A Case Report of an Infant with Robertsonian Translocation (15;22)

Available online at www.annclinlabsci.org 102 Annals of Clinical & Laboratory Science, vol. 46, no. 1, 2016 A Case Report of an Infant with Robertsonian Translocation (15;22)(q10;q10) and Literature Review Chi Hyun Cho1, Jung-Hee Shin2, Myung Hyun Nam1, Chae Seung Lim1, Chang Kyu Lee1, Yunjung Cho1, Young Kee Kim1, and Soo Young Yoon1

1Department of Laboratory Medicine and 2Department of Pediatrics, College of Medicine, Korea University, Seoul, Korea

Abstract. Rob(15; 22) is rare and account for only 0.6% of all Robertsonian translocations. We describe a case with rob(15;22) in which the phenotype includes generalized hypotonia, respiratory distress, tent shaped upper lips, hyporeflexia and single umbilical artery. Chromosome analysis with peripheral blood was performed, while the karyotype was interpreted as 45,XX,der(15;22)(q10;q10). In Prader-Willi/An- gelman Syndrome FISH studies, deletion of the SNRPN gene was not observed, but deletion of 15p11.2 was noted. Prader-Willi/Angelman Syndrome methylation-specific polymerase chain reaction and chromosomal microarrays showed negative findings. Molecular studies associated with spinal muscular atrophy and progressive muscular dystrophy also showed negative findings. We suggest that rob(15;22) and deletion of 15p11.2 could be related to clinical presentation like this case.

Introduction contributory family history. At birth, she had a pulse rate of 110 per minute, respiratory rate of 20 per minute, Robertsonian translocations are one of the most body temperature of 36.5°C and blood pressure of common structural chromosomal rearrangements 55/26 mmHg. But she had weak crying and systemic observed in humans, occurring with a frequency of cyanosis. She showed 5 and 7 of Apgar scores at 1 and 5 0.1% in the general population [1], whereas rob(15; minutes, respectively. Her heart rate dropped intermit- tently below 100 per minute. She received positive end- 22) is rare and account for only 0.6% of all expiratory pressure (PEEP) with FiO2 of 50% in full Robertsonian translocations [1]. Furthermore, a measure and frequent oral suction. Her oxygen satura- case of rob(15;22) with hypotonia, respiratory dis- tion rate was maintained at 80% and transferred to our tress and abnormal facies still has not been report- tertiary neonatal intensive care unit. However, having a ed. We describe a case with rob(15;22) in which the Kussmaul respiratory pattern and cyanosis, she received phenotype includes generalized hypotonia, respira- PEEP with FiO2 of 80%. After Bi-level positive airway tory distress, tent shaped upper lips, hyporeflexia pressure (BiPAP) was kept for 10 minutes, her oxygen and single umbilical artery. In addition, we review saturation rate was stable. Examination of the newborn the literature associated with rob(15;22). showed persistent generalized hypotonia, the presence of an expressionless face, bitemporal flattening, tent shaped upper lips, a carp mouth with a high arched palate, and Case Report an abnormal receding small jaw. Hyporeflexia was also present. The fists clenched, the second and fifth digits The proband is an infant who is the second child of overlapping the third and fourth. She cried like a barking healthy unrelated Korean parents. Her father and moth- dog. She was a floppy infant with poor activity. She had er were 30 and 27 years of age at her birth, respectively. a single umbilical artery. Her eyes and ears were normally Her mother had polyhydramnios at 32 weeks gestation. set. Her external genitalia were normally developed. The infant was born at 37 weeks 1 day gestation following vaginal delivery, with birth weight of 2.67 kg. Chromosome analysis with peripheral blood was per- Examination demonstrated birth length of 50 cm (90th– formed as part of the investigation of hypotonia, respira- 95th centile) and head circumference of 34.5 cm (90th– tory distress and abnormal face. The karyotype was inter- 95th centile). There was no consanguineous marriage or preted as 45,XX,der(15;22)(q10;q10) (Figure 1). For further evaluation, the microdeletion associated with Address correspondence to Soo Young Yoon, Department of Laboratory Medicine, Guro Hospital, Korea University College of Prader-Willi syndrome was investigated by fluorescence Medicine, Guro 2 Dong, Guro Gu, Seoul 152-703, Republic of Korea; in situ hybridization (FISH) studies using the following phone: +82 2 2636 3246; fax: +82 2 2626 1465; e mail: labmd@korea. ac.kr probes: Probes for the 15p11.2 (D15Z1; Spectrum

0091-7370/16/0100-102. © 2016 by the Association of Clinical Scientists, Inc. An Infant with rob(15;22) 103 Green), the SNRPN gene on 15q11-q13 (Spectrum Orange) and the PML gene on 15q22 (Spectrum Orange). Deletion of the SNRPN gene was not observed. But one green signal was observed on 500 interphase cells instead of two green signals (Figure 2A). With 25 metaphase cells, the absence of the green signal was confirmed on the transla- tion chromosome (Figure 2B). Since the above probe for 15p11.2 did not bind to just the centromere of chromosome 15, additional FISH studies were performed, using (1) the satellite enumeration probe CEP15 on 15p11 (red) and (2) the satellite enumeration probes CEP14 on 14p11 (green) Figure 1. G-banded Karyotype demonstrating a Robertsonian translocation (15;22). and CEP 22 on 22p11 (green). The patient’s karyotype was interpreted as 46,XX,der(15;22) man with Ph-positive CML to Cardio-Facio- (q10;q10).ish 15p11.2(D15Z1x1),15q11- Cutaneous Syndrome (Table 1). As shown in table 13(SNRPNx2),15q22(PMLx2)[25].nuc 1, while the case no. 1, 2 and our case had rob(15;22) ish(CEP15x1,SNRPNx2, PMLx2)[500](Figure 2). For as the only chromosomal abnormality, case no. 3 further confirmation, Prader-Willi/Angelman Syndrome had monosomy X as an additional chromosomal methylation-specific polymerase chain reaction (PCR) was abnormality. Since case no. 3 had Turner syndrome- performed, and it tested negative. Since spinal muscular atrophy (SMA) and progressive muscular dystrophy (PMD) like clinical features associated with monosomy X, were considered as differential diseases, additional molecu- case no 1, 2 and our case can explain clinical fea- lar tests were performed. For the former, PCR and restric- tures caused by only rob(15;22) better than case no. tion fragment length polymorphism (RFLP) were per- 3. formed for detection of telomeric spinal motor neuron The great majority of balanced Robertsonian trans- (SMN-T) gene deletion, resulting in negative finding. For locations involve two different chromosomes (a the latter, multiple ligation probe amplification (MLPA) heterologous translocation) [5]. There are three was performed for detection of Duchenne muscular dystro- possible mechanisms of formation of the balanced phy (DMD) gene deletion and duplication, resulting in heterologous translocation: fusion at the centromere negative finding. Chromosomal microarray Affymetrix (centric fusion), union following breakage in one CytoScan 750 K Array (Affymetrix, Santa Clara, CA, USA) for detection of microdeletion, microduplication and loss short arm and one long arm (essentially, a whole- of heterozygosity (LOH) was used and resulted in negative arm reciprocal translocation), and union following finding. After two months follow up, the infant was trans- breaks in both short arms [5]. The first two mecha- ferred to another tertiary hospital for respiratory care. nisms are rare and would produce a translocation Parents refused to have their chromosome study performed. chromosome with one centromere (monocentric), This study received the approval of the Institutional Review while the third results in a chromosome with two Board in the Korea University Ansan Hospital (Number centromeres (dicentric). In our study, while chro- AS15098). mosomal microarray showed no microdeletion, microduplication and LOH in the infant, the micro- Discussion array did not include markers on stalk regions of chromosome 15 and 22. However, FISH studies To our knowledge, there were three cytogenetic stud- with probes on stalk region and centromere of ies worldwide in which rob(15;22) was identified defi- chromosome 15 (Figures 2B and C, respectively) nitely [2-4]. The phenotypes in those cases have showed rob(15q22q) translocation chromosome in ranged from a phenotypically normal 40-year-old our case had the centromere of chromosome 15, 104 Annals of Clinical & Laboratory Science, vol. 46, no. 1, 2016

Table 1. Cytogenetic and clinical findings of the reported cases with Robertsonian translocation(15;22).

Author No. Age and sex Karyotype in PB Clinical findings

Becher et al. (1987) 1 40 year old/male 45,XY,der(15;22)(q10;q10) Phenotypically normal 40-year- old man, Ph-positive CML developed Fryns et al. (1992) 2 5 year 6 month 45,XX,-15,-22,t(15;22) Polyhydramnios during the old/female (p11;q11)mat third trimester; Cardio-Facio- Cutaneous Syndrome (severe growth retardation, coarse facial features, cutaneous symp- toms with hypo- and hyperpig- mentation and hyperkeratic le- sions, borderline intellectual de velopment, mitral valve prolapse) Mario et al. (2010) 3 11 year old/ 44,X,der(15;22)(q10;q10) Short stature, low hair line, female broad neck, high palate, broad thorax, wide spaced nipples, hy- perconvex nails with shortening of the 4th and 5th metacarpals, numerous nevis located mainly at the thorax and the back This case 6 5 year old/male 46,XX,der(15;22)(q10;q10) Generalized hypotonia, respiratory distress, tent shaped upper lips, hyporeflexia and single umbilical artery

Abbreviations: CML, chronic myeloid leukemia; Nil, no study or no information; No., number; PB, peripheral blood. but deletion of chromosome 15p11.2. In addition, Nevertheless, FISH studies showed a deleted segment the centromere of chromosome 22 was observed in 15p11.2 in the infant (Figure 2 B). Until now, two translocation probe (Figure 2D). So the transloca- cases with a deletion of the chromosome 15p11.2 have tion chromosome seems to have been formed by been described [6]. The phenotype of the First case was the Third mechanism, having two centromeres. similar to Angelman syndrome including mental retardation, slight dysmorphism, seizure and abnormal be- In the first place, Prader-Willi syndrome was con- havior (laughter not associated with happiness). The sidered as the cause of generalized hypotonia. second case was diagnosed as autism. In line with those Suggested was the possibility that not rob(15;22) cases, our case suggests that deletion of 15p11.2 could but the microdeletion of Prader-Willi Syndrome be correlated clinically with generalized hypotonia, re- (PWS) gene on 15q11-13, which could not be ob- spiratory distress and dysmorphic face. served visually, would have implicated the phenotype. However, FISH with SNRPN gene probe Recently several molecular studies such as chromo- showed negativity, excluding the possibility of dele- somal microarray have been investigated for detection tion of the PWS gene. Furthermore, PWS methyla- of genetic diseases. However, as shown in our case, tion PCR study also showed negative finding, rul- FISH studies remain still important for evaluation of ing out the possibility of Prader-Willi syndrome. genetic diseases. Especially, as for infants suspected of Accordingly, SMA and PMD were suggested as genetic disease with Robertsonian translocation as the causes of generalized hypotonia and respiratory dis- only chromosomal abnormality, FISH studies with the tresses. Nevertheless, molecular studies associated probes on the stalk regions of involved chromosomes with them showed negative findings. could be considered and applied. An Infant with rob(15;22) 105 Acknowledgment

This research was supported by a Korea University Grant (K1512641). The authors would like to thank the as- sistance of Myung Soon Cho and Jung Hee Kim, Medical Technicians of the Korea University Guro Hospital.

References

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