De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with developmental delay: Case report

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The common cause of mental impairment and the wide range of physical abnormalities is balanced chromosome rearrangement. As such, it is difficult to interpret, posing as a diagnostic challenge in human development. We present a unique case report with a denovo autosomal-balanced reciprocal translocation involving chromosomal regions 4q and 20q.The etiology of the translocation, i.e. 46,XX,t (4;20)(q28;q11) was detected by conventional high-resolution Giemsa-Trypsin-Giemsabanding technique. Parents non-consanguineous, with 2 healthy children. To the best of our knowledge this is the first case reported so far with the balanced reciprocal translocation involving 4q and 20q associated with the delayed milestone development.

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De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with developmental delay: Case report

  1. 1.                                                                                                                                             De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with developmental delay: Case report 
  2. 2. Case Report De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with developmental delay: Case report Kavitha Eppa a,* , Iravathy Goud Kalal b , Pranathi Reddy Guttala c , Sakina Aneeb d a Consultant, Department of Cytogenetics & Molecular Biology, Apollo Health City, Jubilee Hills, Hyderabad, Andhra Pradesh 500033, India b HOD, Consultant, Department of Cytogenetics & Molecular Biology, Apollo Health City, Jubilee Hills, Hyderabad, Andhra Pradesh 500033, India c Consultant, Department of Internal Medicine, Apollo Health City, Jubilee Hills, Hyderabad, Andhra Pradesh 500033, India d Technologist, Department of Cytogenetics & Molecular Biology, Apollo Health City, Jubilee Hills, Hyderabad, Andhra Pradesh 500033, India a r t i c l e i n f o Article history: Received 25 January 2014 Accepted 18 July 2014 Available online xxx Keywords: Developmental delay Translocation Cytogenetic analysis Karyotype a b s t r a c t The common cause of mental impairment and the wide range of physical abnormalities is balanced chromosome rearrangement. As such, it is difficult to interpret, posing as a diagnostic challenge in human development. We present a unique case report with a denovo autosomal-balanced reciprocal translocation involving chromosomal regions 4q and 20q.The etiology of the translocation, i.e. 46,XX,t (4;20)(q28;q11) was detected by con- ventional high-resolution Giemsa-Trypsin-Giemsabanding technique. Parents non- consanguineous, with 2 healthy children. To the best of our knowledge this is the first case reported so far with the balanced reciprocal translocation involving 4q and 20q associated with the delayed milestone development. Conclusion: The reason likely may be due to the rearrangement of genetic material at these breakpoints having a crucial relationship and thus manifesting developmental delay in the proband. Copyright © 2014, Indraprastha Medical Corporation Ltd. All rights reserved. 1. Introduction In humans the incidence of balanced chromosomal trans- locations is approximately 1 in 500.1 In cytogenetic evaluation, balanced chromosome translocations are defined as those rearrangements where no loss or gain of genetic material is observed. Most of the balanced chromosome rearrangements (BCRs) are not considered to be associated with the clinical * Corresponding author. Tel.: þ91 9491226119, þ91 040 23607777x4012; fax: þ91 040 23608050. E-mail addresses: matamkavitha@gmail.com, kavitha_e@apollohospitals.com (K. Eppa). Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/apme a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e3 Please cite this article in press as: Eppa K, et al., De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with developmental delay: Case report, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.07.004 http://dx.doi.org/10.1016/j.apme.2014.07.004 0976-0016/Copyright © 2014, Indraprastha Medical Corporation Ltd. All rights reserved.
  3. 3. (phenotype) abnormalities. But, they are of concern, as the carriers of BCRs offer a greater risk to their descendants with congenital anomalies or recurrent miscarriages. On the basis of a few evaluation procedures, it is estimated that 6.7% of the carriers of de novo BCRs have the risk of phenotypic abnor- malities.2 In the present paper, we describe de novo autosomal-balanced reciprocal translocation involving chro- mosomes 4 and 20 in a child associated with delayed mile- stone development. 2. Case report The proband is a 7 months boy, the third male child of a healthy, young, non-consanguineous couple with 2 other healthy children. No family history. Pregnancy and delivery at 38 weeks were normal. Birth weight was 3.2 kgs. Length was 44 cm and head circumference (HC) was 34 cm. The child was neither focusing nor following the object at 3 months did not attain social smile and has delayed mile stones. At 7 months there was no head control, and was not recognizing the parents. Examination revealed hypotonia (frog posture) with facial asymmetry and microcephaly, HC below 3rd centile. There was no plagiocephaly with closed anterior fontanel. Some dysmorphic features (low set ears, high arched palate, single palmer crease and hypoplastic toe nails) were seen. He was not following and there was no startle. He had horizontal nystagmus. There was axial hypotonia with limbs spasticity and brisk deep tendon reflexes. There was no clonus. He had no organomeghaly. 2.1. Materials & methods Tandem mass: Normal, elevated liver enzymes: ALT-55IU/ L(0e41), AST:86 U/L(0e38). CT brain: smooth brain surface with thick cortex, absent corpus callosum and asymmetry in the lateral ventricles. MRI brain: polymicrogyria and double cortex. Ophthalmology: Impression was visual impairment. The proband was referred for cytogenetic evaluation to the Department of Cytogenetics & Molecular biology, Apollo Hospitals, Jubilee Hills, Hyderabad. 3. Cytogenetic analysis Peripheral blood from the patient and his parents was cultured with phytohemagglutinin (PHA) stimulation for 72 hours before harvest with their informed written consent. Stimulated cultures were set by standard method3 followed by GTG-banded chromosome study.4 About 50 metaphases were scored for all individuals under light transmission microscope and spectral karyotyping software was used for cytogenetic analysis. Metaphases were karyotyped according to Interna- tional System for Human Cytogenetic Nomenclature (ISCN) criteria, Mitelman (2005).5 All metaphases in proband showed balanced reciprocal translocation between chromosome number 4 and long arm (q11) of chromosome number 20, [46, XY, t(4;20)(q28;q11)] [Fig. 1]. Chromosomal studies on the parents showed normal results. 3.1. Results & discussion Cytogenetic evaluation of the GTG-banded metaphases from a lymphocyte culture showed a balanced reciprocal trans- location involving long arm (q28) of chromosome 4 and long arm (q11) of chromosome 20 in all the cells of the proband with a karyotype of 46,XY t(4;20)(q28;q11) [Fig. 1]. Chromo- somal studies on the parents showed normal results. We report a male child with hypotonia and dysmorphic features. Cytogenetic study showed a denovo translocation between 4&20 (q28,q11). Balanced chromosomal trans- locations may cause damage or alteration of the functional genes at the breakpoints of the defective chromosomes resulting in the disease phenotype.6 Linking up the associa- tion of disease consistently with chromosome abnormalities Fig. 1 e Karyotype showing reciprocal translocation of 46 XY t(4;20)(q28;q11). a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e32 Please cite this article in press as: Eppa K, et al., De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with developmental delay: Case report, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.07.004
  4. 4. such as deletions, duplications and translocations would be the simple way of mapping disease genes. Molecular charac- terization of chromosomal breakpoints in carriers of balanced translocation would be one of the vital strategies to be implemented. Thus, disease-associated chromosome rear- rangements that truncate, delete or otherwise inactivate specific genes have been instrumental in the positional clon- ing of many disease genes.7 Inthispaper,wereportaninterestingcasewithapparentlyde novo reciprocal-balanced translocation that has resulted in delayed development of milestones. Delayed milestones or developmental delays are defined as a lag in the child's devel- opment compared to theestablished standard normal ranges for hisorherage. Frombirth to6 yearsof age, 8%of allchildren show delays in one or more areas of development. The present report indicates that the proband had developmental lags in the first year of his life. At the age of 7 months he had no head control, no hand regards and was not recognizing parents. The present case report, however, is the first report of denovo balanced trans- location involving chromosomes 4 and 20 at their respective breakpoint, which shows an association with delayed mile- stones and which has not been reported previously. On the basis ofthechromosomesinvolvedandonthelocationofbreakpoints, the production of normal, balanced or unbalanced gametes is decided.8 In carriers of balanced translocation, the possible reason for the association of malformations could be gene inactivation or disruption at the breakpoint or a position effect.9 The gene PRSS12 that maps at 4q28 encodes a extracellular multidomain serine protease associated with neural devel- opment and plasticity and studies in mouse suggest that the encoded enzyme may be involved in structural re- organizations associated with learning and memory. Molinari et al.,10 reviewed the molecular pathogenesis of autosomal recessive mental retardation caused by neurotrypsin muta- tions. Another important gene NNAT mapped to 20q11 en- codes a proteolipid which participate in the maintenance of segment identity in the hindbrain and pituitary development, and maturation or maintenance of the overall structure of the nervous system, also as a regulatory subunit of ion Channels. Hence, disruption of the gene or group of genes at this breakpoint might suggest a cause for delayed developmental milestones. The possible reason leading to delayed milestones may be due to the consequence of the abnormality described in the patient. Hence, further analysis of the breakpoints and molecular characterization of these genes might help in un- derstanding the basis of delayed development of milestones. Moreover, it is known that the modification or inactivation of specific disease genes at chromosomal breakpoints have been very phenomenal in identifying genes that are associated with a variety of disorders, mostly early-onset disorders.7 4. Conclusion These findings suggest that cytogenetic analysis is useful in the investigation of children with genetic disorders of un- known origin to confirm clinical diagnosis and in view of an increased risk of having congenitally abnormal children, car- riers of balanced reciprocal translocation should, therefore, be advised to seek genetic counseling. Conflicts of interest All authors have none to declare. Acknowledgements The authors acknowledge the parents of the child for accepting to give the consent and samples, technical support of Mr. V. Ravi for cytogenetics and the Management of Apollo Hospitals for their support. r e f e r e n c e s 1. Hook EB, Hamerton JL. The frequency of chromosome abnormalities detected in consecutive newborn studies - differences between studies - results by sex and by severity of phenotypic involvement, population cytogenetics. In: Hook EB, Porter IH, eds. New York: Academic Press; 1977:63e79. 2. Warburton D. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet. 1991;49:995e1013. 3. Moorehead PS, Nowell PC, Mellman WJ, Battips DM, Hungerford DA. Chromosome preparation of leukocytes cultured from human peripheral blood. Exp Cell Res. 1960;20:613e616. 4. Seabright M. A rapid banding technique for human chromosomes. Lancet. 1971;2:971e972. 5. Mitelman F. ISCN. An International System for Human Cytogenetic Nomenclature. Basel: Karger; 2005:1e115. 6. Fryns JP, Kleczkowska A, Kubien E, Van den Berghe H. Excess of mental retardation and/or congenital malformation in reciprocal translocations in man. Hum Genet. 1986;72:1e8. 7. Bugge M, Bruun-Petersen G, Brondum-Nielsen K, et al. Disease associated balanced chromosome rearrangements: a resource for large-scale genotype-phenotype delineation in man. J Med Genet. 2000;37:858e865. 8. Burns JP, Koduru PR, Alonso ML, Chaganti RS. Analysis of meiotic segregation in a man heterozygous for two reciprocal translocations using the hamster in vitro penetration system. Am J Hum Genet. 1986;38:945e964. 9. Buhler EM. Unmasking of heterozygosity by inheriting balanced translocations. Implications for prenatal diagnosis and gene mapping. Ann Genet. 1983;26:133e137. 10. Molinari F, Rio M, Meskenaite V, et al. Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation. Science. 2002;298:1779e1781. a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e3 3 Please cite this article in press as: Eppa K, et al., De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with developmental delay: Case report, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.07.004
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