a dissection of the specific segmental contributions to components of an abnormal phenotype. These various observations of karyotype phenotype correlations give insight concerning whether a particular duplication or deficiency may be minor, major, or lethal effect. We report a case of 4 year old child born to an unrelated couple, and was severely affected with congenital anomalies and systemic disorders. Conventional G banding analysis of somatic chromosomes identified a balanced translocation, t(10;13)(p24.2;q33.1), in mother and an unbalanced rearrangement, der(13)t(10:13)(p24.2;q33.1)mat, in the child. The child has inherited a derivative chromosome 13 with partial deletion of 13(p33.1-pter) and partial trisomy 10(q24.2-qter), which has resulted in abnormal phenotype. The prominent phenotypic features is of dup(10q), including high forehead, flat nasal bridge, congenital heart disease, renal anomalies, and growth retardation which is characteristic of distal trisomy 10q syndrome. The abnormal phenotype could be attributed to an over dosage of genes mapped in this region and particularly at band 10q25 which has been well documented in the literature.

Case Description

A 4-year-old male child born of a non-consanguineous marriage was referred to us for chromosomal analysis to rule out Down’s syndrome. The child has a healthy sibling as a 6-year-old sister.The boy was born at 34 weeks gestational age by an uneventful vaginal delivery [birth weight 2.25 kg (3rd centile); length 46 cm (3rd centile); head circumference 27 cm (<3rd centile); thorax circumference 28 cm (3rd centile)]. On examination at the age of 4 years, his weight and body length were 7.2 kg (<3rd centile) and 87 cm, respectively, with head circumference of 49 cm.
The boy had significant dysmorphic facial features including arching of eyebrows, flattened face, low-set dysmorphic ears, flat and depressed nasal bridge, small bow shaped mouth, microphthalmia, epicanthal folds, drooping of the upper eyelids, ocular hypertelorism. He also had bilateral V clinodactyly of fingers and, muscular hypotonia, dental decay, circular hair pattern on scalp, kyphoscoliosis, overlapping of fingers and equinovarus (Figure 1a,b,c and d). Psychomotor development was retarded. At the age of 4 years, he was not able to walk, could not sit without support and could only speak single words. The boy also experienced repeated lower respiratory tract infections. On 13th day after birth he was investigated for cyanotic spells and echocardiogram and colour Doppler test revealed Tetralogy of Fallot (TOF). On ultrasound examination, right kidney showed gross hydronephrosis with hydro ureter and left kidney showed mild hydronephrosis. Bilateral testis was in the inguinal region.
Figure 1: Dysmorphic features of the child.

Chromosome Analysis

For genomic karyotyping, PHA- stimulated peripheral whole blood culture was performed in ready-to-use Gibco PB-MAX Karyotyping Medium for 72H at 37°C followed by harvesting of cells via standard colchicine-hypotonic-fixation technique. Metaphase slides were processed for GTG-banding and staining. Only complete and well-scattered metaphases were considered for karyotyping using ASI imaging software.
Karyotypic analysis of 20 cells revealed 46,XY, der(13) del(13q32.2-pter) pattern in 20 cells evaluated (Figure 2a). Parental karyotyping was done to figure out if it was inherited as a result of balanced translocation. A similar protocol was followed for parents’ chromosome preparation. Analysis of 20 cells from each parent revealed normal 46,XY pattern of the father, whereas the mother showed 46,XX,t(10;13)(q24.2;q33.1) pattern with a balanced translocation between 10 and 13 (Figures 2b,3a and 3b).
Figure 2: (a) Child karyotype of -showing derivative chromosome 13; (b) Mother karyotype showing balanced translocation between 10 and 13.
Figure 3: (a) Partial karyotype of child-showing normal chromosome 10 with a derivative chromosome 13; (b) Partial karyotype of mother-showing balanced translocation between 10 and 13.
Therefore, the summary of the three karyotypes was as follows: father with an apparently normal male genome, mother with a constitutive balanced translocation, t(10;13) and the child with a constitutive unbalanced translocation with der(13)t(10:13)(q24.2; q33.1)mat.
Therefore, it is apparent that the child was born through fertilization of an apparently normal paternal gamete with an abnormal maternal gamete carrying a der(13) with partial monosomy 13(q33.1-qter) and partial trisomy 10(q24.2-qter).

Discussion

The imbalance as a result of balanced translocation between chromosome 10 and 13 is being reported for the first time as per our knowledge. In the present case, the child was detected with the derivative 13q that was confirmed as the product of a balanced translocation between 10q and 13q present in mother. Therefore, the derivative 13q in the present child actually designates partial trisomy 10q24 and partial monosomy of 13q33. The mother was carrying the constitutive balanced translocation and since the translocation was balanced and apparently there was no deletion or loss of genes, she did not suffer any major clinical problem since childhood. She had a single miscarriage and then conceived and gave birth to a normal female child at full term. She is now six years old and has normal milestones. She could be either a carrier of balanced translocation like her mother or might have normal karyotype that could only be revealed by doing her karyotype. The parents need to be counseled regarding their daughter having risk of giving birth to a child with unbalanced chromosome in future, if she turns to be a carrier of same balanced translocation like her mother.
About 25% of reported patients with distal 10q trisomy die within the first year of life, mostly resulting from internal malformations and respiratory infection, and most survivors suffer from severe mental retardation [1,2]. Trisomy of more distal 10q is associated with a characteristic syndrome and has been described in many cases that are almost always familial [1,2,3]. Since its first description by de Grouchy and Canet [4], over 50 cases have been described with distal trisomy 10q with the breakpoints ranging from 10q22.3 to 10q26.3 [5,6]. A case similar to ours was reported by Chen et, al. with partial trisomy 10q(10q25.1-qter) and partial monosomy 13q (13q34-qter) but it was prenatally diagnosed which was followed by termination of pregnancy, therefore complete information regarding phenotypic expression and milestones development was not possible [7].
The distal trisomy 10q disorder is characterized by unusual prenatal and postnatal growth retardation, hypotonia, mild to severe mental retardation, and mild to severe delaysin the acquisition of skills requiring coordination suggestive of psychomotor retardation. Affected infants and children may also have distinct malformations of the craniofacial area, defects of the hands and/or feet, and/or skeletal, cardiac, renal, and/orrespiratory abnormalities. The range and severityof symptoms and physical findings may vary fromcase to case, depending upon the exact length and location of the duplicated portion of chromosome10q. In most cases, distal trisomy 10q is due to achromosomal balanced translocation in one of the parents. Our patient had the well characterized phenotype of the distal trisomy of 10q in the form of developmental delay, microcephaly, characteristic dysmorphicfacies, limb anomalies, skeletal deformity in the form of kyphoscoliosis, congenital heart defect which was diagnosed as Tetralogy of fallot on echocardiography and defect in genitourinary system. Reported renal abnormalities associated with distal 10q trisomy syndrome include bilateral hydronephrosis [8,9]. 13q deletion syndrome is an exceedingly rare condition which is usually associated with mental retardation, growth deficiency and variable congenital defects [10].
We compared the clinical features of our patients with three previously published patients with deletions of chromosome region 13q33 – 34 [11,12,13]. Developmental delay/mental retardation, microcephaly, and facial dysmorphisms were present in all patients. Notably, apart from genital ambiguities in the male patients no other consistent major malformations were observed (Table 1).
Table 1: Comparison of clinical features between isolated partial trisomy 10q24 and partial monosomy 13q33.
A fetus with partial monosomy 13q (13q33.3qter) was reported to be associated with Dandy-Walker malformation and microcephaly [14], and a fetus with partial monosomy 13q (13q21.32qter) associated with anencephaly [15]. The present case had partial monosomy 13q (13q33qter) but manifested no major brain malformation. However, Walczak-Sztulpa et al. [16] suggested that haploinsufficiency of the ARHGEF7 gene in patients with chromosomal deletions in 13q33-q34 is responsible for mental retardation and microcephaly. ARHGEF7 maps to 13q34 and encodes Rho guanine nucleotide exchange factor 7.
Recent evidence suggests that the critical deletion region responsible for major malformations in this condition is located in the band q32 [17,18]. Indeed, according to the location of the deletion and involvement of this specific band, the 13q– syndrome has been classified into three groups [17]. In group 1 there is a proximal deletion not involving the band q32; in group 2 there is a distal deletion which includes the band q32; and in group 3 there is a more distal deletion which does not involve the band q32. From the clinical point of view, individuals from group 1 have minor abnormalities in association with moderate mental retardation and growth deficiency, whereas those from group 3 have severe mental retardation but without gross abnormalities or growth deficiency. In group 2 where, band q32 is involved, they present with the most serious defects, mainly brain and face anomalies, distal limb abnormalities and gastrointestinal malformations emphasizing the importance of band q32 in the phenotypic expression of the 13q– syndrome [17,18]. In our case, q33 is involved and thus it falls under group 3 however, the boy has mild mental retardation with severe growth deficiency and major systemic involvement which could be very well explained by distal 10q duplication.
The breakpoints in 10 and 13 in the present case were identified by high resolution G-banding. Due to lack of availability of FISH probes for the specific regions in two chromosomes, precise delineation of the breakpoints at sub-band or molecular level could not be performed in the present study. Molecular mapping of the genes altered in the present case could have collected more information on genotypephenotype association.
This study emphasizes that unbalanced chromosomal regions of the long arm of chromosome 10 play an important role in the developmental malformations and that a more severe form is associated with involvement of 10q25. Also, non-involvement of 13q32, which is supposed to be the critical region for the phenotypic expression in 13q syndrome, was responsible for the lack of typical phenotypic expression of 13q syndrome in present case; which is in concordance with the literature. In our case, the child was brought for genetic analysis at 4 years of age, which itself shows lack of awareness of such entity like chromosomal rearrangement among clinicians and relatives. Therefore, there is a need to create awareness regarding such chromosomal imbalances and its consequences among general practitioners and relatives for better management of chromosomally unbalanced child. Also, this paper emphasizes the importance of genetic counseling and prenatal diagnosis to avoid recurrences and associated family stress [19,20].

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